Bis-amidine compounds and salts thereof and methods of using same

Abstract

The disclosure relates, in part, to certain amidine-substituted antifungal compounds and methods of use thereof for treating, preventing, and / or ameliorating fungal infections.

Description

[0001] Attorney Docket No. 047162-7534WOl(02797)

[0002] TITLE OF THE INVENTION

[0003] Bis-Amidine Compounds and Salts Thereof and Methods of Using Same

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U. S. C. § 119(e) to U. S. Provisional Patent Application No. 63 / 748,571. filed January 23, 2025, which is incorporated herein by reference in its entirety.

[0005] BACKGROUND

[0006] Fungal infections are a ubiquitous issue in global health care. The widespread use of a limited selection of antifungal agents has led to the emergence of drug-resistant fungal strains in clinical settings. Compounds within these common antifungal classes, such as the echinocandins, azoles, and polyenes, share well established mechanisms of actions and acquired resistances, which lead to cross-resistance issues.

[0007] There is thus a need in the art for antifungal agents with novel mechanisms of action to address the mounting threat of drug-resistant fungi. The present disclosure addresses this need.

[0008] BRIEF SUMMARY OF THE INVENTION

[0009] In one aspect, the disclosure provides a compound of formula (I), or a salt, stereoisomer, or isotopologue thereof, wherein R1a, R1b, X1, X2, L1, L2, and A are defined elsewhere herein:

[0010] R1a-X1-L1-A-L2-X2— R1b(I)..

[0011] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure and at least one pharmaceutically acceptable excipient.

[0012] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a microbial infection in a subject. In certain embodiments, the method comprises administering to the subject at a therapeutically effective amount of at least one compound of the disclosure of a pharmaceutical composition thereof. In certain embodiments, the method comprises administering to the subject at a therapeutically effective amount of 4,4'-((piperidine-l,4-diylbis(propane-3,l-diyl))bis(oxy))dibenzimidamide or a pharmaceutical composition thereof.Attorney Docket No. 047162-7534WOl(02797)

[0013] BRIEF DESCRIPTION OF THE FIGURES

[0014] The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application.

[0015] FIGs. 1 A-1G: synthetic schemes showing the preparation of certain exemplary compounds of the disclosure: 1-34 (FIG. 1A), 1-74 (FIG. IB), 1-139 (FIG. 1C), 1-143 (FIG. ID), 1-183 and 184 (FIG. IE), 1-152 (FIG. IF), and 1-54 (FIG. 1G).

[0016] FIG. 2: P. capsici mycelial growth on V8 plates 2 days after plating.

[0017] FIG. 3: P. capsici mycelial growth on V8 plates 5 days after plating.

[0018] FIG. 4: Images of Big Jim pepper leaves after administration of compounds or control, wherein compound Z3 showed no toxicity at the vegetative state. Kanamycin: 343 pM (200 pg / mL); Z3 HD: 343 pM; Z3 LD: 34.3 pM. Dose at day 1, 4. 8, and 12.

[0019] FIG. 5: Images of leaves after administration of compounds or control; Botyritis lesions on Chili (10237) pepper was absent or strongly reduced with administration of T2307 (Zl; 200 pg / mL) at 3 days post-inoculum (dpi).

[0020] FIG. 6: Graph quantifying qualitative data presented in FIG. 4. Plants treated with T2307 (Zl) show reduced fungal infection. B. cinerea infection progress after 2307 compound spray, co-inoculation or mock treatments. Box plots represent the mean of necrotic areas measured 3 days post-inoculum (dpi) with imageJ. Statistically significant differences are indicated with asterisks (One-way ANOVA: P<0.05).

[0021] FIG. 7: Images of leaves after administration of compounds or control; Botyrtis lesions on Chili (10237) pepper were absent or strongly reduced with administration of T2307 (Zl; 200 pg / mL) at 10 days post-inoculum (dpi).

[0022] FIG. 8: Images of Lumbre pepper leaves after administration of compounds or control at 4 dpi. Botyrtis lesions on Lumbre pepper leaves were absent or strongly reduced with administration of T2307 (Zl; 200 pg / mL), which showed better efficacy than the positive control.

[0023] FIG. 9: Images of Lumbre pepper leaves after administration of compounds or control at 8 dpi. Botyrtis lesions on Lumbre pepper leaves were significantly and dose-dependently reduced with administration of T2307 (Zl).

[0024] FIG. 10: Images of Lumbre pepper leaves after administration of compounds or control at 8 dpi. Boty rtis lesions on Lumbre pepper leaves w ere significantly reduced with Z2, Z3, Z4, Z5, Z25, or Z8 pre-treatment.Attorney Docket No. 047162-7534WOl(02797)

[0025] FIG. 11: Images of Lumbre pepper leaves after administration of compounds or control at 8 dpi. Botyrtis lesions on Lumbre pepper leaves were significantly reduced with Z12, Z14, or Z15 pre-treatment.

[0026] FIG. 12: Images of tomato leaves after administration of compounds or control at 2, 3, or 4 dpi. Botyrtis lesions on tomato leaves were significantly reduced with T2307 pre- and post-treatment. Species: Solanum lycopersicum Age: 4 weeks old; T2307 (Zl): 200 pg / mL; controls: sprayed with MilliQ water with 0.1% Tween20; Pre-treated: sprayed with T2307 in MilliQ water + 0.1% Tween20; and Post-treated: sprayed with T2307 in MilliQ water + 0.1% Tween20.

[0027] FIG. 13: Representative scheme for the synthesis of compounds of the disclosure. FIG. 14: Scheme depicting synthesis of compound (±)-Z8.

[0028] FIG. 15: Scheme depicting synthesis of compound (±)-Z9.

[0029] FIG. 16: Scheme depicting synthesis of compound (±)-Z10.

[0030] FIG. 17: Scheme depicting synthesis of compound (±)-Zll.

[0031] FIG. 18: Scheme depicting synthesis of compound (±)-Z12.

[0032] FIG. 19: Scheme depicting synthesis of compound (±)-Z13 and (±)-Z14.

[0033] FIG. 20: Scheme depicting synthesis of compound (±)-Z15.

[0034] FIG. 21: Scheme depicting synthesis of compound (±)-Z16.

[0035] FIG. 22: Scheme depicting synthesis of compound (±)-Z17.

[0036] FIG. 23: Scheme depicting synthesis of compound (±)-Z18.

[0037] FIG. 24: Scheme depicting synthesis of compound (±)-Z19.

[0038] FIG. 25: Scheme depicting synthesis of compound (±)-Z20.

[0039] FIG. 26: Scheme depicting synthesis of compound (±)-Z21.

[0040] FIG. 27: Scheme depicting synthesis of compound (±)-Z22 and (±)-Z23.

[0041] FIG. 28: Scheme depicting synthesis of compound (±)-Z25.

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] 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 be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0044] 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 ofAttorney Docket No. 047162-7534WOl(02797)

[0045] the range, but also to include all the individual numerical values or sub-ranges encompassed 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 notjust 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 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.

[0046] 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 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 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.

[0047] 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 conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0048] Description

[0049] Fungal infections are a significant global health concern, exacerbated by drugresistant strains arising from the limited diversity of antifungal agents. New antifungal drugs with novel mechanisms of action are urgently needed to combat this growing issue.

[0050] T-2307 is a novel bis-ary lamidine antifungal agent demonstrating broad and potent activity against many pathogenic yeasts and filamentous fungi. T-2307 hyperaccumulates in fungal cells through poly amine transporter mediated uptake. Additional potency is gained through further hyperaccumulation of compound in the fungal mitochondria, the putativeAttorney Docket No. 047162-7534WOl(02797)

[0051] target of T-2307. T-2307 is known to reduce in vivo fungal burden in multiple animal models and pathogens. Additionally, T-2307 has reportedly passed a phase one clinical trial.

[0052] In one aspect, the disclosure relates to the design, synthesis, and evaluation of T-2307 analogues for use as antifungal agents. Certain exemplary compounds of the disclosure demonstrate high activity' against C. parapsilosis, and / or C. albicans. In certain embodiments, the compounds of the disclosure provide comparable and / or improved antifungal activity over compound T-2307 while potentially offering greater potency and more favorable absorption, distribution, metabolism, and excretion (ADME) profiles.

[0053] Definitions

[0054] The term “about’7as used herein can allow for a degree of variability in a value or 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.

[0055] 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.

[0056] Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3). -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl. pentadienyl, and hexadienyl among others.

[0057] 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 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 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.

[0058] The term “alkyl” as used herein refers to straight chain and branched alkyl groups and 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 alkylAttorney Docket No. 047162-7534WOl(02797)

[0059] 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, 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 halogen groups.

[0060] The term “alkylene” or “alkylenyl” as used herein refers to a bivalent saturated aliphatic radical (e.g., -CH2-, -CH2CH2-, and -CH2CH2CH2-, inter alia). In certain embodiments, the term may be regarded as a moiety derived from an alkene by opening of the double bond or from an alkane by removal of two hydrogen atoms from the same (e.g.. -CH2-) different (e.g., -CH2CH2-) carbon atoms.

[0061] 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, alky nyl 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 -C =CH. -C≡C(CH3), -C=C(CH2CH3). -CH2C≡CH, -CH2OC(CH3), and -CH2C^C(CH2CH3) among others.

[0062] 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, azulenyl, heptalenyl, biphenyl, indaceny 1, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chryseny 1, 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 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.

[0063] The term “crop” as used herein encompasses any desired plant growth.

[0064] The term “cycloalkyl” as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cy clobutyl, cyclopentyd, cyclohexyl, cyclohepty l, and cy clooctyl 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.Attorney Docket No. 047162-7534WOl(02797)

[0065] Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbomyl, adamantyl, bomyl, 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, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbomyl 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.

[0066] The term “cycloalkylene” or “cycloalkylenyl” as used herein refers to a bivalent saturated cycloalkyl radical (e.g, A, V,

[0067]

[0068] U, and '" '", inter alia). In certain embodiments, the term may be regarded as a product of removal of two hydrogen atoms from the corresponding cycloalkane (e.g., cyclobutyl) by removal of two hydrogen atoms from the same (e.g, different (e.g. tZf and ’ ) carbon atoms.

[0069] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.

[0070] 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 further decrease in the animal's state of health.

[0071] A disease or disorder is “ameliorated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.

[0072] 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. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0073] 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, orAttorney Docket No. 047162-7534WOl(02797)

[0074] iodine atom.

[0075] The term “haloalkyl” group, as used herein, includes mono-halo alkyl groups, polyhalo 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-di chloroethyl, l,3-dibromo-3,3-difluoropropyl. perfluorobutyl, and the like.

[0076] The term "heteroanT’ 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, heteroary l 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 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.

[0077] 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 as pyrrolyl. pyrazolyl, triazolyl, tetrazolyl. oxazolyl, isoxazolyl, thiazolyl, pyndinyl, 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 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.

[0078] Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2 -thieny l, 3-thienyl), furyl (2 -fur l, 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-l-yl, l,2,3-triazol-2-yl l,2,3-triazol-4-yl, l,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-Attorney Docket No. 047162-7534WOl(02797)

[0079] quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1 -isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-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-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-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-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 -y 1, 5H-dibenz[b,f] azepine-2-y 1,

[0080] 5H-dibenz[b.f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f|azepine-5-yl), 10.1 l-dihydro-5H-dibenz[b.f| azepine (10.1 l-dihydro-5H-dibenz[b.f] azepine- 1-yl,

[0081] 10.1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,1 l-dihydro-5H-dibenz[b,f|azepine-3-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

[0082] 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 group as defined herein.

[0083] The term “heteroarylene'’ or “heteroarylenyl” as used herein refers to a bivalent heteroaryl radical (e.g., 2,4-pyridylene). In certain embodiments, the term may be regarded as a divalent radical formed by the removal of two hydrogen atoms from one or more rings of a heteroaryl moiety, wherein the hydrogen atoms may be removed from the same or different rings, preferably the same ring.

[0084] The term “heterocycloalkyr' as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems where at least one of the carbon atoms of the ring is replacedAttorney Docket No. 047162-7534WOl(02797)

[0085] with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. A heterocycloalkyl can include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom can be optionally substituted. Representative heterocycloalkyl groups include, but are not limited, to the following exemplary groups: pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl. piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. The term heterocycloalkyl group can also be a C2 heterocycloalkyl, C2-C3 heterocycloalkyl, C2-C4 heterocycloalkyl, C2-C5 heterocycloalky l. C2-C6 heterocycloalkyl, C2-C7 heterocycloalkyl, C2-C8 heterocycloalkyl, C2-C9 heterocycloalky l, C2-C10 heterocycloalkyl, C2-C11 heterocycloalkyl, and the like, up to and including a C2-I45 heterocycloalkyl. For example, a C2heterocycloalkyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocycloalky l comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to. piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, and the like. It is understood that a heterocycloalkyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocycloalkyl ring. The heterocycloalkyl group can be substituted or unsubstituted.

[0086] The term “heterocycloalkylene?’ or “heterocycloalkylenyl" as used herein refers to a H I

[0087] bivalent saturated cycloalkyl radical (e.g., _ / , _ / ,

[0088]

[0089] . and \ — / , inter alia). In certain embodiments, the term may be regarded as a product of removal of two hydrogen atoms from the corresponding heterocycloalkane (e.g., piperidine) by removal of two hydrogen atoms from the same (e.g., -'JDNH) different (e.g.,

[0090]

[0091] and " I / N) carbon atom(s) and / or heteroatom(s).

[0092] The term “heterocyclyf’ 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 poly cy clic, any combination thereof. In some embodiments, heterocyclyl 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 heteroatomsAttorney Docket No. 047162-7534WOl(02797)

[0093] 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 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 (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, 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 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.

[0094] 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 molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups.

[0095] 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-Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (Ci-C4)hydrocarbyl means the hydrocarbyl group can be methyl (Ci), ethyl (C2), propyl (C3). or butyl (C4), and (Co-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group.

[0096] The term “independently selected from” as used herein refers to referenced groups 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, whereAttorney Docket No. 047162-7534WOl(02797)

[0097] X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations.

[0098] 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 described herein. In a non-limiting embodiment, the patient, subject or individual is a human.

[0099] 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 of the components of the composition in w hich it is contained.

[0100] 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.

[0101] 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, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, aceturic, 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), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, ^-hydroxy butyric. salicylic, galactaric and galacturonic acid.

[0102] Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline 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 reacting, for example, the appropriate acid or base with the compound.Attorney Docket No. 047162-7534WOl(02797)

[0103] 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 transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such compounds 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 of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose: starches, such as com 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, com oil and 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 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 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. PA), which is incorporated herein by reference.

[0104] The term “ring-member” as used herein refers to an atom that forms part of the closed loop in a cyclic structure, contributing to the connectivity of the ring. In the context of a monocyclic heterocycloalkyl substituent (e.g., 1-trifluoromethyl-piperidine), each of the five carbon atoms and the nitrogen atom of the piperidine ring comprise a “ring-member” atom, whereas all atoms of the trifluoromethyl substituent, and all hydrogen atoms, are not “ring-Attorney Docket No. 047162-7534WOl(02797)

[0105] member’' atoms, as these atoms do not form part of the ring structure.

[0106] 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 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 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%.

[0107] 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 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 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 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)O-2N(R)C(O)R, (CH2)O-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, (Ci-C100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, orAttorney Docket No. 047162-7534WOl(02797)

[0108] 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.

[0109] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.

[0110] The terms “treat,” “treating” and “treatment,” as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject.

[0111] Compounds

[0112] In one aspect, the disclosure provides a compound of formula (I), or a salt, stereoisomer, or isotopologue thereof:

[0113] R1a-X1-L1-A— L2-X2— R1b(I)wherein:

[0114] A is selected from the group consisting of optionally substituted C2-C8 monocyclic heterocycloalkylenyl, optionally substituted C3-C12 bicyclic heterocycloalkylenyl. and optionally substituted C3-C8 aminocycloalkylenyl,

[0115] wherein the monocyclic heterocycloalkyl in A comprises at least two ring-member nitrogen atoms:

[0116] Rlaand Rlbare each independently selected from the group consisting of Ce-Cio aryl and C2-C10 heteroaryl,

[0117] wherein each Ce-Cio aryl and C2-C10 heteroaryl is substituted with at least one C(=NRB)N(RC)(RD) substituent, and

[0118] wherein each Ce-Cio aryl and C2-C10 heteroaryl is optionally further substituted; L1and L2are each independently selected from the group consisting of Ci-Ce alkylenyl, optionally substituted C2-C6 heteroalkylenyl, and a bond;

[0119] X1and X2are each independently selected from the group consisting of -O-, -S-, and -N(RA);

[0120] each occurrence of RAis independently selected from the group consisting of H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C8 heteroaryl, C(=NRB)N(RC)(RD), C(=O)RB, C(=O)ORB, C(=O)N(RB)(RC), S(=O)RB, S(=O)2RC, S(=O)N(RB)(RC),

[0121]

[0122] S(=O)2N(RB)(RC), and P(=O)(ORB)(ORC);Attorney Docket No. 047162-7534WOl(02797)

[0123] each occurrence of RB, RC, and RDis independently selected from the group consisting of H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally- substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heteroaryl, C(=O)(RE), C(=O)ORE, C(=O)N(RE)(RF), S(=O)RE, S(=O)2RE, S(=O)N(RE)(RF), S(=O)2N(RE)(RF), and P(=O)(ORE)(ORF). or wherein RBand one of RCand RDcan combine with the atoms to which they are bound to form an optionally substituted C2-C5 heterocycloalkyl; and each occurrence of REand RFis independently selected from the group consisting of H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted Ce-Cio aryl.

[0124] In certain embodiments, the compound is not 4,4'-((piperidine-l,4-diylbis(propane-3,l-diyl))bis(oxy))dibenzimidamide.

[0125] In certain embodiments,1indicates a bond between X1and L1.

[0126] In certain embodiments, " indicates a bond between A and L2.

[0127] In certain embodiments, A is selected from the group consisting of

[0128]

[0129] wherein:

[0130] each occurrence of R2and R’ is independently selected from the group consisting of halogen, optionally substituted C i-Ce alkyl, optionally substituted C i-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-Cs heterocycloalkyl, optionally substituted Ce-Cio aryl, and optionally substituted C2-C8 heteroaryl;

[0131] each occurrence of R4is independently selected from the group consisting of halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted Ce-Cio aryl, and optionally substituted C2-C8 heteroaryl;

[0132] each occurrence of I is independently 0, 1, or 2;

[0133] each occurrence of m is independently 0, 1, 2, or 3;Attorney Docket No. 047162-7534WOl(02797)

[0134] each occurrence of / ? is independently 0, 1, 2, 3, 4. or 5;

[0135] each occurrence of o is independently 0. 1, 2, 3, 4, 5, or 6;

[0136] each occurrence of p is independently 0, 1, 2, 3, 4, 5, 6, or 7;

[0137] each occurrence of q is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0138] each occurrence ofr is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0139] each occurrence of 5 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

[0140] In certain embodiments, substitution of a ring system is depicted by showing one or more instances of a substituent (e.g., r instances of R2, or (R2)r) connected to a bond of a ring RAI

[0141] N...

[0142] system (

[0143]

[0144] e.g. ). In such embodiments, each of the r occurrences of R2may substitute any of the hydrogen atoms of the depicted ring. For example, where r is 10,

[0145]

[0146] In certain embodiments, where the substituted moiety comprises a spirocyclic moiety, the one or more instances of a substituent thereof are limited to the ring to which the bond is

[0147] indicated. For example, for spirocyclic moiety

[0148]

[0149] ring A (z.e., left ring) may be substituted with o instances of R2, whereas ring B (z.e., nght ring) may be substituted with o instances of R3.

[0150] In certain embodiments, where the substituted moiety comprises a fused ring system, the one or more instances of a substituent thereof are limited to the ring to the unfused portion of the ring to which the bond is indicated and one of the fused carbon atoms, if

[0151] available. For example, for fused moiety

[0152]

[0153] , one embodiment wherein / is 1 and nAttorney Docket No. 047162-7534WOl(02797)

[0154] R2R2

[0155] N-- N--is 1 isr3, but no embodiments of include R2or

[0156] R3

[0157]

[0158] R3

[0159] In certain embodiments, A is

[0160]

[0161] In certain embodiments, A is

[0162] N-"- N-"-

[0163]

[0164] . In certain embodiments, A is

[0165]

[0166] . In certain embodiments.

[0167] H

[0168] N-"- T""7N-"_

[0169]

[0170] . In certain embodiments, A is H. In certain embodiments. A is

[0171] N-"-

[0172]

[0173] . In certain embodiments, A is

[0174]

[0175] . In certain embodiments, A is

[0176] N-'- N-"-. In certain embodiments, A is. In certain embodiments, A is

[0177] N-"-

[0178]

[0179] . In certain embodiments. A is

[0180] . In certain embodiments. A is

[0181] N-~

[0182]

[0183] . In certain embodiments, A is N„..

[0184] In certain embodiments, A is

[0185]

[0186] -. In certain embodiments, A is H H

[0187] Nv.,

[0188] ,.'N

[0189]

[0190] In certain embodiments, A is

[0191]

[0192] . In certain embodiments, A isAttorney Docket No. 047162-7534WOl(02797)

[0193] In certain embodiments, A is

[0194]

[0195] In certain embodiments, A is

[0196]

[0197] In certain embodiments,

[0198]

[0199] A is In certain embodiments, A is

[0200]

[0201] In certain embodiments, A is. In certain embodiments,

[0202]

[0203]

[0204] In certain embodiments, A is. In certain embodiments,

[0205] In certain embodiments, A is

[0206]

[0207] embodiments, A is ' In certain embodiments, A is. In certain

[0208] embodiments, A is

[0209]

[0210] In certain embodiments, A is

[0211]

[0212] embodiments, A is

[0213]

[0214] In certain embodiments. A is

[0215]

[0216] embodiments, A

[0217]

[0218] is

[0219] In certain embodiments, L1is a bond. In certain embodiments, L1is -(CH2)-. In certain embodiments, L1is -(CH2)2-. In certain embodiments, L1is -(CH2)3-. In certain embodiments, L1is -C(=O)-.Attorney Docket No. 047162-7534WOl(02797)

[0220] In certain embodiments, L2a bond. In certain embodiments, L2is -(CH2)-. In certain embodiments, L2is -(CH2)2- In certain embodiments. L2is -(CH2)3-. In certain embodiments, L2is -C(=O)-.

