Antifungal compounds and methods of use same for inhibiting group i intron splicing

Abstract

The disclosure relates to certain heteroaryl antifungal compounds, pharmaceutical compositions comprising the same, and methods of use thereof for treating fungal infections by inhibiting group I intron splicing: (I).

Description

[0001]Attorney Docket No.047162-7508WO1(02676) TITLE Antifungal Compounds and Methods of Use Same for Inhibiting Group I Intron Splicing CROSS-REFERENCE TO RELATED APPLICATIONS 5 This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No.63 / 670,172, filed July 12, 2024, which is incorporated herein by reference in its entirety. BACKGROUND 10 Drugs against self-splicing group I introns can be promising pan-fungal agents, as that target is necessary for proper mitochondrial function in all fungi. Because humans do not have group I introns in their genome, drugs that target them do not generally show any toxicity in humans. This gives the promise of generating pan-fungal drugs that are so well- tolerated by humans that they can be taken in the bloodstream. 15 However, current antifungal treatments often suffer from limitations such as toxicity, limited spectrum of activity, and the emergence of resistant fungal strains. Many existing drugs can lead to significant side effects. Moreover, some fungal infections remain challenging to treat effectively, particularly in immunocompromised patients. This underscores the necessity for novel antifungal agents with unique mechanisms of action that 20 can overcome these challenges. There is thus a need in the art for improved therapeutics that can be used to treat, prevent, and / or ameliorate fungal infections. The disclosure addresses and satisfies this need. BRIEF SUMMARY 25 In one aspect, the disclosure provides a compound of Formula (I), or a salt, stereoisomer, tautomer, or isotopologue thereof, wherein R1a, R2a, R2b, L, X1, X2, X3, X4, Y, and bond a are defined elsewhere herein: I). In another aspect, the utical composition comprising 30 the compound of the disclosure and at least one pharmaceutically acceptable excipient. - 1 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a fungal infection in a subject. In certain embodiments, the method comprises administering to a subject a group I intron splicing inhibitor. In certain embodiments, the group I intron splicing inhibitor is the compound of the disclosure or a pharmaceutical 5 composition of the disclosure. In another aspect, the disclosure provides a method of reducing or inhibiting splicing of a group I intron in a cell. In certain embodiments, the method comprises administering to the cell an effective amount of at least one compound of the disclosure or a pharmaceutical composition of the disclosure. 10 BRIEF DESCRIPTION OF THE FIGURES The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application. The patent or application file contains at least one drawing executed in color. Copies 15 of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIGs.1A-1B show representative group I introns readily self-splice under near- physiological conditions in the presence of guanosine triphosphate (GTP), whose 3’–OH acts as the reaction nucleophile for initiation of the splicing reaction. FIG.1A shows the self- 20 splicing time course of the C.a.mtLSU intron in the presence of 50 µM GTP is shown. The splicing time courses were performed under a standard group I intron splicing buffer (50 mM K-HEPES pH 7.5, 5 mM MgCl2) incubated at 37oC. The time point samples were analyzed on a 5 % polyacrylamide / 8 M urea gel to resolve individual bands. Bands corresponding to the precursor, splicing intermediate (intron-3’ exon), fully spliced linear intron and the ligated 25 exon are indicated in the figure. The middle part of the gel is not shown as no bands are visible within that region and the top and bottom parts of the gel are indicated in the figure. FIG.1B shows self-splicing time course of the C.au.cytB intron in the presence of 200 µM GTP. FIGs.2A-2D show kinetic and enzymological characterization of the self-splicing of 30 representative fungal group I introns. Guanosine was used as the reaction nucleophile. All reactions were performed in triplicates. Error bars on the graph represent standard errors of the mean (s.e.m.). For the C.a.mtLSU intron, all experiments were performed under an ultra- mild condition (50 mM K-HEPES pH 7.5, 150 mM KCl, 3 mM MgCl2) at ambient temperature (25oC). FIG.2A: Self-splicing time course in the presence of 250 µM - 2 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) guanosine, a concentration near the inflection point of the Michaelis curve, which gives an apparent precursor conversion rate constant (kobs) of 1.07 ± 0.05 min-1. FIG.2B: The Michaelis-Menten plot with kobs plotting against guanosine concentration. The Michaelis constant for guanosine (^^ெீ) is 356 ± 10 µM and the catalytic turnover (kcat) is 2.6 ± 0.2 min- 51. The initial rate plot is shown as the bottom insert, giving the overall catalytic efficiency (kcat / ^^ெீ) of (5.6 ± 0.2) x 104M-1min-1. For the C.au.cytB intron (FIG.2C and FIG.2D), all experiments were performed under a standard group I intron splicing condition (50 mM K- HEPES pH 7.5, 5 mM MgCl2) at 37oC. FIG.2C shows the results of the self-splicing time course in the presence of 50 µM guanosine, a concentration near the inflection point of the 10 Michaelis curve (FIG.2D), which gives an apparent precursor conversion rate constant (kobs) of 0.24 ± 0.02 min-1. FIG.2D shows the related Michaelis-Menten plot of FIG.2C. The Michaelis constant (^^ெீ) is 54 ± 5 µM and the catalytic turnover (kcat) is 0.55 ± 0.02 min-1. The initial rate plot is shown, giving the overall catalytic efficiency (kcat / ^^ெீ) of (6.8 ± 0.4) x 104M-1min-1. 15 FIG.3A shows the biochemical characterization of the P11 pseudoknot in the C.a.mtLSU intron. The schematic shows the wild-type P11 pseudoknot and the unzip mutant. FIG.3B shows radioanalytical self-splicing time courses of the wild-type intron, the P11- unzip mutant and the P11-unzip mutant in the presence of 10% PEG-4000 under the ultra- mild condition (50 mM K-HEPES pH 7.5, 150 mM KCl, 3 mM MgCl2, 20 μM guanosine and 20 25°C). P11-unzip mutant is incapable of self-splicing under this condition. In the presence of 10% PEG-4000, P11-unzip mutant self-splices at an apparent rate constant of 0.03 min-1(compared to 0.10 min-1for the wild-type without PEG-4000). FIGs.4A-4B shows the group I intron structure and splicing mechanism based on the cryo-electron microscopy (EM) structure of the C. albicans mLSU group I intron solved at 25 2.9 Å resolution bound to the guanosine nucleophile FIG.4A shows the cryo-EM structure of the C. albicans mLSU group I intron. FIG.4B shows the two-step splicing reaction of a precursor RNA, where the guanosine nucleophile attacks the 5’-splice-site in the first step, the 5’-exon attacks the 3’-splice site in the second step and ligated exons are released. Cartoon of intron is shown as black line. 30 FIG.5A provides a schematic of an exemplary molecular beacon assay used for the high throughput screening (HTS) described herein. HTS was performed with a compound library at a concentration of 10 µM wherein active, replicable hit compound (circled, compound Z3686288076) was identified. Dots represent individual compound inhibition - 3 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) data. Dots represent background standards for each sample. FIG.5B shows a workflow for high-throughput screening (HTS), structure activity relationships (SAR) and optimization. FIG.6 shows drug discovery flow starting from a compound having an intron splicing IC50of about 0.84 µM affinity to more potent exemplary compounds, including a compound 5 exhibiting an IC50 of 86 nM. FIG.7 shows a cartoon of the molecular beacon assay for splicing measurement. FIGs.8A-8H show the structural basis of ligand recognition in the group I intron active site. FIG.8A: structure of cryo-electron microscopy (EM) structure of C. albicans mtLSU group I intron in complex with compound 86. FIG.8B: binding pocket within the 10 active site occupied by the de novo small molecule compound 86. FIG.8C: atomic model of the small molecule with the surrounding density. Q-scores of the individual atoms are indicated. The overall Q-score of the ligand is 0.798. FIGs.8D-8E: details of molecular recognition of the GMP (FIG.8D) and small molecule (86) (FIG.8E) within the group I intron active site. FIG.8F: metal ion clusters within the catalytic domain of the group I 15 intron; magnesium ions and water molecules are shown within their cryoEM densities. FIG. 8G: interactions of the terminal nucleotide (ωG) of the intron with the P7 domain. FIG.8H: triple helix formed between the 5′ exon and the P1 helix. FIGs.9A-9H: CryoEM structure of the C. albicans group I intron bound to GMP or compound 86. FIG.9A: Secondary structure of the group I intron with coaxially stacked 20 helices indicated. FIG.9B: CryoEM reconstruction of the group I intron with GMP substrate. FIG.9C: atomic model of the 5′ splice site prior to the first step of splicing. The GMP ligand is adjacent to the scissile phosphate. FIG.9D: details of the P11 pseudoknot interaction and the specific base pairing between the P7ext and P6 helices. FIG.9E: nucleotide contacts that form the P7ext-P9.1 tertiary interaction. FIGs.9F-9G: Cartoon schematic (FIG.9F) and 25 atomic model (FIG.9G) of the long-range base-pairing stacking sandwich between J3 / 4, P7, P7ext, and J8 / 7. FIG.9H: cryo-EM structure of C. albicans mtLSU group I intron in complex with compound 86 showing interaction network (dotted lines). FIGs.10A-10D: mechanism of competitive inhibition by the de novo small molecule (86). FIG.10A: comparison of the overall structure of the group I intron bound to GMP 30 (translucent) or the small molecule (86) (solid line). The P1 helix moves outward as indicated by the arrow when the inhibitor is bound. FIG.10B: details of the interactions at the basal stem of P1. Dashed lines indicate contacts that are broken in the small molecule structure. FIG.10C: magnified overlay comparison of the 5′ splice site in the GMP and small molecule atomic models. FIG.10D: cartoon model of the mechanism of inhibition. The small molecule - 4 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) displaces GMP and pushes ωG against the P1 stem. The light gray shade indicates components of the intron not seen in the cryoEM reconstruction. FIG.11A shows prodrugs and conjugates for intracellular compound delivery of compound 86 scaffold. Attachment sites of certain molecules of the disclosure are shown. 5 FIG.11B moieties to recruit active transport mechanisms. FIG.11C shows certain molecular linkages useful for prodrug preparation. FIG.11D shows certain moieties to facilitate passive transport. FIG.12A shows template-based docking results. FIG.12B shows a plot of IC50vs docking scores of compounds of the disclosure. 10 FIGs.13A-13B show representative dose response curves for certain compounds of the disclosure. FIG.13A shows compounds 3, 68, and 51 of the disclosure using the radioanalytic splicing assay where precursor is body-labeled with32P. FIG.13B provides a schematic showing an exemplary orthogonal radioanalytic splicing assay and a dose- dependent inhibition plot for certain compounds of the disclosure. 15 FIGs.14A-14B provide exemplary data for compound 18 of the disclosure. FIG.14A: the observed precursor depletion rate was plotted against the concentration of compound 18. FIG.14B: Lineweaver-Burk (double recipricol) plot of compound 18. G; Guanosine. FIG.15 depicts in cellulo antifungal activity of an exemplary Group I intron inhibitor compound of the disclosure (i.e., compound 17) combined with AmpB. The MIC of AmpB 20 against C. albicans SC314 in RPMI was determined to be 2 µg / mL, then C. albicans were treated with a combination of the inhibitor and different sublethal concentrations of AmpB (i.e., 1.0, 0.75, and 0.5 µg / mL of AmpB), and cellular growth was monitored after 24 h. Circled wells have 16 and 8 µg / mL of compound 17. The first row has no AmpB and the second row contains 1 µg / mL AmpB. 25 DETAILED DESCRIPTION Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will 30 be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter. Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed - 5 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated 5 range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise. In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a 10 nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information 15 that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that 20 of this document; for irreconcilable inconsistencies, the usage in this document controls. In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be 25 conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. Description While fungi and animals share proteomic similarities, their RNA metabolism is very 30 different, as fungi encode many specialized RNAs that are essential for viability. For example, important fungal messenger RNAs contain “self-splicing introns”, which are sections of RNA that must excise themselves for the gene to be functional. Unlike introns in human genes (which are removed by an enzyme known as the spliceosome), self-splicing introns are autocatalytic RNAs (ribozymes) that adopt conformations enabling them to splice - 6 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) themselves from parent transcripts. In fungi and yeasts, self-splicing RNA introns interrupt important housekeeping genes, and their splicing is required for the expression of proteins involved in respiration, protein synthesis and other functions, particularly in mitochondria. For example, fungal cytochrome b (Cytb), cytochrome oxidase (Cox1) and mitochondrial 5 ribosomal RNAs contain a structurally conserved class of RNAs known as self-splicing group I introns that must be spliced for viability (FIG.8A). Inhibition of these introns prevents yeast growth and biofilm formation. These unique elements of fungal metabolism represent an Achilles’ heel that can be exploited for the design of new antifungal drugs. It is important to note that the present approach extends the development of new compound classes that 10 disrupt mitochondrial function in fungal pathogens. Compounds of the disclosure may be clinically efficacious in combination with several known antifungal drugs. Definitions The term “about” as used herein can allow for a degree of variability in a value or 15 range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term “amine” as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, 20 alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term “amine” also includes ammonium ions as used herein. 25 The term “amino group” as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, except for -NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An “alkylamino” group 30 includes a monoalkylamino, dialkylamino, and trialkylamino group. The term “acyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a “formyl” group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, - 7 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) heteroaryl, heteroarylalkyl group or the like. An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning 5 herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a “haloacyl” group. An example is a trifluoroacetyl group. 10 The term “alkenyl” as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - 15 CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. The term “alkoxy” as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and 20 the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple 25 bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith. The term “alkyl” as used herein refers to straight chain and branched alkyl groups and 30 cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, - 8 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and 5 halogen groups. The term “alkynyl” as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to – 10 C^CH, -C^C(CH3), -C^C(CH2CH3), -CH2C^CH, -CH2C^C(CH3), and -CH2C^C(CH2CH3) among others. The term “aralkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and 15 fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. The term “aryl” as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, 20 azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but 25 not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof. As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound described herein with a pharmaceutically acceptable 30 carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration. - 9 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) The term “cycloalkyl” as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. 5 Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, 10 but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or in combination denotes a cyclic alkenyl group. A “disease” is a state of health of an animal wherein the animal cannot maintain 15 homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a 20 further decrease in the animal’s state of health. As used herein, the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. 25 An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. The terms “halo,” “halogen,” or “halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. 30 The term “haloalkyl” group, as used herein, includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like. - 10 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) The term “heteroaryl” as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A 5 heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such 10 as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl 15 groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-20 hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,25 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- 30 isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- - 11 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- 5 benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- 10 benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 15 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like. The term “heteroarylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl 20 group as defined herein. The term “heterocyclylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, 25 tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. The term “heterocyclyl” as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl 30 groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms - 12 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system 5 (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, 10 isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative 15 substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein. The term “hydrocarbon” or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a 20 molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups. As used herein, the term “hydrocarbyl” refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- 25 Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group. The term “independently selected from” as used herein refers to referenced groups 30 being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase “X1, X2, and X3are independently selected from noble gases” would include the scenario where, for example, X1, X2, and X3are all the same, where X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations. - 13 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) The term “monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. The term “organic group” as used herein refers to any carbon-containing functional 5 group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, 10 ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and 15 substituted or unsubstituted (C1-C100)hydrocarbyl, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted. The terms “patient,” “subject,” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods 20 described herein. In a non-limiting embodiment, the patient, subject or individual is a human. As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any 25 of the components of the composition in which it is contained. As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. 30 Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, - 14 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), 5 methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline 10 earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by 15 reacting, for example, the appropriate acid or base with the compound. As used herein, the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or 20 transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples 25 of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and 30 soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical - 15 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the 5 compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, 10 PA), which is incorporated herein by reference. The term “room temperature” as used herein refers to a temperature of about 15 °C to 28 °C. The term “solvent” as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, 15 ionic liquids, and supercritical fluids. The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of” as used herein can mean having none or having a trivial amount of, such that the amount of material present 20 does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term “substantially free of” can mean having a trivial amount of, such that a composition is about 25 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term “substituted” as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained 30 therein are replaced by one or more non-hydrogen atoms. The term “functional group” or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl - 16 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other 5 heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 102N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C1- C100)hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or 15 heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs. As used herein, the term “treatment” or “treating” is defined as the application or 20 administration of a therapeutic agent, i.e., a compound or compounds as described herein (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein or a symptom of a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, 25 remedy, ameliorate, improve or affect a condition contemplated herein, or the symptoms of a condition contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. As used herein, the term “Z3686288076” refers to the compound bearing the Chemical Abstract Service (CAS) Registry Number 2417890-79-8: 30 , 55862232.4 Attorney Docket No.047162-7508WO1(02676) 4-((3R,4S)-3-methoxy-4-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)pyrrolidin-1- yl)pyrimidin-2-amine. Compounds and Compositions 5 In one aspect, the disclosure provides a compound of Formula (I), or a salt, stereoisomer, tautomer, or isotopologue thereof: I), wherein: 13 X is CRaor N; 10 X2is CR3bor N; X3is CR3cor N; X4is CR3d, C(R3d)(R3e), or N; wherein at least one of X1, X3, and X4is N, or X2is N; L is a bond or -(optionally substituted C1-C3alkylenyl)-; 15 Y is N(R1b) or S; R1aand R1b, if present, are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted C2-C8 heterocycloalkyl, wherein R1aand R1bcan combine with the nitrogen atom to which they are 20 bound to form an optionally substituted C2-C8 heterocycloalkyl, and wherein one of R1aand R1bcan combine with one of R3a, R3d, or R3eto form an optionally substituted C2-C8 heterocycloalkyl or optionally substituted C2-C8heteroaryl; R2ais selected from the group consisting of H, halogen, optionally substituted C1-C6 25 alkyl, optionally substituted C2-C8heterocycloalkyl, ORA, CN, and NO2, or R2acan combine with R3dto form an optionally substituted C2-C8 heteroaryl; R2b, if present, is H; R3ais selected from the group consisting of H and optionally substituted C1-C6alkyl; 30 R3bis selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), - 18 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)C(=O)ORB, N(RA)S(=O)2RB, CN, and NO2, or R3bcan combine with R3cto form an optionally substituted C2-C8 heteroaryl; 5 R3cis selected from the group consisting of H and N(RA)(RB), or R3ccan combine with R3bto form an optionally substituted C2-C8heteroaryl; R3dand R3e, if present, are each independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, 10 C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, CN, and NO2, or R3dcan combine with R1aor R1bto form an optionally substituted C2-C8heterocycloalkyl or optionally substituted C2-C8 heteroaryl; bond a is a single bond or a double bond, and one of the following applies: 15 bond a is a single bond, X4is C(R3d)(R3e), and R2aand R2bare present, or bond a is a double bond, X4is CR3dor N, and R2bis absent; each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally 20 substituted C2-C8 heteroaryl. In certain embodiments, Y is NR1b. In certain embodiments, L is a bond. In certain embodiments, L is optionally substituted C1alkylenyl. In certain embodiments, the compound of formula (I) is a compound of formula (Ia): 25 a). In certain embodiments, th la (I) is a compound of formula (Ib): b). In certain embodiments, th a (I) is a compound of formula (Ic): - 19 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) c). In certain embodiments, th la (I) is a compound of formula (Id): ). In certain embodiments, th a (I) is a compound of formula (Ie): 5 e). In certain embodiments, th la (I) is a compound of formula (If): f). In certain embodiments, th la (I) is a compound of formula (Ig): ). 