Covalent Binding Compounds for the Treatment of Disease

INCORPORATION BY REFERENCE

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FIELD OF THE INVENTION

This invention provides heteroaryl sulfonyl compounds and compositions that have a Protein Recognition Moiety bound to a heteroaryl sulfonyl compound for the selective covalent modification of a selected Target Protein to treat a disorder mediated by the Target Protein.

BACKGROUND OF THE INVENTION

Most cells in the body are terminally differentiated with protective mechanisms to prevent cellular proliferation. A small subset of cells undergo cellular proliferation mainly to replenish tissue or blood components, such as hematopoietic cells and their progeny. The body maintains a careful balance between terminally differentiation and cellular proliferation through a complex network of cellular signaling. Disease states can be caused by dysfunction of the carefully balanced cell proliferation natural pathways or through dysfunction in signaling cascades or dysfunctional gene expression. One way to modify disease states is to disable the function of a protein mediating the disease by covalently modifying it.

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).

Despite many years of medical research there are still disorders for which there are no cure or an insufficient cure. It is an object of the present invention to provide new compounds, compositions, treatments and manufactures thereof for medical disorders.

SUMMARY OF THE INVENTION

Heteroaryl sulfonyl compounds and their uses and manufacture are provided that covalently modify a Target Protein to treat a disease mediated by the Target Protein in a host, typically a human. The heteroaryl sulfonyl compound is first typically selectively non-covalently bound to the Target Protein by association of the Target Protein with a Protein Recognition Moiety in the heteroaryl sulfonyl compound. In a typical second step, a reactive tyrosine residue on the Target Protein 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 the Target Protein 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.

The heteroaryl sulfonyl compounds of the present invention are uniquely designed for specificity to their respective Target Protein to maximize therapeutic effect and minimize off-target toxicity, by inclusion of a specific Protein Recognition Moiety as described further herein that selectively binds the selected Targeted Protein 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 the Target Protein while limiting unacceptable off-target effects.

The Protein 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 the Target Protein as an inhibitor or alternatively with no apparent biological effect on the Target Protein. In non-limiting embodiments, the Protein Recognition Moiety is a protein binding domain of a drug or pharmaceutically active compound which modulates the Targeted Protein (or the full drug or pharmaceutically active compound). In alternative embodiments, the Protein 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 Targeted Proteins, 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 Protein 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 Protein Recognition Moiety is located either on the Leaving Group or the Attaching Group in a manner that allows it to associate with the Target Protein 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 the Target Protein. The Attaching Group and the sulfonyl to which it is attached remains on the Target Protein after covalent modification. For example, as used herein, R², R⁵, and R¹³are Attaching Groups.

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

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The Protein Recognition Moiety brings the activated heteroaryl sulfonyl compound of the present invention into close proximity with a reactive amino acid of the Target Protein resulting in covalent modification of the Target Protein and resultant amelioration or elimination of a disease or Target Protein-mediated disorder.

The heteroaryl sulfonyl compound of the present invention is used to modulate a Target Protein's biological activity by covalently modifying the protein, for example, by covalently modifying a tyrosine in or near the active site, or alternatively, a lysine moiety.

In one aspect a heteroaryl sulfonyl compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, 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:

- R¹is selected from:

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- b) a fused bicyclic heteroaryl 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, 0, 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;
- 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;
- in certain embodiments R⁶is not substituted;
- 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;
- in certain embodiments 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, ═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—, 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;
- 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
- Protein Recognition Moiety is a molecule, for example a small molecule, peptide, protein, oligonucleotide, nucleotide, RNA, DNA, SiRNA, a biologic, an antibody or a fragment thereof, which can bind to or otherwise interact with a Target Protein; and
- Target Protein is a mediator of disease.

In certain embodiments the Target Protein 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 active site. In certain embodiments the reactive tyrosine is not in an active site.

In certain embodiments the Target Protein 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 active site. In certain embodiments the reactive lysine is not in an active site.

In certain embodiments the Target Protein 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 active site. In certain embodiments the reactive cysteine is not in an active site.