[0221] In certain embodiments, L1and L2are both -(CH2)3-. In certain embodiments, L1is a bond and L2is -(CH2)3-. In certain embodiments, L1is -(CH2)- and L2is -(CH2)3-. In certain embodiments, L1is -(CH2)2- and L2is -(CH2)3-. In certain embodiments, L1is -(CH2)3- and L2is -(CH2)3-. In certain embodiments, L1is -(CH2)- and L2is -(CH2)3-. In certain embodiments, L1is -(CH2)2- and L2is -(CH2)2-. In certain embodiments, L1is -(CH2)3- and L2is -C(=O)-.

[0222] In certain embodiments, X1is -O-. In certain embodiments, X1is -S-. In certain embodiments, X1is -NH-.

[0223] In certain embodiments, X2is -O-. In certain embodiments, X2is -S-. In certain embodiments, X2is -NH-.

[0224] In certain embodiments, Rlaand Rlbare each independently selected from the group consisting of:

[0225]

[0226] wherein:

[0227] each occurrence of R5 and R6, if present, is independently selected from

[0228] R7is C(=NR8)NH2;

[0229] R8is selected from the group consisting of H and S(=O)2(optionally substituted Ci-Ce alkyl);

[0230] each occurrence of t is independently 0, 1, 2, or 3;

[0231] each occurrence of u is independently 0, 1, 2, 3, or 4.

[0232] In certain embodiments, R8is H. In certain embodiments, R8is S(=O)2CH3.

[0233] In certain embodiments, R7is C(=N[S(=O)2CH3])NH2. In certain embodiments, R7is C(=NH)NH2.

[0234]

[0235] In certain embodiments, Rlais NH In certain embodiments. Rlais NH NH2

[0236]

[0237] . In certain embodiments, Rlais. In certainAttorney Docket No. 047162-7534WOl(02797)

[0238] NH NH2

[0239]

[0240] embodiments, Rlais

[0241]

[0242] certain embodiments. Rlais NH in

[0243] NH

[0244] MeO2

[0245]

[0246] certain embodiments, Rlais NH in certain embodiments, Rlais

[0247] NH2NH

[0248] Br2

[0249]

[0250] NH. in certain embodiments, Rlais NH. in certain embodiments,

[0251] NH2

[0252]

[0253] Rlais

[0254]

[0255] . In certain embodiments, Rlais NH in certain

[0256] NH2

[0257] embodiments,

[0258]

[0259] Rlais NH

[0260] NH2

[0261]

[0262] In certain embodiments, Rlbis NH. In certain embodiments, Rlbis NH NH2

[0263]

[0264] . In certain embodiments, Rlbis

[0265]

[0266] . In certain

[0267] NHNH2 NH H3C embodiments, Rlbis

[0268]

[0269] . In certain embodiments. Rlbis NH in

[0270] NH

[0271] MeO2

[0272]

[0273] certain embodiments, Rlbis NH in certain embodiments, Rlbis

[0274] NH

[0275] F2

[0276]

[0277] NH. in certain embodiments, Rlbis NH. in certain embodiments,Attorney Docket No. 047162-7534WOl(02797)

[0278]

[0279]

[0280] In certain embodiments. Rlbis NH In certain

[0281] embodiments, R

[0282]

[0283] lbis NH

[0284] In certain embodiments, each occurrence of optionally substituted alkyl, optionally substituted alkylenyl, optionally substituted heteroalkylenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylenyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroarylenyl, is independently optionally substituted with at least one substituent selected from the group consisting of Ci-Cs alkyl, Cs-Cs cycloalkyl, C2-C12 heterocycloalkyl, Ci-Ce hydroxyalkyl, halogen, CN, NO2 OR1, N(RI)(Rn), C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, aryl, heteroaryl, (C1-C6alkylenyl)C(=O)N(RI)(RII), (Ci-C6alkylenyl)C(=O)ORI, O(Ci-C3alkylenyl)C(=O)ORn, O(Ci-C3alkylenyl)C(=O)N(RI)(Rn). C(=O)RJ, C(=O)ORI, OC(=O)RI. 0C(=0)0RI, SR1, S(=O)RI. S(=O)2RI, S(=O)2N(RI)(R11). S(=O)2N

[0285]

[0286] RIC(=0)NHR11. N(RI)S(=0)2R11, N(RI)C(=0)Rn, and C(=0)NRIRn, wherein R1and Rnare each independently selected from the group consisting of H, -C(=O)(Ci-Ce alkyl), Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, C3-C8 cycloalkyl, C2-C12 heterocycloalkyl, C7-C12 aralkyl, aryl, and heteroaryl.

[0287] In certain embodiments, the compound is selected from the group consisting of: 4,4'-(((2,7-diazaspiro[4.4]nonane-2,7-diyl)bis(propane-3,l-diyl))bis(oxy))dibenzimidamide;

[0288] 4-(3-(5-(2-(4-carbamimidoylphenoxy)ethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)propoxy)benzimidamide;

[0289] 4-(3-((3aR.5r,6aS)-5-(2-(4-carbamimidoylphenoxy)ethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)propoxy)benzimidamide;

[0290] 4-(3-((3aR,5s,6aS)-5-(2-(4-carbamimidoylphenoxy)ethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)propoxy)benzimidamide;

[0291] 4,4'-(((3-azabicyclo[3.1.0]hexane-3,6-diyl)bis(propane-3,l-diyl))bis(oxy))dibenzimidamide;

[0292] 4,4'-((((lR,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-diyl)bis(propane-3,l-diyl))bis(oxy))dibenzimidamide;Attorney Docket No. 047162-7534WOl(02797)

[0293] 4,4'-((((lR,5S,6s)-3-azabicyclo[3.1.0]hexane-3,6-diyl)bis(propane-3,l-diyl))bis(oxy))dibenzimidamide:

[0294] 4-(3-(6-((4-carbamimidoylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide;

[0295] 4-(3-((lR,5S,6s)-6-((4-carbamimidoylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide;

[0296] 4-(3-((lR,5S,6r)-6-((4-carbamimidoylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide;

[0297] 4-(3-(2-((4-carbamimidoylphenoxy)methyl)-7-azaspiro[3.5]nonan-7-yl)propoxy)benzimidamide;

[0298] 3-((7-(3-(4-carbamimidoylphenoxy)propyl)-7-azaspiro[3.5]nonan-2-yl)methoxy)benzimidamide;

[0299] 4-(3-(6-((4-carbamimidoylphenoxy)methyl)-3,4-dihydroisoquinolin-2(lH)-yl)propoxy)benzimidamide;

[0300] 4-(3-(9-(4-carbamimidoylphenoxy)-3-azaspiro[5.5]undecan-3-yl)propoxy)-N'-(methylsulfonyl)benzimidamide;

[0301] (E)-4-(3-(9-(4-carbamimidoylphenoxy)-3-azaspiro[5.5]undecan-3-yl)propoxy)-N'-(methylsulfonyl)benzimidamide;

[0302] (Z)-4-(3-(9-(4-carbamimidoylphenoxy)-3-azaspiro[5.5]undecan-3-yl)propoxy)-N'-(methylsulfonyl)benzimidamide;

[0303] 4-(3-(4-(2-(4-carbamimidoylphenoxy)ethyl)azepan-l-yl)propoxy)benzimidamide;

[0304] (S)-4-(3-(4-(2-(4-carbamimidoylphenoxy)ethyl)azepan-l-yl)propoxy)benzimidamide; (R)-4-(3-(4-(2-(4-carbamimidoylphenoxy)ethyl)azepan-1-yl)propoxy)benzimidamide; 4-(3-(l-(4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)guanidino)propoxy)benzimidamide;

[0305] 4-(3-(l-((ls,4s)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)guanidino)propoxy)benzimidamide;

[0306] 4-(3-(l-((lr,4r)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)guanidino)propoxy)benzimidamide;

[0307] 4-(3-((4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)amino)propoxy)benzimidamide; 4-(3-(((ls,4s)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)amino)propoxy)benzimidamide;

[0308] 4-(3-(((lr,4r)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)amino)propoxy)benzimidamide;Attorney Docket No. 047162-7534WOl(02797)

[0309] 3-(3-(3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)propoxy)benzimidamide;

[0310] 3-(3-((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)propoxy)benzimidamide;

[0311] 3-(3-((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)propoxy)benzimidamide;

[0312] 3-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[0313] 3-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[0314] 3-(((1R,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[0315] 6-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2-naphthimidamide;

[0316] 6-(((lR,5S.6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2-naphthimidamide;

[0317] 6-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2-naphthimidamide;

[0318] 6-((4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)methyl)-3-(3-(4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)propyl)-3-azabicyclo[3.1.0]hexane;

[0319] (lR,5S,6r)-6-((4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)methyl)-3-(3-(4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)propyl)-3-azabicyclo[3.1.0]hexane;

[0320] (lR,5S.6s)-6-((4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)methyl)-3-(3-(4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)propyl)-3-azabicy clo[3.1.0]hexane;

[0321] 4-((3-(2-(4-carbamimidoylphenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[0322] 4-(((lR,5S,6r)-3-(2-(4-carbamimidoylphenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[0323] 4-(((lR,5S,6s)-3-(2-(4-carbamimidoylphenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[0324] 4-(2-(4-((2-(4-carbamimidoylphenoxy)ethyl)(methyl)amino)cyclohexyl)ethoxy)benzimidamide 4-(2-((lr,4r)-4-((2-(4-carbamimidoylphenoxy)ethyl)(methyl)amino)cyclohexyl)ethoxy)benzi midamide;Attorney Docket No. 047162-7534WOl(02797)

[0325] 4-(2-((lr,4s)-4-((2-(4-carbamimidoylphenoxy)ethyl)(methyl)amino)cyclohexyl)ethoxy)benzi midamide;

[0326] 4-(3-((4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzimidamide;

[0327] 4-(3-(((lr,4r)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzimidamide;

[0328] 4-(3-(((lr,4s)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzimidamide;

[0329] 4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-fluorobenzimidamide;

[0330] 4-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-fluorobenzimidamide;

[0331] 4-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-fluorobenzimidamide;

[0332] 3-(3-(4-carbamimidoylphenoxy)propyl)-N-(4-carbamimidoylphenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

[0333] (lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-N-(4-carbamimidoylphenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

[0334] (lR,5S.6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-N-(4-carbamimidoylphenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

[0335] 5-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)picolinimidamide;

[0336] 5-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)picolinimidamide;

[0337] 5-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)picolinimidamide;

[0338] 4-(((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzimidamide;

[0339] 4-((((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzimidamide;

[0340] 4-((((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzimidamide;

[0341] 4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methylbenzimidamide;Attorney Docket No. 047162-7534WOl(02797)

[0342] 4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methylbenzimidamide;

[0343] 4-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methylbenzimidamide;

[0344] 4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methoxybenzimidamide;

[0345] 4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methoxybenzi midamide;

[0346] 4-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methoxybenzimidamide;

[0347] 3-bromo-4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[0348] 3-bromo-4-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[0349] 3-bromo-4-(((1R,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[0350] 4-(2-(l-(3-(4-carbamimidoylphenoxy)propyl)azepan-4-yl)ethoxy)-3-fluorobenzimidamide.

[0351] In certain embodiments, the compound is a salt of the compound of Formula (I). In certain embodiments, the salt is a hydrochloride salt. In certain embodiments, the salt is a hydrobromide salt. In certain embodiments, the salt is a sulfate salt. In certain embodiments, the salt is a phosphate salt. In certain embodiments, the salt is a methanesulfonate. In certain embodiments, the salt is a benzenesulfonate salt. In certain embodiments, the salt is a citrate salt. In certain embodiments, the salt is a acetate salt. In certain embodiments, the salt is a maleate salt. In certain embodiments, the salt is a fumarate salt.

[0352] In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure and a pharmaceutically acceptable carrier.

[0353] In certain embodiments, the pharmaceutical composition further comprises at least one additional therapeutically effective agent.

[0354] 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. ItAttorney Docket No. 047162-7534WOl(02797)

[0355] is to be understood that the compounds described herein encompass racemic, optically-active, 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 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 by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0356] 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 compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same ty pe 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 compounds described herein exist in unsolvated form.

[0357] In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0358] In certain embodiments, compounds described herein are prepared as prodrugs. A “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.

[0359] 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 this metabolic pathway. In certain embodiments, the appropriate substituent to decrease orAttorney Docket No. 047162-7534WOl(02797)

[0360] eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.

[0361] 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 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. “C,13C.14C,36C1.18F,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 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 reagent in place of the non-labeled reagent otherwise employed.

[0362] 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.

[0363] The compounds described herein, and other related compounds having different 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 Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and 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 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.

[0364] 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.

[0365] In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino,Attorney Docket No. 047162-7534WOl(02797)

[0366] 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 groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0367] 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 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 acid and base stable but hydrolytically removable.

[0368] 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 compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride labile silyl carbamates.

[0369] Allyl blocking groups are useful in the presence of acid- and base- protecting groups 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 and does not react. Once released from the resin, the functional group is available to react.

[0370] Typically blocking / protecting groups may be selected from allyl, benzyl (Bn), benzyloxy carbonyl (Cbz), allyloxycarbonyl (Alloc), methyl, ethyl, / -butyl, t-butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxy carbonyl (Teoc), / -butyloxy carbonyl (Boc), para-methoxybenzyl (PMB), triphenylmethyl (trityl), acetyl, and fluorenylmethoxycarbonyl (FMOC).Attorney Docket No. 047162-7534WOl(02797)

[0371] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective 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.

[0372] Certain starting materials and / or intermediates used to prepare the compounds of the disclosure are known in the art and were prepared according to known procedures, including XI, X4, and X8 (J. Med Chem. 2023, 66(19): 13684-13704), X2 and X7 (J. Med. Chem. 2012, 55(16):7061-7079), X3 and X5 (WO2024151919A1), X6 (commercially available), X9 (W02009001128A1), andXlO (WO2021088992A1).

[0373] The synthesis of certain exemplary compounds of the disclosure are depicted in FIGs.

[0374] 1 A-1G and described in the Examples section herein. Additionally, exemplary compounds of the disclosure are provided as hydrochloride salts (e.g., trihydrochlorides). That said, the skilled artisan appreciates that the compounds of the disclosure may be readily prepared using alternative salts and / or as a free-base. Certain exemplary compounds of the disclosure are provided in Table 1. In certain embodiments, the compound is at least one compound recited in Table 1, or a salt, stereoisomer (e.g., diastereomer or enantiomer), or isotopologue thereof.

[0375] Table 1. Exemplary compounds of the disclosure

[0376] No. Compound

[0377] NH

[0378] T2307NH2

[0379] HN

[0380] 4,4'-((piperidine-l,4-diylbis(propane-3,l-divl))bis(oxy))dibenzimidamide

[0381] ex 'o

[0382] 1-34

[0383] NH2H2N

[0384] 4,4'-(((2,7-diazaspiro[4.4]nonane-2,7-diyl)bis(propane-3,l-

[0385]

[0386]

[0387] diyl))bis(oxy))dibenzimidamideAttorney Docket No. 047162-7534WOl(02797)

[0388] H

[0389] y- N JL / '"\

[0390] H^N f, - X / - \ - Q

[0391] w y°h

[0392] (±)-l- HN / 9

[0393] 74

[0394] ^NH2

[0395] HN

[0396] 4-(3-((3aR,5r,6aS)-5-(2-(4- carbamimidoylphenoxy)ethyl)hexahydrocyclopenta[c]pyrrol-2(lH)- yl)propoxy)benzimidamide

[0397] H

[0398] N—.

[0399] (±)-l- H2N Z=\ / — ' \ Z=\ NH2

[0400] 139 ^-4 #0 H 0A

[0401] HN NH

[0402] 4,4'-((((lR,5S.6s)-3-azabicyclo[3.1.0]hexane-3?6-diyl)bis(propane-3.1- diyl))bis(oxy))dibenzimidamide

[0403] H HN z— x / '" XTN^\

[0404] (±)-Z3 — e 9—0 \ / =. NH2

[0405] 1-143 H2NHO— G

[0406] NH

[0407] 4-(3-((lR,5S,6r)-6-((4-carbamimidoylphenoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide

[0408] H2N / =\ / — N^.

[0409] (±)-Z5 — A #0' — / ' — \NH2

[0410] HN " O— <£ Z —

[0411] 1-83 NH

[0412] 4-(3-(2-((4-carbamimidoylphenoxy)methyl)-7-azaspiro[3.5]nonan-7- yl)propoxy)benzimidamide

[0413] |H2

[0414] HN' / =\ / NH2

[0415] 1-84 L F0A / M

[0416] NH

[0417] 3-((7-(3-(4-carbamimidoylphenoxy)propyl)-7-azaspiro[3.5]nonan-2- yl)methoxy)benzimidamide

[0418] HN z=\ / — G \ \

[0419] — A # ° \N^\

[0420] (±)-Z2 H2N t \ / =\ NH

[0421] 1-152 °A # —

[0422] NH2

[0423] 4-(3-(6-((4-carbamimidoylphenoxy)methyl)-3,4-dihydroisoquinolin-2(lH)-

[0424]

[0425] yl)propoxy)benzi midamideAttomey Docket No. 047162-7534WOl(02797)

[0426] H2N

[0427] O, P )=NH

[0428] ;s-w yoQ

[0429] 1-54

[0430] ^N A / 0

[0431] (Z)-4-(3-(9-(4-carbamimidoylphenoxy)-3-azaspiro[5.5]undecan-3-yl)propoxy)- N'-(methylsulfonyl)benzimidamide

[0432] NH2H2NyNH

[0433] (±)-P- 2A °X^NH2

[0434] NH

[0435] 4-(3-(l.(4.(2-(4- carbamimidoylphenoxy)ethyl)cyclohexyl)guanidino)propoxy)benzimidamide NH2 H

[0436] (±)-P- ° °Yy

[0437] 2B ^yNH2

[0438] NH

[0439] 4-(3-((4-(2-(4- carbamimidoylphenoxy)ethvl)cvclohexyl)amino)propoxy)benzimidamide H NH2

[0440] HN=^ / ""< LNA

[0441] (±)-P- 7=\ / — \ / =\ NH2

[0442] 139A

[0443] JNH

[0444] 3-(3-((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3- azabicyclo[3.1.0]hexan-6-yl)propoxy)benzimidamide

[0445] H

[0446] N^\

[0447] (±)-P- H2N / =\ / — ' \ / =\ NH2

[0448] 139BH

[0449] HN NH

[0450] 4,4'-((((lR,5SAr)-3-azabicyclo[3.1.0]hexane-3A-diyl)bis(propane-3J- diyl))bis(oxy))dibenzimidamide

[0451] H HNN^\

[0452] (±)-P- C y— O A"7' — NH2

[0453] 143B H2NHO— d J) —

[0454] NH

[0455] 4-(3-((lR,5S,6s)-6-((4-carbamimidoylphenoxy)methyl)-3-

[0456]

[0457] azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamideAttorney Docket No. 047162-7534WOl(02797)

[0458] (±)-Z8

[0459] L '^'0% = NH

[0460] S-1-2

[0461] 212 NH0—A / )

[0462] ' — ' NH

[0463] 4-(3-(4-(2-(4-carbamimidoylphenoxy)ethyl)azepan-l-yl)propoxy)benzimidamide NH2 H

[0464] HN\

[0465] (±)-Z9NH2

[0466] LS-1- 214X= / H° A A — v

[0467] NH

[0468] 3-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan- 6-yl)methoxy)benzimidamide

[0469] H

[0470] H2N / =\

[0471] (±)- X y,N^\

[0472] Z10 HN \ 7—0 T""7' — \ z=\ NH2

[0473] \— / H \ / 2

[0474] LS-1- NH

[0475] 215

[0476] 6-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan- 6-yl)methoxy)-2-naphthimidamide

[0477] H

[0478] (±)- <N

[0479] Zll ^NH0— / ) — 1

[0480] LS-1- 217 H

[0481] (lR,5S,6r)-6-((4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)methyl)-3-(3-(4-(4,5- dihydro-lH-imidazol-2-vl)phenoxy)propyl)-3-azabicvclo[3.1.0]hexane

[0482] H

[0483] H2N» )=\

[0484] (±)- ) / —({ 7—0 c '74 7

[0485] Z12 HNH

[0486] LS-1- NH2

[0487] 223 HN

[0488] 4-(((lR,5S,6r)-3-(2-(4-carbamimidoylphenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6- yl)methoxy)benzimidamide

[0489] NH2

[0490] (±)- HN^ y^ll | NH2

[0491] Z13 L. X ^. N,, X.