10 In certain embodiments, t (I) is a compound of formula (Ih): ). In certain embodiments, t (I) is a compound of formula (Ii): - 20 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) i). In certain embodiments, th la (I) is a compound of formula (Ij): j). In certain embodiments, t (I) is a compound of formula (Ik): 5 ). In certain embodiments, t (I) is a compound of formula (Il): l). In certain embodiments, th la (I) is a compound of formula (Im): ). 10 In certain embodiments, th a (I) is a compound of formula (In): n). In certain embodiments, R ependently selected from the group consisting of H, optionally substituted C1-C6alkyl, halogen, CN, NO2, ORC, N(RC)(RD), - 21 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), and S(=O)2ORC. In certain embodiments, R5is selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl. In certain embodiments, R6a, R6b, R6c, and R6dare each independently selected from 5 the group consisting of H, halogen, and optionally substituted C1-C6 alkyl. In certain embodiments, each occurrence of RCand RDis independently selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C8 heteroaryl. 10 In certain embodiments, at least one of R4aand R4bis H. In certain embodiments, both of R4aand R4bare H. In certain embodiments, R5is H. In certain embodiments, at least one of R6a, R6b, R6c, and R6dis H. In certain embodiments, at least two of R6a, R6b, R6c, and R6dare H. In certain embodiments, at least three of R6a, R6b, R6c, and R6dare H. In certain embodiments, each of R6a, R6b, R6c, and R6dare H. 15 In certain embodiments, R1aand R1bare each independently selected from the group consisting of H and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, phenyl, CN, NO2, NRIRII, ORI, C(=O)RI, C(=O)ORI, C(=O)NRIRII, C(=NRI)NRIIRIII, wherein each occurrence of RI, RII, and RIIIis independently selected from the group consisting of H, C1-C6alkyl, C3-C820 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, and C2-C8 heteroaryl. In certain embodiments, R1aand R1bare each independently C1-C6alkyl optionally substituted with at least one . In certain embodiments, each occurrence of Z1is independently selected fro p consisting of -O-, -NRI-, -C(=O)-, -S-, and C1-C6 alkylenyl optionally substituted with RIor C(=O)ORI. In certain embodiments, each 25 occurrence of R7ais independently selected from the group consisting of H, C1-C6 alkyl, C(=O)ORI, and C2-C8heteroaryl optionally substituted with C1-C6alkyl. In certain embodiments, m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, each occurrence of RIis independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, 30 and C2-C8heteroaryl. In certain embodiments, R1ais H. In certain embodiments, R1ais -CH3. In certain embodiments, R1ais -(CH2)Ph. In certain embodiments, R1ais -(CH2)CN. In certain embodiments, R1ais -(CH2)C(=NH)NH2. In certain embodiments, R1ais -(CH2)2NH2. In - 22 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) certain embodiments, R1ais -(CH2)2OH. In certain embodiments, R1ais -(CH2)CH(CH3)NH2. In certain embodiments, R1ais -(CH2)C(CH3)2NH2. In certain embodiments, R1ais - (CH2)2NHCH3. In certain embodiments, R1ais -(CH2)3NH2. In certain embodiments, R1ais - (CH2)4NH2. In certain embodiments, R1ai . In certain embodiments, R1ais 5 . In certain embodiments, R1ai . In certain embodiments, R1ais . a is . In certain embodiments, R1ai . In certain embodiments, R1ais 10 . In certain embodiments, R1ai . In certain embodiments, R1ais . In certain embodiments, R1ai . In certain embodiments, - 23 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) a is is is 5 In certain embodiments, R1ais . In embodiments, R1bis -(CH2)Ph. In certain embodiments, R1bis -(CH2)CN. In certain 10 embodiments, R1bis -(CH2)C(=NH)NH2. In certain embodiments, R1bis -(CH2)2NH2. In certain embodiments, R1bis -(CH2)2OH. In certain embodiments, R1bis -(CH2)CH(CH3)NH2. In certain embodiments, R1bis -(CH2)C(CH3)2NH2. In certain embodiments, R1bis - (CH2)2NHCH3. In certain embodiments, R1bis -(CH2)3NH2. In certain embodiments, R1bis - (CH2)4NH2. In certain embodiments, R1b. In certain embodiments, R1bis 15 . In certain embodiments, R1b. In certain embodiments, R1bis - 24 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) . In certain embodiments, R1bi . In certain embodiments, R1b n certain embodiments, R1bis . 5 is . In certain embodiments, R1bi . In certain embodiments, R1bis n certain embodiments, R1bis is 10 is is 55862232.4 Attorney Docket No.047162-7508WO1(02676) is is . In 5 certain embodiments . In certain em ith the N atom to which they are bound to form a C2-C8 heterocycloalkyl, wherein the C2-C8 heterocycloalkyl is optionally substituted with N(RIV)(RV), ORIV, -(CH2)1-3N(RIV)(RV), -(CH2)1-3ORIV, N(RIV)C(=O)ORIV, N(RIV)C(=NRV)N(RVI)(RVII), C(=O)RIV, C(=O)ORIV, C(=NRIV)N(RV)(RVI), wherein each 10 occurrence of RIV, RV, RVI, and RVIIis independently H, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10aryl, and C2-C8heteroaryl, and wherein each occurrence of C1-C6alkyl in RIV, RV, RVI, and RVIIis independently optionally substituted with at least one selected from the group consisting of NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, C(=O)O(C1-C6alkyl), and C6-C10 aryl. 15 In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form a C2-C8 heterocycloalkyl, wherein the C2-C8 heterocycloalkyl is optionally substituted with . In certain embodiments, each occurrence of Z2is independently selected from the group consisting of -O-, -NRIV-, -C(=O)-, -S-, and C1-C6alkylenyl optionally substituted with RIVor C(=O)ORIV. In certain embodiments, each 20 occurrence of R7bis independently selected from the group consisting of H, C1-C6alkyl, C(=O)ORI, and C2-C8 heteroaryl optionally substituted with C1-C6 alkyl. In certain embodiments, n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, each occurrence of RIVis independently selected from the - 26 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, and C2-C8heteroaryl. In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom 5 to which they are bound to form . In certain embodiments, R1aand R1b combine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are b ound to form . In certain embodiments, R1aand R1bcombine with the N atom to whic nd to form . In certain embodiments, R1aand R1bcombine with the N atom to which they 10 are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1b combine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to w und to form . In certain embodiments, R1aand R1bcombine with the N atom to which 15 they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1b combine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to w e bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they 20 are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to for . In certain embodiments, R1aand R1b - 27 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) combine with the N atom to which they are bound to for . In certain embodiments, R1aand R1bcombine with the N at und to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1b5 combine with the N atom to w hich they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to w bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1b 10 combine with the N atom to which they are bound to for . In certain embodiments, R1aand R1bcombine with the N atom to w bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to for . In certain embodiments, R1aand R1b 15 combine with the N atom to which they are bound to for . In certain 1a embodiments, R and R1bcombine with the N atom to which they are bound to form to 55862232.4 Attorney Docket No.047162-7508WO1(02676) which they are bound to form . In certain embodiments, R1aand R1b combine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to w to form . In certain embodiments, R1aand R1bcombine 5 with the N atom to which they are bound to for . In certain embodiments, R1aand R1bcombine w o form . In certain embodiments, R1aand R1bcom und to form . In certain embodiments, R1aand R1bcombine 10 with the N atom to which they are bound to for . In certain embodiments, R1aand R1bcombine w o form . In certain embodiments, R1aand R1bcom und to form . In certain embodiments, R1aand R1bcombine 15 with the N atom to which they are bound to for . In certain - 29 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, HO N 5 R1aand R1bcombine with the N atom to which they are bound to forO. In certain embodiments, R1aand R1bcombine with the N atom to which nd to form 11hey N atom to which they are bound to for . In certain embodiments, R1aand R1b 10 combine with the N atom to which they are bound to for . In certain embodiments, R1aand R1bcombine with the N atom to w hich they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to for . In certain embodiments, R1aand R1b 15 combine with the N atom to which they are bound to for . In certain embodiments, R1aand R1bcombine with the N atom to w c t ey are bound to form - 30 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1b combine with the N atom to which they are bound to for . In certain 5 embodiments, R1aand R1bcombine with the N atom to w bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1b combine with the N atom to which they are bound to for . In certain embodiments, R1aand R1bcombine with the N atom to w to form 10 . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to for . In certain embodiments, R1aand R1b combine with the N atom to which they are bound to for . In certain embodiments, R1aand R1bcombine with the N ato o form to 55862232.4 Attorney Docket No.047162-7508WO1(02676) which they are bound to form In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to for . In certain embodiments, R1aand R1bcombine with the N atom t rm n certain embodiments, R1aand R1bcombine with the N atom to 5 which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to for . In certain embodiments, R1a and R1bcombine with the N atom to which they are bound to for In certain embodiments, R1aand R1bcombine with the N atom to w d to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are 10 bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1b combine with the N atom to which they are bound to for . In certain embodiments, R1aand R1bcombine with the N atom to w c t ey are bound to form - 32 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) n certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to form . In certain embodiments, R1aand R1bcombine with the N atom to which they are bound to for . In certain embodiments, R1a 5 and R1bcombine with the N atom to which they are bound to for . In certain embodiments, R2ais H. In certain embodiment n certain embodiments, R2ais Cl. In certain embodiments, R2bis H. In certain embodiments, R3ais H. 10 In certain embodiments, R3bis . In certain embodiments, each occurrence of Z3is independently selected from the group consisting of -O-, -NRVIII-, -C(=O)-, -S-, and C1-C6 alkylenyl optionally substituted with RVIIIor C(=O)ORVIII. In certain embodiments, each occurrence of R7cis independently selected from the group consisting of H, C1-C6 alkyl, C(=O)ORVIII, and C2-C8 heteroaryl optionally substituted with C1-C6 alkyl. In certain 15 embodiments, o is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, each occurrence of RVIIIis independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10aryl, and C2-C8 heteroaryl. In certain embodiments, R3bis H. In certain embodiments, R3bis NH2. In certain 20 embodiments, R3bis NH(C1-C6 alkyl). In certain embodiments, R3bis NO2. In certain embodiments, R3bis C(=NH)NH2. In certain embodiments, R3bis is 55862232.4 Attorney Docket No.047162-7508WO1(02676) is is 5 In certain embodiments, R3dis H. In certain embodiments, R3dis CH3. In certain embodiments, R3dis F. In certain embodiments, R3dis Br. In certain embodiments, R3dis NH2. In certain embodiments, R3dis NHC(=O)CH3. In certain embodiments, R3dis NHS(=O)2CH3. In certain embodiments, R3dis (CH2)2S(=O)2CH3. In certain embodiments, the compound of Formula (I) is conjugated to an active or 10 passive transport recruiter. In certain embodiments, the conjugation to an active or passive transport recruiter comprises substitution of the compound of Formula (I) at the R1a, R3a, and / or R3dposition. In certain embodiments, the conjugation to an active or passive transport recruiter comprises a linker. In certain embodiments, the linker is selected from the group consisting of optionally substituted C1-C6alkylenyl and optionally substituted C1-C615 heteroalkylenyl. In certain embodiments, the linker is selected from the group consisting of - O(CH2)2O-, -NH(CH2)2SS-, and -O(CH2)2SS-. In certain embodiments, the active transport recruiter is selected from the group consisting of -C(=O)(CH2)NH-pVEC, -C(=O)(CH2)NH- PAF26, -C(=O)(CH2)NH-penetratin, -C(=O)(CH2)1-10N(OH)C(=O)(CH2)1-10C(=O)NH(CH2)1-10N(OH)C(=O)(C1-C6 alkyl), -C(=O)(CH2)1-10NH(CH2)1-10NH(CH2)1-10NH2, and 20 . In certain embodiments, the passive transport recruiter is selected from the group consisting of -C(=O)(CH2)1-10P(Ph)3 (e. ) and -C(=O)(C1- C12alkyl). In certain embodiments, the compound is selected from the group consisting of: N4-(2-methoxyethyl)-N4-methylpyrimidine-2,4-diamine; - 34 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 4-(3-methoxypyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-methoxypyrrolidin-1-yl)pyrimidin-2-amine; (R)-4-(3-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-aminopyrrolidin-1-yl)pyrimidin-2-amine; 5 (R)-4-(3-aminopyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-aminopyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 10 4-((3R,4S)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-((3S,4R)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-aminoazetidin-1-yl)pyrimidin-2-amine; 1-(2-aminopyrimidin-4-yl)pyrrolidin-3-ol; (R)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-ol; 15 (S)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-ol; (3R,4S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; (3R,4S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; (3S,4S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; (3S,4R)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; 20 (3R,4R)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; 4-morpholinopyrimidin-2-amine; 4-(4-(2-methoxyethyl)piperazin-1-yl)pyrimidin-2-amine; 4-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-amine; (R)-4-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-amine; 25 (S)-4-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-amine; N1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)-N1-methylethane-1,2-diamine; (S)-N1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)-N1-methylethane-1,2-diamine; (R)-N1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)-N1-methylethane-1,2-diamine; (1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)methanol; 30 (S)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)methanol; (R)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)methanol; benzyl (1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; benzyl ((3S,4R)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; benzyl ((3S,4S)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; - 35 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) benzyl ((3R,4R)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; benzyl ((3R,4S)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; 4-(4-aminopiperidin-1-yl)pyrimidin-2-amine; 4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidin-2-amine; 5 (R)-4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-aminopiperidin-1-yl)pyrimidin-2-amine; (S)-4-(3-aminopiperidin-1-yl)pyrimidin-2-amine; (R)-4-(3-aminopiperidin-1-yl)pyrimidin-2-amine; 10 4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-2-amine; 4-((hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 4-((3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 4-((3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 4-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 15 4-((3aS,6aR)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboxylic acid; (S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboxylic acid; (R) 1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboxylic acid; 4-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; 20 (S)-4-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; 4-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 6-((2-aminoethyl)(methyl)amino)pyrimidin-4-ol; 2-amino-6-((2-aminoethyl)(methyl)amino)pyrimidin-4-ol; 25 N1-methyl-N1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)ethane-1,2-diamine; N6-(2-aminoethyl)-N6-methyl-9H-purine-2,6-diamine; N1-methyl-N1-(9H-purin-6-yl)ethane-1,2-diamine; N1-methyl-N1-(pyrimidin-4-yl)ethane-1,2-diamine; N1-methyl-N1-(2-nitropyridin-4-yl)ethane-1,2-diamine; 30 5-(2-aminopyrimidin-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine; N4-(2-aminoethyl)-N4-methylpyrimidine-4,6-diamine; N2-(2-aminoethyl)-N2-methylpyrimidine-2,4-diamine; N4-methyl-N4-(2-(methylamino)ethyl)pyrimidine-2,4-diamine; 4-((2-aminoethyl)thio)pyrimidin-2-amine; - 36 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) N1-methyl-N1-(1H-pyrazolo[3,4-b]pyridin-6-yl)ethane-1,2-diamine; N4-(2-aminoethyl)-N2,N4-dimethylpyrimidine-2,4-diamine; N1-methyl-N1-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)ethane-1,2-diamine; 2-((2-aminopyrimidin-4-yl)(methyl)amino)acetonitrile; 5 2-((2-aminopyrimidin-4-yl)(methyl)amino)acetimidamide; N4-(3-aminopropyl)-N4-methylpyrimidine-2,4-diamine; N4-(4-aminobutyl)-N4-methylpyrimidine-2,4-diamine; N4-(2-aminoethyl)-6-chloro-N4-methylpyrimidine-2,4-diamine; N4-(2-aminoethyl)pyrimidine-2,4-diamine; 10 2-amino-3-((2-aminopyrimidin-4-yl)amino)propanoic acid; (S)-2-amino-3-((2-aminopyrimidin-4-yl)amino)propanoic acid; (R)-2-amino-3-((2-aminopyrimidin-4-yl)amino)propanoic acid; N4,N4-bis(2-aminoethyl)pyrimidine-2,4-diamine; N4-(2-aminoethyl)-N4-methylpyridine-2,4-diamine; 15 N2-(2-aminoethyl)-N2-methyl-1,3,5-triazine-2,4-diamine; N5-(2-aminoethyl)-N5-methylpyridine-2,5-diamine; N-(2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoethyl)-N- methyl-glutamic acid; N-(2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoethyl)-N- 20 methyl-D-glutamic acid; N-(2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoethyl)-N- methyl-L-glutamic acid; (2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoacetyl)-glutamic acid; 25 (2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoacetyl)-D- glutamic acid; (2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoacetyl)-L-glutamic acid; N4-(2-amino-2-methylpropyl)pyrimidine-2,4-diamine; 30 N4-(2-aminopropyl)pyrimidine-2,4-diamine; (S)-N4-(2-aminopropyl)pyrimidine-2,4-diamine; (R)-N4-(2-aminopropyl)pyrimidine-2,4-diamine; 1-(((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)ethyl isobutyrate; - 37 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) (S)-1-(((2-((2-aminopyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)ethyl isobutyrate; (R)-1-(((2-((2-aminopyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)ethyl isobutyrate; 5 2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethan-1-ol ((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)carbamoyl)glutamic acid; (S)-((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)carbamoyl)glutamic acid; (R)- ((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)carbamoyl)glutamic acid; N4-(2-aminoethyl)-5-fluoro-N4-methylpyrimidine-2,4-diamine; 10 4-(3-(aminomethyl)azetidin-1-yl)pyrimidin-2-amine; 1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)guanidine; (S)-1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)guanidine; (R)-1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)guanidine; N4-(3-amino-2,2-dimethylpropyl)pyrimidine-2,4-diamine; 15 N4-(2-aminoethyl)-5-fluoro-N4-methylpyrimidine-2,4-diamine; ((2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)carbonyl)-glutamic acid; ((2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)carbonyl)-L-glutamic acid; ((2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)carbonyl)-D-glutamic acid; 1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboximidamide; 20 (R)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboximidamide; (S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboximidamide; 4-(3-(aminomethyl)piperazin-1-yl)pyrimidin-2-amine; (R)-4-(3-(aminomethyl)piperazin-1-yl)pyrimidin-2-amine; (S)-4-(3-(aminomethyl)piperazin-1-yl)pyrimidin-2-amine; 25 2-((2-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- 30 yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- - 38 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- 5 yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)-10 ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 15 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- 20 yl)(methyl)amino)ethyl)carbamate; 2-((2-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)-25 ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 30 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- - 39 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-ethylhexyl)disulfaneyl)ethyl (1-(2-(((2-((2- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(S)- 5 ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate;10 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(S)- 15 ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate;20 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl methyl(2-(methyl(2-((((5-methyl-2-oxo-1,3- dioxol-4-yl)methoxy)carbonyl)amino)pyrimidin-4-yl)amino)ethyl)carbamate; 1-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridin-6-amine; N4-(3-aminobenzyl)pyrimidine-2,4-diamine; 7-(2-aminoethyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-2-amine; 25 (R)-7-(2-aminoethyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-2-amine; (S)-7-(2-aminoethyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-2-amine; N4-(2-aminoethyl)-N4-methylpyrimidine-2,4,5-triamine; N-(2-amino-4-((2-aminoethyl)(methyl)amino)pyrimidin-5-yl)acetamide; N-(2-amino-4-((2-aminoethyl)(methyl)amino)pyrimidin-5-yl)methanesulfonamide; 30 4-((2-aminoethyl)(methyl)amino)pyrimidine-2-carboximidamide; 6-(2-aminoethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine; methyl 3-((1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4-yl)pyrrolidin-3- yl)oxy)propanoate; methyl (S)-3-((1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4-yl)pyrrolidin-3- - 40 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) yl)oxy)propanoate; methyl (R)-3-((1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4-yl)pyrrolidin-3- yl)oxy)propanoate; methyl 3-((4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- 5 yl)pyrrolidin-3-yl)oxy)propanoate; methyl 3-(((3R,4S)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; methyl 3-(((3S,4R)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; 10 methyl 3-(((3R,4R)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; methyl 3-(((3S,4S)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; 4-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine; 15 N4-(2-aminoethyl)-N4-methylpyrimidine-2,4-diamine; N4-(2-aminoethyl)-N4-benzylpyrimidine-2,4-diamine; and N4-(2-aminoethyl)-5-bromo-N4-methylpyrimidine-2,4-diamine. In certain embodiments, each occurrence of optionally substituted alkyl, optionally substituted alkylenyl, optionally substituted cycloalkyl, optionally substituted 20 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl is independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORa, N(Ra)(Ra), SRa, SSRa, NO2, CN, C(=O)Ra, C(=O)ORa, C(=O)N(Ra)(Ra), C(=NRa)N(Ra)(Ra), N(Ra)C(=O)Ra, N(Ra)C(=O)ORa, N(Ra)C(=O)N(Ra)(Ra), S(=O)ORa, 25 S(=O)Ra, S(=O)2ORa, S(=O)2N(Ra)(Ra), and S(=O)2Ra, wherein each C1-C6alkyl, C3-C8cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C2-C8 heteroaryl is optionally substituted with one to three independently selected Rb; In certain embodiments, each occurrence of Rais independently selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C2-C8heteroaryl, 30 C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6alkyl), C(=O)OH, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Rais independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, - 41 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1- C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)(C1-C6alkyl), S(=O)2OH, and S(=O)2NH2. In certain embodiments, each occurrence of Rais independently selected from the 5 group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORb, N(Rb)(Rb), SRb, SSRb, NO2, CN, C(=O)Rb, C(=O)ORb, C(=O)N(Rb)(Rb), C(=NRb)N(Rb)(Rb), N(Rb)C(=O)Rb, N(Rb)C(=O)ORb, N(Rb)C(=O)N(Rb)(Rb), S(=O)ORb, S(=O)Rb, S(=O)2ORb, S(=O)2N(Rb)(Rb), and S(=O)2Rb, wherein each C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C2-C8 10 heteroaryl in Rais optionally substituted with one to three independently selected Rb. In certain embodiments, each occurrence of Rbis independently selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C2-C8heteroaryl, C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6alkyl), C(=O)OH, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), 15 C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Rbis independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)(C1-C620 alkyl), S(=O)2OH, and S(=O)2NH2. In certain embodiments, each occurrence of Rbis independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORc, N(Rc)(Rc), SRc, SSRc, NO2, CN, C(=O)Rc, C(=O)ORc, C(=O)N(Rc)(Rc), C(=NRc)N(Rc)(Rc), N(Rc)C(=O)Rc, N(Rc)C(=O)ORc, 25 N(Rc)C(=O)N(Rc)(Rc), S(=O)ORc, S(=O)Rc, S(=O)2ORc, S(=O)2N(Rc)(Rc), and S(=O)2Rc, wherein each C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C2-C8 heteroaryl in Rbis optionally substituted with one to three independently selected Rc. In certain embodiments, each occurrence of Rcis independently selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C2-C8heteroaryl, 30 C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6alkyl), C(=O)OH, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Rcis independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, - 42 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1- C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)(C1-C6alkyl), S(=O)2OH, and S(=O)2NH2. In certain embodiments, each occurrence of Rcis independently selected from the 5 group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORd, N(Rd)(Rd), SRd, SSRd, NO2, CN, C(=O)Rd, C(=O)ORd, C(=O)N(Rd)(Rd), C(=NRd)N(Rd)(Rd), N(Rd)C(=O)Rd, N(Rd)C(=O)ORd, N(Rd)C(=O)N(Rd)(Rd), S(=O)ORd, S(=O)Rd, S(=O)2ORd, S(=O)2N(Rd)(Rd), and S(=O)2Rd, wherein each C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C2-C8 10 heteroaryl in Rcis optionally substituted with one to three independently selected Rd. In certain embodiments, each occurrence of Rdis independently selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C2-C8heteroaryl, C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6alkyl), C(=O)OH, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), 15 C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Rdis independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)(C1-C620 alkyl), S(=O)2OH, and S(=O)2NH2. In certain embodiments, each occurrence of Rdis independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORe, N(Re)(Re), SRe, SSRe, NO2, CN, C(=O)Re, C(=O)ORe, C(=O)N(Re)(Re), C(=NRe)N(Re)(Re), N(Re)C(=O)Re, N(Re)C(=O)ORe, 25 N(Re)C(=O)N(Re)(Re), S(=O)ORe, S(=O)Re, S(=O)2ORe, S(=O)2N(Re)(Re), and S(=O)2Re, wherein each C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or C2-C8 heteroaryl in Rdis optionally substituted with one to three independently selected Re. In certain embodiments, each occurrence of Reis independently selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C2-C8heteroaryl, 30 C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6alkyl), C(=O)OH, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Reis independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, - 43 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1- C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)(C1-C6alkyl), S(=O)2OH, and S(=O)2NH2. In certain embodiments, each occurrence of Reis independently selected from the 5 group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C2-C8 heteroaryl, halogen, ORf, N(Rf)(Rf), SRf, SSRf, NO2, CN, C(=O)Rf, C(=O)ORf, C(=O)N(Rf)(Rf), C(=NRf)N(Rf)(Rf), N(Rf)C(=O)Rf, N(Rf)C(=O)ORf, N(Rf)C(=O)N(Rf)(Rf), S(=O)ORf, S(=O)Rf, S(=O)2ORf, S(=O)2N(Rf)(Rf), and S(=O)2Rf, wherein each C1-C6alkyl, l, or C2-C8 heteroaryl in Reis optionally 10 substituted with one to three independently selected Rf. In certain embodiments, each occurrence of Rfis independently selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C2-C8heteroaryl, C6-C10 aryl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6alkyl), C(=O)OH, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), 15 C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), S(=O)2OH, and S(=O)2NH2, wherein each alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl in Rfis independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, halogen, CN, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), OH, O(C1-C6 alkyl), C(=O)OH, C(=O)O(C1- C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6alkyl)(C1-C6alkyl), S(=O)2OH, 20 and S(=O)2NH2. Table 1. Exemplary compounds of the disclosure. Compound Structure Name - - 44 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 3 (R)4(3 i lidi 1 l) i idi 2 ine ne - - 45 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) hli i ii i - - - 46 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 4-((3S4R)-3-amino-4-methoxypyrrolidin-1- - e e - 47 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) (S)-4-(3-(methylamino)pyrrolidin-1-yl)pyrimidin- 26 l ne - 48 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 5-(2-min rimidin-4-l)-1456- e- - - 49 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 2-((2-aminopyrimidin-4- 44 - e - 50 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) N2-(2-aminoethyl)-N2-methyl-1,3,5-triazine-2,4- 52 d - )e - 51 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 2-((2-aminoethyl)(2-aminopyrimidin-4- d 4- - 52 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 4-(3-(aminomethyl)piperazin-1-yl)pyrimidin-2- 2- py 2- py 2- py py - - 53 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 1-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridin-6- 75 - - 55862232.4 Attorney Docket No.047162-7508WO1(02676) methyl (S)-3-((1-(2-amino-5-(2- - - e The compositions containing the compound(s) described herein include a pharmaceutical composition comprising at least one compound as described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, the composition is 5 formulated for an administration route such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal, intravesical, intrapulmonary, intraduodenal, - 55 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In some aspects, provided herein is a pharmaceutical composition comprising a compound provided herein and further comprising a pharmaceutically acceptable excipient. 5 Preparation of Compounds Compounds described herein can be prepared by the general schemes described herein, using the synthetic method known by those skilled in the art. The following examples illustrate non-limiting embodiments of the compound(s) described herein and their 10 preparation. The compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, 15 regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In 20 certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved 25 by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any 30 compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the - 56 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) compounds described herein exist in unsolvated form. In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, compounds described herein are prepared as prodrugs. A 5 “prodrug” refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. In other 10 embodiments, a prodrug is degraded by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate 15 this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic 20 mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,11C,13C,14C,36Cl,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In certain embodiments, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as 25 deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as11C,18F,15O and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled 30 reagent in place of the non-labeled reagent otherwise employed. In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compounds described herein, and other related compounds having different - 57 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and 5 Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of 10 compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. 15 In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective 20 groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to 25 protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both 30 acid and base stable but hydrolytically removable. In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester - 58 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups 5 since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked 10 and does not react. Once released from the resin, the functional group is available to react. Typically blocking / protecting groups may be selected from: . to the creation of protecting groups and their removal are described in Greene & Wuts, Protective 15 Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure. Methods 20 In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a fungal infection in a subject, the method comprising administering to the subject a group I intron splicing inhibitor. In certain embodiments, the group I intron is a group IA1, IB, or ID intron. In certain embodiments, the IA1 intron is positioned in a mtLSU, - 59 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) cytb, or cox1 gene. In certain embodiments, wherein the group I intron splicing inhibitor is a compound of the disclosure or a pharmaceutical composition of the disclosure. In certain embodiments, the fungal infection is caused by a fungus selected from the group consisting of Cryptococcus neoformans, Blastomyces dermatitidis, Cryptococcus 5 gattii, Candida albicans, Candida auris, Candida krusei, Candida glabrata, Candida parapsilosis, Candida guilliermondii, Candida glabrata, Candida tropicalis, Candida lusitaniae, Coccidioides immitis, Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus niger, Aspergillus candidus, Aspergillus ochraceus, Pichia kudriavzevii, Rhizopus oryzae, Rhizopus spp., Histoplasma capsulatum, Coccidioides spp., Paecilomyces 10 variotii, Pneumocystis murina, Pneumocystis jiroveci, Scedosporium spp., Sporotrix spp., and Aspergillus spp., or a combination thereof. In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. In certain embodiments, the fungal infection is at least one selected from the group consisting of aspergillosis, blastomycosis, candidemia (Candida bloodstream 15 infection), Candida intertrigo, candidiasis (yeast infection), coccidioidomycosis (valley fever), cryptococcosis, dermatophytosis, histoplasmosis, mucormycosis, paracoccidioidomycosis, sporotrichosis, tinea capitis (scalp ringworm), tinea corporis (ringworm), tinea cruris (jock itch), tinea pedis (athlete’s foot), and tinea versicolor (pityriasis versicolor). 20 In certain embodiments, the compound is administered orally. In certain embodiments, the subject is immunocompromised and / or immunosuppressed. In certain embodiments, the fungal infection is hospital acquired. In certain embodiments, the fungus is multi-drug resistant. In certain embodiments, the subject is a crop. In certain embodiments, the subject is a 25 plant. In certain embodiments, the crop or plant is selected from the group consisting of almonds, apples, avocados, barley, bananas, beans, blueberries, broccoli, cabbage, carrots, cassava, cherries, chickpeas, citrus fruits, coffee, corn, cotton, cucumbers, eggplants, grapes, lettuce, mangoes, melons, oats, onions, oranges, papayas, peaches, peanuts, pears, peppers, pineapples, potatoes, pumpkins, quinoa, raspberries, rice, rye, sorghum, soybeans, spinach, 30 squash, strawberries, sugarcane, sweet potatoes, tea, tobacco, tomatoes, watermelons, wheat, and yams. In certain embodiments, the fungal infection is selected from the group consisting of Magnaporthe grisea, Magnaporthe spp. (blast diseases), Plasmopara viticola (downy mildew), Erysiphe necator (powdery mildew), Botrytis cinerea (grey mold), Guignardia bidwellii (black rot), Venturia inaequalis (apple scab), Venturia pirina (pear scab), Ustilago - 60 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) maydis (corn smut), Ustilago tritici (wheat smut), Ustilago hordei (barely smut), Ustilago spp., Puccinia graminis f. sp. tritici (wheat stem rust), Claviceps purpurea (ergot), Hemileia vastatrix (coffee rust), and Phakopsora pachyrhizi (soybean rust). In certain embodiments, the compound is administered by a route selected from the 5 group consisting of oral, topical, inhalation, aerosol, intravenous injection, intramuscular injection, and subcutaneous injection. In certain embodiments, the compound is co-administered with at least one additional antifungal agent. In certain embodiments, the at least one additional antifungal agent is selected from the group consisting of allylamines, amphotericin B, amphotericin B liposomal, 10 anidulafungin, azoxystrobin, beanomicins, bifonazole, binapacryl, blasticidin-S, boscalid, cancidas, carboxin, caspofungin, clotrimazole, cyazofamid, echinocandins, econazole, fenpropimorph, fenticonazole, fludioxonil, fluconazole, hexaconazole, ibrexafungerp, imazalil, isavuconazole, isoconazole, itraconazole, kasugamycin, ketoconazole, lucensomycin, micafungin, miconazole, myclobutanil, natamycin, nikkomycins, nystatin, 15 olorofim, oxiconazole, phenpropimorph, piroctone, posaconazole, pradimicins, procymidone, propamocarb, propiconazole, pydiflumetofen, pyrazophos, pyrimethanil, ravuconazole, rezafungin, sertaconazole, sordarins, sulconazole, tecnazene, terconazole, thioconazole, triclosan, and voriconazole, and terbinafine, and derivatives and analogs thereof. The methods described herein include administering to the subject a therapeutically 20 effective amount of at least one compound described herein, which is optionally formulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the subject an additional 25 therapeutic agent that treats a disease state. In certain embodiments, administering the compound(s) described herein to the subject allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating a disease state in the subject. For example, in certain embodiments, the 30 compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect. In certain embodiments, the compound(s) described herein and the therapeutic agent are co-administered to the subject. In other embodiments, the compound(s) described herein - 61 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) and the therapeutic agent are coformulated and co-administered to the subject. In certain embodiments, the subject is a mammal. In other embodiments, the mammal is a human. In another aspect, the disclosure provides a method of reducing or inhibiting splicing 5 of a group I intron in a cell. In certain embodiments, the method comprises administering to the cell an effective amount of at least one compound of the disclosure or a pharmaceutical composition of the disclosure. In certain embodiments, the group I intron is a group IA1, IB, or ID intron. In certain embodiments, the IA1 intron is positioned in a mtLSU, cytb, or cox1 gene. 10 In certain embodiments, the gene function of the cell is controlled. In certain embodiments, gene expression and / or translation of the cell is controlled. In certain embodiments, control of gene expression comprises altering the amount of functional mRNA transcript. 15 Combination Administration and Treatment In various embodiments, a synergistic effect is observed when a compound as described herein is administered with one or more additional therapeutic agents or compounds. A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emaxequation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 20 6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol.114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul.22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the 25 concentration-effect curve, isobologram curve and combination index curve, respectively. Administration / Dosage / Formulations The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset 30 of a disease state. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. - 62 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease state in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to 5 factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease state in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an 10 effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions 15 described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of 20 excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may 25 readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. 30 In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. - 63 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) The dosage unit forms of the compound(s) described herein are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound. 5 In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. The carrier may be a solvent or dispersion medium containing, for example, water, 10 ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for 15 example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. 20 In certain embodiments, the compositions described herein are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the 25 frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be 30 administered to any patient is determined by the attending physician taking all other factors about the patient into account. The compound(s) described herein for administration may be in the range of from about 1 µg to about 10,000 mg, about 20 µg to about 9,500 mg, about 40 µg to about 9,000 mg, about 75 µg to about 8,500 mg, about 150 µg to about 7,500 mg, about 200 µg to about - 64 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 7,000 mg, about 350 µg to about 6,000 mg, about 500 µg to about 5,000 mg, about 750 µg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 5 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween. In some embodiments, the dose of a compound described herein is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or 10 less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 15 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof. 20 In various embodiments, the compound(s) described herein can be administered to a subject in an amount ranging from about 0.01 mg / kg to about 200 mg / kg, or about 0.5 mg / kg to about 190 mg / kg, or about 0.75 mg / kg to about 180 mg / kg, or about 1 mg / kg to about 170 mg / kg, or about 1.5 mg / kg to about 160 mg / kg, or about 2 mg / kg to about 150 mg / kg, or about 2.5 mg / kg to about 140 mg / kg, or about 3 mg / kg to about 130 mg / kg, or about 3.5 25 mg / kg to about 120 mg / kg, or about 4 mg / kg to about 110 mg / kg, or about 4.5 mg / kg to about 100 mg / kg, or about 5 mg / kg to about 95 mg / kg, or about 5.5 mg / kg to about 90 mg / kg, or about 6 mg / kg to about 85 mg / kg, or about 6.5 mg / kg to about 80 mg / kg, or about 7 mg / kg to about 75 mg / kg, or about 7.5 mg / kg to about 70 mg / kg, or about 8 mg / kg to about 65 mg / kg, or about 8.5 mg / kg to about 60 mg / kg, or about 9 mg / kg to about 55 mg / kg or 30 about 9.5 mg / kg to about 50 mg / kg, or about 10 mg / kg to about 45 mg / kg. In various embodiments, the compound(s) described herein can be administered to a subject in an amount that is less than, equal to, or greater than about 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, - 65 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 100 mg / kg, 105 mg / kg, 110 mg / kg, 115 mg / kg, 120 mg / kg, 125 mg / kg, 130 mg / kg, 140 mg / kg, 5 145 mg / kg, 150 mg / kg, 155 mg / kg, 160 mg / kg, 170 mg / kg, 175 mg / kg, 180 mg / kg, 185 mg / kg, 190 mg / kg, 195 mg / kg, or 200 mg / kg. In certain embodiments, a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second 10 pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease state or disorder in a patient. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of 15 administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. 20 Routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and 25 (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, 30 transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are - 66 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) described herein. Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may 5 be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. 