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 the Target Protein. In other embodiments, a selected heteroaryl sulfonyl compound of the present invention reacts with two or more different tyrosines and/or lysines in the Target Protein. 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 the Target Protein.

In certain embodiments one or more amino acids 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 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 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;
- in certain embodiments R¹³is selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, and aryl, 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 a nitrogen 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 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 Selective Protein Recognition Moiety is a Protein Recognition Moiety as defined herein wherein at least one of the following is satisfied:

- i. there are fewer than 80, 70, 60, 50, 40, 30, 20, 15, 10, or 5 endogenous protein kinases to which the Selective Protein Recognition Moiety binds with an K_d50 of 2 μM or less;
- ii. the Selective Protein Recognition Moiety has an K_d50 greater than 1 μM against aurora B kinase, c-Src kinase domain, human serine/threonine-protein kinase MST4, activin receptor type-IIA (ACVR2A), human calcium calmodulin dependent protein kinase II delta isoform 1 (CAMKD), and/or human ste20-like kinase;
  
  and wherein 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

- R^3*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 Protein Recognition Moiety is a small organic molecule (i.e., a non-biologic) that adequately binds to the Target Protein in a manner that it is covalently modified. In an embodiment of the invention, the Protein Recognition Moiety is a peptide or oligonucleotide that adequately binds to the protein in such a manner that it can be covalently modified. In certain embodiments the Protein Recognition Moiety is a residue of a pharmaceutically active compound that binds to the Target Protein (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 can be covalently modified. A plethora of illustrative nonlimiting examples of Protein Recognition Moieties is provided in the Figures and additional Protein Recognition Moieties are readily apparent to the skilled artisan.

The present invention focuses on the covalent modification of a selected protein that mediates disease, for example, abnormal cellular proliferation such as a tumor or cancer. In certain embodiments, a method of treating a disorder mediated by a Target Protein 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 Protein Recognition Moiety that targets a protein that mediates the cancer or tumor.

In certain embodiments, a heteroaryl sulfonyl compound described herein does not have to be administered in as high of a dose or as frequently as the Protein Recognition Moiety 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 the Target Protein, than the Protein Recognition Moiety alone. In certain embodiments, the heteroaryl sulfonyl compound of the present invention is more efficacious in the treatment of a disorder mediated by the Target Protein than the original protein binder corresponding to the Protein Recognition Moiety alone.

In certain 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 the Target Protein is mutated. In other 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 the Target Protein 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 Target Protein than the wild-type Target Protein.

In principle embodiments, the Protein Recognition Moiety is not a fluorophore, not a detectable labeling group, and not a moiety comprising an alkyne.

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 Target Protein binder and covalent modifier.

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 Protein Recognition Moiety.

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 one embodiment, 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 labelling 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 the Target Protein 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 the Target Protein, 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 the Target Protein;
- (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 the Target Protein;
- (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 the Target Protein;
- (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 the Target Protein, 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 the Target Protein;
- (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 the Target Protein;
- (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 the Target Protein;
- (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 R²⁷is 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 custom-character is an Anchor Bond. Anchor Bond is the chemical bond between the Protein 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/.