[0492] ^ / ^o p ] L ll ^

[0493] LS-1-NH

[0494] 225

[0495] 4-(2-((lr,4r)-4-((2-(4- carbamimidoylphenoxy)ethvl)(methyl)amino)cvclohexvl)ethoxy)benzimidamide | NH2

[0496] (±)- Z14

[0497] LS-1- NH

[0498] 230

[0499] 4-(3-(((lr,4r)-4-(2-(4-

[0500]

[0501] carbamimidoylphenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzimidamideAttomey Docket No. 047162-7534WOl(02797)

[0502] H / \ / *

[0503] (±)- F 'X= / NH2

[0504] Z15HN / ""< T

[0505] LS-1- e 9—o

[0506] 29 H2NH

[0507] 4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan- 6-yl)methoxy)-3-fluorobenzimidamide

[0508] (±)- M / °\ H / =\ / /

[0509] H2NH

[0510] Nx= / ' — \ / '■'■£ HN— G / > — \

[0511] Z16 NH2

[0512] LS-1- 0

[0513] 31

[0514] (lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-N-(4-carbamimidoylphenyl)- 3-azabicyclo[3.1.0]hexane-6-carboxamide

[0515] Z \ / 0H / =NNH

[0516] (±)- H2Nx\ o— d

[0517] Z17 N J>^ NH2

[0518] LS-1- H

[0519] 252

[0520] 5-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan- 6-yl)methoxy)picolinimidamide

[0521] / \ / 0H / =\NH

[0522] (±)- H2N \ s— d

[0523] Z18 ^N NH2

[0524] TS-1- H

[0525] 30

[0526] 4-((((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3- azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzimidamide

[0527] HN H3C

[0528] — \ / 0H )=\

[0529] (±>NH

[0530] H2N \ 0— d

[0531] Z19 ^N NH2

[0532] TS-1- H

[0533] 32

[0534] 4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan- 6-yl)methoxy)-3-methylbenzimidamide

[0535] HN H3C-O

[0536] — \ / 0H )=\NH

[0537] (±)- H2N \= / — y 0— d J) —

[0538] Z20

[0539] LS-1- 245 H

[0540] 4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan- 6-yl)methoxy)-3-methoxybenzimidamide

[0541] HN Br

[0542] — \ / 0H / =\NH

[0543] (±> H2N \ O— G

[0544] Z21 ^N NH2

[0545] LS-1- H

[0546] 254

[0547] 3-bromo-4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-

[0548]

[0549] azabicvclo[3.1.0]hexan-6-yl)methoxy)benzimidamideAttorney Docket No. 047162-7534WOl(02797)

[0550] / — \ / 0H / =\

[0551] (±)-NH

[0552] HO-NH 's— < O— A —

[0553] Z22 N Jr - ’fHN-OH

[0554] LS-1- H

[0555] 13

[0556] N-hydroxy-4-(3-((lR,5S,6r)-6-((4-(N-hydroxycarbamimidoyl)phenoxy)methyl)- 3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide

[0557] Z \ / 0HNH

[0558] (±)- H2N- NH \ — V O— £

[0559] Z23 ^N T>— / HN-NH2

[0560] LS-1- H

[0561] 12

[0562] 4-(3-((lR,5S,6r)-6-((4-(hydrazineyl(imino)methyl)phenoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidohydrazide

[0563] (±)- F \ / — \NNHrl2

[0564] Z25 NH2° \\

[0565] TS-81JNH

[0566] 4-(2-(l-(3-(4-carbamimidoylphenoxy)propyl)azepan-4-yl)ethoxy)-3-

[0567]

[0568] fluorobenzimidamide

[0569] Exemplary compounds of the disclosure were obtained as hydrochloride salts (e.g., trihydrochloride salts).

[0570] Methods

[0571] In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a microbial infection in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of the compound of the disclosure or a pharmaceutically composition thereof. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of 4,4'-((piperidine-l,4-diylbis(propane-3,l-diyl))bis(oxy))dibenzimidamide or a pharmaceutical composition thereof.

[0572] In certain embodiments, the microbial infection is a fungal infection. In certain embodiments, the fungal infection is caused by a fungal pathogen selected from the group consisting of Cryptococcus neoformans, Blastomyces dermatitidis, Cryptococcus gattii, Candida albicans, Candida auris, Candida krusei, Candida glabrata, Candida dubliniensis, 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, Fusarium solani, Absidia corymbifera, Lichtheimia corymbifera, Mucor racemosus, Trichosporo nasahii, Malassezia furfur, Rhizopus spp.,Attorney Docket No. 047162-7534WOl(02797)

[0573] Histoplasma capsulatum, Coccidioides spp., Paecilomyces variotii, Pneumocystis murina, Pneumocystis jiroveci, Scedosporium spp., Sporotrix spp., and Aspergillus spp., or a combination thereof.

[0574] In certain embodiments, the microbial infection is a stramenopile infection. In certain embodiments, the stramenopile infection is caused by a stramenopile selected from the group consisting of Albugo laibachii, Albugo candida. Bremia lactucae, Hyaloperonospora arabidopsidis, Hyaloperonospora parasitica, Phytophthora cactorum, Phytophthora capsica, Phytophthora cinnamomic, Phytophthora infestans, Phytophthora ipomoeae, Phytophthora fragariae var. fragariae, Phytophthora mirabilis, Phytophthora palmivora, Phytophthora parasitica, Phytophthora phaseoli, Phytophthora ramorum. Phytophthora sojae, Plasmopara halstedii. Phytophthora agathidicida, Plasmopara viticola, Pseudoperonospora cubensis, Pythium ultimum, Pythium aphanidermatum, Pythium arrhenomanes, Pythium irregulare, Pythium iwayamai, Pythium ultimum var. sporangiiferum, Pythium vexans, Aphanomyces euteiches, and Peronospora manshurica.

[0575] In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. In certain embodiments, the fungal infection is 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), and seborrhoeic dermatitis, or a combination thereof.

[0576] In certain embodiments, the subject is a crop. In certain embodiments, the crop is selected from the group consisting of almonds, apples, avocados, barley, bananas, beans, blueberries, broccoli, cabbage, carrots, cassava, cherries, chickpeas, citrus fruits, coffee, com, 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.

[0577] In certain embodiments, the microbial 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 (com smut), Ustilago tritici (wheat smut), Ustilago hordei (barely smut), UstilagoAttorney Docket No. 047162-7534WOl(02797)

[0578] spp., Puccinia graminis f. sp. tritici (wheat stem rust), Claviceps purpurea (ergot), Hemileia vastatrix (coffee rust), Phakopsora pachyrhizi (soybean rust), and Phytophthora blight.

[0579] In certain embodiments, the compound is administered by a route selected from the group consisting of foliar spray, agroinfiltration, oral, topical, inhalation, aerosol, intravenous injection, intramuscular injection, and subcutaneous injection.

[0580] In certain embodiments, the compound is coadministered with at least one additional antifungal compound.

[0581] In certain embodiments, the at least one additional fungal compound is selected from the group consisting of amphotericin B, amphotericin B liposomal, anidulafungin, bifonazole, carbendazim, caspofungin, clotrimazole, econazole, fenticonazole, fluconazole, fluopyran, ibrexafungerp, isavuconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, nystatin, olorofim, oxiconazole, posaconazole, rezafungin, sertaconazole, sulconazole, terconazole, terbinafme, thioconazole, and voriconazole.

[0582] Administration / Dosage / Formulations

[0583] 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 of the disease or disorder. 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.

[0584] 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 the disease or disorder in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to 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 the disease or disorder 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 nonlimiting example of an 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 effectiveAttorney Docket No. 047162-7534WOl(02797)

[0585] amount of the therapeutic compound without undue experimentation.

[0586] Actual dosage levels of the active ingredients in the pharmaceutical compositions 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.

[0587] 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 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.

[0588] A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may 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.

[0589] 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. 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.

[0590] 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.

[0591] The carrier may be a solvent or dispersion medium containing, for example, water, 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 theAttorney Docket No. 047162-7534WOl(02797)

[0592] 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 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.

[0593] 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 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 administered to any patient is determined by the attending physician taking all other factors about the patient into account.

[0594] The compound(s) described herein for administration may be in the range of from about 1 pg to about 10,000 mg, about 20 pg to about 9,500 mg, about 40 pg to about 9,000 mg, about 75 pg to about 8,500 mg, about 150 pg to about 7,500 mg, about 200 pg to about 7,000 mg, about 350 pg to about 6,000 mg, about 500 pg to about 5,000 mg, about 750 pg 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 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0595] 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 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 secondAttorney Docket No. 047162-7534WOl(02797)

[0596] 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 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.

[0597] 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 pharmaceutical agent; and instructions for using the compound to treat, or reduce one or more symptoms of a disease or disorder in a patient.

[0598] 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 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.

[0599] 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 (trans)rectal), intravesical, intrapul monary. intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0600] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, 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 compositionsAttorney Docket No. 047162-7534WOl(02797)

[0601] described herein are not limited to the particular formulations and compositions that are described herein.

[0602] Oral Administration

[0603] For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may 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. 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.

[0604] For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fdlers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch gly collate); 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 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 (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).

[0605] Parenteral Administration

[0606] For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or 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.Attorney Docket No. 047162-7534WOl(02797)

[0607] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known 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 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 polyoxy ethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.

[0608] Additional Administration Forms

[0609] 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;

[0610] 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 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.

[0611] Controlled Release Formulations and Drug Delivery Systems

[0612] 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.

[0613] The term sustained release is used in its conventional sense to refer to a drug 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.Attorney Docket No. 047162-7534WOl(02797)

[0614] For sustained release, the compounds may be formulated with a suitable polymer or 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.

[0615] 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 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 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.

[0616] 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 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 characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects.

[0617] 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 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.

[0618] Controlled-release of an active ingredient can be stimulated by various inducers, for 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 ofAttorney Docket No. 047162-7534WOl(02797)

[0619] the active ingredient. 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. 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.

[0620] The term delayed release is used herein in its conventional sense to refer to a drug 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.

[0621] 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 profiles of the drug after drug administration.

[0622] 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.

[0623] 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 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.

[0624] 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 whole or partial increments thereof after drug administration.

[0625] Dosing

[0626] 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 progression of the disease or disorder in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors. The skilled artisan is similarly able to determine appropriate dosages for the compounds of the disclosure, based on the half-life and daily maximum exposure achievable with the compound.

[0627] 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 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 4Attorney Docket No. 047162-7534WOl(02797)

[0628] 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.

[0629] It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, even,' 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.

[0630] 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 (z.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 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%.

[0631] 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.

[0632] 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 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.

[0633] Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic andAttorney Docket No. 047162-7534WOl(02797)

[0634] therapeutic effects is the therapeutic index, which is expressed as the ratio between LDso 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 preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0635] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

[0636] It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

[0637] The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings or disclosure of the present disclosure as set forth herein.

[0638] EXAMPLES

[0639] 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.

[0640] Materials and Methods

[0641] Fungal MIC Procedure

[0642] Broad dilution MICs; Control drugs: amphotericin B (top concentrations 32 pg / rnL); Bis-arylamidines (top concentrations 0.004 pg / mL); Strains: C. parapsilosis (ATCC 22019), C. albicans (ATCC MYA2876); DMSO concentration: 1%.Attorney Docket No. 047162-7534WOl(02797)

[0643] 1. Make a stock solution of AB at 3.2 mg / mL in DMSO and u.s-ary I ami dines at 0.0004 mg / mL in DMSO.

[0644] 2. Set up dilution plate with 100 pL of stock solutions in column 1 and 50 pL DMSO in columns 2-11.

[0645] 3. Serially dilute 50 pL from columns 2-10; column 11 will be a no drug control, and column 12 will be a sterility control.

[0646] 4. Transfer 2.5 pL of each compound dilution to a second compound plate.

[0647] 5. Add 122.5 pL of RPMI 1640 to each well, providing a 50-fold dilution in media and 2% DMSO.

[0648] 6. Transfer 50 pL of each of well to the assay plate.

[0649] 7. Prepare an inoculum in 1 mL RPMI 1640 from ~5 colonies of a 24 hour culture of MYA2876 or a 48 hour culture of ATCC 22019.

[0650] 8. Vortex briefly and adjust to 0.5 McFarland standard (-ODeso = 0.9-1.0; 1 to 5 x 106CFU / rnL).

[0651] 9. Dilute 1:50, and again 1:20 into 5 mL RPMI 1640 medium (1 to 5 x 103CFU / mL). 10. Mix 50 pL of inoculum with the 50 pL of drug dilutions in the assay plate in columns 1-11.

[0652] 11. Inoculate column 12 with 50 pL of sterile media.

[0653] 12. Read after 24 hours (C. albicans) or 48 hours (C. parapsilosis) by assigning a score of 0 - 4: 0 (optically clear). 1 (slightly hazy’)- 2 (prominent decrease in turbidity), 3 (slightly decrease in turbidity ), 4 no reduction of turbidity.

[0654] 13. The MIC for amphotericin B is read as the lowest concentration that gives a 0 reading.

[0655] 14. The MIC for arylamidines is read as the lowest concentration that gives a 2 reading (-50% reduction in turbidity).

[0656] 15. Read again after 48 hours (C. albicans) or 72 hours (C. parapsilosis).

[0657] Cytotoxicity protocol for HEK-293 cells

[0658] 1. Flasks out of the 37°C incubator, check for confluency.

[0659] 2. If cells are -80% confluent, vacuum-aspirate the media, treat the cells with 2.5 ml of dissociation reagent (trypLE Express®, Life Technologies™) at 37 °C, check up on the cells every 3 min. If after 3 min the cells are not lifted, tap the side of the flask against the table and check again. If the cells are still not lifted, put back in the incubator for another 3 min. Usually the cells will lift after 3-6 min.Attorney Docket No. 047162-7534WOl(02797)

[0660] 3. After the cells are lifted, add 8 mL of media to inactivate the trypsin. Transfer the cells to a 50 ml Falcon tube, take an aliquot and add to a pre-warmed flask with media for next passage.

[0661] 4. Spin down the remaining cells at 200-300 ref for 3 min.

[0662] 5. Vacuum-aspirate most of the media, leaving ~1 mL.

[0663] 6. Resuspend the cells in that remaining 1 mL of media with Pl 000.

[0664] 7. Count the cells. To use the Cellometer, transfer a 20 pL aliquot of resuspended cells into an Eppendorf tube, add 20 pL of Trypan Blue dye, pipet 20 pL of the mixture onto the slide and count the cells. To use the BioRad cell counter, transfer a 10 pL aliquot of resuspended cells into an epi tube, add 10 pL of Trypan Blue dye, pipet 10 pL of the mixture onto the slide and count the cells.

[0665] 8. Dilute the cells with media in a 50 mL Falcon tube to obtain 100000 cells / ml 9. Aliquot 100 pL of cells per well (10000 cells per well) into cell-culture treated 96- well plates (black, clear-bottom, Coming™ Costar 3606).

[0666] 10. Put plates in the incubator at 37 °C, 5% CO2, for 5 h.

[0667] 11. After 5 h. prepare 2 reagent reservoirs and media without FBS. Tilt the plates, remove the old media from the cells into one of the reservoirs using a multichannel pipet (do it quickly so that the cells do not dry' out). Add 100 pL of media w ithout FBS to serum-starve cells. Put back in the incubator at 37 °C, 5% CO2, for 24h.

[0668] 12. Prepare the compound plate: first column - 100 pL of a compound at 1.6 or 0.0004 mg / ml. Add 50 pL DMSO to the rest of the plate. Last well of the first column - DMSO only control. Do a serial 1:2 dilution using a multichannel pipet: transfer 50 pL from the first column to the second column, mix, then transfer 50 pL from the second column to the third, mix, etc. The last well does not have any compound, it will be a DMSO-only cell growth control. Prepare a 96-well plate with 19 pL of fresh medium in each well (dilution plate). Then transfer 1 pL from each well of the compound plate to each well of the dilution plate. Carefully w ithdraw 20 pL of medium from each well of the assay plate into an empty reservoir and substitute with 20 pL of compound solution from the dilution plate. Put cell plates in the incubator at 37 °C, 5% CO2, for 48 hours. Take Cell Titer Gio assay out of the freezer to defrost in the fridge overnight the night before taking a reading.

[0669] 13. Combine buffer and substrate of CellTiter-Glo® assay (Promega™), pour into a reagent reservoir, add 100 pL to each well, shake for 10 min and analyze on the plate reader using luminescence settingsAttorney Docket No. 047162-7534WOl(02797)

[0670] General Procedure A

[0671] Appel Reaction. Triphenylphosphine (1.2 equiv.) and carbon tetrabromide (1.2 equiv.) were added to a 0.3 M solution of alcohol substrate (1.0 equiv.) in dichloromethane. The solution was stirred at 0 °C for 1 hour and room temperature for 1 hour. Solvent was removed in vacuo and the residue was purified by Biotage® to give the bromide product.

[0672] General Procedure B

[0673] O-alkylation. A stirred suspension of 60% sodium hydride oil dispersion (1.2 equiv.) in anhydrous DMF (0.4M relative to 4-cyanophenol) under nitrogen was treated in portions with 4-cyanophenol (1.15 equiv.) and stirred 30 minutes. A IM solution alkyl bromide (1.0 equiv.) in anhydrous DMF was added, and the mixture heated to 60 °C for 3 hours, then cooled to room temperature and diluted with water (10 reaction volumes). The aqueous mixture was cooled on ice, stirred until a solid formed, then filtered and the solid rinsed with water, collected and air dried overnight. The solid was dissolved in EtOAc (50 mL), extracted with brine (2 x 25 mL), dried over MgSOr. and filtered. The filtrate was removed in vacuo to furnish the product. Purification via Biotage® may be performed if needed.

[0674] General Procedure C

[0675] Boc Deprotection. A solution of Boc protected material in anhydrous DCM under nitrogen was treated with TFA to afford a 1:2 TFA: DCM 0.22M solution. The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residual oil was dissolved in methanol (3 reaction volumes). This solution was treated with DOWEX 550 OH resin to a pH of 9-10 and stirred for 15 minutes. The mixture was filtered, the resin washed with methanol several times, and the filtrate concentrated in vacuo to provide free base for direct use in X-alkylation.

[0676] General Procedure D

[0677] A-alkylation. A stirred solution of bromide (1.0 equiv.) and free base amine (1.10 equiv.) in anhydrous acetonitrile (0.05 M) under nitrogen was treated with potassium carbonate (2.2 equiv.) and potassium iodide (0.05 equiv.). The reaction was heated to 80 °C for 12 h and then cooled to room temperature. The suspension was filtered through C elite® and the filtrate was concentrated in vacuo. The residue was purified via Biotage® to furnish product.Attorney Docket No. 047162-7534WOl(02797)

[0678] General Procedure E

[0679] Pinner imidate Formation. Bisnitrile material (1.0 equiv.) was dissolved in anhydrous n-BuOH (0.07 M). Gaseous HC1 was bubbled through for 30 minutes and the reaction was stirred at room temperature. The reaction was monitored by LCMS. After 16 hours the solvent was removed, and the residue was place on a high-vacuum pump for several hours.

[0680] Pinner amidine Formation. The crude imidate (1.0 equiv) was dissolved 2M NH? in EtOH to afford a 0.05 M solution. The reaction was heated to 70 °C and stirred overnight. After that time, the reaction was cooled to room temperature and the solvent was removed. The residue was dissolved in 5 mL of water and 1 mL of IM HC1 was added. The mixture was stirred for 20 minutes before being frozen solid and placed on the lyophilizer to furnish the 3HC1 salt product.

[0681] General Procedure F

[0682] Amidine Formation via LiHMDS. Bisnitrile product (1.0 equiv.) was dissolved in IM LiHMDS in THF (5 equiv.) and stirred overnight. An additional 2.5 equivalents of IM LiHMDS solution were added after 16 hours and the reaction was stirred for an additional 4 hours at 40 °C. The reaction was cooled to room temperature and 4M HC1 in dioxanes (30 equiv.) was added followed by iPrOH (1 initial reaction volume) and water (1 / 2 initial reaction volume). The reaction was stirred overnight. The reaction was filtered to give a solid and the filter cake was washed with ether. The ether caused a yellow oil to separate from the filtrate. This oil was collected, diluted with water, washed with DCM (2x), frozen, and lyophilized. The filter cake was dissolved in 2 mL of MeOH and Dowex 550A OH resin was added until the pH was ~10. The solution was diluted with ACN and filtered through an PTFE HPLC filter (0.45pm-pore, 25mm diameter). The solvent was removed in vacuo, the residue taken up in water, and lyophilized to furnish the free base as a white solid. Depending on the substrate, the desired product will crash out of solution or remain in the aqueous layer.

[0683] Example 1: Synthesis of 4,4'-(((2,7-diazaspiro[4.4]nonane-2,7-diyl)bis(propane-3,l-diyl))bis(oxy))dibenzimidamide (Compound 1-34)Attorney Docket No. 047162-7534WOl(02797)

[0684] NH2H2N

[0685] Synthesis of compound 1-29

[0686]

[0687] Compounds X2 (59 mg, 0.3 mmol, 1.0 equiv.) and XI (214 mg, 0.6 mmol, 2.0 equiv.) were dissolved in DMF (1.5 rnL) before the addition of K2CO3 (207 mg, 1.5 mmol, 5.0 equiv.) and KI (100 mg, 0.6 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 16 hours. After TLC analysis indicated the consumption of the starting material, the reaction solution was quenched with water and the aqueous layer was extracted with EtOAc (3x). The combined organic layer was washed with brine (lx), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by automated column chromatography twice (25 g column, DCM-> 0-15% MeOH in DCM with 0.5% TEA 1strun, DCM-> 0-15% MeOH with 0.5% NH₄OH in DCM 2ndrun) to furnish compound 1-29 as a white solid (64.6 mg, 0.095 mmol, 32%). ¹H NMR (400 MHz, CD₃OD) 57.70 (d, J = 8.9 Hz, 4H), 6.88 (d, J= 8.9 Hz, 4H), 4.00 (t, J= 6.1 Hz, 4H), 2.72 - 2.44 (m, 12H), 1.91 (dt, J= 14.9, 6.3 Hz. 4H), 1.87 - 1.73 (m, 4H), 1.42 (s, 18H).13C NMR (151 MHz, CD3OD) 5 169.67, 164.78, 163.56, 130.60, 128.08, 115.35, 80.27, 68.07, 67.32, 54.95, 54.44, 39.79, 29.10, 28.52, 28.12. HRMS: C₃₇H₅₄N₆O₆⁺H Calc. 679.41776, Found 679.4150.