10 The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable 15 excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film 20 coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents 25 (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid). Compositions as described herein can be prepared, packaged, or sold in a formulation suitable for oral or buccal administration. A tablet that includes a compound as described 30 herein can, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by - 67 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, dispersing agents, surface-active agents, 5 disintegrating agents, binding agents, and lubricating agents. Suitable dispersing agents include, but are not limited to, potato starch, sodium starch glycollate, poloxamer 407, or poloxamer 188. One or more dispersing agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more dispersing agents can each be individually 10 present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Surface-active agents (surfactants) include cationic, anionic, or non-ionic surfactants, 15 or combinations thereof. Suitable surfactants include, but are not limited to, behentrimonium chloride, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, carbethopendecinium bromide, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylpyridine chloride, didecyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dimethyldioctadecylammonium chloride, domiphen 20 bromide, lauryl methyl gluceth-10 hydroxypropyl dimonium chloride, tetramethylammonium hydroxide, thonzonium bromide, stearalkonium chloride, octenidine dihydrochloride, olaflur, N-oleyl-1,3-propanediamine, 2-acrylamido-2-methylpropane sulfonic acid, alkylbenzene sulfonates, ammonium lauryl sulfate, ammonium perfluorononanoate, docusate, disodium cocoamphodiacetate, magnesium laureth sulfate, perfluorobutanesulfonic acid, 25 perfluorononanoic acid, perfluorooctanesulfonic acid, perfluorooctanoic acid, potassium lauryl sulfate, sodium alkyl sulfate, sodium dodecyl sulfate, sodium laurate, sodium laureth sulfate, sodium lauroyl sarcosinate, sodium myreth sulfate, sodium nonanoyloxybenzenesulfonate, sodium pareth sulfate, sodium stearate, sodium sulfosuccinate esters, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, cocamide diethanolamine, 30 cocamide monoethanolamine, decyl glucoside, decyl polyglucose, glycerol monostearate, octylphenoxypolyethoxyethanol CA-630, isoceteth-20, lauryl glucoside, octylphenoxypolyethoxyethanol P-40, Nonoxynol-9, Nonoxynols, nonyl phenoxypolyethoxylethanol (NP-40), octaethylene glycol monododecyl ether, N-octyl beta- D-thioglucopyranoside, octyl glucoside, oleyl alcohol, PEG-10 sunflower glycerides, - 68 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) pentaethylene glycol monododecyl ether, polidocanol, poloxamer, poloxamer 407, polyethoxylated tallow amine, polyglycerol polyricinoleate, polysorbate, polysorbate 20, polysorbate 80, sorbitan, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, Triton X-100, and Tween 80. One or more surfactants can each be 5 individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more surfactants can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage 10 form. Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate, Cellactose ® 80 (75 % ^- lactose monohydrate and 25 % cellulose powder), mannitol, pre-gelatinized starch, starch, 15 sucrose, sodium chloride, talc, anhydrous lactose, and granulated lactose. One or more diluents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more diluents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 20 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Suitable granulating and disintegrating agents include, but are not limited to, sucrose, copovidone, corn starch, microcrystalline cellulose, methyl cellulose, sodium starch glycollate, pregelatinized starch, povidone, sodium carboxy methyl cellulose, sodium 25 alginate, citric acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, colloidal silicone dioxide, crosspovidone and alginic acid. One or more granulating or disintegrating agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more granulating or disintegrating agents can each be individually present in the composition in an 30 amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Suitable binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized - 69 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) maize starch, polyvinylpyrrolidone, anhydrous lactose, lactose monohydrate, hydroxypropyl methylcellulose, methylcellulose, povidone, polyacrylamides, sucrose, dextrose, maltose, gelatin, polyethylene glycol. One or more binding agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the 5 dosage form. One or more binding agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Suitable lubricating agents include, but are not limited to, magnesium stearate, 10 calcium stearate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, mineral oil, polyethylene glycol, poloxamer 407, poloxamer 188, sodium laureth sulfate, sodium benzoate, stearic acid, sodium stearyl fumarate, silica, and talc. One or more lubricating agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more lubricating agents can 15 each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Tablets can be non-coated or they may be coated using known methods to achieve 20 delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Patent Nos.4,256,108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets. Tablets may further 25 comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation. Tablets can also be enterically coated such that the coating begins to dissolve at a certain pH, such as at about pH 5.0 to about pH 7.5, thereby releasing a compound as 30 described herein. The coating can contain, for example, EUDRAGIT ® L, S, FS, and / or E polymers with acidic or alkaline groups to allow release of a compound as described herein in a particular location, including in any desired section(s) of the intestine. The coating can also contain, for example, EUDRAGIT ® RL and / or RS polymers with cationic or neutral groups to allow for time controlled release of a compound as described herein by pH-independent - 70 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) swelling. Parenteral Administration For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or 5 infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used. Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known 10 in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. Sterile, fixed oils are conventionally 15 employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain 20 alcohol diluent or dispersant, such as such as lauryl, stearyl, or oleyl alcohols, or similar alcohol. Additional Administration Forms Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S. Patents Nos.6,340,475; 25 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as 30 described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757. Controlled Release Formulations and Drug Delivery Systems - 71 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) In certain embodiments, the formulations described herein can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations. The term sustained release is used in its conventional sense to refer to a drug 5 formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form. For sustained release, the compounds may be formulated with a suitable polymer or 10 hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation. In some cases, the dosage forms to be used can be provided as slow or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl 15 cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Thus, single unit dosage 20 forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets, that are adapted for controlled-release are encompassed by the compositions and dosage forms described herein. Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an 25 optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other 30 characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects. Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended - 72 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various inducers, for 5 example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term “controlled-release component” is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient. In some embodiments, the compound(s) described herein are 10 administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. In some embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. The term delayed release is used herein in its conventional sense to refer to a drug 15 formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma 20 profiles of the drug after drug administration. The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration. As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 25 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all 30 whole or partial increments thereof after drug administration. Dosing The therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the - 73 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) progression of a disease state in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors. A suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for 5 example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. 10 It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. 15 In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 20 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. 25 Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and / or infection. 30 The compounds described herein can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of - 74 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the 5 determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies 10 preferably within a range of circulating concentrations that include the ED50with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized. EXAMPLES 15 Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein. Materials and Methods 20 Mitochondrial genome retrieval, group I intron discovery, annotation and structural analysis Reference mitochondrial genomes of human pathogenic fungi were retrieved from the NCBI GenBank database. To survey genomes for the presence of group I introns, the RNAweasel pipeline (https: / / megasun[dot]bch[dot]umontreal[dot]ca / cgi- bin / RNAweasel / RNAweaselInterface[dot]pl) was first used to identify the location of 25 conserved intron secondary motifs P3 / P8 / P7 and P4-P6. Mitochondrial genomes with putative group I intron(s) identified were then further annotated using the MFannot pipeline (https: / / megasun[dot]bch[dot]umontreal[dot]ca / cgi-bin / dev_mfa / mfannotInterface[dot]pl). The annotations were further subjected to manual inspection to validate flanking gene identities. Intron boundaries were then manually identified using established group I intron 30 splice site selection rules. Once the span of intron sequence had been identified, secondary structures were predicted using mfold with constraints generated from the RNAweasel pipeline. These were output in the connection table format and secondary structure diagrams were created using Adobe Illustrator following the established Cech representation. - 75 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) DNA constructs, RNA in vitro transcription and purification DNA fragments containing a T7 promoter, 40-nt flanking exons, the intron and a terminal BamHI cleavage site were commercially synthesized (Eurofins Blue Heron) and cloned into the pUCminusMCS vector. To generate a precursor construct for the C.au.cytB 5 intron, the basal stem of intron P2 was preserved while additional sequences (containing intronic ORF sequence) were reduced to a simple UUCG tetraloop that caps the basal stem of P2. Plasmids containing the sequences of the intron self-splicing constructs (denoted as pLTS202 for the C.au.cytB intron, pLTS204 for the C.a.mtLSU intron; sequences of plasmid inserts were linearized using BamHI (New England Biolabs) to generate DNA templates for 10 in vitro transcription. The P11-unzip mutant construct of the C.a.mtLSU intron was prepared using a PfuUltra II Hotstart PCR Master Mix (Agilent) with routine site-directed mutagenesis protocol. The sequence of the resulting plasmid (denoted pLTS227) was verified with Sanger sequencing (Quintara Biosciences). Radiolabeled precursor RNA transcripts were prepared as follows: 5 μg of linearized plasmid, 3.6 mM of each NTP (except UTP), 1 mM of UTP along 15 with 50 μCi of [α-32P]-UTP (PerkinElmer), and T7 RNA polymerase (P266L mutant, expressed and purified in-house) were added to a transcription buffer containing 40 mM Tris- HCl pH 8.0, 10 mM NaCl, 15 mM MgCl2, 2 mM spermidine, 0.01 % Triton X-100 and 10 mM DTT. The reaction was incubated at 37 °C for 1.5 h, followed by DNase I (Invitrogen) digestion for 10 min and subsequent purification on a 0.4 mm-thickness 5 % denaturing 20 polyacrylamide (29:1) gel. The band corresponding to precursor RNA was cut and eluted overnight in a gel elution buffer (10 mM Na-MOPS pH 6.0, 300 mM NaCl and 1 mM EDTA). The RNA transcripts were ethanol precipitated and resuspended in an RNA storage buffer (6 mM Na-MES pH 6.0). The RNA stock solution was aliquoted and stored frozen. 25 Self-splicing assay for the C.a.mtLSU intron For pilot self-splicing assays, body-labelled precursor RNA transcribed from plasmid pLTS204 (10 nM final concentration) was incubated in 50 mM K-HEPES pH 7.5 at 90 °C for 1 min, followed by incubation at 37 °C for 5 min.2 μl of 10x MgCl2 stock solution was then added to the final concentration of 5 mM and folded for additional 5 min. The splicing 30 reaction was initiated by adding 2 μl of 10x GTP stock solution (MedChemExpress) to the final concentration of 50 μM. The final reaction volume was 20 μl and the reaction was incubated at 37 °C. To monitor reaction time courses, 1 μl was removed from the reaction mixture at specific time points and quenched by mixing with 2x formamide loading buffer (72 % (v / v) formamide, 10 % sucrose, 0.2 % bromophenol blue dye, 0.2 % xylene cyanol dye - 76 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) and 50 mM EDTA) and placing on ice. The timepoint samples were then loaded onto a 0.4 mm-thickness 5 % denaturing polyacrylamide gel to resolve individual bands. For enzymological characterization, body-labelled precursor RNA (10 nM final concentration) was incubated in 50 mM K-HEPES pH 7.5 at 90 °C for 1 min, followed by incubation at 25 5 °C for 5 min.5 μl of 4x KCl stock solution was first added to the final concentration of 150 mM.2 μl of 10x MgCl2stock solution was then added to the final concentration of 3 mM and folded for additional 5 min. The splicing reaction was initiated by adding 2 μl of 10x guanosine stock solution in DMSO (Sigma) to a final volume of 20 μl, leading to a final DMSO% of 10 % (v / v) in the reaction. Reactions were incubated at 25 °C and the time 10 course samples were analyzed. For comparison of the wild-type intron and the P11-unzip mutant, body-labelled precursor RNA (10 nM final concentration; transcribed from either pLTS204 for the wild- type or pLTS227 for the unzip mutant) was incubated in 50 mM K-HEPES pH 7.5 at 90 °C for 1 min, followed by incubation at 25 °C for 5 min.5 μl of 4x KCl stock solution was first 15 added to the final concentration of 150 mM, followed by the addition of 4 μl of 50 % (v / v) PEG-4000 (Hampton Research).2 μl of 10x MgCl2 stock solution was then added to the final concentration of 3 mM and folded for additional 5 min. The splicing reaction was initiated by adding 2 μl of 10x (200 μM) guanosine stock solution in water to a final volume of 20 μl. Reactions were incubated at 25 °C and the time course samples were analyzed as described 20 before. Self-splicing assay for C.au.cytB intron For pilot self-splicing assays, body-labelled precursor RNA transcribed from plasmid pLTS202 (10 nM final concentration) was incubated in 50 mM K-HEPES pH 7.5 at 90 °C for 25 1 min, followed by incubation at 37 °C for 5 min.2 μl of 10x MgCl2stock solution was then added to the final concentration of 5 mM and folded for additional 5 min. The splicing reaction was initiated by adding 2 μl of 10x GTP stock solution to the final concentration of 200 μM. The final reaction volume was 20 μl and the reaction was incubated at 37 °C. For enzymological characterization, body-labelled precursor RNA (10 nM final concentration) 30 was incubated in 50 mM K-HEPES pH 7.5 at 90 °C for 1 min, followed by incubation at 37 °C for 5 min.2 μl of 10x MgCl2stock solution was then added to the final concentration of 5 mM and folded for additional 5 min. The splicing reaction was initiated by adding 2 μl of 10x guanosine stock solution in DMSO to a final volume of 20 μl, leading to a final DMSO% of 10 % (v / v) in the reaction. The reactions were incubated at 37 °C. - 77 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) Data analysis Gels containing the separated reaction products were dried and exposed to phosphor screens overnight. The screens were scanned using a Typhoon RGB Biomolecular imager 5 (Cytiva). Individual bands were quantified using ImageQuant 8.2 software (GE Healthcare). Band intensity was corrected for the uridine content of corresponding species and internally calibrated by calculating the fraction of each intron-containing species in the reaction. The precursor depletion time course data were analyzed and plotted using Kaleidagraph 4.5.4 (Synergy Software). The data were fitted by a monophasic depletion kinetic model (Eq.1) 10 (Eq.1) where fprecursoris the ly converting precursor, kobs is the observed rate and finactive is the fraction of non-converting precursor. All reaction time courses were performed in triplicate and error bars in the kinetic plots were reported as standard errors of the mean (s.e.m.). To determine the enzymological parameters 15 for group I intron catalysis, the observed rate constant (kobs) was obtained from the precursor depletion time course, plotted against the titration of guanosine concentration and fitted to the Michaelis-Menten equation (Eq.2). The experiments were performed in triplicate to ensure reproducibility and all values are reported as mean ± s.e.m. (Eq.2) 20 where kobs is the apparent ra over number, ^^ெீis the Michaelis constant and [G] is the guanosine concentration. Determination of the rate constant of splicing (kobs) Reaction conditions included 50 mM HEPES pH 7.5, 10 nM RNA, 150 mM KCl, 3 25 mM MgCl2, 20 µM Guanosine, and 10 µM of test compound at 25 °C. Measurements included a time course of measurement of: 0 min, 1.5 min, 3 min, 5 min, 7.5 min, 10 min, 20 min, 30 min, 45 min, and 60 min. The reference rate for uninhibited kobsof C.a.mtLSU was 0.12 ± 0.01 min-1(50 mM K-HEPES pH 17.5, 150 mM KCl, 3 mM MgCl2, 20 µM Guanosine) 25 °C. The reference of uninhibited kobsof C.a.mtLSU: 0.08 ± 0.01 min-1(50 mM 30 K-HEPES pH 17.5, 150 mM KCl, 3 mM MgCl2, 20 µM Guanosine) at 25 °C. (*Fold change = kobs,ref(kobswithout compound) ÷ kobs,i(kobswith compound)). Comparison of the uninhibited reference rate and rate with compound indicates effect of compound to kobs - 78 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) change. Higher value implies better inhibition. IC50 procedures Radioanalytic assay was performed with body-labeled C. albicans precursor RNA, gel 5 purified, folded first in Mg2+and then reacted as below; and optionally undergoing folding SOP. IC50was measured for compounds only when they exhibited better than a threshold kobs< 0.1 min-1rate. The purity of test compounds was >95 % unless specified. Compounds were stored at YSB 309D fridge / freezer (-20 °C) in DMSO stock. A pilot IC50was used to determine the proper concentration range for a quantitative IC50. Compound concentrations 10 tested included: 0.03, 0.1, 0.3, 1, 3, 10, 30 μM. Reaction conditions were 50 mM HEPES pH 7.5, 10 nM RNA, 150 mM KCl, 3 mM MgCl2, 20 µM Guanosine at 25 °C for 5 min. Radioanalytical assay was used for quantitative IC50procedures. Quantitative measurement was performed with a tailored concentration range that was determined from the pilot IC50 and used to determine the kobsfor each compound. Reaction conditions were 50 mM HEPES 15 pH 7.5, 10 nM RNA, 150 mM KCl, 3 mM MgCl2, 20 µM Guanosine at 25 °C for 5 min. Quantitative IC50 Determination Radioanalytic assay was performed with body-labeled C. albicans precursor RNA, gel purified, folded first in Mg2+and then reacted as below; and optionally undergoing folding 20 SOP. IC50 was measured for compounds only when they exhibited better than a threshold kobs < 0.1 min-1rate. The purity of test compounds was >95 % unless specified. Compounds were stored at YSB 309D fridge / freezer (-20 °C) in DMSO stock. A pilot IC50 was used to determine the proper concentration range for a quantitative IC50. Compound concentrations tested included: 0.03, 0.1, 0.3, 1, 3, 10, 30 μM. Reaction conditions were 50 mM HEPES pH 25 7.5, 10 nM RNA, 150 mM KCl, 3 mM MgCl2, 20 µM Guanosine at 25 °C for 5 min. Radioanalytical assay was used for quantitative IC50 procedures. Quantitative measurement was performed with a tailored concentration range that was determined from the pilot IC50 and used to determine the kobs for each compound. Reaction conditions were 50 mM HEPES pH 7.5, 10 nM RNA, 150 mM KCl, 3 mM MgCl2, 20 µM Guanosine at 25 °C 30 for 5 min. Determination of the rate constant of splicing (kobs) Reaction conditions included 50 mM HEPES pH 7.5, 10 nM RNA, 150 mM KCl, 3 mM MgCl2, 20 µM Guanosine, and 10 µM of test compound at 25 °C. Measurements - 79 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) included a time course of measurement of: 0 min, 1.5 min, 3 min, 5 min, 7.5 min, 10 min, 20 min, 30 min, 45 min, and 60 min. The reference rate for uninhibited kobsof C.a.mtLSU was 0.12 ± 0.01 min-1(50 mM K-HEPES pH 17.5, 150 mM KCl, 3 mM MgCl2, 20 µM Guanosine) 25 °C. The reference of uninhibited kobsof C.a.mtLSU: 0.08 ± 0.01 min-1(50 mM 5 K-HEPES pH 17.5, 150 mM KCl, 3 mM MgCl2, 20 µM Guanosine) 25 °C. (*Fold change = kobs,ref(kobswithout compound) ÷ kobs,I(kobswith compound)). Comparison of the uninhibited reference rate and rate with compound indicates effect of compound to kobs change. Higher value implies better inhibition. 10 Minimum inhibitory concentration (MIC) C. albicans growth inhibition was measured for compounds where kobs > 0.1 min-1. Compound concentrations tested included: 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 µg / mL. Test compounds were incubated for 24 hours. 15 Example 1: Self-splicing of the Candida albicans mtLSU Group IA1 intron (C.a.mtLSU) Candida albicans contains two group IA1 introns in its mtLSU gene (Table 2), both of which lack an intronic ORF. Since the mtLSU.I2 intron is devoid of the P2 motif, a peripheral structural motif known to promote in vitro self-splicing, and lacks homologs across fungal species, mtLSU.I1 (referred to as the C.a.mtLSU intron hereafter) was selected, 20 which maintains a complete intron structure , as the model intron for examining the mechanistic behavior of the prevalent group IA1 lineage. Importantly, the C.a.mtLSU intron should not be confused with the C.a.LSU intron. The latter is a group IE2 intron inserted within the nuclear-encoded ribosomal large subunit gene, and it lacks homologs across different fungal pathogens. 