FIGS. 1A, 1B and 1C present non-limiting examples of ligands that bind to isocitrate dehydrogenase cytoplasmic protein (IDH1), including the compounds NDP, 70Q, NAP, 59D, 70P, C81, 6VN, HJQ, 9UO, 1BX, DWP, DWM, DWG, DWJ, DWS, 6MX, 6N3, 7J2, VVS, 42V, 42W, LJY, LJV, PWV, AOU, QWM, 1K9, 69Q, and K32. For additional non-limiting examples and related ligands, see ligands identified by Xie et al., “Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity”, Structure, 2017, 25: 506-513; Rendina et al., “Mutant IDH1 Enhances the Production of 2-Hydroxyglutarate Due to Its Kinetic Mechanism”, Biochemistry, 2013, 52: 4563-4577; Okoye-Okafor et al., “New IDH1 mutant inhibitors for treatment of acute myeloid leukemia”, Nat Chem Biol., 2015, 11: 878-886; Cho et al., “Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor”, ACS Med Chem Lett., 2017, 8: 1116-1121; Pusch et al., “Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo”, Acta Neuropathol., 2017, 133: 629-644; Chaturvedi et al., “In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site”, Leukemia, 2020, 34: 416-426; Ma et al., “Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2”, Biochem Biophys Res Commun., 2018, 503: 2912-2917; Zheng et al., “Crystallographic Investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase”, ACS Med Chem Lett., 2013, 4: 542-546; Jakob et al., “Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315”, J Med Chem., 2018, 61: 6647-6657; Jones et al., “Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells”, J Med Chem., 2016, 59: 11120-11137; Yang et al., “Molecular mechanisms of “off-on switch” of activities of human IDH1 by tumor-associated mutation R132H”, Cell Res., 2010, 20: 1188-1200; Levell et al., “Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1”, ACS Med Chem Lett., 2017, 8: 151-156; Deng et al., “Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (Idh1) Via Disruption of a Metal Binding Network by an Allosteric Small Molecule”, J Biol Chem., 2015, 290: 762; Wu et al., “Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds”, J Med Chem., 2015, 58: 6899-6908; Lin et al., “Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors”, J Med Chem., 2019, 62: 6575-6596; Caravella et al., “Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor”, J Med Chem., 2020, 63: 1612-1623; Machida et al., “A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model”, Mol Cancer Ther., 2020, 19: 375-383; Dang et al., “Cancer-associated IDH1 mutations produce 2-hydroxyglutarate”, Nature, 2009, 462: 739-744; Konteastis et al., “Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma”, ACS Med Chem Lett., 2020, 11: 101-107; “Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation”, Science, 2013, 340: 622-626; and Yen et al., “AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations”, Cancer Discov., 2017, 7: 478-493.

FIG. 2 presents non-limiting examples of ligands that bind to phosphoglycerate mutase 1 (PGAM1), including the compounds AZN, 8KX, AW6, 8LF, HKB, 9HU, and 9JF. For additional non-limiting examples and related ligands, see ligands identified by Zhou et al., “X-ray structure of Phosphoglycerate Mutase 1 (PGAM1) complexed with a small molecule”, to be published; Jiang et al., “Phosphoglycerate mutase 1 (PGAM1) complexed with its inhibitor PGMI-004A”, to be published; Jiang et al., “Phosphoglycerate mutase 1 complexed with a small molecule inhibitor”, to be published; Jiang et al., “Phosphoglycerate mutase 1 complexed with a small molecule inhibitor KH1”, to be published; Jiang et al., “Phosphoglycerate mutase 1 complexed with a small molecule inhibitor KH2”, to be published; Jiang et al., “Phosphoglycerate mutase 1 complexed with a small molecule inhibitor In-AC”, to be published; and Jiang et al., “Acetylation of lysine 100 of Phosphoglycerate mutase 1 complexed with KH_ol”, to be published.

