AMINOPYRIMIDINE COMPOUNDS AND METHODS OF THEIR USE

TECHNICAL FIELD

Disclosed herein are substituted aminopyrimidine compounds, pharmaceutical compositions that include such compounds, and methods of using such compounds.

BACKGROUND

Various approaches have been employed in the past to block the activity of tyrosine kinases. These kinase inhibitors are often small molecules. These small molecules can be used to target these kinases to block the development, growth or spread of cancer.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate a wide range of physiologic cellular processes, such as embryonic development, differentiation, proliferation, survival, migration, and angiogenesis. The FGF family comprises 18 secreted ligands (FGFs) which are readily sequestered to the extracellular matrix by heparin sulfate proteoglycans (HPSGs). For signal propagation, FGFs are released from the extracellular matrix by proteases or specific FGF-binding proteins, with the liberated FGFs subsequently binding to a cell surface FGF-receptor (FGFR) in a ternary complex consisting of FGF, FGFR and HPSG (Beenken, A., Nat. Rev. Drug Discov. 2009; 8:235-253).

FGFR signaling components are frequently altered in human cancer, and several preclinical models have provided compelling evidence for the oncogenic potential of aberrant FGFR signaling in carcinogenesis, thereby validating FGFR signaling as an attractive target for cancer treatment.

Compounds that inhibit FGFR are needed.

SUMMARY

The present disclosure provides compounds that inhibit FGFR. In particular, the disclosure provides compounds of formula I:

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- or pharmaceutically acceptable salts thereof,
- wherein:
  - Ar is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, each optionally substituted;
  - R¹is H, F, Cl, Br, C_1-6alkyl, CN, C_1-6haloalkyl, —C(O)NH₂, —C(O)NH(C₁-6alkyl), or —C(O)N(C_1-6alkyl)₂;
  - R²is a:
    - 9-membered bicyclic heteroaryl comprising a 6-5-fused ring system wherein the 5-membered ring contains at least one nitrogen atom and the 6 membered ring is substituted with at least one E; or
    - 13-membered tricyclic heteroaryl comprising a 6-5-6-fused ring system wherein the 5-membered ring contains at least one nitrogen atom and one of the 6 membered rings is substituted with at least one E; or
    - 12- or 13-membered tricyclic group comprising a 5- or 6-membered cycloalkyl or heterocycloalkyl ring fused to a 9-membered bicyclic heteroaryl comprising a 6-5-fused ring system wherein the 5-membered ring contains at least one nitrogen atom and the 6 membered ring is substituted with at least one E;
  - wherein E is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

Pharmaceutical compositions and methods of using and making the compounds of the disclosure are also provided.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The following terms are used to describe the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure.

The term “optionally substituted,” as used herein to describe a substituent defined herein, means that the substituent may be, but is not required to be, substituted with one or more of: halo (i.e., —F, —Cl, —Br, —I), cyano (—CN), —OH, —C₁-C₆alkyl, C₃-C₆cycloalkyl, 5-7 membered heterocycloalkyl, 5-7 membered spirocycloalkyl, or 5-7 membered spiroheterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl (e.g., —CF₃; —CHF₂, —CH₂CF₃, and the like), —C₁-C₆alkoxy (e.g., —OC₁-C₆alkyl; —O(optionally substituted C₁-C₆alkyl)), —C₁-C₆haloalkoxy (e.g., —OCF₃; —OCHF₂, —OCH₂CF₃, and the like), C₁-C₆alkylthio (e.g., —SCH₃; —SCH₂CH₃, and the like), C₁-C₆alkylamino (e.g., —CH₂NH₂, —CH₂CH₂NH₂, and the like), —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂(e.g., —N(C₁-C₆alkyl)(optionally substituted C₁-C₆alkyl)), —NH(C₁-C₆alkoxy), —C(O)NHC₁-C₆alkyl, —C(O)N(C₁-C₆alkyl)₂, —COOH, —C₁-C₆alkylCOOH, —C₃-C₆cycloalkylCOOH, —C(O)NH₂, —C₁-C₆alkylCONH₂, —C₃-C₆cycloalkylCONH₂, C₁-C₆alkylCONHC₁-C₆alkyl, C₁-C₆alkylCON(C₁-C₆alkyl)₂, —C(O)C₁-C₆alkyl, —C(O)OC₁-C₆alkyl, —NHCO(C₁-C₆alkyl), —N(C₁-C₆alkyl)C(O)(C₁-C₆alkyl), —S(O)C₁-C₆alkyl, —S(O)₂C₁-C₆alkyl, oxo (i.e., ═O), —NHSO₂(C₁-C₆alkyl), —N(C₁-C₆alkyl)SO₂(C₁-C₆alkyl), SO₂NH(C₁-C₆alkyl), SO₂N(C₁-C₆alkyl)₂, 6-12 membered aryl, 4-6-membered heterocycloalkyl, or 5 to 12 membered heteroaryl groups. In some embodiments, each of the above optional substituents are themselves optionally substituted by one or two of these groups.

In some embodiments wherein an optionally substituted alkyl group (e.g., optionally substituted C₁-C₆alkyl) is substituted with halogen, the group is referred to as a haloalkyl group.