25 A first self-splicing was tested under a standard set of conditions for group I intron splicing (50 mM K-HEPES pH 7.5, 5 mM MgCl2, 50 μM GTP at 37 °C). The C.a.mtLSU intron efficiently catalyzes both steps of self-splicing without undergoing further cyclization, giving rise to fully spliced linear intron and ligated exon (FIG.1A). After sampling a diversity of self-splicing conditions, it was surprising to observe that the intron undergoes 30 efficient self-splicing even at ambient temperatures (25 °C) under a near-physiological salt condition (50 mM K-HEPES pH 7.5, 150 mM KCl, 3 mM MgCl2), which inspired an experiment to conduct detailed characterization using this exceptionally mild condition (FIG. 2A). A guanosine nucleoside rather than GTP was used as the reaction cofactor because it is uncharged, and therefore lacks an electrostatic component that can influence affinity between - 80 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) cofactor and intron. Indicative of robust, uniform intron folding, the intron precursor converted to product in a kinetic time course without a lag phase, fitting well to a single exponential equation (FIG.2A). Quantitation of the data yielded an apparent precursor depletion rate constant of 1.07 ± 0.05 min−1at 250 μM guanosine (FIG.2A). Such robust 5 biochemical activity under ambient temperature and physiological salt concentration is unprecedented for group I introns, which often become caught in rate-limiting kinetic folding traps and require temperatures exceeding 30 °C for catalysis. To gain further insights into the molecular origin of the observed exceptional biochemical robustness, an unzip mutant disrupting the P11 pseudoknot (FIG.3A) was designed and showed that the mutant intron is10 no longer able to self-splice at this exceptionally mild condition (FIG.3B), while the self- splicing activity of the mutant can be partially rescued by the addition of crowding agent PEG-4000 (polyethylene glycerol 4000) (FIG.3B), which is known to promote RNA folding and catalytic efficiency. Hence, it was biochemically established that P11 is the key structural element that strengthens intron folding and contributes to the unprecedented catalytic 15 robustness of the C.a.mtLSU intron, in line with the previous observations made on the yeast mtLSU IA1 intron. Given the apparent efficiency of this reaction, it was of interest to obtain a full set of guanosine-dependent enzymological parameters for C.a.mtLSU intron self-splicing under near-physiological conditions. To this end, splicing time courses were obtained at varying 20 guanosine concentrations and the resulting reaction rate constants were plotted as function of guanosine concentration (FIG.3B). The resulting hyperbolic plot was fit with a standard Michaelis-Menten equation, enabling the calculation of the apparent binding constant for guanosine (^^ெீ, 356 ± 10 μM). The Michaelis constant is comparable to that of the yeast bI5 intron (310 μM), a group IA1 intron that requires a protein cofactor for splicing. The apparent 25 guanosine affinity is slightly weaker than reported for Azoarcus (17 μM), Anabaena (240 μM) and Tetrahymena (30 μM) introns. Remarkably, the catalytic turnover number (kcat) reaches 2.6 ± 0.2 min−1, which is an order of magnitude higher than that reported for the Azoarcus (0.2 min−1) and Anabaena (0.3 min−1) introns and three times higher than the Tetrahymena (0.9 min−1) intron. As such, C.a.mtLSU intron demonstrates the most rapid 30 turnover number among group I introns studied to date, despite the mild reaction conditions. The overall catalytic efficiency (kcat / ^^ெீ) is (5.6 ± 0.01) × 104M−1min−1, as determined from the initial rate plot (FIG.2B), which is nearly 50-fold higher than the same IA1-lineage yeast bI5 intron (1.2 × 103M−1min−1),51 comparable to that of the Anabaena (4.6 × 104M−1min−1) - 81 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) and Tetrahymena (2.8 × 104M−1min−1) introns, while smaller than the Azoarcus (12 × 104M−1min−1) intron as a result of weaker guanosine binding. Collectively, results herein demonstrate that the C.a.mtLSU intron rapidly self-splices without protein cofactor even under conditions that do not support the self-splicing of other legacy group I introns, while 5 maintaining a high level of catalytic efficiency. More importantly, at a saturating cofactor (guanosine) concentration, the turnover number is unusually high, suggesting a particularly robust catalytic mechanism that is unprecedented for group I intron splicing catalysis. Table 2. Group I introns in human pathogens of medical importance. GenBank ORF Organism Accession Intron Subclass Position 10 Example 2: Self-splicing of the Candida auris cytB group ID intron (C.au.cytB) The group ID intron in the C. auris cytB gene (referred to as the C.au.cytB intron - 82 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) hereafter) also displays robust self-splicing activity under the standard splicing condition (50 mM K-HEPES pH 7.5, 5 mM MgCl2, 200 μM GTP at 37 °C) (FIG.1B), though there are differences in the salt and temperature dependence as well as cofactor affinity relative to the C.a.mtLSU intron (FIG.2C and FIG.2D). The intron cannot undergo self-splicing when 5 incubated at ambient temperatures; rather the optimal reaction temperature for splicing is higher (37 °C). The intron also requires slightly higher concentration of Mg2+(5 mM) for efficient precursor conversion. Therefore, a standard salt condition (50 mM K-HEPES pH 7.5, 5 mM MgCl2) was chosen with a titration of guanosine concentration for subsequent enzymological characterization. The apparent rate constant at 50 μM guanosine (FIG.2C) is 10 0.24 ± 0.02 min−1, a slower rate than the C.a.mtLSU intron (FIG.2A) despite the fact that it was obtained at elevated temperature and higher Mg2+concentration. This biochemical observation suggests that folding and catalysis by this intron is less robust than that of the C.a.mtLSU intron, which is likely due to the structural differences between the two introns. The C.au.cytb intron has a much smaller core (P6) for the scaffolding domain, which may 15 confer reduced mechanical stability relative to the C.a.mtLSU intron, which has a larger and more stable P6. Full splicing time courses with varying guanosine concentrations were then conducted and the resulting kobs values were plotted as a function of guanosine and fit to the Michaelis-Menten equation (FIG.2D), enabling derivation of the apparent binding constant for guanosine (^^ெீ, 54.5 μM), which is much tighter than that of the C.a.mtLSU intron and on 20 par with that of the Azoarcus and Tetrahymena introns. The turnover number at saturating guanosine concentration (^^^ீ^௧) is 0.55 ± 0.02 min−1, which is typical of group I introns. The overall catalytic efficiency of the intron (kcat / ^^ெீ) is (6.8 ± 0.4) × 104M−1min−1, as determined from the initial rate plot (FIG.2D), which is relatively high due to the tighter binding of guanosine to this intron. Overall, the C.au.cytB intron self-splices with reasonable 25 efficiency under conditions that are not far from those found in living organisms, therefore capable of catalyzing its own excision from the precursor transcript in the context of infection without apparent reliance on additional protein cofactors, thereby ensuring efficient expression of cytochrome b, an indispensable part of the electron transport chain complex. 30 Example 3: Identification of group I intron splicing inhibitors Having identified a representative intron within the mitogenome of C. albicans, screening was performed to identify small molecules that inhibit the self-splicing reaction. For enzymological analysis a "splicing system in a test tube" was created, whereby the - 83 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) splicing precursor construct (containing the candidate intron, flanked by a set of short exons, FIGs.4A-4B), is generated by T7 RNA transcription from a synthetic DNA template. The precursor RNA was purified by electrophoresis and incubated under diverse buffer conditions to stimulate splicing, enabling establishment of optimal reaction conditions and obtain kinetic 5 parameters for the splicing reaction. To carry out chemical screening, a molecular beacon was designed to match the exon sequences of the C. albicans intron (FIG.7) enabling sensitive monitoring of splicing reactions at high-throughput. Screening of a compound library was then performed and identified specific inhibitors of the C. albicans intron. Results were obtained with the Enamine RNA-focused library (0.2% hit rate and high replicability) 10 (FIGs.5A-5B). Systematic SAR and optimization were carried out by iterative chemical synthesis and IC50testing for splicing inhibition, enabling distinguishment of compound substituents required for intron engagement from regions that can be manipulated to enhance potency and facilitate derivatization (FIG.6). Systematic SAR and optimization were carried out by 15 iterative chemical synthesis and IC50 testing for splicing inhibition, enabling compound substituents required for intron engagement to be distinguished and regions that can be manipulated to enhance potency and facilitate derivatization to be identified (FIG.6). Significantly, the hit and its derivatives are all competitive inhibitors of the guanosine cofactor, thereby establishing a clear mode of action and binding site. This was confirmed by 20 subsequent cryo-EM studies of the C. albicans intron in complex with guanosine, and with potent inhibitor compound 86 (FIG.6 and FIG.8A, FIG.9A, and FIG.9H), establishing that the cofactor and inhibitors bind to the same position within the intron. Given the unusually high enzymatic activity of the C. albicans mtLSU intron, the paucity of structural information on intron-bound inhibitors, and potential value of structure- 25 based design for new compounds, the structure of the intron in complex with guanosine was solved, as well as with a potent inhibitor (compound 86). Map quality is unusually high due to a uniform distribution of particles and the high quality of the data (FIGs.11A-11D). The structure (global resolution of 2.5 Å and local active-site resolution of 2.4 Å) reveals a well- ordered active-site with specific interactions between the known “guanosine binding site” of 30 group I introns and privileged moieties on the heterocyclic ring. The primary amine forms a network of interactions with proximal phosphate groups, helping to enclose the active-site. The active site contains many additional functional groups with the potential to interact with substituents on designed ligands, interacting via stacking hydrophobic interactions and the formation of electrostatic and hydrogen-bonding contacts. The effect of compound 86 on C. - 84 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) albicans growth was tested, but as expected for its low calculated log P value (< 0), antifungal activity was not observed without coadministration of drugs that disrupt the fungal cell wall (such as amphotericin B). 5 Example 4: Optimization of group I intron splicing inhibitors SAR Studies Based upon analysis of the active site and the compound 86 interaction network (FIGs.8-10), an expanded set of analogs for enhancing affinity can be synthesized using existing structure activity relationships (FIG.11A). Without being bound by theory, three10 areas are apparent for additional ligand-RNA interactions in the structure, namely the above- plane active-site residues (A-152, U-315), the binding cavity Mg2+,and the U-257 residue. The interactions gained by newly designed substituents are expected to improve binding affinity while reducing log P and potentially enhancing cell uptake. 15 Computational Studies Complementing the classical medicinal chemistry approach, for compounds within a structurally validated hit series (e.g., compound 86), a template-based docking approach can be used to help guide the design of analogs and prioritize them for synthesis and testing. To assess the similarity between docked poses of candidate ligands and the cryo-EM ligand, the 20 measure maximum common substructure (MCS) root mean square distance (RMSD) can be used as a quantitative measure. MCS-RMSDs can be measured for all poses with docking scores within 3 kcal mol-1of the most favorable pose for each candidate. Compounds can be prioritized for synthesis and inhibition assays if they have favorable docking scores and MCS-RMSD ≤ 2 Å. For each compound the top 2-3 most highly populated protonation states 25 at pH 7.4, as predicted by Marvin tools (ChemAxon MarvinSketch version 23.8) can be docked. The docksolv scoring function in rDock can be used. Although the correlation of docking scores and IC50values is generally low, data have revealed meaningful trends that can likely be enhanced by considering additional properties of the ligands and the binding site. For example, using simple binary classification a positive predictive value (PPV = 30 TP / (TP+FP)) of 84% for a set of 21 ligands with IC50 measurements was achieved (FIGs. 12A-12B, green dotted line indicates score that best distinguishes between strong (<1 µM) and weak binders). To improve predictive power, a regression model can be trained to predict IC50values from docking scores and physicochemical descriptors. The model can undergo iterative refinement as new IC50 measurements are obtained. - 85 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) Biochemical Testing To assess relative potency, IC50 values for compounds are obtained using two orthogonal assays: The rapid molecular beacon assay (FIG.7), and a radioanalytic splicing 5 assay in which the intron precursor is observed as it transforms into products (FIGs.13A- 13B). The two assays produce quantitative results. However, the latter assay is important because, despite its lower throughput, it is not confounded by optical artifacts that can accompany assays based on fluorescence. As such, the radioanalytic assay is conducted on all promising compound candidates, ensuring rigor. 10 Antifungal testing The in vitro testing on diverse strains and species, thereby providing parallel chemical / antifungal SAR for all promising compounds. Testing of Candida species is important since it is the most common cause of disseminated fungal infections in 15 immunocompromised patients. Additionally, drug resistant clinical isolates of C. albicans, the multidrug resistant clades of C. auris, and other non-albicans Candida species such as C. glabrata and C. parapsilosis that have also gained notoriety in causing catheter-related systemic infections. Other fungal strains encompass filamentous fungi such as Aspergillus fumigatus that cause lethal fungal pneumonia. In fact, A. fumigatus has an almost identical 20 intron to that of C. albicans (a IA1 class intron) thereby making it an ideal candidate for testing the broad-spectrum activity of the inhibitors. The activity of the compounds against cryptic aspergilli known to have drug resistance to current antifungal agents (e.g. A. calidoustus, and A. lentulus). Other molds include Mucorales fungi (cause of invasive mucormycosis), Fusarium spp., Scedosporium spp and Lamentospora. Compounds that reach 25 an MIC threshold of < 5 µM and which lack mammalian toxicity can be prioritized and those with a high therapeutic index of 10 can be evaluated further, in vivo. In-vitro toxicity screening Drug candidates are evaluated using a well-established viability assay in which 96- 30 well plates of HEK293 cells are allowed to grow (24 hours), before receiving a dose of compound (varying from 0.25 µg / ml to 128 µg / ml, with a final [DMSO] less than 1%). After additional growth (24-72 hours), they are treated with the Cell-Titer Glo cell viability assay (Promega G7571). Compounds with IC50> 64 µg / ml are considered nontoxic in this assay. Toxicity can be measured toxicity against primary human vascular endothelial cells by using - 86 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) the51Cr-release assay that is the gold standard in toxicity testing, ensuring rigorous orthogonal analysis. Optimization of fungal cell uptake and mitochondrial delivery 5 In parallel with optimization of the chemical interaction network, properties essential for bioavailability and selective delivery into the fungal cell can be optimized. Derivatives that enhance LogP, LogS and reduce TPSA are a main goal of antifungal drug design; these properties are correlated with cell permeability, bioavailability, and the overall drug-likeness. These properties can be optimized during design using RDKit, Swiss-ADME, and similar 10 tools to calculate molecular properties of candidate compounds. Although property space guidelines such as Lipinski’s rule of 5 and others have limitations, a general aim for compounds with computed properties of a molecular weight < 500, a cLogP ≤ 5, a Log D ≤ 2, aqueous solubility ≥ 10 ^M, number of hydrogen bond donors ≤ 2, number of hydrogen bond acceptors ≤ 6, and topological polar surface area ≤ 90 Å, while being mindful of the 15 parameters known to maintain strong RNA binding. One design strategy is to append transporter epitopes to the variable positions on compound 86 (FIG.11A) with various cleavable linkers. Epitopes include cell penetrating peptides, spermidine, and siderophore mimetics (FIG.11B). Prodrug linkers center on the established modalities of disulfide reduction and esterase induced cleavage (FIG.11C), both known in fungal systems. 20 Another design strategy is to synthesize prodrugs to facilitate passive diffusion and mitochondrial accumulation. Simple nonpolar groups enable passive transmembrane diffusion (FIG.11D). Triphenyl phosphonium compounds can penetrate cells via a passive mechanism, and their tendency to hyperaccumulate in mitochondria is documented. Prodrugs can move directly to in vitro antifungal testing as the bioactive form is only achieved once the 25 compound enters the cell. Animal infection studies Compounds that meet the affinity, toxicity, and potency thresholds can be tested for activity against a broad panel of fungal organisms, such as strains of Candida, molds, 30 dimorphic fungi, with an emphasis on drug-resistant strains. Compounds that display pan-fungal efficacy have a distinct advantage for drug development, however compounds with fungicidal effects on individual fungal classes (such as Candida) or fungistatic effects on pathogens of exceptionally high clinical value due to - 87 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) failure of conventional treatment (such as the rare molds, Aspergillus fumigatus, etc) also provide a distinct value in treating infections. A reasonable target is to design nontoxic compounds with significantly reduced IC50 < 10 nM and a MIC < 1 µg / ml for one or more fungal strains. Lead molecules can be used as adjunct therapies along with existing clinically 5 approved antifungal drugs, the efficacy of the lead compounds in combination with clinically used antifungal drugs such as azoles (fluconazole), echinocandins (micafungin) or polyenes (liposomal amphotericin B), can also be analyzed via a checkerboard assay. Drug combinations with enhanced antifungal synergy can be evaluated for in vivo efficacy. Tolerability and therapeutic index are then assessed, potentially leading to additional stages 10 of synthetic optimization to enhance properties such as pharmacokinetics. The most efficacious lead is advanced for more elaborate in vivo testing with optimized dosing (via PK studies) with or without one or more antibiotics. Mouse models of C. albicans and C. auris infection can be used for compounds which demonstrate in vitro activity. To optimize treatment, pharmacokinetics (PK) is first conducted on the chosen molecules for in vivo 15 testing. Mice can be administered with three different concentrations of drug candidates (guided by the MIC results) by i.p. injection (mimicking the route of administration in humans). At 0.5, 1.0, 2.0, 4.0, 8.0 and 24 h post injection, blood is collected from three mice each by cardiac puncture. The drug titers in serum can be determined by using HPLC. Key parameters such as the time to maximum plasma concentration (Tmax), maximum plasma 20 concentration (Cmax), Cmax / Dose, area under plasma concentration-time curve from zero to infinity (AUC0-∞), AUC0-∞ / Dose, apparent volume of distribution after extravascular administration at (Vz / F), apparent plasma clearance of drug after extravascular administration (CL / F), and half-life (t1 / 2) can be calculated from this data. Lead drugs are administered via i.p. route 24 h post infection with the organism under 25 investigation and repeated at time points determined from the PK studies. For studies with antibiotics, infected mice are treated with the drug candidates and antibiotics (fluconazole or first-line echinocandin for C. auris), 48 h post infection to allow for determination of potential synergy between the lead drugs and antibiotics. Time to moribundity serves as a primary endpoint. As secondary end points, the treatment efficacy on reducing CFU in 30 kidneys and spleen is determined, as well as histopathological examination using Grocott methenamine silver (GMS) and periodic acid Schiff (PAS). The PK results can guide dosing and time of treatment. Optimization efforts aim for half-lives of ~24 hours and high Cmaxvalues for drug candidates. One strategy for combination treatment is to use echinocandins in combination with compounds of the - 88 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) disclosure. Without being bound by theory, disruption of fungal cellular membranes by echinocandins may aid in absorption of compounds of the disclosure. Several other antifungal combinations may also exhibit synergistic effects in vivo. 5 Example 5: Exemplary intron splicing inhibitory data for certain compounds of the disclosure Certain compounds of the disclosure were found to have good efficacy for inhibiting the self-splicing process in vitro and in cellular C. albicans growth. The disclosure provides exemplary data for certain compounds of the disclosure, including Ki measurements (Table 10 3), kobsvalues (Table 4), intron splicing half-maximal inhibition (IC50) data (Table 5), and minimum inhibitory concentration (MIC) data (Table 6). Several compounds showed unexpectedly favorable properties as inhibitors of group I intron splicing. Table 3. Affinity constant (Ki) values determined by plotting kobsvs. [inhibitor] Cmpd KiCmpd KiCmpd Ki15 Table 4.obs(at 10 µM; m n ) o exemp ary compounds Cmpd kobs(%) Cmpd kobs(%) Cmpd kobs(%) - 89 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 13 0.043 38 0.014 68 0.022 14 <0.001 39 0.160 69 0.000006 Table 5. Half-maximal inhibitor concentration (IC50) values for certain exemplary 5 compounds*Cmpd IC50 (µM) Cmpd IC50 (µM) Cmpd IC50 (µM) inhibitor. - 90 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) Table 6. Minimum inhibition concentration (MIC) values for certain exemplary compounds*Cmpd MIC (µg / mL) Cmpd MIC (µg / mL) Cmpd MIC (µg / mL) 1>12822>12849>128s . administration of compound at a concentration of 128 µg / mL, which was the highest 5 concentration tested. Enumerated Embodiments The following enumerated embodiments are provided, the numbering of which is not to be construed as designating levels of importance: 10 Embodiment 1 provides a compound of Formula (I), or a salt, stereoisomer, tautomer, or isotopologue thereof: - 91 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) I), wherein: X1is CR3aor N; X2is CR3bor N; 5 X3is CR3cor N; X4is CR3d, C(R3d)(R3e), or N; wherein at least one of X1, X3, and X4is N, or X2is N; L is a bond or -(optionally substituted C1-C3 alkylenyl)-; Y is N(R1b) or S; 10 R1aand R1b, if present, are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted C2-C8 heterocycloalkyl, wherein R1aand R1bcan combine with the nitrogen atom to which they are bound to form an optionally substituted C2-C8heterocycloalkyl, and 15 wherein one of R1aand R1bcan combine with one of R3a, R3d, or R3eto form an optionally substituted C2-C8heterocycloalkyl or optionally substituted C2-C8 heteroaryl; R2ais selected from the group consisting of H, halogen, optionally substituted C1-C6alkyl, optionally substituted C2-C8 heterocycloalkyl, ORA, CN, and NO2, or 20 R2acan combine with R3dto form an optionally substituted C2-C8heteroaryl; R2b, if present, is H; R3ais selected from the group consisting of H and optionally substituted C1-C6 alkyl; R3bis selected from the group consisting of H, halogen, optionally substituted C1-C625 alkyl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=OB, CN, and NO2, R3bcan combine with R3cto form an optionally substituted C2-C8heteroaryl; 30 R3cis selected from the group consisting of H and N(RA)(RB), or R3ccan combine with R3bto form an optionally substituted C2-C8- 92 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) heteroaryl; R3dand R3e, if present, are each independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, 5 N(RA)S(=O)2RB, CN, and NO2, or R3dcan combine with R1aor R1bto form an optionally substituted C2-C8heterocycloalkyl or optionally substituted C2-C8 heteroaryl; bond a is a single bond or a double bond, and one of the following applies: bond a is a single bond, X4is C(R3d)(R3e), and R2aand R2bare present, or 10 bond a is a double bond, X4is CR3dor N, and R2bis absent; each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8heteroaryl. 