FIGS. 3A, 3B, and 3C present non-limiting examples of ligands that bind to glutathione S-transferase P (GSTP1), including the compounds GTX, GTB, GSH, GTS, GPR, GDN, OHH, VWW, BSP, SAS, CBD, GF5, LEE, GTD, OHG, LZ6, GBX, GSN, and 07Z. For additional non-limiting examples and related ligands, see ligands identified by Kyrieleis et al., “Mouse C14A Glutathione-S-Transferase Mutant in Complex with S-hexyl glutathione”, to be published; Kyrieleis et al., “Structural and Kinetic Analyses of Glutathione S-Transferase Mutants”, to be published; Garcia-Saez et al., “Molecular structure at 1.8 A of mouse liver class pi glutathione S-transferase complexed with S-(p-nitrobenzyl)glutathione and other inhibitors”, J Mol Biol., 1994, 237: 298-314; Parraga et al., “The three-dimensional structure of a class-Pi glutathione S-transferase complexed with glutathione: the active-site hydration provides insights into the reaction mechanism”, Biochem J., 1998, 333 (Pt 3): 811-816; Vega et al., “The three-dimensional structure of Cys-47-modified mouse liver glutathione S-transferase P1-1. Carboxymethylation dramatically decreases the affinity for glutathione and is associated with a loss of electron density in the alphaB-310B region”, J Biol Chem., 1998 273: 2844-2850; Ji et al., “Structure and function of the xenobiotic substrate-binding site and location of a potential non-substrate-binding site in a class pi glutathione S-transferase”, Biochemistry, 1997, 36: 9690-9702; Oakley et al., “The ligandin (non-substrate) binding site of human Pi class glutathione transferase is located in the electrophile binding site (H-site)”, J Mol Biol., 1999, 291: 913-926; Oakley et al., “The structures of human glutathione transferase P1-1 in complex with glutathione and various inhibitors at high resolution”, J Mol Biol., 1997, 274: 84-100; Shishido et al., “A covalent G-site inhibitor for glutathione S-transferase Pi (GSTP1-1)”, Chem Commun (Camb)., 2017, 53: 11138-11141; Reinemer et al., “Three-dimensional structure of class pi glutathione S-transferase from human placenta in complex with S-hexylglutathione at 2.8 A resolution”, J Mol Biol., 1992, 227: 214-226; Prade et al., “Structures of class pi glutathione S-transferase from human placenta in complex with substrate, transition-state analogue and inhibitor”, Structure, 1997, 5: 1287-1295; Parket et al., “The anti-cancer drug chlorambucil as a substrate for the human polymorphic enzyme glutathione transferase P1-1: kinetic properties and crystallographic characterization of allelic variants”, J Mol Biol., 2008, 380: 131-144; Ji et al., “Structure and function of residue 104 and water molecules in the xenobiotic substrate-binding site in human glutathione S-transferase P1-1”, Biochemistry, 1999, 38: 10231-10238; Tellez-Sanz et al., “Calorimetric and structural studies of the nitric oxide carrier S-nitrosoglutathione bound to human glutathione transferase P1-1”, Protein Sci., 2006, 15: 1093-1105; and Worth et al., “The interaction of IAA-94 with the soluble conformation of the CLIC1 protein and its structural homolog hGSTP1-1”, to be published.

FIG. 4 presents non-limiting examples of ligands that bind to nucleoside diphosphate kinase B (NME2), including the compounds DG, DA, and GDP. For additional non-limiting examples and related ligands, see ligands identified by Dexheimer et al., “NM23-H2 may play an indirect role in transcriptional activation of c-myc gene expression but does not cleave the nuclease hypersensitive element III1”, Mol Cancer Ther., 2009, 8: 1363-1377; Morera et al., “X-ray structure of human nucleoside diphosphate kinase B complexed with GDP at 2 A resolution”, Structure, 1995, 3: 1307-1314.

FIG. 5 presents non-limiting examples of ligands that bind to Biliverdin reductase A (BLVRA), including the compounds NAP and NAD. For additional non-limiting examples and related ligands, see ligands identified by Kavanagh et al., “Crystal Structure of Human Biliverdin Reductase A”, to be published; Whitby et al., “Crystal structure of a biliverdin IXalpha reductase enzyme-cofactor complex”, J Mol Biol., 2002, 319: 1199-1210.

FIG. 6 presents non-limiting examples of ligands that bind to Ras-related C3 botulinum toxin substrate 3 (RAC3), including the compounds GDP. For additional non-limiting examples and related ligands, see ligands identified by Debreczeni et al., “Crystal Structure of the Human Rac3 in Complex with Gdp”, to be published.

FIG. 7 presents non-limiting examples of ligands that bind to Thymidine kinase, cytosolic (TK1), including the compounds TTP. For additional non-limiting examples and related ligands, see ligands identified by Welin et al., “Structures of thymidine kinase 1 of human and mycoplasmic origin”, Proc Natl Acad Sci USA., 2004, 101: 17970-17975.