[0688] Synthesis of compound 1-34

[0689]

[0690] Attorney Docket No. 047162-7534WOl(02797)

[0691] Compound 1-29 (34 mg, 0.05 mmol, 1.0 equiv.) was dissolved in 4M HC1 in dioxanes (0.5 mL) and stirred at room temperature for 4 hours. After that time the solvent was removed in vacuo, the residue was taken up in water (3.0 mL), frozen solid, and lyophilized.

[0692] Compound 1-34 was obtained as a light green foamy solid (24.5 mg, 0.0445 mmol, 89%). ¹H NMR (400 MHz, D₂O) δ 7.74 (d, J= 8.9 Hz, 4H), 7.12 (d, J= 8.9 Hz, 4H), 4.21 (t, J= 5.7 Hz. 4H), 3.99 - 3.81 (m, 4H), 3.48 (t, J= 7.9 Hz, 4H),3.44 - 3.24 (m, 4H), 2.54 - 2.02 (m.

[0693] 8H).13C NMR (151 MHZ, D2O) 5 165.85, 162.57. 129.83. 120.07, 114.99, 65.10. 61.08 (m), 53.76 (m), 53.31 (m), 47.06 (m), 35.02 (m), 24.99. (multiplets due to varying protonation of amine core). HRMS: C₂₇H₃₈N₆O₂⁺H Calc. 479.31290, Found 479.3135.

[0694] Example 2: Synthesis of 4-(3-((3aR,5r,6aS)-5-(2-(4-carbamimidoylphenoxy)ethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)propoxy)benzimidamide (Compound 1-74)

[0695] HN

[0696] Synthesis of compound 1-68

[0697] Kl, K, CO, DMF, 23°C, 16 h Quant

[0698]

[0699] Compounds X3 (340 mg, 1.69 mmol, 2.0 equiv.) and XI (301.8 mg, 0.845 mmol, 1.0 equiv.) were dissolved in DMF (8.5 mL) before the addition of K₂CO₃ (581 mg, 4.2 mmol.

[0700] 5.0 equiv.) and KI (140 mg, 0.845 mmol, 1.0 equiv.). The mixture was stirred at room temperature for 16 hours. After TLC analysis indicated the consumption of the starting material, the reaction solution was quenched with water and extracted with EtOAc (3x). The combined organic layer was washed with brine (lx), dried over Na2SO4, and concentrated under reduced pressure. Compound 1-68 was obtained as a light-yellow oil (716 mg. 1.69 mmol, 100%). The residue was divided in half and used directly in the next reaction. 'H NMR (400 MHz, CD3OD) 57.80 (d, J= 8.6 Hz, 2H), 6.99 (d, J= 8.9 Hz, 2H), 4.10 (t, J= 6.1 Hz, 2H), 3.56 (t, J= 6.9 Hz, 2H), 2.69 - 2.40 (m, 6H), 2.21 - 1.78 (m, 6H), 1.72 - 1.54Attorney Docket No. 047162-7534WOl(02797)

[0701] (m, 3H), 1.52 (s, 9H), 1.01 (td, J= 11.9, 7.9 Hz, 2H). ¹³C NMR (151 MHz, d6-DMSO) 5 166.07. 164.17, 162.05, 129.87, 126.73, 114.39. 77.91, 66.59, 60.83, 60.60, 51.98, 42.21, 40.88, 39.26, 38.28, 28.45, 28.43. HRMS: C24H37N3O4+H Calc. 432.28568, Found 432.2828.

[0702] Synthesis of compound 1- 71

[0703] TsCI, DMAP, TEA. DCM, 23°C 1.5 h 40%

[0704]

[0705] Compound 1-68 (358 mg, 0.829 mmol, 1.0 equiv.) was dissolved in DCM (2.2 mL). TEA(168 mg, 1.66 mmol, 2.0 equiv.) and pyridine (132 mg, 1.66 mmol 2.0 equiv.) were added. DMAP (9.8 mg, 0.0829 mmol, 0.10 equiv.) was added followed by TsCI (237 mg, 1.24 mmol, 1.5 equiv.) as a solution in DCM (1.1 mL). The reaction was stirred at room temperature for 1.5 hours. The reaction as diluted with EtOAc, washed with saturated NaHCOs (aq) (lx) and brine (lx). The organic layer was dried over MgSOr, filtered, and the solvent removed in vacuo. The residue was purified by automated column chromatography twice (25 g column, EtOAc-> DCM-> 0-18% MeOH in DCM with 0.5% TEA 1strun, DCM-> 0-18% MeOH in DCM 2ndrun) to furnish compound 1-71 as a white foam (198 mg, 0.33 mmol, 40%). 'H NMR (600 MHz, d6-DMSO) 59.60 - 8.61 (m, 2H), 7.91 (d, J= 8.9 Hz, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.46 (d, J= 7.6 Hz, 2H), 6.96 (d, J= 9.0 Hz, 2H), 4.05 (t, J = 6.3 Hz. 2H), 3.97 (t, J= 6.2 Hz, 2H), 2.59 - 2.43 (m, 4H), 2.40 (s, 3H). 2.39 - 2.31 (m, 2H), 2.19 - 2.04 (m. 2H). 1.88 - 1.78 (m. 4H), 1.66 - 1.51 (m. 3H), 1.42 (s, 9H), 0.79 (q, J= 11.5 Hz, 2H).13C NMR (151 MHz, d6-DMSO) 8 166.03, 164.16, 162.00, 145.30, 132.88, 130.59, 129.86, 128.02, 126.76, 114.41, 77.92, 70.85, 69.49, 66.50, 60.56, 51.87, 42.02, 38.60, 33.54, 28.45, 28.19, 21.52. HRMS: C₃₁H₄₃N₃O₆S⁺H Calc. 586.29453, Found 586.2949.

[0706] Synthesis of compound 1- 72

[0707] Cs₂CO₃, KI, DMF, 85°C 16 h

[0708]

[0709] 32% Compound 1-71 (123 mg, 0.209 mmol, 1.0 equiv.) was dissolved in DMF (1.0 mL) and compound X4 (100 mg, 0.418 mmol, 2.0 equiv.) was added followed by CS2CO3 (148Attorney Docket No. 047162-7534WOl(02797)

[0710] mg, 0.459 mmol, 2.2 equiv.) and KI (35 mg, 0.209 mmol, 1.0 equiv.) The reaction was stirred at 85°C for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc. extracted with water (2x), brine (lx), dried over MgSO4, and filtered. The solvent was removed in vacuo and the residue was purified by automated column chromatography (25 g column, EtOAc-> DCM-> 0-18% MeOH in DCM with 0.5% TEA) and by pTLC (93:7 DCM: MeOH) to furnish compound 1-72 as a white film ( 43.4 mg, 0.066 mmol, 32%). 'H NMR (600 MHz, d6-Acetone) 58.01 (d, J= 8.8 Hz, 4H). 6.99 (dd. J= 8.9. 6.3 Hz. 4H). 4.16 (t, J= 6.4 Hz, 2H), 4.07 (t, J= 6.6 Hz, 2H), 2.78 - 2.44 (m, 6H), 2.32 - 2.12 (m, 2H), 2.12 -2.06 (m, 2H), 2.02 - 1.87 (m, 3H), 1.82 (q, J= 6.7 Hz, 2H), 1.48 (s, 18H), 1.17 - 1.03 (m, 2H). ¹³C NMR (151 MHz, d6-Acetone) 8 166.16, 164.51, 162.28, 162.19, 129.23,129.23, 126.90. 126.85, 114.01, 113.99, 77.51, 67.34, 66.19, 60.30, 51.52, 42.16. 40.48, 39.14. 33.83, 27.57. (Overlap on 166.16, 164.51, 77.51, 40.48, 27.57). HRMS: C₃₆H₅₁N₅O₆⁺H Calc.

[0711] 650.39121, Found 650.3914.

[0712] Synthesis of compound 1-74

[0713] H

[0714]

[0715] HN Compound 1-72 (16 mg. 0.024 mmol, 1.0 equiv.) was dissolved in DCM (0.15 mL) and TFA (0.15 mL) was added. The reaction was stirred at room temperature for 3 hours before the solvent was removed. The residue was dissolved in MeOH (0.15 mL) and several drops of 4M HC1 in dioxanes were added. The mixture was evaporated and the process repeated twice. The residue taken up in water (0.5 mL). The aqueous layer was extracted with DCM (3x) and the water was stripped with benzene (5x) to furnish compound 1-72 as a white film (13.2 mg, 0.0235 mmol, 98%). 'H NMR (400 MHz, D2O) 87.77 (d, J= 8.3 Hz, 4H), 7.14 (dd, J= 9.1, 2.6 Hz, 4H), 4.24 (q, 5.6 Hz, 2H), 4.18 (t, J= 6.6 Hz, 2H), 3.85 - 3.53 (m, 2H), 3.42 (q, J= 8.6 Hz, 2H), 3.22 - 2.79 (m, 4H), 2.38 - 2.13 (m, 4H), 2.09 - 1.96 (m, 1H), 1.95 - 1.78 (m, 2H), 1.28 - 0.99 (m, 2H).13C NMR (176 MHz, D2O) 5 165.95, 163.07, 163.06, 162.71, 162.68, 129.92, 129.90, 120.13, 119.76, 115.19, 115.11, 67.99, 67.98, 65.65, 65.43, 59.84, 59.67, 52.13, 51.85, 41.76, 41.56, 40.65, 39.08, 37.67, 33.16, 32.69, 25.14, 25.09. (Overlap on 165.95, All aliphatic and 1-phenol carbon signals doubled). HRMS:

[0716] C₂₆H₃₅N₅O₂⁺H Calc. 450.28635. Found 450.2870.Attorney Docket No. 047162-7534WOl(02797)

[0717] Example 3: Synthesis of 4,4'-((((lR,5S,6s)-3-azabicyclo[3.1.0]hexane-3,6-diyl)bis(propane-3,l-diyl))bis(oxy))dibenzimidamide (Compound 1-139)

[0718] H

[0719] Synthesis of compound 1-125

[0720]

[0721] Compounds X5 (340 mg, 1.92 mmol, 2.0 equiv.) and XI (342 mg, 0.96 mmol, 1.0 equiv.) were dissolved in DMF (8.0 mL) before the addition of K2CO3 (663 mg, 4.798 mmol, 5.0 equiv.) and KI (128 mg, 0.9595, 1.0 equiv.). The mixture was stirred at 45 °C for 16 hours. After TLC analysis indicated the consumption of the starting material, the reaction solution was quenched with water and extracted with EtOAc (3x). The combined organic layer was washed with brine (lx), dried over Na2SO4, and concentrated under reduced pressure. This residue was purified by automated column chromatography (25 g column.

[0722] DCM-> 0-18% MeOH with 0.5% NH4OH in DCM). Compound 125 was obtained as a white foam (292.3 mg, 0.70 mmol, 73%). ‘H NMR (600 MHz, d6- Acetone) 5 8.02 (d, J= 8.9 Hz, 2H), 6.99 (d, J= 8.9 Hz, 2H), 4.10 (t, J= 6.3 Hz, 2H), 3.54 (t, J= 6.6 Hz, 2H), 3.10 - 2.98 (m, 2H), 2.67 - 2.54 (m, 2H), 2.40 - 2.21 (m, 2H), 1.99 - 1.86 (m, 2H), 1.56 (p, J= 6.8 Hz, 2H), 1.48 (s, 9H), 1.23 (q, J= 7.2 Hz, 2H), 1.18 - 1.12 (m, 2H), 1.11 (t, J= 7.0 Hz, 1H).13C NMR (151 MHz, d6-Acetone) 5 167.04, 165.43, 163.13, 130.13, 127.79, 114.91, 78.41, 66.91, 62.10, 55.87, 52.34, 33.54, 28.98, 28.48, 23.41, 20.36, 15.61. HRMS: C₂₃H₃₅N₃O₄⁺H Calc. 418.27003, Found 418.2679.

[0723] Synthesis of compound 1-130

[0724]

[0725] Attorney Docket No. 047162-7534WOl(02797)

[0726] Compound 1-125 (101 mg, 0.24 mmol, 1.0 equiv.) and DMAP (3 mg, 0.025 mmol, 0.1 equiv.) were dissolved in anhydrous DCM (0.75 mL) and TEA (51 mg, 70 uL, 0.5 mmol, 2.0 equiv.) was added. The reaction was cooled to 0°C and solid TsCl was added in one charge (57mg, 0.3 mmol, 1.2 equiv.) After 30 minutes the reaction was warmed to room temperature and the reaction was stirred for a total of 1.5 hours. At that time the reaction was diluted with DCM, extracted with saturated NaHCOs <aq) (lx), water (3x), and brine (lx). The solution was dried over MgSCU. filtered, and the solvent removed in vacuo. The residue was purified by automated column chromatography (12 g column, DCM-> 0-18% MeOH in DCM) to furnish compound 1-130 as a white foam (110 mg, 0.203 mmol, 81%). 'H NMR (600 MHz, d6-Acetone) 88.02 (d, J= 8.9 Hz, 2H), 7.80 (d, J= 8.3 Hz, 2H), 7.48 (d, J= 7.9 Hz. 2H), 6.98 (d. J= 8.9 Hz. 2H), 4.08 (dt, J= 11.0, 6.4 Hz, 4H). 3.08 - 2.90 (m. 2H), 2.65 - 2.48 (m, 2H), 2.45 (s, 3H), 2.33 - 2.17 (m, 2H), 1.94 - 1.85 (m, 2H), 1.76 - 1.64 (m, 2H), 1.48 (s, 9H), 1.19 (q, J= 7.2 Hz, 2H), 1.10 - 1.03 (m, 2H), 1.02 - 0.89 (m, 1H).13C NMR (151 MHz, d6-Acetone) 8 167.03, 165.48, 163.11, 145.73, 134.42, 130.86, 130.13, 128.68, 127.79. 114.91, 78.40, 71.23, 66.88, 55.70, 52.26. 28.48, 28.30. 23.29, 21.52, 19.61. (Two signals missing). HRMS: C₃₀H₄₁N₃O₆S⁺H Calc. 572.27888, Found 572.2750.

[0727] Synthesis of compound 1-132

[0728] NH

[0729]

[0730] Compound 1-130 (110 mg, 0.203 mmol, 1.0 equiv.) was dissolved in DMF (1.0 mL) and compound X4 (100 mg, 0.418 mmol, 2.06 equiv.) was added followed by CS2CO3 (148 mg, 0.459 mmol. 2.26 equiv.). The reaction was stirred at 85°C for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc, extracted with water (2x), brine (lx), dried over MgSO4, and fdtered. The solvent was removed in vacuo and the residue was purified by automated column chromatography (25 g column, EtOAc-> DCM-> 0-18% MeOH in DCM with 0.25% TEA) followed by pTLC (9: 1 DCM MeOH) to furnish 1-132 as a white foam (21.7 mg, 0.034 mmol, 17%). ’H NMR (600 MHz, d6-Acetone) 8 8.01 (dd, J = 8.9, 2.3 Hz, 4H), 6.98 (dd, J= 10.8, 9.0 Hz, 4H), 4.10 (t, J= 6.4 Hz, 4H), 3.014 - 2.98 (m, 2H), 2.69 - 2.54 (m, 2H), 2.42 - 2.25 (m, 2H), 1.99 - 1.90 (m, 2H), 1.91 - 1.83 (m, 2H), 1.48 (s, 18H), 1.37 (q. J = 7.3 Hz. 2H), 1.24 - 1.15 (m. 3H).13C NMR (151 MHz, d6-Acetone) 8 166.98, 165.35, 163.12, 130.15, 130.13, 127.78, 127.75, 114.90, 78.44, 68.37, 66.83, 55.81,Attorney Docket No. 047162-7534WOl(02797)

[0731] 52.25, 29.64, 28.90, 28.48, 23.39, 20.07, 15.61. (Overlap on 166.98, 165.35, 163.12, 114.90, 78.44, 28.48). HRMS: C₃₅H₄₉N₅O₆⁺H Calc. 636.37556, Found 636.3745.

[0732] Synthesis of compound 1-139

[0733]

[0734] 1-139 Compound 1-132 (21.7 mg, 0.034 mmol, 1.0 equiv.) was dissolved in DCM (0.2 mL) and TFA (0.2 mL) was added. The reaction was stirred at room temperature for 3 hours before the solvent was removed. The residue was dissolved in MeOH (0.15 mL) and several drops of 4M HC1 in dioxanes were added. The mixture was evaporated and the process repeated twice. The residue taken up in water (2.0 mL). The aqueous layer was extracted with DCM (3x), frozen solid, and lyophilized. Compound 1-139 was obtained as a fluffy white solid (18.2 mg, 0.033 mmol, 98%). ¹H NMR (600 MHz, D₂O) δ 7.58 (dd,.7= 8.9, 7.4 Hz, 4H), 6.95 (dd, J= 10.4, 8.8 Hz, 1H), 4.02 (dt, J= 24.5, 6.0 Hz, 4H), 3.90 - 3.84 (m, 0.4H), 3.60 (d, J = 11.4 Hz, 1.6H), 3.32 - 3.13 (m, 3.2H), 3.15 - 3.07 (m, 0.4H), 2.64 (d, J= 12.1 Hz, 0.4H), 2.13 - 1.93 (m. 2H), 1.77 - 1.70 (m. 2H), 1.66 - 1.62 (m, 0.4H), 1.53 (s, 1.6H), 1.30 (q, J = 7.1 Hz, 2H), 1.17 - 1.06 (m, 0.2H), 0.89 - 0.68 (m, 0.8H).13C NMR (151 MHz, D2O) 8 165.82, 163.01, 162.54, 129.81, 119.99, 119.62, 115.08, 114.96, 68.08, 65.36, 56.16, 52.78, 27.56, 26.86, 25.10, 21.26, 20.08. (Overlap on 165.82, 129.81) HRMS: C₂₅H₃₃N₅O₂⁺H Calc. 436.27070. Found 436.2682.

[0735] Example 4: Synthesis of 4-(3-((lR,5S,6r)-6-((4-carbamimidoylphenoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide (Compound 1-143)

[0736] H

[0737] Synthesis of compound 1-124

[0738] KI, K2CO3DMF,45°C, 16 h

[0739]

[0740] 77%Attorney Docket No. 047162-7534WOl(02797)

[0741] Compounds X6 (2.96 mmol, 336 mg, 2.0 equiv.) and XI (535 mg, 1.5 mmol, 1.0 equiv.) were dissolved in DMF (12 mL) before the addition of K2CO3 (1000 mg, 7.5 mmol, 5.0 equiv.) and KI (200 mg, 1.5 mmol, 1.0 equiv.). The mixture was stirred at 45°C temperature for 16 hours. After TLC analysis indicated the consumption of the starting material, the reaction solution was quenched with water and extracted with EtOAc (3x). The combined organic layer was washed with brine (lx), dried over Na2SO4, and concentrated under reduced pressure. This residue was purified by automated column chromatography (25 g column, DCM-> 0-18% MeOH with 0.5% NH4OH in DCM). Compound 1-124 was obtained as a white foam (452.3 mg, 1.16 mmol, 77%).1H NMR (600 MHz, d6-Acetone) 5 8.01 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 4.10 (t, J= 6.4 Hz, 2H), 3.34 (d, J = 6.8 Hz. 2H), 3.04 (d. J = 8.6 Hz. 2H), 2.59 (t, J = 7.1 Hz, 2H), 2.30 (d, J = 8.7 Hz, 2H), 1.92 (p, J = 6.7 Hz, 2H), 1.48 (s, 9H), 1.41 - 1.36 (m, 1H), 1.31 - 1.26 (m, 2H).13C NMR (151 MHz, d6-Acetone) 5 166.11, 164.49, 162.24, 129.22, 126.89, 113.99, 77.51, 65.97, 63.48, 54.67, 51.30, 28.22, 27.57, 22.27, 20.54. HRMS: C₂₁H₃₁N₃O₄⁺H Calc. 390.23873, Found 390.2370.

[0742] Synthesis of compound 1-135

[0743]

[0744] Compound 1-124 product (200 mg, 0.51 mmol, 1.0 equiv.) and DMAP (6 mg, 0.05 mmol, 0.1 equiv.) were dissolved in anhydrous DCM (1.5 mL). TEA (125 mg, 170 uL, 1.25 mmol, 2.5 equiv.) was added. The reaction was cooled to 0°C and solid TsCl was added in one charge (124 mg, 0.65 mmol, 1.3 equiv.) After 30 minutes the reaction was warmed to room temperature and the reaction was stirred for a total of 1.5 hours. At that time the reaction was diluted with DCM, extracted with saturated NaHCCh (aq) (lx), water (3x), and brine (lx). The solution was dried over MgSCh, filtered, and the solvent removed in vacuo. The residue was purified by automated column chromatography (25 g column. DCM-> 0-18% MeOH in DCM). Compound 1-135 was obtained as a white foam (151 mg, 0.277 mmol, 54%). 'H NMR (400 MHz, d6-Acetone)) 5 8.02 (d, J= 8.9 Hz, 2H), 7.79 (d, J= 8.4 Hz, 1.6H), 7.69 (d, J= 8.1 Hz, 0.4H), 7.46 (d, J = 1.1 Hz, 1.6H), 7.16 (d, J = 7.5 Hz, 0.4H), 6.98 (d, J= 8.9 Hz, 2H), 4.08 (t, J= 6.3 Hz, 2H). 3.92 (d, J= 7.6 Hz, 1.8H). 3.70 (d, J= 1A Hz, 0.2H), 3.01 (d, J= 8.6 Hz, 2H), 2.67 - 2.50 (m, 2H), 2.44 (s, 3H), 2.37 - 2.30 (m, 2H), 1.91Attorney Docket No. 047162-7534WOl(02797)

[0745] (p, J= 6.7 Hz, 2H), 1.48 (s, 9H). 1.44 - 1.35 (m, 2H), 1.15 - 1.08 (m, 1H). HRMS:

[0746] C₂₈H₃₇N₃O₆S⁺H Calc. 544.24758, Found 544.2462.