15 Embodiment 2 provides the compound of Embodiment 1, wherein Y is NR1b. Embodiment 3 provides the compound of Embodiment 1 or 2, wherein L is selected from the group consisting of a bond and optionally substituted C1 alkylenyl. Embodiment 4 provides the compound of any one of Embodiments 1-3, which is selected from the group consisting of: 20 ), ), Ii), 55862232.4 Attorney Docket No.047162-7508WO1(02676) Il), wherein: R4aand R4b, if present, are each independently selected from the group consisting of 5 H, optionally substituted C1-C6 alkyl, halogen, CN, NO2, ORC, N(RC)(RD), C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), and S(=O)2ORC; R5, if present, is selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl; R6a, R6b, R6c, and R6d, if present, are each independently selected from the group 10 consisti f H h l n, and optionally substituted C1-C6 alkyl; each occurrence of RCand RDis independently selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C8 heteroaryl. 15 Embodiment 5 provides the compound of Embodiment 4, wherein at least one of the following applies: (a) at least one of R4aand R4bis H; (b) both of R4aand R4bare H; (c) R5is H; 20 (d) at least one of R6a, R6b, R6c, and R6dis H; (e) at least two of R6a, R6b, R6c, and R6dare H; (f) at least three of R6a, R6b, R6c, and R6dare H; and (g) each of R6a, R6b, R6c, and R6dare H. Embodiment 6 provides the compound of any one of Embodiments 1-5, wherein at 25 least one of the following applies: (a) R1aand R1bare each independently selected from the group consisting of H - 94 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with at least one substituent selected from the group consisting of C1-C6alkyl, phenyl, CN, NO2, NRIRII, ORI, C(=O)RI, C(=O)ORI, C(=O)NRIRII, C(=NRI)NRIIRIII, wherein each occurrence of RI, RII, and RIIIis independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C2-C85 heterocycloalkyl, C6-C10 aryl, and C2-C8 heteroaryl; and (b) R1aand R1bare each independently C1-C6alkyl optionally substituted with at least one , wherein: (i) each occurrence of Z1is independently selected from the group consisting of -O-, -NRI-, -C(=O)-, -S-, and C1-C6alkylenyl optionally 10 substituted with RIor C(=O)ORI; (ii) each occurrence of R7ais independently selected from the group consisting of H, C1-C6 alkyl, C(=O)ORI, and C2-C8 heteroaryl optionally substituted with C1-C6alkyl; (iii) m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 15 7, 8, 9, or 10; wherein each occurrence of RIis independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10 aryl, and C2-C8 heteroaryl. Embodiment 7 provides the compound of any one of Embodiments 1-6, wherein R1a20 and R1bare each independently selected from the group consisting of H, -CH3, -(CH2)Ph, - (CH2)CN, -(CH2)C(=NH)NH2, -(CH2)2NH2, -(CH2)2OH, -(CH2)CH(CH3)NH2, - 25 , 55862232.4 Attorney Docket No.047162-7508WO1(02676) , 5 ein at least one of the following applies: (a) R1aand R1bcombine with the N atom to which they are bound to form a C2-C810 heterocycloalkyl, wherein the C2-C8 heterocycloalkyl is optionally substituted with N(RIV)(RV), ORIV, -(CH2)1-3N(RIV)(RV), -(CH2)1-3ORIV, N(RIV)C(=O)ORIV, N(RIV)C(=NRV)N(RVI)(RVII), C(=O)RIV, C(=O)ORIV, C(=NRIV)N(RV)(RVI), wherein each occurrence of RIV, RV, RVI, and RVIIis independently H, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10 aryl, and C2-C8 heteroaryl, and wherein each occurrence of C1-C6 15 alkyl in RIV, RV, RVI, and RVIIis independently optionally substituted with at least one selected from the group consisting of NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C(=O)O(C1-C6 alkyl), and C6-C10aryl; and (b) R1aand R1bcombine with the N atom to which they are bound to form a C2-C8 heterocycloalkyl, wherein the C2-C8heterocycloalkyl is optionally substituted with 20 , wherein: - 96 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) (i) each occurrence of Z2is independently selected from the group consisting of -O-, -NRIV-, -C(=O)-, -S-, and C1-C6alkylenyl optionally substituted with RIVor C(=O)ORIV; (ii) each occurrence of R7bis independently selected from the group 5 consisting of H, C1-C6 alkyl, C(=O)ORI, and C2-C8 heteroaryl optionally substituted with C1-C6alkyl; (iii) n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein each occurrence of RIVis independently selected from the 10 group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10 aryl, and C2-C8 heteroaryl. Embodiment 9 provides the compound of any one of Embodiments 1-8, wherein R1aand R1bcombine with the N atom to which they are bound to form a moiety selected from the group consisting of , , , , 15 , 20 55862232.4 Attorney Docket No.047162-7508WO1(02676) O S S O N N H 5 , 10 , R2ais selected from the group consisting of H, OH, and Cl. Embodiment 11 provides the compound of any one of Embodiments 1-10, wherein - 98 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) R2bis H. Embodiment 12 provides the compound of any one of Embodiments 1-11, wherein R3ais H. Embodiment 13 provides the compound of any one of Embodiments 1-12, wherein at 5 least one of the following applies: (a) R3bis selected from the group consisting of H, NH2, NH(C1-C6alkyl), NO2, and C(=NH)NH2; and (b) R3bis , wherein: (i) each occurrence of Z3is independently selected from the group 10 consisting of -O-, -NRVIII-, -C(=O)-, -S-, and C1-C6 alkylenyl optionally substituted with RVIIIor C(=O)ORVIII; (ii) each occurrence of R7cis independently selected from the group consisting of H, C1-C6alkyl, C(=O)ORVIII, and C2-C8heteroaryl optionally substituted with C1-C6 alkyl; 15 (iii) o is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein each occurrence of RVIIIis independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, and C2-C8heteroaryl. 20 Embodiment 14 provides the compound of any one of Embodiments 1-13, wherein R3bis selected from the group consisting of H, NH2, NHCH3, NO2, C(=NH)NH2, , diments 1-14, wherein 25 R3cis H. Embodiment 16 provides the compound of any one of Embodiments 1-15, wherein R3dis selected from the group consisting of H, CH3, F, Br, NH2, NHC(=O)CH3, NHS(=O)2CH3, and (CH2)2S(=O)2CH3. Embodiment 17 provides the compound of any one of Embodiments 1-16, wherein - 99 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) the compound is selected from the group consisting of: N4-(2-methoxyethyl)-N4-methylpyrimidine-2,4-diamine; 4-(3-methoxypyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 5 (R)-4-(3-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-aminopyrrolidin-1-yl)pyrimidin-2-amine; (R)-4-(3-aminopyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-aminopyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 10 4-((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-((3R,4S)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-((3S,4R)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-aminoazetidin-1-yl)pyrimidin-2-amine; 15 1-(2-aminopyrimidin-4-yl)pyrrolidin-3-ol; (R)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-ol; (S)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-ol; (3R,4S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; (3R,4S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; 20 (3S,4S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; (3S,4R)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; (3R,4R)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; 4-morpholinopyrimidin-2-amine; 4-(4-(2-methoxyethyl)piperazin-1-yl)pyrimidin-2-amine; 25 4-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-amine; (R)-4-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-amine; N1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)-N1-methylethane-1,2-diamine; (S)-N1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)-N1-methylethane-1,2-diamine; 30 (R)-N1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)-N1-methylethane-1,2-diamine; (1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)methanol; (S)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)methanol; (R)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)methanol; benzyl (1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; - 100 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) benzyl ((3S,4R)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; benzyl ((3S,4S)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; benzyl ((3R,4R)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; benzyl ((3R,4S)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; 5 4-(4-aminopiperidin-1-yl)pyrimidin-2-amine; 4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidin-2-amine; (R)-4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-aminopiperidin-1-yl)pyrimidin-2-amine; 10 (S)-4-(3-aminopiperidin-1-yl)pyrimidin-2-amine; (R)-4-(3-aminopiperidin-1-yl)pyrimidin-2-amine; 4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-2-amine; 4-((hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 4-((3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 15 4-((3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 4-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 4-((3aS,6aR)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboxylic acid; (S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboxylic acid; 20 (R) 1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboxylic acid; 4-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; 4-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 25 6-((2-aminoethyl)(methyl)amino)pyrimidin-4-ol; 2-amino-6-((2-aminoethyl)(methyl)amino)pyrimidin-4-ol; N1-methyl-N1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)ethane-1,2-diamine; N6-(2-aminoethyl)-N6-methyl-9H-purine-2,6-diamine; N1-methyl-N1-(9H-purin-6-yl)ethane-1,2-diamine; 30 N1-methyl-N1-(pyrimidin-4-yl)ethane-1,2-diamine; N1-methyl-N1-(2-nitropyridin-4-yl)ethane-1,2-diamine; 5-(2-aminopyrimidin-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine; N4-(2-aminoethyl)-N4-methylpyrimidine-4,6-diamine; N2-(2-aminoethyl)-N2-methylpyrimidine-2,4-diamine; - 101 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) N4-methyl-N4-(2-(methylamino)ethyl)pyrimidine-2,4-diamine; 4-((2-aminoethyl)thio)pyrimidin-2-amine; N1-methyl-N1-(1H-pyrazolo[3,4-b]pyridin-6-yl)ethane-1,2-diamine; N4-(2-aminoethyl)-N2,N4-dimethylpyrimidine-2,4-diamine; 5 N1-methyl-N1-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)ethane-1,2-diamine; 2-((2-aminopyrimidin-4-yl)(methyl)amino)acetonitrile; 2-((2-aminopyrimidin-4-yl)(methyl)amino)acetimidamide; N4-(3-aminopropyl)-N4-methylpyrimidine-2,4-diamine; N4-(4-aminobutyl)-N4-methylpyrimidine-2,4-diamine; 10 N4-(2-aminoethyl)-6-chloro-N4-methylpyrimidine-2,4-diamine; N4-(2-aminoethyl)pyrimidine-2,4-diamine; 2-amino-3-((2-aminopyrimidin-4-yl)amino)propanoic acid; (S)-2-amino-3-((2-aminopyrimidin-4-yl)amino)propanoic acid; (R)-2-amino-3-((2-aminopyrimidin-4-yl)amino)propanoic acid; 15 N4,N4-bis(2-aminoethyl)pyrimidine-2,4-diamine; N4-(2-aminoethyl)-N4-methylpyridine-2,4-diamine; N2-(2-aminoethyl)-N2-methyl-1,3,5-triazine-2,4-diamine; N5-(2-aminoethyl)-N5-methylpyridine-2,5-diamine; N-(2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoethyl)-N- 20 methyl-glutamic acid; N-(2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoethyl)-N- methyl-D-glutamic acid; N-(2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoethyl)-N- methyl-L-glutamic acid; 25 (2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoacetyl)-glutamic acid; (2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoacetyl)-D- glutamic acid; (2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoacetyl)-L-glutamic 30 acid; N4-(2-amino-2-methylpropyl)pyrimidine-2,4-diamine; N4-(2-aminopropyl)pyrimidine-2,4-diamine; (S)-N4-(2-aminopropyl)pyrimidine-2,4-diamine; (R)-N4-(2-aminopropyl)pyrimidine-2,4-diamine; - 102 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 1-(((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)ethyl isobutyrate; (S)-1-(((2-((2-aminopyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)ethyl isobutyrate; 5 (R)-1-(((2-((2-aminopyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)ethyl isobutyrate; 2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethan-1-ol; ((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)carbamoyl)glutamic acid; (S)-((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)carbamoyl)glutamic acid; 10 (R)- ((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)carbamoyl)glutamic acid; N4-(2-aminoethyl)-5-fluoro-N4-methylpyrimidine-2,4-diamine; 4-(3-(aminomethyl)azetidin-1-yl)pyrimidin-2-amine; 1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)guanidine; (S)-1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)guanidine; 15 (R)-1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)guanidine; N4-(3-amino-2,2-dimethylpropyl)pyrimidine-2,4-diamine; N4-(2-aminoethyl)-5-fluoro-N4-methylpyrimidine-2,4-diamine; ((2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)carbonyl)-glutamic acid; ((2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)carbonyl)-L-glutamic acid; 20 ((2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)carbonyl)-D-glutamic acid; 1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboximidamide; (R)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboximidamide; (S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboximidamide; 4-(3-(aminomethyl)piperazin-1-yl)pyrimidin-2-amine; 25 (R)-4-(3-(aminomethyl)piperazin-1-yl)pyrimidin-2-amine; (S)-4-(3-(aminomethyl)piperazin-1-yl)pyrimidin-2-amine; 2-((2-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 30 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- - 103 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 5 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- 10 yl)(methyl)amino)ethyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)-15 ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 20 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 2-((2-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- 25 yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)-30 ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; - 104 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-ethylhexyl)disulfaneyl)ethyl (1-(2-(((2-((2- 5 ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate;10 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(S)- 15 ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate;20 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl methyl(2-(methyl(2-((((5-methyl-2-oxo-1,3- dioxol-4-yl)methoxy)carbonyl)amino)pyrimidin-4-yl)amino)ethyl)carbamate; 1-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridin-6-amine; 25 N4-(3-aminobenzyl)pyrimidine-2,4-diamine; 7-(2-aminoethyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-2-amine; (R)-7-(2-aminoethyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-2-amine; (S)-7-(2-aminoethyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-2-amine; N4-(2-aminoethyl)-N4-methylpyrimidine-2,4,5-triamine; 30 N-(2-amino-4-((2-aminoethyl)(methyl)amino)pyrimidin-5-yl)acetamide; N-(2-amino-4-((2-aminoethyl)(methyl)amino)pyrimidin-5-yl)methanesulfonamide; 4-((2-aminoethyl)(methyl)amino)pyrimidine-2-carboximidamide; 6-(2-aminoethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine; methyl 3-((1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4-yl)pyrrolidin-3- - 105 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) yl)oxy)propanoate; methyl (S)-3-((1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4-yl)pyrrolidin-3- yl)oxy)propanoate; methyl (R)-3-((1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4-yl)pyrrolidin-3- 5 yl)oxy)propanoate; methyl 3-((4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; methyl 3-(((3R,4S)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; 10 methyl 3-(((3S,4R)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; methyl 3-(((3R,4R)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; methyl 3-(((3S,4S)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- 15 yl)pyrrolidin-3-yl)oxy)propanoate; 4-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine; N4-(2-aminoethyl)-N4-methylpyrimidine-2,4-diamine; N4-(2-aminoethyl)-N4-benzylpyrimidine-2,4-diamine; and N4-(2-aminoethyl)-5-bromo-N4-methylpyrimidine-2,4-diamine. 20 Embodiment 18 provides a pharmaceutical composition comprising the compound of any one of Embodiments 1-17 and at least one pharmaceutically acceptable excipient. Embodiment 19 provides a method of treating, preventing, and / or ameliorating a fungal infection in a subject, the method comprising administering to the subject a group I intron splicing inhibitor. 25 Embodiment 20 provides the method of Embodiment 19, wherein the group I intron is a group IA1, IB, or ID intron. Embodiment 21 provides the method of Embodiment 20, wherein the IA1 intron is positioned in a mtLSU, cytb, or cox1 gene. Embodiment 22 provides the method of any one of Embodiments 19-21, wherein the 30 group I intron splicing inhibitor is the compound of any one of Embodiments 1-17 or the pharmaceutical composition of Embodiment 18. Embodiment 23 provides the method of any one of Embodiments 19-22, wherein the fungal infection is caused by a fungus selected from the group consisting of Cryptococcus neoformans, Blastomyces dermatitidis, Cryptococcus gattii, Candida albicans, Candida - 106 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) auris, Candida krusei, Candida glabrata, Candida parapsilosis, Candida guilliermondii, Candida glabrata, Candida tropicalis, Candida lusitaniae, Coccidioides immitis, Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus niger, Aspergillus candidus, Aspergillus ochraceus, Pichia kudriavzevii, Rhizopus oryzae, Rhizopus spp., Histoplasma 5 capsulatum, Coccidioides spp., Paecilomyces variotii, Pneumocystis murina, Pneumocystis jiroveci, Scedosporium spp., Sporotrix spp., and Aspergillus spp., or a combination thereof. Embodiment 24 provides the method of any one of Embodiments 19-23, wherein the subject is a mammal. Embodiment 25 provides the method of Embodiment 24, wherein the mammal is a 10 human. Embodiment 26 provides the method of Embodiment 24 or 25, wherein the fungal infection is at least one selected from the group consisting of aspergillosis, blastomycosis, candidemia (Candida bloodstream infection), Candida intertrigo, candidiasis (yeast infection), coccidioidomycosis (valley fever), cryptococcosis, dermatophytosis, 15 histoplasmosis, mucormycosis, paracoccidioidomycosis, sporotrichosis, tinea capitis (scalp ringworm), tinea corporis (ringworm), tinea cruris (jock itch), tinea pedis (athlete’s foot), and tinea versicolor (pityriasis versicolor). Embodiment 27 provides the method of any one of Embodiments 19-23, wherein the subject is a crop and / or a plant. 20 Embodiment 28 provides the method of Embodiment 27, wherein the crop or plant is selected from the group consisting of almonds, apples, avocados, barley, bananas, beans, blueberries, broccoli, cabbage, carrots, cassava, cherries, chickpeas, citrus fruits, coffee, corn, cotton, cucumbers, eggplants, grapes, lettuce, mangoes, melons, oats, onions, oranges, papayas, peaches, peanuts, pears, peppers, pineapples, potatoes, pumpkins, quinoa, 25 raspberries, rice, rye, sorghum, soybeans, spinach, squash, strawberries, sugarcane, sweet potatoes, tea, tobacco, tomatoes, watermelons, wheat, and yams. Embodiment 29 provides the method of Embodiment 27 or 28, wherein the fungal infection is selected from the group consisting of Magnaporthe grisea, Magnaporthe spp. (blast diseases), Plasmopara viticola (downy mildew), Erysiphe necator (powdery mildew), 30 Botrytis cinerea (grey mold), Guignardia bidwellii (black rot), Venturia inaequalis (apple scab), Venturia pirina (pear scab), Ustilago maydis (corn smut), Ustilago tritici (wheat smut), Ustilago hordei (barely smut), Ustilago spp., Puccinia graminis f. sp. tritici (wheat stem rust), Claviceps purpurea (ergot), Hemileia vastatrix (coffee rust), Phakopsora pachyrhizi (soybean rust). - 107 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) Embodiment 30 provides the method of any one of Embodiments 19-29, wherein the compound is administered by a route selected from the group consisting of oral, topical, inhalation, aerosol, intravenous injection, intramuscular injection, and subcutaneous injection. 5 Embodiment 31 provides the method of any one of Embodiments 19-30, wherein the subject is further administered at least one additional antifungal agent. Embodiment 32 provides the method of Embodiment 31, wherein the at least one compound and the at least one additional antifungal agent are coadministered. Embodiment 33 provides the method of Embodiment 31 or 32, wherein the at least 10 one compound and the at least one additional antifungal agent are coformulated. Embodiment 34 provides the method of any one of Embodiments 25-27, wherein the at least one antifungal agent is selected from the group consisting of allylamines, amphotericin B, amphotericin B liposomal, anidulafungin, azoxystrobin, beanomicins, bifonazole, binapacryl, blasticidin-S, boscalid, cancidas, carboxin, caspofungin, clotrimazole, 15 cyazofamid, echinocandins, econazole, fenpropimorph, fenticonazole, fludioxonil, fluconazole, hexaconazole, ibrexafungerp, imazalil, isavuconazole, isoconazole, itraconazole, kasugamycin, ketoconazole, lucensomycin, micafungin, miconazole, myclobutanil, natamycin, nikkomycins, nystatin, olorofim, oxiconazole, phenpropimorph, piroctone, posaconazole, pradimicins, procymidone, propamocarb, propiconazole, pydiflumetofen, 20 pyrazophos, pyrimethanil, ravuconazole, rezafungin, sertaconazole, sordarins, sulconazole, tecnazene, terconazole, thioconazole, triclosan, and voriconazole. Embodiment 35 provides the method of any one of Embodiments 19-26 and 30-34, wherein the compound is administered orally. Embodiment 36 provides the method of any one of Embodiments 19-26 and 30-35, 25 wherein the subject is immunocompromised and / or immunosuppressed. Embodiment 37 provides a method of reducing or inhibiting splicing of a group I intron in a cell, the method comprising administering to the cell an effective amount of at least one compound of any one of Embodiments 1-17 or the pharmaceutical composition of Embodiment 18. 30 Embodiment 38 provides the method of Embodiment 37, wherein the group I intron is a group IA1, IB, or ID intron. Embodiment 39 provides the method of Embodiment 38, wherein the IA1 intron is positioned in a mtLSU, cytb, or cox1 gene. Embodiment 40 provides the method of any one of Embodiments 37-38, wherein - 108 - 55862232.4 Attorney Docket No.047162-7508WO1(02676) gene function of the cell is controlled. Embodiment 41 provides the method of any one of Embodiments 37-40, wherein gene expression and / or translation of the cell is controlled. Embodiment 42 provides the method of Embodiment 41, wherein control of gene 5 expression comprises altering the amount of functional mRNA transcript. The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present 10 application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application. - 109 - 55862232.4