In some embodiments, excluded from substituents encompassed by “optionally substituted” are substituents that have the following general formula:

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wherein W is —CH₂—, —C(O)—, —CH(OH)— or —N(R¹⁰)—; R¹⁰is —H, optionally substituted C₁-C₆-alkyl, optionally substituted C₁-C₆-alkenyl, or —C₃-C₆-cycloalkyl; and each R⁹is independently optionally substituted C₁-C₆-alkyl, optionally substituted C₁-C₆-alkenyl, or C₃-C₆-cycloalkyl.

When a range of carbon atoms is used herein, for example, “C₁-C₆” (or equivalently “C_1-6”), all ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C₁-C₃” includes C₁-C₃, C₁-C₂, C₂-C₃, C₁, C₂, and C₃. Thus, for example, a “C₁to C₄alkyl” group refers to all alkyl groups having from 1 to 4 carbons (e.g., 1, 2, 3, or 4), that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—. A “C₁to C₆alkyl” group refers to all alkyl groups having from 1 to 6 carbons (e.g., 1, 2, 3, 4, 5, or 6).

As used herein, the term “alkyl” refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The “alkyl” group may also be a medium size alkyl having 1 to 12 carbon atoms. The “alkyl” group could also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted. By way of example only, “C₁-C₅alkyl” indicates that there are one to five carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), etc. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. In several embodiments, “Me” is methyl (e.g., CH₃).

The term “C₁-C₆alk” when used alone or as part of a substituent group refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, —CH₂—, —CH(CH₃)—, —CH(CH₃)—CH₂—, and —C(CH₃)₂—. The term “-C₀alk-” refers to a bond.

As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstituted or substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups may contain between 3 and 12 carbon atoms. For example, a C₃-C₆cycloalkyl group indicates that there three to six carbon atoms in the ring, that is, the ring is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. A cycloalkyl group may be unsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C₆-C₁₄aryl group, a C₆-C₁₀aryl group, or a C₆aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

The term “haloalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of haloalkyl groups of the disclosure include, for example, trifluoromethyl (—CF₃), chloromethyl (—CH₂Cl), and the like.

As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl rings may also include bridge head nitrogen atoms. For example but not limited to: pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, and pyrazolo[1,5-a]pyrimidine. A heteroaryl group may be substituted or unsubstituted.

As used herein, “heterocycloalkyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycloalkyl may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. A heterocycloalkyl may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogen atom in a heterocycloalkyl may be quaternized. Heterocycloalkyl groups may be unsubstituted or substituted. Examples of such “heterocycloalkyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, 3,4-methylenedioxyphenyl).

As used herein, the term “amino” refers to a —NH₂group.

As used herein, the term “hydroxy” refers to a —OH group.

As used herein, the term “halo” or “halogen” refers to an atom that is fluorine, chlorine, bromine and/or iodine.

As used herein, “alkoxy” and “alkylthio” (or thioalkoxy) refer to alkyl groups attached to the remainder of a molecule via an oxygen atom or a sulfur atom, respectively.

The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In several embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Thus, pharmaceutically acceptable salts include, but are not limited to, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, teoclate, and tosylate salts. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)-methylamine, C₁-C₇alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. It is also understood that, in any compound described herein, all isotopes of the included atoms are envisioned. For example, any instance of hydrogen, may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium) or other isotopes; any instance of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes; any instance of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes; any instance of fluorine may include one or more of fluorine-18, fluorine-19, or other isotopes; any instance of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

The term “gatekeeper mutation” when used herein denotes mutations in a kinase enzyme that modulate the accessibility of the kinase ATP-binding pocket.

The term “target sequence” or “target nucleic acid sequence” shall be given its ordinary meaning and shall also include and also refer to the particular nucleotide sequence of the target nucleic acid to be detected (e.g., through amplification). The target sequence may include a probe-hybridizing region contained within the target molecule with which a probe will form a stable hybrid under desired conditions. The “target sequence” may also include the complexing sequences to which the oligonucleotide primers complex and be extended using the target sequence as a template. Where the target nucleic acid is originally single-stranded, the term “target sequence” also refers to the sequence complementary to the “target sequence” as present in the target nucleic acid. If the “target nucleic acid” is originally double-stranded, the term “target sequence” refers to both the plus (+) and minus (−) strands.

As used herein, the term “kinase inhibitor” means any compound, molecule or composition that inhibits or reduces the activity of a kinase. The inhibition can be achieved by, for example, blocking phosphorylation of the kinase (e.g., competing with adenosine triphosphate (ATP), a phosphorylating entity), by binding to a site outside the active site, affecting its activity by a conformational change, or by depriving kinases of access to the molecular chaperoning systems on which they depend for their cellular stability, leading to their ubiquitylation and degradation.

As used herein, “subject,” “host,” “patient,” and “individual” are used interchangeably and shall be given its ordinary meaning and shall also refer to an organism that has FGFR proteins. This includes mammals, e.g., a human, a non-human primate, ungulates, canines, felines, equines, mice, rats, and the like. The term “mammal” includes both human and non-human mammals. In some aspects, the “subject,” “host,” “patient,” or “individual” is human.