[0747] Synthesis of compound 1-136

[0748] NH

[0749]

[0750] Compounds 1-135 (117.4 mg, 0.216 mmol, 1.0 equiv.) was dissolved in DMF (1.1 mL) and X4 (127 mg, 0.54 mmol, 2.5 equiv.) was added followed by CS2CO3 (176 mg, 0.54 mmol, 2.5 equiv.). The reaction was stirred at 85°C for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc, extracted with water (2x), brine (lx), dried over MgSO4, and fdtered. The solvent was removed in vacuo and the residue was purified by automated column chromatography (25 g column, EtOAc-> DCM-> 0- 18% MeOH in DCM with 0.25% TEA) and pTLC (9: 1 DCM MeOH) to furnish compound 1-136 as a white foam (18.2 mg, 0.0299 mmol, 14%). ¹H NMR (600 MHz, d6-Acetone) δ 8.01 (d, J= 8.9 Hz, 4H), 6.97 (t, J= 8.6 Hz, 4H), 4.11 (t, J = 6.3 Hz, 2H), 3.91 (d, J = 7.1 Hz, 2H), 3.09 (d, J = 8.6 Hz, 2H), 2.61 (t, J = 6.9 Hz, 2H), 2.33 (d, J = 8.5 Hz, 2H), 1.98 - 1.87 (m, 2H), 1.48 (d, J= 1.0 Hz, 18H), 1.41 - 1.38 (m, 2H), 1.31 - 1.28 (m, 1H).13C NMR (151 MHz, d6-Acetone) 8 166.97, 165.36, 163.17, 163.05, 130.13, 130.12, 127.76, 127.74, 114.97, 114.90, 78.43, 71.01, 66.86, 55.29, 51.97, 29.17, 28.48, 21.94, 19.38. (Overlap on 166.97, 165.36, 78.43, 28.48). HRMS: C₃₃H₄₅N₅O₆⁺H Calc. 608.34426, Found 608.3440.

[0751] Synthesis of compound 1-143

[0752] H H

[0753]

[0754] Compound 1-136 (18.2 mg, 0.0299 mmol, 1.0 equiv.) was dissolved in DCM (0.2 mL) and TFA (0.2 mL) was added. The reaction was stirred at room temperature for 3 hours before the solvent was removed. The residue was dissolved in MeOH (0.1 mL) and several drops of 4M HC1 in dioxanes were added. The mixture was evaporated and the process repeated twice. The residue taken up in water (2.0 mL). The aqueous layer was extracted with DCM (3x), frozen solid, and lyophilized. Compound 1-143 was obtained as a fluffy white solid (13.3 mg. 0.0257 mmol, 86%). 'H NMR (400 MHz. D2O) 57.77 (d, J= 8.9 Hz, 4H).Attorney Docket No. 047162-7534WOl(02797)

[0755] 7.12 (d, J= 8.9 Hz, 4H), 4.22 (q, J= 5.5 Hz, 2H), 4.07 (d, J= 7.0 Hz, 2H), 3.91 - 3.79 (m, 2H), 3.57 - 3.35 (m, 4H), 2.32 - 2.14 (m, 2H), 2.09 - 1.98 (m, 2H), 1.58 - 1.47 (m, 1H).13C NMR (151 MHz, D2O) 513C NMR (151 MHz, D2O) 5 165.87, 162.57, 129.86, 129.83, 120.05, 115.07, 114.98, 69.09, 65.25, 55.84, 52.95, 25.14, 20.14, 19.12. (Overlap on 165.87, 162.57, 120.05). HRMS: C23H29N5O2+H Calc. 408.23940, Found 408.2371.

[0756] Example 5: Synthesis of 4-(3-(2-((4-carbamimidoylphenoxy)methyl)-7-azaspiro[3.5]nonan-7-yl)propoxy)benzimidamide (Compound 1-83)

[0757] Synthesis of compound 1- 76

[0758] KI, K2CO3DMF, 23°C, 16 h Carried forward

[0759]

[0760] 1-76 Compounds X7 (340 mg, 1.69 mmol, 2.0 equiv.) and XI (301.8 mg, 0.845 mmol, 1.0 equiv.) were dissolved in DMF (8.5 mL) before the addition of K2CO3 (581 mg, 4.2 mmol, 5.0 equiv.) and KI (140 mg, 0.845 mmol, 1.0 equiv.). The mixture was stirred at room temperature for 16 hours. After TLC analysis indicated the consumption of the starting material, the reaction solution was quenched with water and extracted with EtOAc (3x). The organic layer was washed with brine (lx), dried over Na2SC>4, and concentrated under reduced pressure to yield compound 1-76 deemed suitably pure for use in further reactions. 'H NMR (400 MHz, CD3OD) 57.80 (d. J= 8.8 Hz. 2H), 6.99 (d. J= 8.8 Hz. 2H), 4.08 (t, J = 6.1 Hz, 2H), 3.50 (d, J= 6.6 Hz, 2H), 2.69 - 2.24 (m, 6H), 2.07 - 1.97 (m, 2H), 1.92 - 1.83 (m, 2H), 1.77 - 1.65 (m, 2H), 1.62 - 1.47 (m, 4H), 1.52(s, 9H) 1.31-1.16 (m, 1H).

[0761] Synthesis of compound 1- 78

[0762] TsCI, DMAP, TEA, DCM, 23°C, 1.5 h 48% from bromide

[0763]

[0764] 1-76 Compound 1-76 (447 mg, 0.845 mmol, 1.0 equiv.), TEA (202 mg, 2 mmol, 2.4 equiv.) and Pyridine (159 mg, 2.4 mmol, 2.0 equiv.) were dissolved in anhydrous DCM (2.6 mL).Attorney Docket No. 047162-7534WOl(02797)

[0765] DMAP (12 mg, 0.1 mmol, 0.10 equiv.) was added followed by TsCl (284 mg, 1.5 mmol, 1.8 eq.) in DCM (1.1 mL). The reaction was stirred at room temperature for 1.5 hours. The reaction as diluted with EtOAc, washed with saturated NaHCOs (aq) (lx) and brine (lx). The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo. The residue was purified by automated column chromatography twice (25 g column, EtOAc-> DCM-> 0-18% MeOH in DCM with 0.25 vol% TEA 1strun, DCM-> 0-18% MeOH in DCM 2ndrun) to furnish 1-78 (240 mg, 0.406 mmol, 48%). 1H NMR (400 MHz. d6- Acetone) 5 8.02 (d. J= 8.9 Hz, 2H), 7.80 (d, J= 8.3 Hz, 2H), 7.49 (d, J= 8.0 Hz, 2H), 6.99 (d, J= 8.9 Hz, 2H), 4.11 (t, J = 6.4 Hz, 2H), 4.00 (d, J= 6.6 Hz, 2H), 2.55 (dt, J= 15.2, 6.8 Hz, 1H), 2.46 (s, 3H), 2.44 -2.18 (m, 6H), 1.98 - 1.88 (m, 2H). 1.86 - 1.76 (m, 2H), 1.60 (t, J= 5.2 Hz, 2H), 1.51 - 1.39 (m. 4H), 1.48 (s, 9H).13C NMR (151 MHz, d6-Acetone) 5 167.05, 165.47, 163.14. 145.73, 134.50, 130.84, 130.12, 128.67, 127.80, 114.91, 75.52, 67.12, 55.59, 51.12, 50.87, 40.00, 37.61, 34.94, 28.48, 28.17, 27.52, 21.50.

[0766] Synthesis of compound 1- 79

[0767]

[0768] Compound 1-78 (120 mg, 0.209 mmol, 1.0 equiv.) was dissolved in DMF (1 mL) and compound X4 (100 mg, 0.418 mmol, 2.0 equiv.) was added followed by CS2CO3 (148 mg, 0.459 mmol, 2.2 equiv). The reaction was stirred at 85°C for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc, extracted with water (2x), with brine (lx), dried over MgSO4, and filtered. The solvent was removed in vacuo and the residue was purified by automated column chromatography twice (25 g column, EtOAc-> DCM-> 0-18% MeOH in DCM with 0.25 vol% TEA 1strun, DCM-> 0-18% MeOH in DCM 2ndrun) to furnish compound 1-79 as a white film (55.0 mg, 0.0846 mmol, 40%).XH NMR (600 MHz, d6-Acetone) 5 8.03 (dd, J= 8.8, 1.4 Hz, 4H), 7.00 (dd, J= 8.9, 4.9 Hz, 4H), 4.18 (t, J= 6.2 Hz. 2H), 4.06 (d, J= 6.3 Hz. 2H), 3.13 - 2.64 (m, 8H), 2.28 (br, 2H), 2.00 - 1.84 (m. 4H), 1.83 - 1.73 (m. 2H), 1.48 (s. 18H), 1.37 - 1.27 (m, 1H).13C NMR (151 MHz, d6-Acetone) 6 166.96, 165.40, 163.21, 162.84, 130.17, 130.16, 128.04, 127.86, 114.95, 114.94, 78.42, 73.15, 66.79, 54.98, 50.53, 50.30, 46.23, 35.15, 34.01, 28.48, 28.41. (Overlap on 78.42, 28.48). HRMS: C36H51N5O6+H Calc. 650.39121, Found 650.3907.

[0769] Synthesis of compound 1-83Attorney Docket No. 047162-7534WOl(02797)

[0770]

[0771] Compound 1-79 (20.9 mg, 0.032 mmol, 1.0 equiv.) was dissolved in DCM (0.2 mL) and TFA (0.2 mL) was added. The reaction was stirred at room temperature for 3 hours before the solvent was removed. The residue was dissolved in MeOH (0.15 mL) and several drops of 4M HCl in dioxanes were added. The mixture was evaporated and the process repeated twice. The residue taken up in water (2 mL). The aqueous layer was extracted with DCM (3x), frozen solid, and lyophilized. Compound 1-83 was obtained as a light tan solid (16.1 mg, 0.028 mmol. 90%).

[0772] ’H NMR (600 MHz, D2O) 57.62 (dd, J= 8.9, 4.9 Hz, 4H), 6.99 (d, J= 8.9 Hz, 4H), 4.09 (t, J = 5.7 Hz, 2H), 4.00 (d, J= 6.7 Hz, 2H), 3.37 (dd, J= 40.6, 13.2 Hz, 2H), 3.20 - 3.14 (m, 2H), 2.91 (td, J= 12.7, 2.6 Hz, 1H), 2.82 (td, J= 12.7, 2.6 Hz, 1H), 2.66 (hept, J = 8.3 Hz, 1H), 2.12 (dq, J= 11.5, 5.8 Hz, 2H), 2.04 - 1.96 (m, 2H), 1.90 - 1.76 (m, 2H), 1.74 - 1.58 (m, 4H).13C NMR (151 MHz, D2O) 5 165.86, 163.13, 162.58, 129.83, 129.81, 120.04, 119.74, 115.10, 114.99, 72.98, 65.41, 49.98, 49.71, 46.58, 34.12, 31.83, 26.61, 23.44. (Overlap on 165.86) HRMS: C26H35N5O2+H Calc. 450.28635, Found 450.2863.

[0773] Example 6: Synthesis of 3-((7-(3-(4-carbamimidoylphenoxy)propyl)-7-azaspiro[3.5]nonan-2-yl)methoxy)benzimidamide (Compound 1-84)

[0774] Synthesis of compound 1-82

[0775]

[0776] Compounds 1-78 (104 mg. 0.178 mmol, 1.0 equiv.) was dissolved in DMF (0.85 mL) and compound X8 (84 mg, 0.356 mmol, 2.0 equiv.) was added followed by CS2CO3 (124 mg, 0.445mmol, 2.5 equiv.). The reaction was stirred at 85°C for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc, extracted with water (2x), brine (lx), dried over MgSO4, and fdtered. The solvent was removed in vacuo and the residue was purified by automated column chromatography twice (25 g column, EtOAc-> DCM-> 0-18% MeOH inAttorney Docket No. 047162-7534WOl(02797)

[0777] DCM with 0.25 vol% TEA 1strun, DCM-> 0-18% MeOH in DCM 2ndrun) and once by pTLC (9:1 DCM: MeOH) to furnish compound 1-82 as a white film (18.96 mg. 0.0292 mmol, 16.4%). 'H NMR (600 MHz, d6-Acetone) 88.02 (d, J= 8.9 Hz, 2H), 7.62 - 7.56 (m, 2H), 7.36 (t, J= 8.2 Hz, 1H), 7.11 (dd, J= 8.2, 1.6 Hz, 1H), 7.01 - 6.98 (m, 2H), 4.13 (t, J= 6.4 Hz, 2H), 4.01 (d, J = 6.4 Hz, 2H), 2.72 (hept, J= 8.3 Hz, 1H), 2.56 - 2.17 (m, 6H), 2.01 -1.92 (m, 4H), 1.74 - 1.63 (m, 4H). 1.63 - 1.57 (m, 2H), 1.48 (d, J= 4.5 Hz, 18H).13C NMR (151 MHz. d6-Acetone) δ 166.55, 166.13, 164.54, 162.24, 159.36. 136.55. 129.33, 129.22, 126.89, 119.47, 118.08, 114.01, 113.18, 77.81, 77.49, 72.54, 66.23, 54.72, 50.33, 50.10, 39.30, 36.89, 34.66, 27.74, 27.57, 27.53. (Overlap on 164.54). HRMS: C36H51N5O6+H Calc. 650.39121, Found 650.3904.

[0778] Synthesis of compound 1-84

[0779] NH

[0780]

[0781] Compound 1-82 (19 mg. 0.029 mmol, 1.0 equiv.) was dissolved in DCM (0.2 mL) and TFA (0.2 mL) was added. The reaction was stirred at room temperature for 3 hours before the solvent was removed. The residue was dissolved in MeOH (0.15 mL) and several drops of 4M HC1 in dioxanes were added. The mixture was evaporated and the process repeated twice. The residue was taken up in water (2.0 mL). The aqueous layer was extracted with DCM (3x), frozen solid, and lyophilized. Compound 1-84 was obtained as a yellow solid (14.2 mg, 0.025 mmol, 87%). 'H NMR (600 MHz, D2O) 87.77 (d, J= 8.6 Hz, 2H), 7.54 (t, J= 7.9 Hz, 1H), 7.38 (d, J= 7.8 Hz, 1H), 7.33 (d, J= 9.8 Hz, 2H), 7.14 (d, J= 8.7 Hz, 2H), 4.24 (t, J = 5.4 Hz. 2H), 4.13 (d, J= 6.7 Hz, 2H), 3.52 (dd, J= 40.8, 12.8 Hz, 3H), 3.36 - 3.25 (m. 2H), 3.01 (dt, J= 52.1, 12.0 Hz, 2H). 2.80 (hept, J = 7.6 Hz, 1H), 2.31 - 2.23 (m, 2H), 2.21 - 2.08 (m, 2H), 2.05 - 1.90 (m, 2H), 1.88 - 1.71 (m, 4H).13C NMR (151 MHz, D2O) 8 166.50, 165.84, 162.56, 158.58, 130.65, 129.81, 129.19, 120.38, 120.33, 120.02, 114.96, 113.73, 73.24, 65.38, 53.96, 49.96, 49.69, 34.16, 31.83, 26.63, 23.42. HRMS: C26H35N5O2+H Calc.

[0782] 450.28635. Found 450.2865.

[0783] Example 7: Synthesis of 4-(3-(6-((4-carbamimidoylphenoxy)methyl)-3,4-dihydroisoquinolin-2(lH)-yl)propoxy)benzimidamide (Compound 1-152)Attorney Docket No. 047162-7534WOl(02797)

[0784] Synthesis of compound 1-146

[0785]

[0786] Compounds X9 (1.9 mmol, 2 equiv.) and compound XI (339 mg, 0.95 mmol, 1.0 equiv.) were dissolved in DMF (9.5 mL), then K2CO3 (657 mg, 4.75mmol, 5.0 equiv.) and KI (158.5 mg, 0.95 mmol, 1.0 equiv.) were added. The mixture was stirred at 40°C for 16 hours. After TLC analysis indicated the consumption of the starting material, the reaction solution was quenched with water and extracted with EtOAc (3x). The organic layer was washed with brine (lx), dried over MgSO-i. and concentrated under reduced pressure. This residue was purified by automated column chromatography (40 g column, DCM-> 0-18% MeOH in DCM). Compound 1-146 was obtained as a white foam (309 mg. 0.77 mmol. 70%).rH NMR (600 MHz, d6-Acetone) 88.00 (d, J= 8.9 Hz, 2H), 7.12 - 7.05 (m, 2H), 7.01 - 6.97 (m, 3H), 4.54 (s, 2H), 4.17 (t, J= 6.4 Hz, 2H), 3.60 (s, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.72 (t, J = 5.9 Hz, 2H), 2.67 (t, J= 6.9 Hz, 2H), 2.05 - 2.02 (m, 2H), 1.47 (s, 9H).13C NMR (151 MHz, d6-Acetone) 6 167.00. 165.36, 163.14, 141.08, 135.05, 134.53. 130.13, 127.78, 127.55, 127.09, 124.85, 114.91, 78.42, 67.09, 64.55, 56.77, 55.33, 51.82, 28.47, 27.62. (One signal missing). HRMS: C25H33N3OCH Calc. 440.25438, Found 440.2541.

[0787] Synthesis of compound 1-147

[0788] TsCI, DMAP, TEA, DCM, 23°C, 1.5 h

[0789]

[0790] 34% Compounds 1-146 (105 mg, 0.24 mmol, 1.0 equiv.) and DMAP (3 mg, 0.025 mmol, 0. lequiv.) were dissolved in anhydrous DCM (0.75 mL) with TEA (51 mg, 70 uL, 0.5 mmol, 2.0 equiv.). The reaction was cooled to 0°C and solid TsCI was added in one charge (57 mg, 0.325 mmol, 1.3 equiv.) After 30 minutes the reaction was warmed to room temperature and the reaction was stirred for a total of 1.5 hours. At that time the reaction was diluted withAttorney Docket No. 047162-7534WOl(02797)

[0791] DCM, extracted with water(lx), and brine (lx). A heavy emulsion formed, the reaction was further diluted with DCM and filtered. When the solution was dried over MgSO4, filtered, and the solvent removed in vacuo. The residue was purified by automated column chromatography (25 g column, DCM-> 0-12% MeOH in DCM) to furnish compound 1-147 as a white foam (37.5 mg, 0.0819 mmol, 34%).

[0792] Synthesis of compound 1-148

[0793] NH

[0794]

[0795] Compound 1-147 product (30 mg, 0.0655 mmol, 1.0 equiv.) was dissolved in DMF (0.3 mL) and compound X4 (45 mg, 0.190 mmol, 2.9 equiv.) was added followed by CS2CO3 (47 mg, 0.144 mmol, 2.2 equiv.). The reaction was stirred at 65°C overnight. The reaction was cooled to room temperature, diluted with EtOAc. extracted with water (2x), brine (lx), dried over MgSO4, and filtered. The solvent was removed in vacuo and the residue was purified by automated column chromatography (12 g column, EtOAc-> 0-5% MeOH in EtOAc-> DCM-> 0-20% MeOH in DCM) and pTLC (9:1 EtOAc: MeOH) to furnish compound 1-148 as a white foam (7.26 mg, 0.011 mmol, 17%). 'H NMR (400 MHz, d6-Acetone) 58.02 (dd. J = 9.0. 2.8 Hz, 4H). 7.24 (d. J = 6.8 Hz, 2H). 7.12 - 6.96 (m. 5H), 5.14 (s, 2H), 4.19 (t, J= 6.4 Hz, 2H), 3.72 (s, 2H), 2.92 - 2.79 (m, 4H), 2.12 (p, J= 6.7 Hz, 2H), 1.48 (s, 18H).13C NMR (176 MHz, d6-Acetone) 5 166.90, 165.33, 163.14, 162.80, 135.69, 135.46. 130.15, 128.78, 128.16, 127.85, 127.56. 126.04, 115.33, 114.96, 78.47, 78.44, 70.60, 67.05, 66.12. 55.17, 51.53, 28.49, 27.39. (Overlap on 166.90. 165.33, 28.49, one signal missing). HRMS: C37H47N5O6+H Calc. 658.35991, Found 658.3593.

[0796]

[0797] Compounds 1-148 (7.26 mg, 0.011 mmol) was dissolved in DCM (0.3 mL) and TFA (0.3 mL) was added. After 2 hours the solvent was removed. The residue was dissolved in MeOH (0.15 mL) and several drops of 4M HC1 in di oxanes were added. The mixture was evaporated and the process was repeated twice. The residue taken up in water (2.0 mL). TheAttorney Docket No. 047162-7534WOl(02797)

[0798] aqueous layer was extracted with DCM (3x), frozen solid, and lyophilized. Compound 1-148 was obtained as a fluffy white solid (5.8 mg, 0.0102 mmol, 93%). 'H NMR (400 MHz, D2O) 57.75 (d, J= 8.8 Hz, 4H), 7.44 - 7.32 (m, 2H), 7.25 (d, J= 8.4 Hz, 1H), 7.15 (dd, J = 26.3, 8.9 Hz, 4H), 5.22 (s, 2H), 4.67 (d, J = 15.5 Hz, 1H), 4.38 (d, J = 15.6 Hz, 1H), 4.28 (t, J = 5.6 Hz, 2H), 3.93 - 3.81 (m, 1H), 3.54 (t, J= 7.5 Hz, 2H), 3.50 - 3.38 (m, 1H), 3.35 - 3.10 (m, 2H), 2.48 - 2.28 (m, 2H).13C NMR (176 MHz, D2O) 5 165.96, 165.94. 162.66, 162.61, 136.28. 131.29, 129.93, 128.14, 127.36. 127.21. 126.66, 120.25, 120.18, 115.55. 115.13.