Claims

Attorney Docket No.047162-7508WO1(02676) CLAIMS What is claimed is:

1. A compound of Formula (I), or a salt, stereoisomer, tautomer, or isotopologue thereof: I), wherein: X1is CR3aor N;X2is CR3bor N; X3is CR3cor N; X4is CR3d, C(R3d)(R3e), or N; wherein at least one of X1, X3, and X4is N, or X2is N; L is a bond or -(optionally substituted C1-C3 alkylenyl)-; Y is N(R1b) or S; R1aand R1b, if present, are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted C2-C8heterocycloalkyl, wherein R1aand R1bcan combine with the nitrogen atom to which they are bound to form an optionally substituted C2-C8heterocycloalkyl, and wherein one of R1aand R1bcan combine with one of R3a, R3d, or R3eto form an optionally substituted C2-C8heterocycloalkyl or optionally substituted C2-C8 heteroaryl; R2ais selected from the group consisting of H, halogen, optionally substituted C1-C6alkyl, optionally substituted C2-C8 heterocycloalkyl, ORA, CN, and NO2, or R2acan combine with R3dto form an optionally substituted C2-C8heteroaryl; R2b, if present, is H; R3ais selected from the group consisting of H and optionally substituted C1-C6 alkyl; R3bis selected from the group consisting of H, halogen, optionally substituted C1-C6alkyl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=OB, CN, and NO2,- 110 - 55862232.4Attorney Docket No.047162-7508WO1(02676) R3bcan combine with R3cto form an optionally substituted C2-C8 heteroaryl; R3cis selected from the group consisting of H and N(RA)(RB), or R3ccan combine with R3bto form an optionally substituted C2-C8heteroaryl; R3dand R3e, if present, are each independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, CN, and NO2, or C2-C8heterocycloalkyl or optionally substituted C2-C8 heteroaryl; bond a is a single bond or a double bond, and one of the following applies: bond a is a single bond, X4is C(R3d)(R3e), and R2aand R2bare present, or bond a is a double bond, X4is CR3dor N, and R2bis absent; each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl.

2. The compound of claim 1, wherein Y is NR1b.

3. The compound of claim 1 or 2, wherein L is selected from the group consisting of a bond and optionally substituted C1alkylenyl.

4. The compound of any one of claims 1-3, which is selected from the group consisting of: c),55862232.4Attorney Docket No.047162-7508WO1(02676) , Ii), Il), whereinR4aand R4b, if present, are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, halogen, CN, NO2, ORC, N(RC)(RD), C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), and S(=O)2ORC; R5, if present, is selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl; R6a, R6b, R6c, and R6d, if present, are each independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl; each occurrence of RCand RDis independently selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl.

5. The compound of claim 4, wherein at least one of the following applies: (a) at least one of R4aand R4bis H; - 112 - 55862232.4Attorney Docket No.047162-7508WO1(02676) (b) both of R4aand R4bare H; (c) R5is H; (d) at least one of R6a, R6b, R6c, and R6dis H; (e) at least two of R6a, R6b, R6c, and R6dare H; (f) at least three of R6a, R6b, R6c, and R6dare H; and (g) each of R6a, R6b, R6c, and R6dare H.

6. The compound of any one of claims 1-5, wherein at least one of the following applies: (a) R1aand R1bare each independently selected from the group consisting of H and C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, phenyl, CN, NO2, NRIRII, ORI, C(=O)RI, C(=O)ORI, C(=O)NRIRII, C(=NRI)NRIIRIII, wherein each occurrence of RI, RII, and RIIIis independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10aryl, and C2-C8heteroaryl; and (b) R1aand R1bare each independently C1-C6 alkyl optionally substituted with at least one , wherein:each occurrence of Z1is independently selected from the group consisting of -O-, -NRI-, -C(=O)-, -S-, and C1-C6 alkylenyl optionally substituted with RIor C(=O)ORI; (ii) each occurrence of R7ais independently selected from the group consisting of H, C1-C6alkyl, C(=O)ORI, and C2-C8heteroaryl optionally substituted with C1-C6 alkyl; (iii) m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein each occurrence of RIis independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10 aryl, and C2-C8 heteroaryl.

7. The compound of any one of claims 1-6, wherein R1aand R1bare each independently selected from the group consisting of: H, -CH3, -(CH2)CN, -(CH2)Ph, -(CH2)C(=NH)NH2, -(CH2)2NH2, -(CH2)2OH, - (CH2)CH(CH3)NH2, -(CH2)C(CH3)2NH2, -(CH2)2NHCH3, -(CH2)3NH2, -(CH2)4NH2, - 113 - 55862232.4Attorney Docket No.047162-7508WO1(02676) ,8. The compound of any one of claims 1-7, wherein at least one of the following applies: (a) R1aand R1bcombine with the N atom to which they are bound to form a C2-C8- 114 - 55862232.4Attorney Docket No.047162-7508WO1(02676) heterocycloalkyl, wherein the C2-C8 heterocycloalkyl is optionally substituted with N(RIV)(RV), ORIV, -(CH2)1-3N(RIV)(RV), -(CH2)1-3ORIV, N(RIV)C(=O)ORIV, N(RIV)C(=NRV)N(RVI)(RVII), C(=O)RIV, C(=O)ORIV, C(=NRIV)N(RV)(RVI), wherein each occurrence of RIV, RV, RVI, and RVIIis independently H, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10 aryl, and C2-C8 heteroaryl, and wherein each occurrence of C1-C6 alkyl in RIV, RV, RVI, and RVIIis independently optionally substituted with at least one selected from the group consisting of NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C(=O)O(C1-C6 alkyl), and C6-C10aryl; and (b) R1aand R1bcombine with the N atom to which they are bound to form a C2-C8 heterocycloalkyl, wherein the C2-C8heterocycloalkyl is optionally substituted with , wherein: each occurrence of Z2is independently selected from the groupconsisting of -O-, -NRIV-, -C(=O)-, -S-, and C1-C6alkylenyl optionally substituted with RIVor C(=O)ORIV; (ii) each occurrence of R7bis independently selected from the group consisting of H, C1-C6 alkyl, C(=O)ORI, and C2-C8 heteroaryl optionally substituted with C1-C6alkyl; (iii) n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein each occurrence of RIVis independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10 aryl, and C2-C8 heteroaryl.