“Diagnosis” as used herein shall be given its ordinary meaning and shall also include determination of a subject's susceptibility to a disease or disorder, determination as to whether a subject is presently affected by a disease or disorder, prognosis of a subject affected by a disease or disorder (e.g., identification of cancer or cancerous states, stages of cancer, or responsiveness of cancer to therapy), and use of therametrics (e.g., monitoring a subject's condition to provide information as to the effect or efficacy of therapy).

The term “sample” or “biological sample” shall be given its ordinary meaning and also encompasses a variety of sample types obtained from an organism and can be used in an imaging, a diagnostic, a prognostic, or a monitoring assay. The term encompasses blood and other liquid samples of biological origin, solid tissue samples, such as a biopsy specimen or tissue cultures or cells derived therefrom and the progeny thereof. The term encompasses samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components. The term encompasses a clinical sample, and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.

The terms “treatment,” “treating,” “treat” and the like shall be given its ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease. “Treatment” as used herein shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, e.g., arresting its development; and/or (c) relieving the disease symptom, e.g., causing regression of the disease or symptom.

The terms “cancer,” “neoplasm,” and “tumor” are used interchangeably herein, shall be given its ordinary meaning and shall also refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In general, cells of interest for detection or treatment in the present application include precursors, precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells. As used herein, “FGFR related cancer” denotes those cancers that involve an increased activity in a mutant FGFR kinase, for example, the continued activation of FGFR.

The term “control” refers shall be given its ordinary meaning and shall also include a sample or standard used for comparison with a sample which is being examined, processed, characterized, analyzed, etc. In several embodiments, the control is a sample obtained from a healthy patient or a non-tumor tissue sample obtained from a patient diagnosed with a tumor. In several embodiments, the control is a historical control or standard reference value or range of values. In several embodiments, the control is a comparison to a wild-type FGFR arrangement or scenario.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the described subject matter in any way. All literature and similar materials cited in this application, including but not limited to, patents, patent applications, articles, books, treatises, and internet web pages are expressly incorporated by reference in their entirety for any purpose. When definitions of terms in incorporated references appear to differ from the definitions provided in the present teachings, the definition provided in the present teachings shall control. It will be appreciated that there is an implied “about” prior to the temperatures, concentrations, times, etc. discussed in the present teachings, such that slight and insubstantial deviations are within the scope of the present teachings herein. In this application, the use of the singular includes the plural unless specifically stated otherwise. Also, the use of “comprise”, “comprises”, “comprising”, “contain”, “contains”, “containing”, “include”, “includes”, and “including” are not intended to be limiting. It is to be understood that both the general description and the following detailed description are exemplary and explanatory only and are not restrictive. The term “and/or” denotes that the provided possibilities can be used together or be used in the alternative. Thus, the term “and/or” denotes that both options exist for that set of possibilities.

Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term “including” should be read to mean “including, without limitation,” “including but not limited to,” or the like; the term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term “having” should be interpreted as “having at least;” the term “includes” should be interpreted as “includes but is not limited to;” the term “example” is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like “preferably,” “preferred,” “desired,” or “desirable,” and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction “and” should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as “and/or” unless expressly stated otherwise. Similarly, a group of items linked with the conjunction “or” should not be read as requiring mutual exclusivity among that group, but rather should be read as “and/or” unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

In some aspects, the disclosure is directed to compounds of formula I:

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- or pharmaceutically acceptable salts thereof,
- wherein:
- Ar is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, each optionally substituted;
- R¹is H, F, Cl, Br, C_1-6alkyl, CN, C_1-6haloalkyl, —C(O)NH₂, —C(O)NH(C_1-6alkyl), or —C(O)N(C_1-6alkyl)₂;
- R²is a 9-membered bicyclic heteroaryl comprising a 6-5-fused ring system wherein the 5-membered ring contains at least one nitrogen atom and the 6 membered ring is substituted with at least one E; or a 13-membered tricyclic heteroaryl comprising a 6-5-6-fused ring system wherein the 5-membered ring contains at least one nitrogen atom and one of the 6 membered rings is substituted with at least one E; or a 12- or 13-membered tricyclic group comprising a 5- or 6-membered cycloalkyl or heterocycloalkyl ring fused to a 9-membered bicyclic heteroaryl comprising a 6-5-fused ring system; wherein the 5-membered ring contains at least one nitrogen atom and the 6 membered ring is substituted with at least one E; wherein E is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

In some embodiments of the compounds of formula I, or pharmaceutically acceptable salts thereof, Ar is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, each optionally substituted; R¹is H, F, Cl, Br, C_1-6alkyl, CN, C_1-6haloalkyl, —C(O)NH₂, —C(O)NH(C_1-6alkyl), or —C(O)N(C_1-6alkyl)₂; R²is a 9-membered bicyclic heteroaryl comprising a 6-5-fused ring system wherein the 5-membered ring contains at least one nitrogen atom and the 6 membered ring is substituted with at least one E; wherein E is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

In other embodiments of the compounds of formula I, or pharmaceutically acceptable salts thereof, Ar is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, each optionally substituted; R¹is H, F, Cl, Br, C_1-6alkyl, CN, C_1-6haloalkyl, —C(O)NH₂, —C(O)NH(C_1-6alkyl), or —C(O)N(C_1-6alkyl)₂; R²is a 13-membered tricyclic heteroaryl comprising a 6-5-6-fused ring system wherein the 5-membered ring contains at least one nitrogen atom and one of the 6 membered rings is substituted with at least one E; wherein E is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