[0799] 69.83, 65.45, 53.50, 53.00, 50.05, 24.77, 23.66. (Overlap on 129.93). HRMS: C27H31N5O2+H Calc. 458.25505, Found 458.2558.

[0800] Example 8: Synthesis of (Z)-4-(3-(9-(4-carbamimidoylphenoxy)-3-azaspiro[5.5]undecan- 3-yl)propoxy)-N'-(methylsuIfonyl)benzimidamide (Compound 1-54)

[0801] Synthesis of compound 1-37

[0802]

[0803] Compound X10 (215.6 mg, 1.2 mmol, 2.0 equiv.) and compound XI (214 mg, 0.6 mmol, 1.0 equiv.) were dissolved in DMF (6.0 mL) before the addition of K2CO3 (415 mg.

[0804] 3.0 mmol, 5.0 equiv.) and KI (100 mg, 0.6 mmol, 1.0 equiv.). The mixture was stirred at room temperature overnight. After TLC analysis indicated the consumption of the starting material, the reaction solution was quenched with water and extracted with EtOAc (3x). The organic layer was washed with brine (lx), dried over Na2SO4. and concentrated under reduced pressure. This residue was transferred to a scintillation vial with MeOH, the solvent reduced by -90% and water (5.0 mL) was added. This suspension was frozen solid, and lyophilized to furnish compound 1-37 as an off-white foam (236 mg, 0.561 mmol, 94%). 1H NMR (400 MHz, CDCl3) 8 7.83 (d, J= 8.8 Hz, 2H), 6.91 (d, J= 8.9 Hz, 2H), 4.05 (t, J= 6.3 Hz, 2H).

[0805] 3.74 - 3.57 (m, 1H), 2.66 - 2.29 (m, 4H), 2.04-1.97 (m, 2H), 1.79 – 1.60 (m, 6H), 1.55 (s, 9H), 1.49 - 1.32 (m, 6H), 1.17 (t, J= 12.5 Hz, 2H).Attorney Docket No. 047162-7534WOl(02797)

[0806] Synthesis of compound 1-49

[0807]

[0808] Compound 1-37 (235 mg 0.527 mmol. 1.0 equiv.) was dissolved in anhydrous DCM (10 mL) and TEA ( 117 mg, 161 uL, 1.16 mmol, 2.2 equiv.) was added. The reaction was cooled to 0°C. Mesyl chloride (1.05 mmol, 81 uL, 2.0 equiv.) was added dropwise and the reaction was warmed to room temperature. The reaction was stirred for 1 hour before it was diluted with DCM. washed with saturated NaHCO3 (aq) (1x) and brine (lx), and dried over Na2SO4. The solution was filtered, the solvent removed in vacuo, and the residue purified by automated column chromatography (25 g column, DCM-> 0-10% MeOH in DCM).

[0809] Compound 1-49 was obtained as a white solid (207 mg, 0.342 mmol, 65%). 'H NMR (600 MHz, d6-Acetone) 57.64

[0810]

[0811] (d, 8.9 Hz, 2H), 7.02 (d, 8.9 Hz, 2H), 4.71 - 4.62 (m. 1H), 4.17 (t. J= 6.4 Hz. 2H), 3.12 (s, 3H), 3.07 (s, 3H), 2.60 - 2.30 (m, 4H). 2.02 - 1.95 (m, 2H). 1.92 - 1.85 (m, 2H), 1.79 - 1.70 (m, 2H), 1.69 - 1.63 (m, 2H), 1.61 - 1.51 (m, 2H), 1.50 -1.44 (m, 2H), 1.42 (s, 9H), 1.36 - 1.29 (m, 2H). 13C NMR (151 MHz, d6-Acetone) 5 163.77, 162.75, 150.55, 132.34, 126.33, 114.66, 81.68, 67.26, 50.20, 49.98, 42.67, 38.40, 37.52, 35.13, 33.41. 30.79, 28.11. 27.89, 27.37. HRMS: C27H43N3O8S2+H Calc. 602.25643, Found 602.2577.

[0812] Synthesis of compound 1-51

[0813] NH

[0814] BocHN

[0815]

[0816] Compound 1-49 (200 mg, 0.33 mmol, 1.0 equiv.) was dissolved in DMF (1.0 mL) and compound X4 (237 mg, 1.00 mmol, 3.0 equiv.), CS2CO3 (325 mg, 1.0 mmol, 3.0 equiv.) and KI (0.33 mmol, 55 mg, 1.0 equiv.) were added. The reaction was stirred at 85°C for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc, extracted with water (2x), brine (lx), dried over MgSO4, and filtered. The solvent was removed in vacuo and the residue was purified by automated column chromatography (25 g column, EtOAc-> DCM-> 0-15% MeOH in DCM with 0.25% TEA) and pTLC (93:7 DCM: MeOH) to furnish compound 1-51Attorney Docket No. 047162-7534WOl(02797)

[0817] as a yellow film (23.5 mg, 0.032 mmol, 9.6%). 1H NMR (400 MHz, CD3OD) δ 7.78 (d, J= 8.9 Hz. 2H), 7.60 (d. J= 8.8 Hz. 2H), 6.98 (dd, J= 8.9, 1.9 Hz, 4H), 4.51 - 4.43 (m, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.11 (s, 3H), 2.82 - 2.52 (m, 6H), 2.15 - 2.00 (m, 2H), 1.89 (d, J = 5.2 Hz, 2H), 1.81 - 1.56 (m, 8H), 1.52 (s, 9H), 1.42 (s, 9H), 1.40 - 1.28 (m, 2H).13C NMR (151 MHz, CD3OD) 5 168.27, 163.32, 162.27, 161.02, 130.82, 129.17, 126.28, 115.02, 113.55. 82.20, 78.82, 74.66, 66.01, 55.01, 49.10, 48.91, 41.01, 35.60. 33.49, 29.87. 27.09, 26.68, 25.87. 168.27, 163.32 (Overlap 126.28).

[0818] Synthesis of compound 1-54

[0819]

[0820] Compound 1-51 (23.4 mg, 0.0315 mmol, 1.0 equiv.) was dissolved in DCM (0.2 mL) and TFA (0.2 mL) was added. The reaction was stirred at room temperature for 3 hours before the solvent was removed. The residue was dissolved in MeOH (0.15 mL) and several drops of 4M HC1 in dioxanes were added. The mixture was evaporated and the was process repeated twice. The residue was taken up in water (2.0 mL). The aqueous layer was extracted with DCM (3x), frozen solid, and lyophilized. Compound 1-54 was obtained as a fluffy white solid (19.4 mg. 0.0299 mmol, 95%). ’H NMR (400 MHz, D2O) 57.74 (dd, J= 21.6, 8.9 Hz, 4H), 7.07 (dd, J= 32.3, 8.9 Hz, 4H). 4.62 - 4.49 (m, 1H). 4.19 (t. J= 5.6 Hz. 2H), 3.46 (d. J = 12.5 Hz, 2H), 3.36 - 3.27 (m, 2H), 3.13 (s, 3H), 3.12 - 3.02 (m, 2H), 2.22 (dq, J= 11.9, 5.9 Hz, 2H), 2.06 (d, J= 14.3 Hz, 1H), 1.96 - 1.76 (m, 2H), 1.73 - 1.33 (m, 7H).13C NMR (151 MHz, D2O) 5 165.76, 165.19, 161.81, 161.64, 129.88, 129.81, 125.09, 119.68, 116.29, 114.57. 75.61, 65.36, 54.04, 48.88, 48.74, 40.18, 33.24, 31.08, 29.09. 26.73. HRMS:

[0821] C28H39N5O4S+H Calc. 542.27955. Found 542.2778.

[0822] Example 9: Synthesis of compound (±)-Z8 (LS- 1-212)

[0823]

[0824] Compound (±)-Z8 was prepared according to the synthetic scheme depicted in FIG.

[0825] 14.Attorney Docket No. 047162-7534WOl(02797)

[0826] TS-1-53: tert- butyl 4-(2-bromoethyl)azepane-l-carboxylate. 'll NMR (500 MHz, DMSO-d6, 90 °C) 83.53 (t, J= 7.1 Hz, 2H). 3.50 - 3.43 (m, 1H). 3.41 - 3.35 (m, 1H), 3.29 -3.23 (m, 1H), 3.22 - 3.16 (m, 1H), 1.83 - 1.73 (m, 4H), 1.70 - 1.59 (m, 2H), 1.57 - 1.48 (m, 1H), 1.42 (s, 9H), 1.35 - 1.26 (m, 1H), 1.25 - 1.16 (m, 1H).13C NMR (126 MHz, DMSO-d6, 90 °C) 6 154.14, 77.70, 45.70, 44.16, 39.11, 36.37, 33.08, 32.22, 31.66, 27.76, 25.89.

[0827] LS- 1-201: 4-(3-(4-(2-(4-cyanophenoxy)ethyl)azepan-l-yl)propoxy)benzonitrile.

[0828] 1H NMR (600 MHz. CDCh) 87.59 - 7.54 (m, 4H). 6.95 - 6.90 (m. 4H), 4.07 (t, J = 6.2 Hz, 2H), 4.02 (t, J= 6.5 Hz, 2H), 2.82 - 2.60 (m, 6H), 2.05 - 1.97 (m, 2H), 1.87 - 1.78 (m, 4H), 1.78 - 1.74 (m, 2H), 1.68 - 1.60 (m, 1H), 1.55 - 1.44 (m, 1H), 1.41 - 1.34 (m, 1H).13C NMR (151 MHz, CDCh) 8 162.32, 162.30, 133.99, 119.28, 119.27, 115.21. 115.18, 103.85, 103.79, 66.55, 66.50. 55.66, 54.84, 53.48, 36.49, 35.12, 33.92, 33.15. 26.96, 26.10. HRMS-ESI m / z calculated for C25H30N3O2+ [M+H+] 404.2333, found 404.2305.

[0829] LS-212: 4-(3-(4-(2-(4-carbamimidoylphenoxy)ethyl)azepan-l-yl)propoxy)benzimidamide. 'H NMR (400 MHz, D2O) 8 7.59 (d, J= 8.8 Hz, 4H), 6.97 (dd, J= 8.9. 1.9 Hz, 4H), 4.04 (dt, J= 15.7, 5.9 Hz, 4H). 3.51 - 3.26 (m, 2H). 3.25 - 2.85 (m, 4H), 2.16 - 2.05 (m. 2H), 1.97 - 1.72 (m, 5H), 1.71-1.43 (dq. J= 12.3. 6.2 Hz. 3H), 1.31 -1.11 (m, 1H).13C NMR (151 MHZ, D2O) 8 165.82, 165.80, 162.97, 162.61, 129.84, 129.81, 119.99, 119.65, 115.10, 115.03, 66.45, 65.35, 55.21, 54.81, 54.61, 54.48, 53.41, 51.89, 34.93, 34.91, 34.55, 33.78, 32.75, 31.10, 29.97, 27.56, 23.78, 23.73, 22.81, 21.11. HRMS-ESI m / z calculated for C25H35N5O2+ [M+H+] 438.2864, found 438.2854.

[0830] Example 10: Synthesis of compound (±)-Z9 (LS-1-214)

[0831] ‘2

[0832] N NH

[0833]

[0834] Compound (±)-Z9 was prepared according to the synthetic scheme depicted in FIG.

[0835] LS-1-181: tert-butyl (1R,5S,6r)-6-((3-cyanophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 'H NMR (400 MHz, CDCh) 57.39 - 7.33 (m. 1H), 7.24 (dt, J= 7.7, 1.2 Hz, 1H), 7.12 - 7.08 (m, 2H), 3.97 - 3.77 (m, 2H), 3.64 (dd, J= 24.7, 10.9 Hz, 2H), 3.39 (d, J= 10.7 Hz, 2H), 1.59 - 1.55 (m, 2H), 1.44 (s, 9H), 1.16 - 1.10 (m, 1H). 13C NMR (101 MHz, CDCl3) 8 158.83, 154.95, 130.41, 124.64, 119.89, 118.74, 117.39, 113.23. 79.58, 69.77, 48.07, 47.79, 28.50, 21.82, 21.42, 20.97.Attorney Docket No. 047162-7534WOl(02797)

[0836] LS-1-192: 3-(((lR,5S,6r)-3-(3-(4-cyanophenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzonitrile.

[0837]

[0838] NMR (600 MHz, CDCh) 57.58 -7.55 (m, 2H), 7.37 - 7.33 (m, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.12 - 7.09 (m, 2H), 6.94 - 6.91 (m, 2H), 4.04 (t, J= 6.2 Hz, 2H), 3.81 (d, J= 6.8 Hz, 2H), 3.27 - 2.99 (m, 2H), 2.75 - 2.54 (m, 2H), 2.51 - 2.27 (m, 2H), 2.08 - 1.87 (m, 2H), 1.77 - 1.59 (m, 1H), 1.54 - 1.37 (m, 2H).

[0839] 13C NMR (151 MHz, CDCl3) 8 162.33, 158.98, 134.01, 130.37. 124.50, 119.97, 119.30, 118.79. 117.43, 115.20, 113.19, 103.83, 70.56, 66.33. 54.78, 51.50. 28.18, 21.28. 18.61. HRMS-ESI m / z calculated for C23H24N3O2+ [M+H+] 374.1863, found 374.1866.

[0840] LS-1-214: 3-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide. 'H NMR (400 MHz, D2O) 8 7.74 (d, J= 8.8 Hz, 2H), 7.57 - 7.49 (m, 1H), 7.38 (d, J= 7.6 Hz, 1H), 7.34 - 7.27 (m, 2H). 7.12 (d, J = 8.9 Hz, 1H), 4.21 (t, J= 5.6 Hz, 2H), 4.03 (d, J = 7.0 Hz, 2H), 3.87 (d, J = 11.6 Hz, 2H), 3.57 - 3.39 (m, 4H), 2.29 - 2.17 (m, 2H), 2.06 - 1.99 (m, 2H), 1.60 - 1.50 (m, 1H).13C NMR (151 MHz, D2O) 8 166.42, 165.85, 162.58, 158.11, 130.75, 129.85, 129.23, 120.63, 120.44. 120.00, 115.02, 113.80, 69.34, 65.27, 55.85, 52.94, 25.15, 20.15, 19.18. HRMS-ESI m / z calculated for C23H30N5O2+ [M+H+] 408.2394, found 408.2385.

[0841] Example 11: Synthesis of compound (±)-Z10 (LS-1-215)

[0842]

[0843] Compound (±)-Z10 was prepared according to the synthetic scheme depicted in FIG.

[0844] 16.

[0845] LS-182: tert-butyl ( l / ?, SS',6r)-6-(((6-cyanonaphthalen-2-yl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. 'H NMR (400 MHz, CDCh) 88.10 (d, J= 1.6 Hz, 1H), 7.74 (dd, J= 11.9, 8.8 Hz, 2H). 7.53 (dd, J= 8.5, 1.6 Hz, 1H), 7.22 (dd, J = 9.0. 2.5 Hz, 1H), 7.07 (d. J= 2.5 Hz. 1H), 4.09 - 3.87 (m, 2H), 3.66 (dd, J= 27.5, 10.9 Hz. 2H), 3.44 -3.34 (m, 2H), 1.60 (t,.7= 3.2 Hz, 2H), 1.43 (s, 9H), 1.22 - 1.15 (m, 1H).13C NMR (101 MHz, CDCh) 8 159.17, 154.99, 136.37, 133.79, 130.07, 127.79, 127.74, 127.11, 120.86, 119.60, 106.76, 106.61, 79.59, 69.60, 48.14. 47.83, 28.50, 21.87, 21.50, 20.97.

[0846] LS-1-209: 6-(((lR, 5S, 6 r)-3-(3-(4-cyanophenoxy)propyl)-3- azabicyclo [3.1.0] hexan-6-yl)methoxy)-2-naphthonitrile. 'H NMR (400 MHz, DMSO-d6) 8 8.45 (s, 1H), 7.95 (t, J = 8.3 Hz, 2H), 7.77 - 7.68 (m, 3H), 7.41 (d, J= 2.4 Hz, 1H), 7.32 (dd, J= 9.0, 2.2 Hz, 1H),Attorney Docket No. 047162-7534WOl(02797)

[0847] 7.08 (d, J= 8.8 Hz, 2H), 4.07 (t, J= 6.2 Hz, 2H), 3.97 (d, J= 7.2 Hz, 2H), 3.02 (d, J= 8.6 Hz. 2H), 2.55 - 2.50 (m. 2H), 2.27 (d, J= 8.0 Hz. 2H), 1.84 (p, J= 7.2 Hz, 2H), 1.63 - 1.55 (m, 1H), 1.49 (s, 2H).13C NMR (151 MHz, DMSO-d6) δ 162.14, 159.00, 136.24, 134.18, 133.94, 130.14, 127.97, 127.24, 126.88, 120.68, 119.52, 119.17, 115.51, 106.89, 105.53, 102.63, 70.13, 66.27, 54.93, 54.21, 50.85, 27.78, 20.83, 18.20. HRMS-ESI m / z calculated for C27H26N3O2+[M+H+] 424.2020, found 424.2011.

[0848] LS- 1-215: 6-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2-naphthimidamide. 'H NMR (400 MHz, D2O+acetic acid-d6) δ 8.20 (s, 1H), 7.88 (d, J= 9.0 Hz, 1H), 7.83 (d, J= 8.7 Hz, 1H), 7.62 - 7.55 (m, 3H), 7.26 (d, J= 2.5 Hz, 1H), 7.21 (dd, J= 9.0, 2.5 Hz, 1H). 6.98 (d, J= 8.6 Hz, 2H), 4.10 (t, J= 5.6 Hz, 2H), 4.01 (d, J= 7.0 Hz, 2H), 3.79 (d, J= 11.5 Hz, 2H), 3.35 (dd, J = 20.3, 10.1 Hz, 4H), 2.17 - 2.07 (m, 2H), 2.00 - 1.94 (m, 2H), 1.54 - 1.47 (m, 1H).13C NMR (151 MHz, D2O+acetic acid-d6) δ 167.71, 167.08, 163.93, 159.65, 138.50, 132.42, 131.13, 130.40, 129.38, 128.95, 124.87, 123.97, 121.44, 121.23, 116.31, 108.58, 70.31, 66.70, 57.20, 54.36, 26.49. 21.50, 20.43. HRMS-ESI m / z calculated for C27H32N5O2+[M+H+] 458.2551. found 458.2526.

[0849] Example 12: Synthesis of compound (±)-Zll (LS-1-217)

[0850]

[0851] Compound (±)-Zll was prepared according to the synthetic scheme depicted in FIG.

[0852] 17.

[0853] TS-1-3: tert- butyl (17?,5A,6r)-6-((4-cyanophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.

[0854]

[0855] NMR (400 MHz, CDCl3) δ 7.60 – 7.54 (m, 2H), 6.94 - 6.89 (m, 2H), 3.97 (dd, J= 10.1, 6.6 Hz, 1H), 3.83 (dd, J= 10.1. 7.3 Hz, 1H), 3.68 (d, J= 10.9 Hz, 1H), 3.61 (d, J= 10.9 Hz, 1H), 3.43 - 3.34 (m. 2H), 1.57 (t, J= 3.6 Hz, 2H), 1.44 (s, 9H), 1.17 - 1.10 (m, 1H).13C NMR (101 MHz, CDCl3) δ 162.05, 154.93, 134.05, 119.23, 115.21, 104.05, 79.58, 69.73, 48.07, 47.76, 28.50, 21.86, 21.35, 20.98.

[0856] TS-1-4: 4-(((lJ?,55,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzonitrile. 'H NMR (400 MHz, CDCl3+acetic acid-d4) δ 7.58 – 7.51 (m, 2H), 6.92 - 6.86 (m. 2H), 3.90 (d. J= 6.4 Hz. 2H), 3.53 - 3.43 (m. 4H), 1.82 (t, J= 3.2 Hz, 2H), 1.59 - 1.52 (m, 1H).13C NMRAttorney Docket No. 047162-7534WOl(02797)

[0857] (101 MHz, CDCl3+acetic acid-d4) δ 161.71, 134.04, 118.96, 115.15, 104.20, 68.35, 47.24, 20.95, 19.26.

[0858] TS-1-5: 4-(3-((U?,55,6r)-6-((4-cyanophenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzonitrile. 'H NMR (400 MHz, CDCl3) δ 7.56 (d, J= 8.4 Hz, 4H), 6.96 - 6.88 (m, 4H), 4.03 (t, J= 6.4 Hz, 2H), 3.83 (d, J= 7.1 Hz, 2H), 3.10 (d, J= 8.7 Hz, 2H), 2.58 (t, J = 6.9 Hz. 2H), 2.35 (d. J= 8.7 Hz. 2H), 1.92 (p, J= 6.7 Hz. 2H), 1.67 - 1.61 (m, 1H), 1.44 (s, 2H).13C NMR (101 MHz, CDCl3) δ 162.39, 162.26, 133.98, 119.33, 119.30. 115.23. 115.19, 103.78, 103.72, 70.66, 66.39, 54.68, 51.38, 28.32, 21.35, 18.46. HRMS-ESI m / z calculated for C23H24N3O2+[M+H+] 374.1863, found 374.1846.