FIG. 8 presents non-limiting examples of ligands that bind to Glutamine synthetase (GLUL or GS), including the compounds ADP. For additional non-limiting examples and related ligands, see ligands identified by Krajewski et al., “Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design”, J Mol Biol., 2008 375: 217-228.

FIG. 9 presents non-limiting examples of ligands that bind to Eukaryotic initiation factor 4A-III (EIF4A3), including the compounds ANP. For additional non-limiting examples and related ligands, see ligands identified by Bono et al., “The crystal structure of the exon junction complex reveals how it maintains a stable grip on Mrna”, Cell, 2006, 126: 713; Anderson et al., “Structure of the exon junction core complex with a trapped DEAD-box ATPase bound to RNA”, Science, 2006, 313: 1968-1972.

FIG. 10 presents non-limiting examples of ligands that bind to Hypoxanthine-guanine phosphoribosyltransferase (HPRT or HPRT1), including the compounds IMU. For additional non-limiting examples and related ligands, see ligands identified by Shi et al., “The 2.0 A structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with a transition-state analog inhibitor”, Nat Struct Biol., 1999, 6: 588-593.

FIG. 11 presents non-limiting examples of ligands that bind to Glycogen phosphorylase, brain form (PYGB), including the compounds AMP. For additional non-limiting examples and related ligands, see ligands identified by Mathieu et al., “Insights into Brain Glycogen Metabolism: the structure of human brain glycogen phosphorylase”, J Biol Chem., 2016, 291: 18072-18083.

FIG. 12 presents non-limiting examples of ligands that bind to Vinculin (VCL) including the compounds PIO For additional non-limiting examples and related ligands, see ligands identified by Chinthalapudi et al., “Differential lipid binding of vinculin isoforms promotes quasi-equivalent dimerization”, Proc Natl Acad Sci USA., 2016, 113: 9539-9544.

FIG. 13 presents non-limiting examples of ligands that bind to cytosolic Branched-chain-amino-acid aminotransferase (BCAT1), including the compounds PLP, GBN and CBC. For additional non-limiting examples and related ligands, see ligands identified by Goto et al., “Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin”, J Biol Chem., 2005, 280: 37246-37256; Hu et al., “The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases”, Bioorg Med Chem Lett., 2006, 16: 2337-2340.

FIG. 14 presents non-limiting examples of ligands that bind to Nucleoside diphosphate kinase A (NME1), including the compounds ADP and A7Z. For additional non-limiting examples and related ligands, see ligands identified by Giraud et al., “Crystal Structures of S120G Mutant and Wild Type of Human Nucleoside Diphosphate Kinase A in Complex with ADP”, J Bioenerg Biomembr., 2006, 38: 261-264; Mortenson et al., “Inverse drug discovery” strategy to identify proteins that are targeted by latent electrophiles as exemplified by Aryl Fluorosulfates”, J Am Chem Soc., 2018, 140: 200-210.

FIG. 15 presents non-limiting examples of ligands that bind to Adenylosuccinate lyase (ADSL), including the compounds AMP and 2SA. For additional non-limiting examples and related ligands, see ligands identified by Stenmark et al., “Crystal Structure of Human Adenylosuccinate Lyase”, to be published; Stenmark et al., “Human Adenylosuccinate Lyase in Complex with its Substrate N6-(1,2-Dicarboxyethyl)-AMP, and its Products AMP and Fumarate”, to be published.

FIG. 16 presents non-limiting examples of ligands that bind to ADP-ribose pyrophosphatase, mitochondrial (NUDT9), including the compounds RP5 and BGC. For additional non-limiting examples and related ligands, see ligands identified by Shen et al., “The crystal structure and mutational analysis of human NUDT9”, J Mol Biol., 2003, 332: 385-398.

FIG. 17 presents non-limiting examples of ligands that bind to Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), including the compound GIA. For additional non-limiting examples and related ligands, see ligands identified by Zhang et al., “Structural basis for high-affinity peptide inhibition of human Pin1”, ACS Chem Biol., 2007, 2: 320-328; Dong et al., “Structure-based design of novel human Pin1 inhibitors (II)”, Bioorg Med Chem Lett., 2010, 20: 2210-2214.