In other embodiments of the compounds of formula I, or pharmaceutically acceptable salts thereof, Ar is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, each optionally substituted; R¹is H, F, Cl, Br, C_1-6alkyl, CN, C_1-6haloalkyl, —C(O)NH₂, —C(O)NH(C_1-6alkyl), or —C(O)N(C_1-6alkyl)₂; R²is a 12- or 13-membered tricyclic group comprising a 5- or 6-membered cycloalkyl or heterocycloalkyl ring fused to a 9-membered bicyclic heteroaryl comprising a 6-5-fused ring system; wherein the 5-membered ring contains at least one nitrogen atom and the 6 membered ring is substituted with at least one E; wherein E is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

In some aspects, Ar in formula I is a 6-10-membered aryl group or a 5-10-membered heteroaryl group, each optionally substituted.

In some embodiments, Ar is an optionally substituted 6-10-membered aryl group. In some embodiments, Ar is an unsubstituted 6-10-membered aryl group, for example, an unsubstituted phenyl group, or an unsubstituted naphthyl group.

In other embodiments, Ar is a substituted 6-10-membered aryl group, for example, a substituted phenyl group, or a substituted naphthyl group.

In some embodiments, Ar is an optionally substituted phenyl group.

In some embodiments, Ar is a substituted phenyl group.

In some embodiments wherein Ar is a substituted phenyl group, the phenyl group is substituted with one or more optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted 4-6-membered heterocycloalkyl, —N(C₁-C₆alkyl)(optionally substituted C₁-C₆alkyl), —O(optionally substituted C₁-C₆alkyl), —CN, or halogen.

In some embodiments wherein Ar is a substituted phenyl group that is substituted with one or more optionally substituted C₁-C₆alkyl, the optionally substituted C₁-C₆alkyl is —CH₃, —CH₂CH₃, isopropyl, —CH₂CF₃, —CHF₂, —CF₃, —C_1-6alk-cyclopropyl, —CH₂-cyclopropyl, —C_1-6alk-(optionally substituted 5 or 6-membered heterocycloalkyl), —CH₂-(optionally substituted 5 or 6-membered heterocycloalkyl), or —CH₂CH₂OH.

In some embodiments wherein Ar is a substituted phenyl group that is substituted with one or more optionally substituted C₁-C₆alkyl, at least one optionally substituted C₁-C₆alkyl is —CH₃.

In some embodiments wherein Ar is a substituted phenyl group that is substituted with one or more optionally substituted C₁-C₆alkyl, at least one substituted C₁-C₆alkyl is —CH₂CF₃.

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In some embodiments wherein Ar is a substituted phenyl group that is substituted with one or more optionally substituted C₁-C₆alkyl, the optionally substituted C₁-C₆alkyl is —CH₂CH₂OH.

In some embodiments wherein Ar is a substituted phenyl group that is substituted with one or more optionally substituted C₃-C₆cycloalkyl, the optionally substituted C₃-C₆cycloalkyl is cyclopropyl or cyclobutyl.

In some embodiments wherein Ar is a substituted phenyl group that is substituted with one or more optionally substituted 4-6-membered heterocycloalkyl, the optionally substituted 4-6-membered heterocycloalkyl is

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In some embodiments wherein Ar is a substituted phenyl group that is substituted with one or more N(C₁-C₆alkyl)(optionally substituted C₁-C₆alkyl), the N(C₁-C₆alkyl)(optionally substituted C₁-C₆alkyl) is

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In some embodiments wherein Ar is a substituted phenyl group that is substituted with one or more —O(optionally substituted C₁-C₆alkyl), the —O(optionally substituted C₁-C₆alkyl) is —OCH₃, —OCH₂CH₃, or

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In some embodiments wherein Ar is a substituted phenyl group that is substituted with one or more —O(optionally substituted C₁-C₆alkyl), the —O(optionally substituted C₁-C₆alkyl) is

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In some embodiments wherein Ar is a substituted phenyl group, the phenyl group is substituted with —CN.

In some embodiments wherein Ar is a substituted phenyl group that is substituted with one or more halogen, at least one halogen is —F.

In some embodiments, Ar in formula I is

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In some aspects, Ar in formula I is an optionally substituted 5-10-membered heteroaryl group, such as, for example, furan, furazan, thiophene, benzothiphene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, or triazine, each optionally substituted.

In some embodiments, the optionally substituted 5-10-membered heteroaryl group is a pyridinyl, a pyrazolyl, a triazolyl, an imidazolyl, a pyrazolopyrimidine, or a triazolopyridine, each optionally substituted.

In some embodiments, Ar is an unsubstituted 5-10-membered heteroaryl group.

In some embodiments, Ar is a substituted 5-10-membered heteroaryl group.

In some embodiments, Ar is a substituted pyrazolyl group.

In some embodiments wherein Ar is a substituted 5-10-membered heteroaryl group, the substituted 5-10-membered heteroaryl group is substituted with one or more optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted 4-6-membered heterocycloalkyl, —N(C₁-C₆alkyl)(optionally substituted C₁-C₆alkyl), —O(optionally substituted C₁-C₆alkyl), —CN, or halogen.