[0859] LS-217: (l / ?,55',6r)-6-((4-(4,5-dihydro-l / 7-imidazol-2-yl)phenoxy)methyl)-3-(3-(4-(4,5-dihydro-l / / -imidazol-2-yl)phenoxy)propyl)-3-azabicyclo|3.1.0|hexane. 'H NMR (400 MHz, d2o) δ 7.79 – 7.73 (m, 4H), 7.16 - 7.09 (m, 4H), 4.22 (t, J= 5.7 Hz, 2H), 4.06 (d, J= 6.9 Hz, 2H), 4.03 (s, 8H), 3.87 (d, J= 11.5 Hz, 2H), 3.52 - 3.39 (m, 4H), 2.29 - 2.18 (m, 2H), 2.04 (t, J= 3.7 Hz, 2H), 1.58 - 1.50 (m, 1H).13C NMR (151 MHz, d2o) δ 165.77, 165.75. 162.87, 130.18, 130.16, 115.22, 115.15. 114.57, 69.12, 65.26, 55.83, 52.89, 44.28, 25.13, 20.15. 19.11. HRMS-ESI m / z calculated for C27H34N5O2+[M+H+] 460.2707, found 460.2682.

[0860] Example 13: Synthesis of compound (±)-Z12 (LS- 1-223)

[0861]

[0862] HN

[0863] Compound (±)-Z12 was prepared according to the synthetic scheme depicted in FIG.

[0864] 18.

[0865] LS- 1-221: 4-(((lR,5S,6r)-3-(2-(4-cyanophenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzonitrile. 'H NMR (600 MHz, CDCh) 57.59 - 7.54 (m, 4H), 6.95 - 6.89 (m, 4H), 4.19 - 4.01 (m, 2H), 3.84 (d, J= 6.9 Hz, 2H), 3.32 - 3.08 (m, 2H), 3.03 - 2.81 (m, 2H), 2.68 - 2.39 (m, 2H), 1.79 - 1.61 (m, 1H), 1.57 - 1.46 (m, 2H).13C NMR (151 MHz, CDCh) 5 162.19, 161.94, 134.04, 134.00, 119.27. 119.19, 115.26, 115.25, 104.14, 103.87, 70.38, 67.45, 55.27, 53.47, 21.32, 18.49. HRMS-ESI m / z calculated for C22H22N3O2+[M+H+] 360.1707, found 360.1689.Attorney Docket No. 047162-7534WOl(02797)

[0866] LS- 1-223: 4-(((lR,5S,6r)-3-(2-(4-carbamimidoylphenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide. 'H NMR (400 MHz, D2O+acetic acid-d6) δ 7.68 – 7.51 (m, 4H), 7.07 - 6.86 (m, 4H), 4.33 - 4.20 (m, 2H), 3.91 - 3.81 (m, 2H), 3.81 - 3.64 (m, 2H), 3.61 - 3.50 (m, 2H), 3.49 - 3.34 (m, 2H), 1.99 - 1.76 (m, 2H), 1.54 - 1.37 (m, 1H).13C NMR (151 MHz, d2o) δ 167.00, 166.97, 164.00, 163.17, 131.24, 131.19, 121.80. 121.15, 116.46, 70.37, 64.46, 57.68. 55.40, 21.66. HRMS-ESI m / z calculated for C22H28N5O2+[M+H+], 394.2238, found 394.2236.

[0867] Example 14: Synthesis of compound (±)-Z13 (LS-1-225) and (±)-Z14 (LS-1-230)

[0868]

[0869] NH Compounds (±)-Z13 and (±)-Z14 were prepared according to the synthetic scheme depicted in FIG. 19.

[0870] LS-184: tert-butyl ((lr,4r)-4-(2-bromoethyl)cyclohexyl)carbamate.1H NMR (600 MHz, CDCl3) δ 4.37 (s, 1H), 3.42 (t, J= 7.0 Hz, 2H), 3.41 - 3.32 (m, 1H), 2.03 - 1.98 (m, 2H), 1.80 - 1.73 (m, 4H), 1.48 - 1.40 (m, 10H), 1.14 - 1.06 (m, 2H), 1.06 - 0.98 (m. 2H).13C NMR (151 MHz, CDCl3) δ 155.27, 79.16. 49.78, 39.57, 35.26, 33.23, 31.81. 31.19, 28.47.

[0871] LS-185: tert-butyl ((lr,4r)-4-(2-(4-cyanophenoxy)ethyI)cyclohexyl)carbamate. 'H NMR (600 MHz, CDCl3) δ 7.58 – 7.55 (m, 2H), 6.93 - 6.91 (m, 2H), 4.37 (s, 1H), 4.02 (t, J = 6.5 Hz, 2H), 3.44 - 3.33 (m, 1H), 2.05 - 1.99 (m, 2H), 1.85 - 1.79 (m, 2H), 1.70 (q, J= 6.6 Hz. 2H), 1.45 - 1.42 (m. 10H), 1.12 - 1.07 (m, 4H).13C NMR (151 MHz, CDCl3) δ 162.36, 155.27, 134.02, 119.33, 115.20, 103.80, 79.17, 66.31, 49.77, 35.77, 33.70, 33.34, 31.78, 28.47.

[0872] LS-189: tert-butyl ((lr,4r)-4-(2-(4-cyanophenoxy)ethyl)cyclohexyl)(methyl)carbamate. 'H NMR (400 MHz, CDCl3) δ 7.59 – 7.54 (m, 2H), 6.95 - 6.90 (m, 2H), 4.02 (t, J= 6.4 Hz, 2H), 2.71 (s, 3H), 1.89 - 1.81 (m, 2H), 1.74 - 1.66 (m, 4H), 1.50 - 1.38 (m, 13H), 1.17 - 1.05 (m, 2H).13C NMR (101 MHz, CDCl3) δ 162.35, 155.71, 134.00, 119.33, 115.18, 103.76, 79.23, 66.29, 35.78, 33.74, 32.18, 29.70, 28.54, 28.29.

[0873] LS-191: 4-(2-((lr,4 / ')-4-(methylamino)cyclohexyl)ethoxy)benzonitrile. 'H NMR (400 MHz, CDCl3) δ 7.50 – 7.42 (m, 2H), 6.87 - 6.79 (m, 2H), 3.93 (q, J= 6.4 Hz, 2H), 2.32 (d,.7= 6.2 Hz, 3H), 2.24 - 2.13 (m, 1H), 1.92 - 1.79 (m, 2H), 1.78 – 1.66 (m, 2H), 1.61 (p, J = 6.5 Hz. 2H), 1.45 - 1.32 (m, 1H), 1.03 - 0.86 (m, 4H).13C NMR (101 MHz, CDCl3) δ 162.09. 133.63, 119.02, 114.92, 103.30. 66.21, 58.40. 35.62, 34.04. 33.50, 32.63. 31.47.

[0874] LS-193: 4-(2-((lr,4r)-4-((2-(4-cyanophenoxy)ethyl)(methyl)amino)cyclohexyl)ethoxy)benzonitrile.1H NMR (600 MHz, CDCl3) δ 7.59 – 7.55 (m, 4H), 6.96 - 6.91 (m. 4H), 4.08 (t, J= 6.0 Hz, 2H), 4.03 (t, J= 6.5 Hz. 2H), 2.88 (t, J = 6.0 Hz, 2H), 2.48 - 2.41 (m, 1H), 2.38 (s, 3H). 1.91 - 1.85 (m, 4H). 1.70 (q, J= 6.6 Hz, 2H), 1.50 - 1.42 (m, 1H), 1.34 - 1.24 (m, 2H), 1.08 - 0.99 (m, 2H).13C NMR (151 MHz, CDCl3) δ 162.33, 162.04, 134.01, 119.30, 119.23, 115.29, 115.18, 104.08, 103.81, 67.13, 66.34, 63.50, 52.15, 38.85, 35.80, 34.31, 32.27, 27.98. HRMS-ESI m / z calculated for C25H30N3O2+[M+H+], 404.2333, found 404.2357.

[0875] LS-228: 4-(3-(((lr,4r)-4-(2-(4-cyanophenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzonitrile.1H NMR (400 MHz, CDCl3) δ 7.61 – 7.54 (m, 4H), 6.96 - 6.90 (m, 4H), 4.07 (t, J= 6.1 Hz, 2H), 4.02 (t, J = 6.5 Hz, 2H), 2.67 (t, J= 7.2 Hz, 2H), 2.53 - 2.40 (m, 1H), 2.33 (s, 3H). 2.06 - 1.96 (m, 2H), 1.87 (d, J= 11.5 Hz. 4H), 1.69 (q, J= 6.6 Hz. 2H), 1.51 - 1.39 (m, 1H), 1.37 - 1.24 (m, 2H), 1.09 - 0.95 (m, 2H).13C NMR (101 MHz, CDCl3) δ 162.32, 134.01, 119.31, 115.21, 115.17, 103.80, 66.41, 66.34, 63.09, 49.99, 37.69, 35.82, 34.31, 32.30, 27.76, 27.13. HRMS-ESI m / z calculated for C26H32N3O2+[M+H+] 418.2489, found 418.2518.

[0876] LS-225: 4-(2-((lr,4r)-4-((2-(4-carbamimidoylphenoxy)ethyl)(methyl)amino)cyclohexyl)ethoxy)benzimidamide. H NMR (400 MHz, CD3OD) δ 9.02 (d, J= 28.3 Hz, 3H), 8.52 (d, J= 33.1 Hz, 3H), 7.76 (d, J = 8.4 Hz, 2H), 7.71 (d, J= 8.5 Hz, 2H), 7.17 (d, J= 8.5 Hz, 2H), 7.04 (d, J= 8.6 Hz, 2H), 4.48 - 4.38 (m, 2H), 4.08 (t, J= 5.9 Hz, 2H), 3.77 - 3.68 (m. 1H), 3.51 - 3.41 (m, 1H), 3.37 - 3.27 (m, 1H), 2.87 (s, 3H), 2.10 (t, J= 12.1 Hz, 2H). 1.97 (d. J= 11.7 Hz, 2H), 1.73 - 1.65 (m, 2H), 1.64 - 1.51 (m, 3H), 1.19 - 1.08 (m, 2H).13C NMR (151 MHz, DMSO-d6) δ 164.69, 164.66, 162.99, 161.82, 130.25, 130.20, 120.19, 119.29, 114.97, 114.78, 66.15, 63.84, 63.16, 50.94, 36.66, 34.95, 33.01, 30.63, 30.55, 25.88, 24.79. HRMS-ESI m / z calculated for C25H36N5O2+[M+H+] 438.2864. found 438.2847.Attorney Docket No. 047162-7534WOl(02797)

[0877] LS-230: 4-(3-(((lr,4r)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzimidamide. ’l l NMR (400 MHz, D2O) 57.79 - 7.71 (m, 4H), 7.17 - 7.09 (m, 4H), 4.24 (t, J= 5.6 Hz, 2H), 4.18 (t, J= 6.4 Hz, 2H), 3.52 - 3.41 (m, 1H), 3.38 - 3.25 (m, 2H), 2.83 (s, 3H), 2.35 - 2.17 (m, 2H), 2.07 - 1.94 (m, 4H), 1.72 (q, J= 6.4 Hz, 2H), 1.62 - 1.50 (m, 3H), 1.19 - 1.07 (m, 2H).13C NMR (151 MHz, D2O) δ 165.82. 162.99, 162.58, 129.85, 129.80, 120.03. 119.62, 115.10. 115.05, 66.65, 65.32, 64.52. 50.81, 36.20. 34.48, 32.80. 30.42, 30.30, 26.64, 24.88, 23.82. HRMS-ESI m / z calculated for C26H38N5O2+[M+H+] 452.3020, found 452.3012.

[0878] Example 15: Synthesis of compound (±)-Z15 (TS-1-29)

[0879]

[0880] Compound (±)-Z15 was prepared according to the synthetic scheme depicted in FIG.

[0881] 20.

[0882] TS-1-8: tert-butyl (1R,5S,6r)-6-((4-cyano-2-fluorophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. 'H NMR (400 MHz, CDCl3) δ 7.43 – 7.33 (m, 2H), 6.96 (t, J= 8.3 Hz, 1H), 4.09 (dd, J= 10.2. 6.6 Hz, 1H), 3.90 (dd, 10.2, 7.4 Hz, 1H), 3.68 (d, J= 10.9 Hz. 1H), 3.61 (d. J= 10.8 Hz, 1H), 3.43 - 3.34 (m, 2H). 1.62 - 1.57 (m, 2H), 1.43 (s, 9H), 1.21 - 1.14 (m, 1H);13C NMR (101 MHz, CDCl3) δ 154.88, 151.92 (d, J = 250.3 Hz), 151.03 (d, J= 10.3 Hz), 129.64 (d, J= 3.8 Hz), 119.82 (d, J= 21.4 Hz), 118.01 (d, J= 2.8 Hz), 114.82 (d, J = 2.5 Hz), 104.15 (d, J= 8.4 Hz), 79.57, 70.95, 48.01. 47.69, 28.49, 21.95, 21.16. 20.98;19F NMR (376 MHz, CDCl3) δ -130.85.

[0883] TS-1-10: 4-(((l / ?,55,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-fluorobenzonitrile. 'H NMR (400 MHz, CDCl3) δ 7.40 – 7.35 (m, 1H), 7.35 - 7.30 (m, 1H), 6.95 (t, J = 8.3 Hz, 1H), 3.98 (d, J = 7.0 Hz, 2H), 3.04 (d, J= 11.3 Hz, 2H), 2.90 (d, J= 12.1 Hz. 2H), 2.03 (s, 1H), 1.53 - 1.45 (m, 2H), 1.12 (tt, J = 6.9, 3.2 Hz. 1H).13C NMR (101 MHz, CDCl3) δ 151.83 (d. J = 250.1 Hz). 151.12 (d, J = 10.3 Hz), 129.57 (d. J = 3.8 Hz), 119.66 (d, J = 21.5 Hz), 118.00 (d, J = 2.6 Hz), 114.77 (d, J = 2.6 Hz), 103.82 (d, J = 8.3 Hz), 71.43, 48.58, 23.23, 17.32.19F NMR (376 MHz, CDCl3) δ -130.93.

[0884] TS-1-16: 4-(((17?,55,6r)-3-(3-(4-cyanophenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-fluorobenzonitrile. 'H NMR (400 MHz, CDCl3) δ 7.59 – 7.54 (m, 2H), 7.42 – 7.33 (m, 2H), 6.99 - 6.90 (m, 3H), 4.03 (t, J = 6.3 Hz, 2H), 3.92 (d, J = 7.2 Hz, 2H),Attorney Docket No. 047162-7534WOl(02797)

[0885] 3.09 (d, J = 8.7 Hz, 2H), 2.58 (t, J = 6.9 Hz, 2H), 2.34 (d, J = 8.6 Hz, 2H), 1.92 (p, J = 6.7 Hz. 2H), 1.72 - 1.65 (m. 1H), 1.48 - 1.44 (m, 2H).13C NMR (101 MHz, CDCl3) δ 162.39. 151.91 (d, J = 250.2 Hz), 151.34, 151.23, 133.99, 129.63 (d, J= 3.9 Hz), 119.72 (d, J= 21.5 Hz), 119.34, 118.09 (d, J= 2.4 Hz), 115.21, 114.78 (d, J= 2.7 Hz), 103.75, 71.90, 66.40, 54.64, 51.37, 28.33, 21.42, 18.31.19F NMR (376 MHz, CDCl3) δ -131.00.

[0886] TS-1-25: 4-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-fluorobenzimidamide. 'H NMR (600 MHz, D2O+acetic acid-d4) δ 7.73 (d, J= 8.4 Hz, 2H), 7.61 - 7.55 (m, 2H), 7.22 (t, J= 8.4 Hz, 1H), 7.11 - 7.07 (m, 2H), 4.18 (t, J= 5.7 Hz, 2H), 4.09 (d, J= 7.1 Hz, 2H), 3.85 (d, J= 11.6 Hz, 2H), 3.44 (d, J= 11.3 Hz, 2H), 3.40 (t, J= 8.1 Hz, 2H), 2.23 - 2.17 (m, 2H), 2.04 - 1.99 (m, 2H), 1.58 - 1.50 (m, 1H).13C NMR (151 MHz, D2O+acetic acid-d4) δ 167.14, 166.36, 163.94, 152.82 (d, J = 245.7 Hz), 152.14, 152.07, 131.16, 126.65 (d, J= 3.4 Hz), 121.67 (d, J = 7.1 Hz), 121.32, 117.00 (d, J= 21.6 Hz), 116.33, 71.57, 66.56, 57.14, 54.28, 26.48, 21.54, 20.32.19F NMR (376 MHz, D2O+acetic acid-d4) δ -133.31.

[0887] Example 16: Synthesis of compound (±)-Z16 (TS-1-31)

[0888]

[0889] Compound (±)-Z16 was prepared according to the synthetic scheme depicted in FIG.

[0890] 21.

[0891] TS-1-18: tert-butyl (17?,55,6r)-6-((4-cyanophenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. 'H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 7.76 -7.71 (m, 2H), 7.58 - 7.53 (m, 2H), 3.67 (d, J= 11.2 Hz, 1H), 3.59 - 3.44 (m, 3H), 2.17 (t, J = 2.9 Hz, 2H), 1.48 (s, 9H), 1.46 - 1.43 (m, 1H).13C NMR (101 MHz, CDCl3) δ 170.21, 155.07. 143.02, 133.18, 119.13, 106.20, 80.57, 48.11, 28.49, 26.78. 26.06, 25.36.

[0892] TS-1-21: (17?,55,6r)-3-(3-(4-cyanophenoxy)propyl)-7V-(4-cyanophenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide. *HNMR (400 MHz, CDCl3+methanol-d4) δ 7.66 – 7.61 (m, 2H), 7.57 - 7.51 (m, 4H), 6.93 - 6.88 (m, 2H), 4.01 (t, J= 6.0 Hz, 2H), 3.14 (d, J = 9.5 Hz. 2H), 2.65 (t, J= 7.7 Hz, 2H), 2.50 (d, 9.4 Hz, 2H), 2.02 (t, J= 2.6 Hz, 2H). 1.99 - 1.91 (m, 2H), 1.87 (t, J= 3.1 Hz, 1H).13C NMR (101 MHz, CDCl3+methanol-d4) δ 162.05, 142.81, 133.91, 133.02, 119.11, 119.00, 118.95, 115.00, 105.74, 103.53, 65.97, 54.82, 52.38, 27.94, 25.70, 23.94.Attorney Docket No. 047162-7534WOl(02797)

[0893] TS-1-27: (1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-N-(4-carbamimidoylphenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide. 'H NMR (600 MHz, D2O+acetic acid-d4) δ 7.76 (t, J= 6.5 Hz, 4H), 7.67 (d, J= 8.4 Hz, 2H), 7.13 (d, J= 8.4 Hz, 2H), 4.21 (t, J= 5.7 Hz, 2H), 3.95 (d, J= 11.9 Hz, 2H), 3.58 (d, J= 12.2 Hz, 2H), 3.46 (t, J = 7.8 Hz, 2H), 2.50 - 2.38 (m, 2H), 2.28 - 2.19 (m, 2H), 2.11 - 2.03 (m, 1H).13C NMR (151 MHz, D2O+acetic acid-d4) δ 172.11. 167.09, 163.86, 143.54, 131.10, 130.85. 130.19, 124.72, 121.86. 121.28, 116.28, 66.35. 56.93, 54.37. 26.45, 25.41.

[0894] Example 17: Synthesis of compound (±)-Z17 (LS- 1-252)

[0895]

[0896] Compound (±)-Z17 was prepared according to the synthetic scheme depicted in FIG.

[0897] 22. LS-1-252: 6-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)nicotinimidamide. 'H NMR (600 MHz, D2O) δ 8.44 (d, J = 2.4 Hz, 1H), 8.07 (d, J= 8.8 Hz, 1H), 7.77 (d, J= 8.5 Hz, 2H), 7.58 (dd, J= 8.7, 2.4 Hz. 1H), 7.14 (d, J= 8.5 Hz. 2H), 4.25 (t, J = 5.7 Hz, 2H), 4.16 (d, J= 7.0 Hz, 2H), 3.91 (d, J = 11.6 Hz, 2H), 3.51 (d, J= 11.2 Hz, 2H). 3.48 - 3.44 (m. 2H), 2.33 - 2.23 (m. 2H), 2.11 -2.07 (m, 2H), 1.64 - 1.58 (m, 1H).

[0898] Example 18: Synthesis of compound (±)-Z18 (TS-1-30)

[0899]

[0900] Compound (±)-Z18 was prepared according to the synthetic scheme depicted in FIG.

[0901] 23.

[0902] TS-1-19: tert-butyl (17?,55,6r)-6-(((4-cyanophenyl)thio)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. 'HNMR (400 MHz, CDCl3) δ 7.55 – 7.51 (m, 2H), 7.32 - 7.28 (m. 2H), 3.60 (d. J= 10.9 Hz, 1H), 3.51 (d, J= 10.9 Hz, 1H). 3.33 (t. J= 9.7 Hz.

[0903] 2H), 3.03 - 2.87 (m, 2H), 1.50 - 1.46 (m, 2H), 1.42 (s, 9H), 0.96 - 0.89 (m, 1H).13C NMR (101 MHz, CDCl3) δ 154.86, 144.74, 132.32, 127.13, 118.86, 108.42, 79.55, 48.21, 47.92, 34.83, 28.48, 24.17, 23.50, 21.24.Attorney Docket No. 047162-7534WOl(02797)

[0904] TS-1-22: 4-((((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzonitrile.

[0905] 'H NMR (400 MHz, CDCl3) δ 7.55 – 7.48 (m, 2H), 7.33 – 7.27 (m, 2H), 3.01 – 2.94 (m, 4H), 2.89 - 2.83 (m, 2H), 2.04 (s, 1H), 1.44 - 1.38 (m, 2H), 0.93 - 0.85 (m, 1H).13C NMR (101 MHz, CDCl3) δ 145.03, 132.13, 126.88, 118.83, 108.01, 48.73, 34.81, 25.54, 17.24.