9. The compound of any one of claims 1-8, wherein R1aand R1bcombine with the N atom to which they are bound to form a moiety selected from the group consisting of: ,55862232.4Attorney Docket No.047162-7508WO1(02676) , , , ,- 116 - 55862232.4Attorney Docket No.047162-7508WO1(02676) and10. The compound of any one of claims 1-9, wherein R2ais selected from the group consisting of H, OH, and Cl.

11. The compound of any one of claims 1-10, wherein R2bis H.

12. The compound of any one of claims 1-11, wherein R3ais H.

13. The compound of any one of claims 1-12, wherein at least one of the following applies: (a) R3bis selected from the group consisting of H, NH2, NH(C1-C6 alkyl), NO2, and C(=NH)NH2; and (b) R3bis , wherein:rrence of Z3is independently selected from the group consisting of -O-, -NRVIII-, -C(=O)-, -S-, and C1-C6alkylenyl optionally substituted with RVIIIor C(=O)ORVIII; (ii) each occurrence of R7cis independently selected from the group consisting of H, C1-C6 alkyl, C(=O)ORVIII, and C2-C8 heteroaryl optionally substituted with C1-C6 alkyl; (iii) o is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; - 117 - 55862232.4Attorney Docket No.047162-7508WO1(02676) wherein each occurrence of RVIIIis independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10aryl, and C2-C8 heteroaryl.

14. The compound of any one of claims 1-13, wherein R3bis selected from the group ,15. The compound of any one of claims 1-14, wherein R3cis H.

16. The compound of any one of claims 1-15, wherein R3dis selected from the group consisting of H, CH3, F, Br, NH2, NHC(=O)CH3, NHS(=O)2CH3, and (CH2)2S(=O)2CH3.

17. The compound of any one of claims 1-16, wherein the compound is selected from the group consisting of: N4-(2-methoxyethyl)-N4-methylpyrimidine-2,4-diamine; 4-(3-methoxypyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-methoxypyrrolidin-1-yl)pyrimidin-2-amine; (R)-4-(3-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-aminopyrrolidin-1-yl)pyrimidin-2-amine; (R)-4-(3-aminopyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-aminopyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-((3R,4S)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; - 118 - 55862232.4Attorney Docket No.047162-7508WO1(02676) 4-((3S,4R)-3-amino-4-methoxypyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-aminoazetidin-1-yl)pyrimidin-2-amine; 1-(2-aminopyrimidin-4-yl)pyrrolidin-3-ol; (R)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-ol; (S)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-ol; (3R,4S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; (3R,4S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; (3S,4S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; (3S,4R)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; (3R,4R)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3,4-diol; 4-morpholinopyrimidin-2-amine; 4-(4-(2-methoxyethyl)piperazin-1-yl)pyrimidin-2-amine; 4-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-amine; (R)-4-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-amine; N1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)-N1-methylethane-1,2-diamine; (S)-N1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)-N1-methylethane-1,2-diamine; (R)-N1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)-N1-methylethane-1,2-diamine; (1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)methanol; (S)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)methanol; (R)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)methanol; benzyl (1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; benzyl ((3S,4R)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; benzyl ((3S,4S)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; benzyl ((3R,4R)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; benzyl ((3R,4S)-1-(2-aminopyrimidin-4-yl)-4-methoxypyrrolidin-3-yl)carbamate; 4-(4-aminopiperidin-1-yl)pyrimidin-2-amine; 4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidin-2-amine; (R)-4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidin-2-amine; 4-(3-aminopiperidin-1-yl)pyrimidin-2-amine; (S)-4-(3-aminopiperidin-1-yl)pyrimidin-2-amine; (R)-4-(3-aminopiperidin-1-yl)pyrimidin-2-amine; 4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-2-amine; - 119 - 55862232.4Attorney Docket No.047162-7508WO1(02676) 4-((hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 4-((3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 4-((3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 4-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 4-((3aS,6aR)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-2-amine; 1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboxylic acid; (S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboxylic acid; (R) 1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboxylic acid; 4-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; (S)-4-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; 4-(4-methylpiperazin-1-yl)pyrimidin-2-amine; 6-((2-aminoethyl)(methyl)amino)pyrimidin-4-ol; 2-amino-6-((2-aminoethyl)(methyl)amino)pyrimidin-4-ol; N1-methyl-N1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)ethane-1,2-diamine; N6-(2-aminoethyl)-N6-methyl-9H-purine-2,6-diamine; N1-methyl-N1-(9H-purin-6-yl)ethane-1,2-diamine; N1-methyl-N1-(pyrimidin-4-yl)ethane-1,2-diamine; N1-methyl-N1-(2-nitropyridin-4-yl)ethane-1,2-diamine; 5-(2-aminopyrimidin-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine; N4-(2-aminoethyl)-N4-methylpyrimidine-4,6-diamine; N2-(2-aminoethyl)-N2-methylpyrimidine-2,4-diamine; N4-methyl-N4-(2-(methylamino)ethyl)pyrimidine-2,4-diamine; 4-((2-aminoethyl)thio)pyrimidin-2-amine; N1-methyl-N1-(1H-pyrazolo[3,4-b]pyridin-6-yl)ethane-1,2-diamine; N4-(2-aminoethyl)-N2,N4-dimethylpyrimidine-2,4-diamine; N1-methyl-N1-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)ethane-1,2-diamine; 2-((2-aminopyrimidin-4-yl)(methyl)amino)acetonitrile; 2-((2-aminopyrimidin-4-yl)(methyl)amino)acetimidamide; N4-(3-aminopropyl)-N4-methylpyrimidine-2,4-diamine; N4-(4-aminobutyl)-N4-methylpyrimidine-2,4-diamine; N4-(2-aminoethyl)-6-chloro-N4-methylpyrimidine-2,4-diamine; N4-(2-aminoethyl)pyrimidine-2,4-diamine; 2-amino-3-((2-aminopyrimidin-4-yl)amino)propanoic acid; - 120 - 55862232.4Attorney Docket No.047162-7508WO1(02676) (S)-2-amino-3-((2-aminopyrimidin-4-yl)amino)propanoic acid; (R)-2-amino-3-((2-aminopyrimidin-4-yl)amino)propanoic acid; N4,N4-bis(2-aminoethyl)pyrimidine-2,4-diamine; N4-(2-aminoethyl)-N4-methylpyridine-2,4-diamine; N2-(2-aminoethyl)-N2-methyl-1,3,5-triazine-2,4-diamine; N5-(2-aminoethyl)-N5-methylpyridine-2,5-diamine; N-(2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoethyl)-N- methyl-glutamic acid; N-(2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoethyl)-N- methyl-D-glutamic acid; N-(2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoethyl)-N- methyl-L-glutamic acid; (2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoacetyl)-glutamic acid; (2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoacetyl)-D- glutamic acid; (2-(2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)-2-oxoacetyl)-L-glutamic acid; N4-(2-amino-2-methylpropyl)pyrimidine-2,4-diamine; N4-(2-aminopropyl)pyrimidine-2,4-diamine; (S)-N4-(2-aminopropyl)pyrimidine-2,4-diamine; (R)-N4-(2-aminopropyl)pyrimidine-2,4-diamine; 1-(((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)ethyl isobutyrate; (S)-1-(((2-((2-aminopyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)ethyl isobutyrate; (R)-1-(((2-((2-aminopyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamoyl)oxy)ethyl isobutyrate; 2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethan-1-ol; ((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)carbamoyl)glutamic acid; (S)-((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)carbamoyl)glutamic acid; (R)- ((2-((2-aminopyrimidin-4-yl)(methyl)amino)ethyl)carbamoyl)glutamic acid; N4-(2-aminoethyl)-5-fluoro-N4-methylpyrimidine-2,4-diamine; 4-(3-(aminomethyl)azetidin-1-yl)pyrimidin-2-amine; - 121 - 55862232.4Attorney Docket No.047162-7508WO1(02676) 1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)guanidine; (S)-1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)guanidine; (R)-1-(1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl)guanidine; N4-(3-amino-2,2-dimethylpropyl)pyrimidine-2,4-diamine; N4-(2-aminoethyl)-5-fluoro-N4-methylpyrimidine-2,4-diamine; ((2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)carbonyl)-glutamic acid; ((2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)carbonyl)-L-glutamic acid; ((2-((2-aminoethyl)(2-aminopyrimidin-4-yl)amino)ethoxy)carbonyl)-D-glutamic acid; 1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboximidamide; (R)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboximidamide; (S)-1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboximidamide; 4-(3-(aminomethyl)piperazin-1-yl)pyrimidin-2-amine; (R)-4-(3-(aminomethyl)piperazin-1-yl)pyrimidin-2-amine; (S)-4-(3-(aminomethyl)piperazin-1-yl)pyrimidin-2-amine; 2-((2-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- - 122 - 55862232.4Attorney Docket No.047162-7508WO1(02676) yl)(methyl)amino)ethyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4- yl)(methyl)amino)ethyl)carbamate; 2-((2-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl (2-((2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyridin-4- yl)(methyl)amino)ethyl)(methyl)carbamate; 2-((2-ethylhexyl)disulfaneyl)ethyl (1-(2-(((2-((2- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(S)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(S)- - 123 - 55862232.4Attorney Docket No.047162-7508WO1(02676) ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(S)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3S)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; 2-((2-(R)-ethylhexyl)disulfaneyl)ethyl ((3R)-1-(2-(((2-((2-(R)- ethylhexyl)disulfaneyl)ethoxy)carbonyl)amino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate; (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl methyl(2-(methyl(2-((((5-methyl-2-oxo-1,3- dioxol-4-yl)methoxy)carbonyl)amino)pyrimidin-4-yl)amino)ethyl)carbamate; 1-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridin-6-amine; N4-(3-aminobenzyl)pyrimidine-2,4-diamine; 7-(2-aminoethyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-2-amine; (R)-7-(2-aminoethyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-2-amine; (S)-7-(2-aminoethyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-2-amine; N4-(2-aminoethyl)-N4-methylpyrimidine-2,4,5-triamine; N-(2-amino-4-((2-aminoethyl)(methyl)amino)pyrimidin-5-yl)acetamide; N-(2-amino-4-((2-aminoethyl)(methyl)amino)pyrimidin-5-yl)methanesulfonamide; 4-((2-aminoethyl)(methyl)amino)pyrimidine-2-carboximidamide; 6-(2-aminoethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine; methyl 3-((1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4-yl)pyrrolidin-3- yl)oxy)propanoate; methyl (S)-3-((1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4-yl)pyrrolidin-3- yl)oxy)propanoate; methyl (R)-3-((1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4-yl)pyrrolidin-3- yl)oxy)propanoate; methyl 3-((4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; methyl 3-(((3R,4S)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; methyl 3-(((3S,4R)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; methyl 3-(((3R,4R)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- - 124 - 55862232.4Attorney Docket No.047162-7508WO1(02676) yl)pyrrolidin-3-yl)oxy)propanoate; methyl 3-(((3S,4S)-4-amino-1-(2-amino-5-(2-(methylsulfonyl)ethyl)pyrimidin-4- yl)pyrrolidin-3-yl)oxy)propanoate; 4-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine; N4-(2-aminoethyl)-N4-methylpyrimidine-2,4-diamine; N4-(2-aminoethyl)-N4-benzylpyrimidine-2,4-diamine; and N4-(2-aminoethyl)-5-bromo-N4-methylpyrimidine-2,4-diamine.

18. A pharmaceutical composition comprising the compound of any one of claims 1-17 and at least one pharmaceutically acceptable excipient.

19. A method of treating, preventing, and / or ameliorating a fungal infection in a subject, the method comprising administering to the subject a group I intron splicing inhibitor.

20. The method of claim 19, wherein the group I intron is a group IA1, IB, or ID intron.

21. The method of claim 20, wherein the IA1 intron is positioned in a mtLSU, cytb, or cox1 gene.

22. The method of any one of claims 19-21, wherein the group I intron splicing inhibitor is the compound of any one of claims 1-17 or the pharmaceutical composition of claim 18.

23. The method of any one of claims 19-22, wherein the fungal infection is caused by a fungus selected from the group consisting of Cryptococcus neoformans, Blastomyces dermatitidis, Cryptococcus gattii, Candida albicans, Candida auris, Candida krusei, Candida glabrata, Candida parapsilosis, Candida guilliermondii, Candida glabrata, Candida tropicalis, Candida lusitaniae, Coccidioides immitis, Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus niger, Aspergillus candidus, Aspergillus ochraceus, Pichia kudriavzevii, Rhizopus oryzae, Rhizopus spp., Histoplasma capsulatum, Coccidioides spp., Paecilomyces variotii, Pneumocystis murina, Pneumocystis jiroveci, Scedosporium spp., Sporotrix spp., and Aspergillus spp., or a combination thereof.

24. The method of any one of claims 19-23, wherein the subject is a mammal. - 125 - 55862232.4Attorney Docket No.047162-7508WO1(02676) 25. The method of claim 24, wherein the mammal is a human.

26. The method of claim 24 or 25, wherein the fungal infection is at least one selected from the group consisting of aspergillosis, blastomycosis, candidemia (Candida bloodstream infection), Candida intertrigo, candidiasis (yeast infection), coccidioidomycosis (valley fever), cryptococcosis, dermatophytosis, histoplasmosis, mucormycosis, paracoccidioidomycosis, sporotrichosis, tinea capitis (scalp ringworm), tinea corporis (ringworm), tinea cruris (jock itch), tinea pedis (athlete’s foot), and tinea versicolor (pityriasis versicolor).

27. The method of any one of claims 19-23, wherein the subject is a crop or plant.

28. The method of claim 27, wherein the crop or plant is selected from the group consisting of almonds, apples, avocados, barley, bananas, beans, blueberries, broccoli, cabbage, carrots, cassava, cherries, chickpeas, citrus fruits, coffee, corn, cotton, cucumbers, eggplants, grapes, lettuce, mangoes, melons, oats, onions, oranges, papayas, peaches, peanuts, pears, peppers, pineapples, potatoes, pumpkins, quinoa, raspberries, rice, rye, sorghum, soybeans, spinach, squash, strawberries, sugarcane, sweet potatoes, tea, tobacco, tomatoes, watermelons, wheat, and yams.

29. The method of claim 27 or 28, wherein the fungal infection is selected from the group consisting of Magnaporthe grisea, Magnaporthe spp. (blast diseases), Plasmopara viticola (downy mildew), Erysiphe necator (powdery mildew), Botrytis cinerea (grey mold), Guignardia bidwellii (black rot), Venturia inaequalis (apple scab), Venturia pirina (pear scab), Ustilago maydis (corn smut), Ustilago tritici (wheat smut), Ustilago hordei (barely smut), Ustilago spp., Puccinia graminis f. sp. tritici (wheat stem rust), Claviceps purpurea (ergot), Hemileia vastatrix (coffee rust), and Phakopsora pachyrhizi (soybean rust).

30. The method of any one of claims 19-29, wherein the compound is administered by a route selected from the group consisting of oral, topical, inhalation, aerosol, intravenous injection, intramuscular injection, and subcutaneous injection.

31. The method of any one of claims 19-30, wherein the subject is further administered at least one additional antifungal agent. - 126 - 55862232.4Attorney Docket No.047162-7508WO1(02676) 32. The method of claim 31, wherein the at least one compound and the at least one additional antifungal agent are coadministered.

33. The method of claim 31 or 32, wherein the at least one compound and the at least one additional antifungal agent are coformulated.

34. The method of any one of claims 25-27, wherein the at least one antifungal agent is selected from the group consisting of allylamines, amphotericin B, amphotericin B liposomal, anidulafungin, azoxystrobin, beanomicins, bifonazole, binapacryl, blasticidin-S, boscalid, cancidas, carboxin, caspofungin, clotrimazole, cyazofamid, echinocandins, econazole, fenpropimorph, fenticonazole, fludioxonil, fluconazole, hexaconazole, ibrexafungerp, imazalil, isavuconazole, isoconazole, itraconazole, kasugamycin, ketoconazole, lucensomycin, micafungin, miconazole, myclobutanil, natamycin, nikkomycins, nystatin, olorofim, oxiconazole, phenpropimorph, piroctone, posaconazole, pradimicins, procymidone, propamocarb, propiconazole, pydiflumetofen, pyrazophos, pyrimethanil, ravuconazole, rezafungin, sertaconazole, sordarins, sulconazole, tecnazene, terconazole, thioconazole, triclosan, and voriconazole.

35. The method of any one of claims 19-26 and 30-34, wherein the compound is administered orally.

36. The method of any one of claims 19-26 and 30-35, wherein the subject is immunocompromised and / or immunosuppressed.

37. A method of reducing or inhibiting splicing of a group I intron in a cell, the method comprising administering to the cell an effective amount of at least one compound of any one of claims 1-17 or the pharmaceutical composition of claim 18.

38. The method of claim 37, wherein the group I intron is a group IA1, IB, or ID intron.

39. The method of claim 38, wherein the IA1 intron is positioned in a mtLSU, cytb, or cox1 gene. - 127 - 55862232.4Attorney Docket No.047162-7508WO1(02676) 40. The method of any one of claims 37-38, wherein gene function of the cell is controlled.

41. The method of any one of claims 37-40, wherein gene expression and / or translation of the cell is controlled.

42. The method of claim 41, wherein control of gene expression comprises altering the amount of functional mRNA transcript. - 128 - 55862232.4

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