In some embodiments wherein Ar is a substituted 5-10-membered heteroaryl group, the substituted 5-10-membered heteroaryl group is substituted with one or more —C(O)—O(optionally substituted C₁-C₆alkyl), such as, for example, —C(O)O-t-butyl.

In some embodiments wherein Ar is a substituted 5-10 membered heteroaryl group that is substituted with one or more optionally substituted C₁-C₆alkyl, the optionally substituted C₁-C₆alkyl is —CH₃, —CH₂CH₃, isopropyl, —CH₂CF₃, —CHF₂, —CF₃, —CH₂-cyclopropyl, —CH₂-(optionally substituted 5 or 6-membered heterocycloalkyl), or —CH₂CH₂OH.

In some embodiments wherein Ar is a substituted 5-10 membered heteroaryl group that is substituted with one or more optionally substituted C₁-C₆alkyl, the optionally substituted C₁-C₆alkyl is —CH₂CH(OH)CH₃, —C(CN)(CH₃)₂, —CH₂CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂C(OH)(CH₃)₂, —CH₂CH₂OCH₂CH₃, —CH₂CH₂OCH(CH₃)₂, CH₂CH(OCH₃)CH₃, —CH₂CHF₂, —CH₂CH₂N(CH₃)₂, —CH₂CH₂-(optionally substituted 5 or 6-membered heterocycloalkyl), or —CH₂-optionally substituted cyclopropyl.

In some embodiments wherein Ar is a substituted 5-10 membered heteroaryl group that is substituted with one or more optionally substituted C₁-C₆alkyl, at least one optionally substituted C₁-C₆alkyl is —CH₃.

In some embodiments wherein Ar is a substituted 5-10 membered heteroaryl group that is substituted with one or more optionally substituted C₁-C₆alkyl, at least one substituted C₁-C₆alkyl is —CH₂CF₃.

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In some embodiments wherein Ar is a substituted 5-10 membered heteroaryl group that is substituted with one or more optionally substituted C₃-C₆cycloalkyl, the optionally substituted C₃-C₆cycloalkyl is cyclopropyl or cyclobutyl.

In some embodiments wherein Ar is a substituted 5-10 membered heteroaryl group that is substituted with one or more optionally substituted 4-6-membered heterocycloalkyl, the optionally substituted 4-6-membered heterocycloalkyl is

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In some embodiments wherein Ar is a substituted 5-10 membered heteroaryl group that is substituted with one or more N(C₁-C₆alkyl)(optionally substituted C₁-C₆alkyl), the N(C₁-C₆alkyl)(optionally substituted C₁-C₆alkyl) is

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In some embodiments wherein Ar is a substituted 5-10 membered heteroaryl group that is substituted with one or more —O(optionally substituted C₁-C₆alkyl), the —O(optionally substituted C₁-C₆alkyl) is —OCH₃, —OCH₂CH₃, or

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In some embodiments wherein Ar is a substituted 5-10 membered heteroaryl group, the phenyl group is substituted with —CN.

In some embodiments wherein Ar is a substituted 5-10 membered heteroaryl group that is substituted with one or more halogen, the halogen is —F.

In some embodiments, Ar in the compounds of formula I is

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In some embodiments, Ar in the compounds of formula I is

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In other embodiments, Ar in the compounds of formula I is

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In other embodiments, Ar in the compounds of formula I is

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In other embodiments, Ar in the compounds of formula I is

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In other embodiments, Ar in the compounds of formula I is

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In other embodiments, Ar in the compounds of formula I is

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In other embodiments, Ar in the compounds of formula I is

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In other embodiments, Ar in the compounds of formula I is

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In other embodiments, Ar in the compounds of formula I is

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In other embodiments, Ar in the compounds of formula I is

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In some aspects, R¹in formula I is H, F, Cl, Br, C_1-6alkyl, CN, C_1-6haloalkyl, —C(O)NH₂, —C(O)NH(C_1-6alkyl), or —C(O)N(C_1-6alkyl)₂.

In some embodiments, R¹is H, —Cl, —F, —CH₃, or —CN.

In some embodiments, R¹is —C₁or —CH₃.

In some embodiments, R¹is H.

In some embodiments, R¹is F, with the proviso that when R¹is F, Ar is not

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In some embodiments, R¹is C₁. In some embodiments, R¹is Br.

In some embodiments, R¹is C_1-6alkyl, such as, for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.

In some embodiments, R¹is —CH₃.

In some embodiments, R¹is CN.

In some embodiments, R¹is C_1-6haloalkyl, such as, for example, C₆haloalkyl, C₅haloalkyl, C₄haloalkyl, C₃haloalkyl, C₂haloalkyl, C₁haloalkyl, —CF₃, —CHF₂, —CH₂CF₃, and the like.

In some embodiments, R¹is —C(O)NH₂.

In some embodiments, R¹is —C(O)NH(C_1-6alkyl), such as, for example, —C(O)NH(C₆alkyl), —C(O)NH(C₅alkyl), —C(O)NH(C₄alkyl), —C(O)NH(C₃alkyl), —C(O)NH(C₂alkyl), —C(O)NH(C₁alkyl), —C(O)NH(CH₃), —C(O)NH(CH₂CH₃), —C(O)NH(CH₂CH₂CH₃), and the like.