FIG. 18 presents non-limiting examples of ligands that bind to 14-3-3 protein beta/alpha (YWHAB), including the compound NAG. For additional non-limiting examples and related ligands, see ligands identified by De Vink et al., “A Binary Bivalent Supramolecular Assembly Platform Based on Cucurbit[8]uril and Dimeric Adapter Protein 14-3-3”, Angew Chem Int Ed Engl., 2017, 56: 8998-9002; Toleman et al., “Structural basis of O-GlcNAc recognition by mammalian 14-3-3 proteins”, Proc Natl Acad Sci USA., 2018, 115: 5956-5961.

FIGS. 19A and 19B present non-limiting examples of ligands that bind to Bifunctional purine biosynthesis protein ATIC (ATIC), including the compounds BW2, XMP, AMZ, 8US, and 8UM. For additional non-limiting examples and related ligands, see ligands identified by Cheong et al., “Crystal Structures of Human Bifunctional Enzyme Aminoimidazole-4-carboxamide Ribonucleotide Transformylase/IMP Cyclohydrolase in Complex with Potent Sulfonyl-containing Antifolates”, J Biol Chem., 2004, 279: 18034-18045; Fales et al., “Discovery of N-(6-Fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide (LSN 3213128), a Potent and Selective Nonclassical Antifolate Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase (AICARFT) Inhibitor Effective at Tumor Suppression in a Cancer Xenograft Model”, J Med Chem., 2017, 60: 9599-9616.

FIG. 20 presents non-limiting examples of ligands that bind to Glucose-6-phosphate 1-dehydrogenase (G6PD), including the compounds BG6 and NAP. For additional non-limiting examples and related ligands, see ligands identified by Ranzani et al., “Mutations in the tetramer interface of human glucose-6-phosphate dehydrogenase reveals kinetic differences between oligomeric states”, FEBS Lett., 2017, 591: 1278-1284; Au et al., “Human Glucose-6-Phosphate Dehydrogenase: The Crystal Structure Reveals a Structural Nadp+ Molecule and Provides Insights Into Enzyme Deficiency”, Structure, 2000, 8: 293; Kotaka et al., “Structural Studies of Glucose-6-Phosphate and Nadp+ Binding to Human Glucose-6-Phosphate Dehydrogenase”, Acta Crystallogr D Biol Crystallogr., 2005, 61: 495; Au et al., “Crystal structure of Human G6PD Canton”, to be published.

FIG. 21 presents non-limiting examples of ligands that bind to Glycogen phosphorylase, liver form (PYGL), including the compounds AMP, PLP, 25D, 26B, 055, AVE, AVF and NBG. For additional non-limiting examples and related ligands, see ligands identified by Rath et al., “Activation of human liver glycogen phosphorylase by alteration of the secondary structure and packing of the catalytic core”, Mol Cell, 2000, 6: 139-148; Thomson et al., “Anthranilimide based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Part 3: X-ray crystallographic characterization, core and urea optimization and in vivo efficacy”, Bioorg Med Chem Lett., 2009, 19: 1177-1182; Pautsch et al., “Molecular recognition of the protein phosphatase 1 glycogen targeting subunit by glycogen phosphorylase”, J Biol Chem., 2008, 283: 8913-8918; Anderka et al., “Thermodynamic characterization of allosteric glycogen phosphorylase inhibitors”, Biochemistry, 2008, 47: 4683-4691.

FIG. 22 presents non-limiting examples of ligands that bind to GDP-mannose 4,6 dehydratase (GMDS), including the compounds NAP, GDD, FZE, NDP and GDP. For additional non-limiting examples and related ligands, see ligands identified by Pfeiffer et al., “A Parsimonious Mechanism of Sugar Dehydration by Human GDP-Mannose-4,6-dehydratase”, ACS Catal., 2019, 9: 2962-2968; Vedadi et al., “Crystal Structure and Biophysical Characterization of Human GDP-D-mannose 4,6-dehydratase”, to be published.