In some embodiments, R¹is —C(O)N(C_1-6alkyl)₂, wherein each C_1-6alkyl can be the same or different, such as, for example, —C(O)N(C₆alkyl)₂, —C(O)N(C₅alkyl)₂, —C(O)N(C₄alkyl)₂, —C(O)N(C₃alkyl)₂, —C(O)N(C₂alkyl)₂, —C(O)N(C₁alkyl)₂, —C(O)N(CH₃)₂, —C(O)N(CH₂CH₃)₂, —C(O)N(CH₂CH₃)(CH₃), and the like.

In some aspects, R²in formula I is a 9-membered bicyclic heteroaryl comprising a 6-5-fused ring system wherein the 5-membered ring contains at least one nitrogen atom and the 6 membered ring is substituted with at least one E, wherein E is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety. Exemplary E groups are described herein.

In these embodiments of R², the 9-membered bicyclic heteroaryl comprising a 6-5-fused ring system is any fully aromatic 6-5 fused ring system in which the 5-membered ring contains at least one nitrogen atom. The 5-membered ring may also contain, in addition to the nitrogen, one more additional heteroatoms that may be another nitrogen, an oxygen, or a sulfur. The 6-membered ring may contain one or more nitrogen atoms.

In other aspects, R²in formula I is a 13-membered tricyclic heteroaryl comprising a 6-5-6-fused ring system wherein the 5-membered ring contains at least one nitrogen atom and one of the 6 membered rings is substituted with at least one E, wherein E is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

In these embodiments of R², the 13-membered tricyclic heteroaryl comprising a 6-5-6-fused ring system is any fully aromatic 6-5-6 fused ring system in which the 5-membered ring contains at least one nitrogen atom. The 5-membered ring may also contain, in addition to the nitrogen, one more additional heteroatoms that may be another nitrogen, an oxygen, or a sulfur. The 6-membered rings may contain one or more nitrogen atoms.

In other aspects, R²in formula I is a 12- or 13-membered tricyclic group comprising a 5- or 6-membered cycloalkyl or heterocycloalkyl ring fused to a 9-membered bicyclic heteroaryl comprising a 6-5-fused ring system; wherein the 5-membered ring contains at least one nitrogen atom and the 6 membered ring is substituted with at least one E; wherein E is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety.

In some embodiments of formula I, R²is

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wherein

- Q¹is N or C—R^3A;
- Q²is N or C—R^3A,
  - R^3Ais H, C₁-C₆alkyl, —CN, —C₁-C₆haloalkyl, halo, —CON(R)₂, —NR₂, cycloalkyl, —CH₂cycloalkyl, —COR, —CH(OH)R, —CO-cycloalkyl, —CH(OH)cycloalkyl, —SR, or —SO₂R;
    - each R is independently H, or C₁-C₆alkyl;
  - or, when Q¹is C—R^3Aand Q²is C—R^3A, the R^3Aof Q¹and the R^3Aof Q², together with the carbon atoms to which they are attached, for a 5- or 6-membered cycloalkyl or heterocycloalkyl ring, or a phenyl ring;
- Q³, Q⁴, Q⁵, and Q⁶are each independently N or C—R^3B; each R^3Bis independently H, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —CN, C₃-C₇cycloalkyl, or E, provided that at least one of Q³, Q⁴, Q⁵, and Q⁶is C-E, wherein E is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety; and
- R⁴is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, or SO₂(C₁-C₆alkyl); or, when Q¹is C—R^3A, the R^3Aof Q¹and R⁴, together with the atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl ring.

In some embodiments of formula I, R²is

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- Q¹is N or C—H;
- Q²is N or C—R^3A,
  - R^3Ais H, C₁-C₆alkyl, —CN, —C₁-C₆haloalkyl, halo, —CON(R)₂, —NR₂, cycloalkyl, —CH₂cycloalkyl, —COR, —CH(OH)R, —CO-cycloalkyl, —CH(OH)cycloalkyl, —SR, or —SO₂R;
    - each R is independently H, or C₁-C₆alkyl;
- Q³, Q⁴, Q⁵, and Q⁶are each independently N or C—R^3B;
  - each R^3Bis independently H, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —CN, C₃-C₇cycloalkyl, or E, provided that at least one of Q³, Q⁴, Q⁵, and Q⁶is C-E, wherein E is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety; and
- R⁴is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, or SO₂(C₁-C₆alkyl).

In some embodiments of formula I, R²is

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In some embodiments of R², Q¹is N.

In other embodiments of R², Q¹is C—R^3A. In such embodiments, R^3Ais H, C₁-C₆alkyl, —CN, —C₁-C₆haloalkyl, halo, —CON(R)₂, —NR₂, cycloalkyl, —CH₂cycloalkyl, —COR, —CH(OH)R, —CO-cycloalkyl, —CH(OH)cycloalkyl, —SR, or —SO₂R, wherein each R is independently H, or C₁-C₆alkyl.

In other embodiments of R², Q¹is C—H.

In other embodiments of R², Q¹is C—CH₃.

In some embodiments of R², Q²is N.

In other embodiments of R², Q²is C—R^3A.

In some embodiments, R^3Ais H, C₁-C₆alkyl, —CN, —C₁-C₆haloalkyl, halo, —CON(R)₂, —NR₂, cycloalkyl, —CH₂cycloalkyl, —COR, —CH(OH)R, —CO-cycloalkyl, —CH(OH)cycloalkyl, —SR, or —SO₂R, wherein each R is independently H, or C₁-C₆alkyl.

In some embodiments, R^3Ais H.

In other embodiments, R^3Ais C₁-C₆alkyl, such as, for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.

In some embodiments, R^3Ais methyl.

In some embodiments, R^3Ais ethyl.

In some embodiments, R^3Ais —CN.

In other embodiments, R^3Ais C_1-6haloalkyl, such as, for example, C₆haloalkyl, C₅haloalkyl, C₄haloalkyl, C₃haloalkyl, C₂haloalkyl, C₁haloalkyl, —CF₃, —CHF₂, —CH₂CF₃, and the like.

In some embodiments, R^3Ais halo, i.e., —F, —Cl, Br, or —I.

In some embodiments, R^3Ais —CON(R)₂, wherein each R is independently H, or C₁-C₆alkyl (such as, for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.). Thus, in some embodiments wherein R^3Ais —CON(R)₂, R^3Ais, for example, —CONH₂, —CON(CH₃)₂, —CON(CH₂CH₃)₂, —CONH(CH₃), —CONH(CH₂CH₃), —CON(CH₃)(CH₂CH₃), and the like.

In some embodiments, R^3Ais —NR₂, wherein each R is independently H, or C₁-C₆alkyl (such as, for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.). Thus, in some embodiments wherein R^3Ais —NR₂, R^3Ais, for example, —NH₂, —N(CH₃)₂, —N(CH₂CH₃)₂, —NH(CH₃), —NH(CH₂CH₃), —N(CH₃)(CH₂CH₃), and the like.

In some embodiments, R^3Ais -cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

In some embodiments, R^3Ais —CH₂cycloalkyl, such as, for example, —CH₂cyclopropyl, —CH₂cyclobutyl, —CH₂cyclopentyl, —CH₂cyclohexyl, and the like.

In some embodiments, R^3Ais —COR, wherein R is independently H, or C₁-C₆alkyl (such as, for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.). Thus, in some embodiments wherein R^3Ais —COR, R^3Ais, for example, —COH, —COCH₃, —COCH₂CH₃, and the like.

In some embodiments, R^3Ais —CH(OH)R, wherein R is independently H, or C₁-C₆alkyl (such as, for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.). Thus, in some embodiments wherein R^3Ais —CH(OH)R, R^3Ais, for example, —CH₂(OH), —CH(OH)CH₃, —CH(OH)CH₂CH₃, and the like.

In some embodiments, R^3Ais —CO-cycloalkyl. Thus, in some embodiments wherein R^3Ais —CO-cycloalkyl, R^3Ais, for example, —CO-cyclopropyl, —CO-cyclobutyl, —CO— cyclopentyl, —CO-cyclohexyl, and the like.

In some embodiments, R^3Ais —CH(OH)-cycloalkyl. Thus, in some embodiments wherein R^3Ais —CH(OH)-cycloalkyl, R^3Ais, for example, —CH(OH)-cyclopropyl, —CH(OH)— cyclobutyl, —CH(OH)-cyclopentyl, —CH(OH)-cyclohexyl, and the like.

In some embodiments, R^3Ais —SR wherein each R is independently H, or C₁-C₆alkyl (such as, for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.). Thus, in some embodiments wherein R^3Ais —SR, R^3Ais, for example, —SH, —SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃, and the like.

In some embodiments, R^3Ais —SO₂R wherein each R is independently H, or C₁-C₆alkyl (such as, for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.). Thus, in some embodiments wherein R^3Ais —SO₂R, R^3Ais, for example, —SO₂H, —SO₂CH₃, —SO₂CH₂CH₃, —SO₂CH₂CH₂CH₃, and the like.

In some embodiments of R², Q³is N or C—R^3B.

In some embodiments wherein Q¹is C—R^3Aand Q²is C—R^3A, the R^3Aof Q¹and the R^3Aof Q²are both —CH₃.

In some embodiments wherein Q¹is C—R^3Aand Q²is C—R^3A, the R^3Aof Q¹and the R^3Aof Q², together with the carbon atoms to which they are attached, form a 5- or 6-membered cycloalkyl or heterocycloalkyl ring; or a 6-membered phenyl ring.

In some embodiments wherein Q¹is C—R^3Aand Q²is C—R^3A, the R^3Aof Q¹and the R^3Aof Q², together with the carbon atoms to which they are attached, form a 5-membered cycloalkyl ring. Thus, in some embodiments, R²is

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In other embodiments wherein Q¹is C—R^3Aand Q²is C—R^3A, the R^3Aof Q¹and the R^3Aof Q², together with the carbon atoms to which they are attached, form a 6-membered cycloalkyl ring. Thus, in some embodiments, R²is

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In other embodiments wherein Q¹is C—R^3Aand Q²is C—R^3A, the R^3Aof Q¹and the R^3Aof Q², together with the carbon atoms to which they are attached, form a phenyl ring. Thus, in some embodiments, R²is

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In some embodiments Q³is N.