FIGS. 23A, 23B, and 23C present non-limiting examples of ligands that bind to Peptidyl-prolyl cis-trans isomerase FKBPlA (FKBPlA), including the compounds GPI, TST, 818, FK5, SUB, AP1, SB3, SBX, SB1, B7G, 858, ARD, RAD, RAP, 001, FKA, and 587. For additional non-limiting examples and related ligands, see ligands identified by Burkhard et al., “X-ray structures of small ligand-FKBP complexes provide an estimate for hydrophobic interaction energies”, J Mol Biol., 2000, 295: 953-962; Sich et al., “Solution structure of a neurotrophic ligand bound to FKBP12 and its effects on protein dynamics”, Eur J Biochem., 2000, 267: 5342-5354; Becker et al., “FK-506-binding protein: three-dimensional structure of the complex with the antagonist L-685,818”, J Biol Chem., 1993, 268: 11335-11339; Van Duyne et al., “Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex”, Science, 1991, 252: 839-842; Wilson et al., “Comparative X-ray structures of the major binding protein for the immunosuppressant FK506 (tacrolimus) in unliganded form and in complex with FK506 and rapamycin”, Acta Crystallogr D Biol Crystallogr., 1995, 51: 511-521; Sun et al., “Design and structure-based study of new potential FKBP12 inhibitors”, Biophys J., 2003, 85: 3194-3201; Clarkson et al., “Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity”, Proc Natl Acad Sci USA., 1998, 95: 10437-10442; Holt et al., “Design, synthesis, and kinetic evaluation of high-affinity FKBP ligands and the x-ray crystal-structures of their complexes with FKBP12”, J Am Chem Soc., 1993, 115: 9925-9938; Becket et al., “32-Indolyl ether derivatives of ascomycin: three-dimensional structures of complexes with FK506-binding protein”, J Med Chem., 1999, 42: 2798-2804; Liang et al., “Refined structure of the FKBP12-rapamycin-FRB ternary complex at 2.2 A resolution”, Acta Crystallogr D Biol Crystallogr., 1999, 55: 736-744; Wu et al., “Rational design and implementation of a chemically inducible heterotrimerization system”, Nat Methods, 2020, 17: 928-936; Choi et al., “Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP”, Science, 1996, 273: 239-242; Dubowchik et al., “2-Aryl-2,2-difluoroacetamide FKBP12 ligands: synthesis and X-ray structural studies”, Org Lett., 2001, 3: 3987-3990; Schultz et al., “Chemical inducers of dimerization: the atomic structure of FKBP12-FK1012A-FKBP12”, Bioorg Med Chem Lett., 1998, 8: 1-6; Van Duyne et al., “Atomic Structure of the Rapamycin Human Immunophilin Fkbp-12 Complex”, J Am Chem Soc., 1991, 113: 7433; and Fulton et al., “Energetic and structural analysis of the role of tryptophan 59 in FKBP12”, Biochemistry, 2003, 42: 2364-2372.

FIG. 24 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 a Target Protein to treat a disease that is mediated by the Target Protein in a host, typically a human. In one aspect of the invention a heteroaryl sulfonyl compound described herein reacts with a tyrosine residue on the Target Protein to form a covalent bond. In another aspect a heteroaryl sulfonyl compound described herein reacts with a lysine residue on the Target Protein 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 Protein 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 the Target Protein 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:

embedded image

or a pharmaceutically acceptable salt thereof.

Embodiments of Formula VII

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

embedded image

or a pharmaceutically acceptable salt thereof.

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

embedded image

or a pharmaceutically acceptable salt thereof.

Embodiments of Formula VIII

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

embedded image

or a pharmaceutically acceptable salt thereof.

Embodiments of Formula I′

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

embedded image

or a pharmaceutically acceptable salt thereof.

Embodiments of Formula II′

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

embedded image

or a pharmaceutically acceptable salt thereof.

Embodiments of Formula III′

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

embedded image

or a pharmaceutically acceptable salt thereof.

Embodiments of Formula IV′

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

embedded image

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.

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

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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 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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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.