In some embodiments Q³is C—R^3B.

In some embodiments Q⁴is N.

In some embodiments Q⁴is C—R^3B.

In some embodiments Q⁵is N.

In some embodiments Q⁵is C—R^3B.

In some embodiments Q⁶is N.

In some embodiments Q⁶is C—R^3B.

In embodiments in which Q³, Q⁴, Q⁵, and/or Q⁶is C—R^3B, each R^3Bis independently H, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —CN, C₃-C₇cycloalkyl, or E.

In some embodiments, R^3Bis H.

In other embodiments, R^3Bis C₁-C₆alkyl, such as, for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.

In some embodiments, R^3Bis methyl.

In some embodiments, R^3Bis —CN.

In other embodiments, R^3BIS C_1-6haloalkyl, such as, for example, C₆haloalkyl, C₅haloalkyl, C₄haloalkyl, C₃haloalkyl, C₂haloalkyl, C₁haloalkyl, —CF₃, —CHF₂, —CH₂CF₃, and the like.

In some embodiments, R^3Bis —C₃-C₇cycloalkyl, such as, for example, —C₃cycloalkyl, —C₄cycloalkyl, —C₅cycloalkyl, —C₆cycloalkyl, —C₇cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

In some embodiments, R^3Bis E wherein E is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety. Exemplary E groups are further described herein.

In some embodiments, R⁴is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, or SO₂(C₁-C₆alkyl).

In some embodiments, R⁴is C₁-C₆alkyl, such as, for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.

In some embodiments, R⁴is C_1-6haloalkyl, such as, for example, C₆haloalkyl, C₅haloalkyl, C₄haloalkyl, C₃haloalkyl, C₂haloalkyl, C₁haloalkyl, —CF₃, —CHF₂, —CH₂CF₃, and the like.

In some embodiments, R⁴is —C₃-C₇cycloalkyl, such as, for example, —C₃cycloalkyl, —C₄cycloalkyl, —C₅cycloalkyl, —C₆cycloalkyl, —C₇cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

In some embodiments, R⁴is —SO₂(C₁-C₆alkyl), such as, for example, —SO₂(C₁alkyl), —SO₂(C₂alkyl), —SO₂(C₃alkyl), —SO₂(C₄alkyl), —SO₂(C₅alkyl), —SO₂(C₆alkyl), —SO₂(CH₃), —SO₂(CH₂CH₃), —SO₂(CH₂CH₂CH₃), and the like.

In some embodiments wherein Q¹is C—R^3A, the R^3Aof Q¹and R⁴, together with the atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl ring.

In some embodiments wherein Q¹is C—R^3A, the R^3Aof Q¹and R⁴, together with the atoms to which they are attached, form a 5-membered heterocycloalkyl ring. Thus, in some embodiments, R²is

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In some embodiments wherein Q¹is C—R^3A, the R^3Aof Q¹and R⁴, together with the atoms to which they are attached, form a 6-membered heterocycloalkyl ring. Thus, in some embodiments, R²is

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In some embodiments wherein Q³is C—R^3B, R^3Bis —CH₃.

In some embodiments wherein Q⁵is C—R^3B, R^3Bis —CH₃.

In some embodiments, R²is

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and the like.

In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some embodiments, R²is

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In some aspects, E in the compounds of the disclosure is an electrophilic moiety that is capable of reacting with a nucleophile so as to form a covalent bond between an atom of the nucleophile and an atom of the electrophilic moiety. Such electrophilic moieties include, but are not limited to, α-β unsaturated amides, α-β unsaturated esters, α-β unsaturated ketones, α-β unsaturated sulfoxides, α-β unsaturated sulfones, α-β unsaturated sulfinates, α-β unsaturated sulfonates, α-β unsaturated sulfinamides, α-β unsaturated sulfonamides, α-β unsaturated succinimides, α-β epoxy amides, α-β epoxy esters, α-β epoxy ketones, α-halo amides, α-halo esters, α-halo ketones, and the like.

In some embodiments, E is

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wherein each R⁵and each R⁶is independently H, optionally substituted C₁-C₆alkyl, or halogen; R⁸is H or C₁-C₆alkyl; and X is halogen.

In some embodiments, R⁵is H.

In other embodiments, R⁵is optionally substituted C₁-C₆alkyl, such as, for example, optionally substituted C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.

In other embodiments, R⁵is halogen, i.e., —F, —Cl, —Br, or —I.

In some embodiments, R⁶is H.

In other embodiments, R⁶is optionally substituted C₁-C₆alkyl, such as, for example, optionally substituted C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.

In other embodiments, R⁶is halogen, i.e., —F, —Cl, —Br, or —I.

In some embodiments, R⁸is H.

In other embodiments, R⁸is C₁-C₆alkyl, such as, for example, C₆alkyl, C₅alkyl, C₄alkyl, C₃alkyl, C₂alkyl, C₁alkyl, methyl, ethyl, propyl, and the like.

In some embodiments, X is halogen, i.e., —F, —Cl, —Br, or —I.