[0906] TS-1-23: 4-((((l / ?,55,6r)-3-(3-(4-cyanophenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzonitrile. 'H NMR (400 MHz, CDCl3) δ 7.58 – 7.53 (m, 2H), 7.53 -7.48 (m, 2H), 7.32 - 7.27 (m, 2H). 6.94 - 6.88 (m, 2H). 4.00 (t. J= 6.3 Hz. 2H), 3.03 (d. J = 8.9 Hz, 2H), 2.88 (d, J= 7.3 Hz, 2H), 2.55 (t, J= 7.0 Hz, 2H), 2.30 (d, J= 8.6 Hz, 2H), 1.90 (p, J= 6.8 Hz, 2H), 1.48 - 1.41 (m, 1H), 1.38 - 1.34 (m, 2H).13C NMR (101 MHz, CDCl3) δ 162.36, 145.36, 133.98, 132.22, 126.87, 119.32, 118.96, 115.19, 108.07, 103.76, 66.42, 54.91, 51.48. 35.41, 28.34, 23.89, 18.24.

[0907] TS-1-28: 4-((((17?,55,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzimidamide. 'H NMR (600 MHz, D2O+acetic acid-d4) δ 7.72 – 7.61 (m, 4H), 7.48 (d, J= 8.1 Hz, 2H), 7.02 (d, J= 8.5 Hz, 2H), 4.12 (d, J= 5.9 Hz, 2H), 3.73 (d, J= 11.6 Hz, 2H), 3.40 - 3.26 (m, 4H), 3.03 (d, J= 7.0 Hz, 2H), 2.17 - 2.09 (m. 2H), 1.91 - 1.82 (m, 2H), 1.32 - 1.24 (m, 1H).13C NMR (151 MHz, D2O+acetic acid-d4) δ 167.24, 167.10, 163.94, 145.79, 131.16, 129.52, 128.83, 125.72, 121.24, 116.31, 66.73, 59.35, 57.28, 54.30, 34.31, 26.45, 23.49.

[0908] Example 19: Synthesis of compound (±)-Z19

[0909]

[0910] Compound (±)-Z19 was prepared according to the synthetic scheme depicted in FIG.

[0911] 24.

[0912] TS-1-9: tert-butyl (1R,5S,6r)-6-((4-cyano-2-methylphenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. 'H NMR (400 MHz, CDCl3) δ 7.45 (dd, J= 8.4, 2.2 Hz, 1H), 7.41 (d, J = 3.0 Hz, 1H), 6.78 (d, J= 8.5 Hz, 1H), 4.00 - 3.87 (m, 2H), 3.71 -3.64 (m, 1H), 3.63 - 3.53 (m, 1H), 3.43 - 3.35 (m, 2H), 2.22 (s, 3H), 1.59 - 1.58 (m, 1H), 1.44 (s. 9H), 1.43 (s, 1H), 1.17 - 1.11 (m, 1H).13C NMR (101 MHz, CDCl3) δ 160.30, 154.95. 134.06, 131.89, 128.39, 119.51. 110.99. 103.51, 79.55, 69.44, 48.12. 47.81, 28.52.

[0913] 21.60, 21.48, 20.94, 16.13.Attorney Docket No. 047162-7534WOl(02797)

[0914] TS-1-17: 4-(((1R,5S,6r)-3-(3-(4-cyanophenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methylbenzonitrile. 'H NMR (400 MHz, CDCl3) δ 7.59 – 7.54 (m, 2H),

[0915] 7.44 (dd, J = 8.4, 2.2 Hz, 1H), 7.41 - 7.38 (m, 1H), 6.96 - 6.91 (m, 2H), 6.78 (d, J = 8.5 Hz, 1H), 4.04 (t, J= 6.3 Hz, 2H), 3.86 (d, J= 6.8 Hz, 2H), 3.10 (d, J= 8.7 Hz, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.37 (d, J= 9.2 Hz, 2H), 2.22 (s, 3H), 1.94 (p, J= 6.7 Hz, 2H), 1.68 - 1.61 (m, 1H), 1.48 - 1.44 (m, 2H).13C NMR (101 MHz, CDCl3) δ 162.38, 160.53, 133.99, 133.97, 131.86. 128.36, 119.58, 119.31, 115.21, 111.08. 103.77. 103.24, 70.32. 66.45, 54.80. 51.58, 28.34, 21.21, 18.64, 16.15.

[0916] TS-1-26: 4-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methylbenzimidamide. ’H NMR (600 MHz, D2O+acetic acid-d4) δ 7.70 (d. J = 8.4 Hz. 2H), 7.60 - 7.56 (m, 2H), 7.07 (d, J= 8.4 Hz, 2H), 7.02 (d, J = 8.5 Hz, 1H), 4.16 (t, J = 5.8 Hz, 2H), 4.03 (d, J= 6.6 Hz, 2H), 3.83 (d, J = 11.5 Hz, 2H), 3.47 - 3.33 (m, 4H), 2.22 (s, 3H), 2.21 - 2.16 (m, 2H), 2.03 - 1.96 (m, 2H), 1.54 -1.47 (m, 1H).13C NMR (151 MHz, D2O+acetic acid-d4) δ 167.05, 167.03, 163.86, 162.30, 131.19. 131.07, 129.45, 128.71, 121.21, 120.72. 116.24, 113.34, 70.26, 66.52, 57.09. 54.18, 26.38, 21.24, 20.46, 16.54.

[0917] Example 20: Synthesis of compound (±)-Z20 (LS- 1-245)

[0918]

[0919] H

[0920] Compound (±)-Z20 was prepared according to the synthetic scheme depicted in FIG.

[0921] 25.

[0922] LS- 1-234: tert-butyl (17?,5N,6r)-6-((4-cy ano-2-methoxy phenoxy )methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. 1H NMR (400 MHz, CDCl3) 57.24 (dd, J= 8.3, 1.9 Hz. 1H), 7.08 (d. J= 1.9 Hz. 1H), 6.85 (d. J= 8.3 Hz. 1H), 4.09 - 4.01 (m, 1H), 3.89 (s, 4H), 3.72 - 3.59 (m, 2H), 3.42 - 3.32 (m, 2H), 1.61 - 1.56 (m, 2H), 1.43 (s, 9H), 1.22 - 1.18 (m, 1H). 13C NMR (101 MHz, CDCl3) 5 154.86, 152.17, 149.53, 126.34, 119.26, 114.36, 112.73, 104.10, 79.51, 70.64, 56.18, 48.01, 47.73, 28.49, 21.96, 21.20, 21.03.

[0923] LS- 1-237: 4-(((lR,5S,6r)-3-(3-(4-cyanophenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methoxybenzonitrile. 'H NMR (600 MHz.

[0924] CDCh) 7.58 - 7.55 (m, 2H), 7.25 - 7.22 (m, 1H), 7.07 (d,.7= 1.5 Hz, 1H), 6.94 - 6.91 (m, 2H), 6.86 (d, J= 8.4 Hz, 1H), 4.02 (t, J= 6.3 Hz, 2H), 3.90 - 3.88 (m, 5H), 3.09 (d, J= 8.7Attorney Docket No. 047162-7534WOl(02797)

[0925] Hz, 2H), 2.57 (t, J= 6.9 Hz, 2H), 2.33 (d, J= 8.3 Hz, 2H), 1.91 (p, J= 6.6 Hz, 2H), 1.74 - 1.69 (m, 1H), 1.45 (t, J= 2.6 Hz, 2H).13C NMR (151 MHz, CDCl3) δ 162.41, 152.42, 149.49, 133.99, 126.37, 119.34, 119.32, 115.22, 114.31, 112.70, 103.82, 103.75, 71.57, 66.40, 56.20, 54.70, 51.33, 28.34, 21.48, 18.38. HRMS-ESI m / z calculated for C24H26N3O3+[M+H+] 404.1969, found 404.1990.

[0926] LS- 1-245: 4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methoxybenzimidamide. 'H NMR (400 MHz, D2O+acetic acid-d6) δ 7.64 (d, J= 8.5 Hz, 2H), 7.33 (dd, J= 8.5, 2.2 Hz, 1H), 7.27 (d, J= 2.2 Hz, 1H), 7.01 (d,.7= 8.6 Hz, 3H), 4.10 (t, J= 5.7 Hz, 2H), 3.96 (d, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.78 (d, J = 11.5 Hz, 2H), 3.42 - 3.28 (m, 4H), 2.18 - 2.10 (m, 2H), 1.95 - 1.89 (m. 2H), 1.49 - 1.42 (m. 1H).13C NMR (151 MHz. D2O+acetic acid-d6) δ 167.13. 167.08, 164.00, 153.37, 149.83, 131.20, 123.45, 121.59, 121.30, 116.39, 114.11, 112.11, 71.16, 66.63, 57.22, 57.18, 54.32, 26.52, 21.59, 20.39. HRMS-ESI m / z calculated for C24H32N5O3+[M+H+] 438.2500, found 438.2523.

[0927] Example 21: Synthesis of compound (±)-Z21 (LS- 1-254)

[0928]

[0929] Compound (±)-Z21 was prepared according to the synthetic scheme depicted in FIG.

[0930] 26.

[0931] LS-1-238: tert-butyl (1R,5S,6r)-6-((2-bromo-4-cyanophenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. 'H NMR (400 MHz, CDCl3) δ 7.82 (d, J= 2.0 Hz, 1H), 7.56 (dd, J= 8.6, 2.0 Hz, 1H), 6.88 (d, J= 8.6 Hz, 1H), 4.12 - 4.04 (m, 1H), 4.01 - 3.94 (m, 1H), 3.68 (d,.7= 11.0 Hz, 1H), 3.59 (d, J= 11.0 Hz, 1H), 3.43 - 3.36 (m, 2H), 1.66 -1.63 (m, 2H), 1.44 (s, 9H). 1.19 - 1.14 (m, 1H).13C NMR (101 MHz, CDCl3) δ 158.70, 154.93, 136.82, 133.07, 117.78, 112.94, 112.85, 105.32, 79.58, 70.49, 48.07, 47.77, 28.50, 21.73, 21.11, 20.98.

[0932] LS- 1-246: 3-bromo-4-(((lR,5S,6r)-3-(3-(4-cyanophenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzonitrile. 'H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 1.9 Hz, 1H), 7.57 (d. J= 8.9 Hz. 2H), 7.56 - 7.54 (m. 1H), 6.95 - 6.92 (m, 2H), 6.88 (d, J = 8.6 Hz, 1H), 4.04 (t, J= 6.3 Hz, 2H), 3.96 (d,,7= 6.8 Hz, 2H), 3.10 (d, J= 8.7 Hz, 2H), 2.59 (t, J= 7.0 Hz, 2H), 2.36 (d, J= 8.3 Hz, 2H), 1.93 (p, J= 6.6 Hz, 2H), 1.70 - 1.65 (m,Attorney Docket No. 047162-7534WOl(02797)

[0933] 1H), 1.54 - 1.49 (m, 2H).13C NMR (151 MHz, CDCh) 8 162.39, 158.95, 136.77, 133.99, 133.04. 119.32, 117.85, 115.22, 113.03, 112.83, 105.07. 103.78, 71.55, 66.45, 54.72, 51.48, 28.37, 21.35, 18.26. HRMS-ESI m / z calculated for C^tfeBrNsCh [M+H+] 454.0968, found 454.0968.

[0934] LS- 1-254: 3-bromo-4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide.

[0935] 'H NMR (600 MHz, D2O) 88.01 (s. 1H), 7.73 (d. J= 7.4 Hz. 3H), 7.18 (d. J= 8.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 4.12 (t, J = 6.2 Hz, 2H), 4.06 (d, J = 7.0 Hz, 2H), 3.13 (d, J = 9.7 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.62 (d, J= 9.5 Hz, 2H), 2.01 - 1.93 (m, 2H), 1.69 -1.63 (m, 2H), 1.54 - 1.49 (m, 1H).,3C NMR (151 MHz, D2O) 8 165.73, 164.75, 162.90, 159.10. 132.65, 129.74, 128.98, 121.16. 119.62. 115.01, 114.19, 111.91, 72.03. 66.74, 54.66.

[0936] 52.28, 26.97, 21.16, 19.30. HRMS-ESI m / z calculated for C2H29BrN5O2+[M+H+] 488.1499, found 488.1485.

[0937] Example 22: Synthesis of compound (±)-Z22 (TS-1-13) and (±)-Z23 (TS-1-12)

[0938]

[0939] Compounds (±)-Z22 and (±)-Z23 was prepared according to the synthetic scheme depicted in FIG. 27.

[0940] TS-1-6: 4-(3-((l / ?,5N,6 / )-6-((4-(hydrazineyl(imino)methyl)phenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidohydrazide. 'H NMR (600 MHz, D2O+acetic acid-A) 87.70 - 7.64 (m, 4H), 7.04 - 7.00 (m, 4H), 4.15 (t, J= 5.8 Hz, 2H), 4.00 (d, J= 7.0 Hz, 2H), 3.82 (d, J= 11.5 Hz, 2H), 3.42 (d, J= 11.5 Hz, 2H), 3.38 (t, J= 8.0 Hz, 2H), 2.21 - 2.14 (m, 2H), 2.00 - 1.96 (m, 2H), 1.50 - 1.44 (m, 1H).,3C NMR (151 MHz, D2O+acetic acid-dr) 8 163.01, 135.84. 135.81, 121.33, 116.68, 116.56, 104.37, 104.35.70.33, 66.59, 57.18, 54.34, 26.43, 21.46, 20.37. HRMS-ESI m / z calculated for C23H32N7O2+[M+H+] 438.2612, found 438.2599.Attorney Docket No. 047162-7534WOl(02797)

[0941] TS-1-7:.\-hydroxy-4-(3-((l / ?.5. S’.6 / )-6-((4-(.\-hydroxycarbamimidoyl)phenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide. 'HNMR (600 MHz, D2O+acetic acid-u ) 57.65 - 7.61 (m, 4H), 7.10 - 7.07 (m, 4H), 4.16 (t, J= 5.7 Hz, 2H), 4.00 (d, J= 6.9 Hz, 2H), 3.83 (d, J= 11.5 Hz, 2H), 3.48 - 3.34 (m, 4H), 2.22 - 2.16 (m, 2H), 2.03 - 1.96 (m, 2H), 1.54 - 1.43 (m, 1H).

[0942] 13C NMR (151 MHZ, D2O+acetic acid-t / r) 5 163.59. 163.57, 162.36, 162.34, 130.76, 130.74.

[0943] 118.60. 118.58, 116.56, 116.49, 70.36. 66.47, 57.11. 54.21, 26.44, 21.42, 20.44. HRMS-ESI m / z calculated for C23H3oN504+[M+H+] 440.2292, found 440.2294.

[0944] Example 23: Synthesis of compound (±)-Z25 (TS-1-81)

[0945]

[0946] Compound (±)-Z25 was prepared according to the synthetic scheme depicted in FIG.

[0947] 28.

[0948] TS-1-42: tert-butyl 4-(2-(4-cyano-2-fluorophenoxy)ethyl)azepane-l-carboxylate.

[0949] XH NMR (500 MHz, DMSO-c / r>. 90 °C) 5 7.69 (dd, J= 11.2, 2.1 Hz, 1H), 7.59 (dt, J= 8.6, 1.5 Hz, 1H), 7.33 (t, J= 8.5 Hz, 1H), 4.21 (t, J= 6.5 Hz, 2H), 3.51 - 3.43 (m, 1H), 3.41 - 3.34 (m, 1H), 3.30 - 3.22 (m, 1H), 3.22 - 3.15 (m, 1H), 1.87 - 1.76 (m, 2H), 1.77 - 1.69 (m, 4H), 1.69 - 1.62 (m. 1H), 1.57 - 1.48 (m. 1H), 1.40 (s, 9H), 1.29 - 1.21 (m, 1H).13C NMR (126 MHz, DMSO-6 / 6. 90 °C) 5 154.20. 150.92 (d, J = 247.7 Hz), 150.52 (d. J= 10.1 Hz). 129.73 (d,.7= 3.7 Hz), 119.11 (d, J= 21.8 Hz), 117.38 (d, J= 2.6 Hz), 115.51, 102.60 (d, J= 8.7 Hz), 77.70, 67.53, 45.70, 44.23, 35.10, 34.65, 33.63, 32.21, 27.76, 25.96.

[0950] TS-1-78: 4-(2-(l-(3-(4-cyanophenoxy)propyl)azepan-4-yl)ethoxy)-3-fluorobenzonitrile. 'H NMR (500 MHz, DMSO-t / e, 90 °C) 57.72 - 7.67 (m. 3H), 7.59 (dt, J = 8.8, 1.7 Hz, 1H), 7.32 (t, J= 8.5 Hz, 1H), 7.11 - 7.06 (m, 2H), 4.19 (t, J= 6.5 Hz, 2H), 4.13 (t, J= 6.3 Hz, 2H), 2.83 - 2.75 (m, 1H), 2.74 - 2.61 (m, 5H), 1.91 (p, J= 6.7 Hz, 2H), 1.82 -1.76 (m, 2H), 1.76 - 1.69 (m, 4H), 1.62 - 1.52 (m, 1H), 1.50 - 1.41 (m, 1H), 1.40 - 1.31 (m, 1H).13C NMR (126 MHZ, DMSO-Je, 90 °C) 5 161.82, 150.90 (d. J = 248.0 Hz), 150.53 (d, J = 10.5 Hz), 133.56, 129.74 (d, J= 3.6 Hz), 119.12 (d, J= 21.8 Hz), 118.44, 117.39 (d, J = 2.5 Hz), 115.52, 115.28, 102.59, 67.64, 66.15, 54.50, 53.66, 52.52, 35.47, 34.28, 32.86, 32.26, 26.20, 25.28.Attorney Docket No. 047162-7534WOl(02797)

[0951] TS-1-81: 4-(2-(l-(3-(4-carbamimidoylphenoxy)propyl)azepan-4-yl)ethoxy)-3-fluorobenzimidamide. 'H NMR (400 MHz, d2o) 57.60 - 7.55 (m. 2H), 7.46 - 7.39 (m, 2H), 7.11 (t, J = 8.6 Hz, 1H), 6.96 - 6.90 (m, 2H), 4.09 - 3.99 (m, 4H), 3.47 - 3.37 (m, 1H), 3.36 -3.25 (m, 1H), 3.23 - 3.15 (m, 2H), 3.13 - 3.03 (m, 1H), 3.02 - 2.90 (m, 1H), 2.12 - 2.03 (m, 2H), 1.89 - 1.80 (m, 2H), 1.79 - 1.70 (m, 2H), 1.69 - 1.58 (m, 3H), 1.54 - 1.42 (m, 1H), 1.29 - 1.11 (m, 1H). HRMS-ESI m / z calculated for C^HssFNsO [M+H+] 456.2769, found 456.2794.

[0952] Example 24: Antifungal activity of exemplary compounds of the disclosure

[0953] In one aspect, the disclosure relates to the design, synthesis, and evaluation of new analogs of T- 2307 for use as antifungal agents. A series of new chemical entities have been synthesized and tested against Candida albicans and C. parapsilosis, with cytotoxicity and metabolic stability further evaluated in human cell lines (HEK-293T).

[0954] Minimum inhibitory concentrations (MICs) were measured for certain exemplary compounds of the disclosure (i.e., compounds 1-34, 1-54. 1-74. 1-83. 1-84. 1-139, and 1-143) and compound T-2307, with certain compounds thereof demonstrating high activity against C. parapsilosis and C. albicans (i.e., compounds 1-74, 1-83, 1-139, and 1-143) (Table 2). Notably, the performance of compound 1-143 was comparable to that of T-2307 against C. parapsilosis and only marginally lower than T-2307 against C. albicans. The antifungal activity of certain compounds of the disclosure was further evaluated against C. parapsilosis, C. albicans, C. auris, and.4. Fumigatus (Tables 3-5).

[0955] These results indicate that bis-amidines have wide-spectrum anti-fungal activity. It is hypothesized herein that exploration of additional species will yield pathogens which are highly susceptible to these compounds.

[0956] Table 2. Minimum Inhibitory Concentration (MIC) for certain exemplary compounds Cmpd 48 h MIC (jig / mL) 24 h MIC (ug / mL) 48 h MIC (ug / mL) No. C. parapsilosis C albicans HEK-293T 1-34 >0.004 >0.004 >16

[0957] 1-54 >0.004 >0.004 Not tested

[0958] 1-74 0.004 0.001 >16

[0959] 1-83 0.002 0.001 >16

[0960] 1-84 >0.004 0.004 Not tested

[0961] 1-139 0.002 0.002 Not tested

[0962] 1-143 0.001 0.00025 Not tested

[0963]

[0964] T-2307 0.001 0.00025-0.000125 >16

[0965] * Compounds administered as trihydrochloride salt.Attomey Docket No. 047162-7534WOl(02797)

[0966] Table 3. Antifungal activities of certain exemplary compounds of the disclosure against C.

[0967] Albicans and C. Parapsilosis _ _

[0968] Compound 24h MIC for C. albicans, 48h MIC for C. parapsilosis, ug / ml ug / ml

[0969] Z2 0.0040 0.0080

[0970] (±)-Z8 (LS-1-212) 0.00025 0.0015

[0971] (±)-Z9 (LS-1-214) 0.0033 >0.032

[0972] (±)-Z10(LS-l-215) 0.016 >0.032

[0973] (±)-Zll(LS-l-217) >0.032 >0.032

[0974] (±)-Z12 (LS-1- 0.0010 0.012

[0975] 223)

[0976] (±)-Z13 (LS-1- 0.0040 0.0080

[0977] 225)

[0978] (±)-Z14 (LS-1- 0.0017 0.0053

[0979] 230)

[0980] (±)-Z15 (TS-1-29) 0.00067 0.0020

[0981] (±)-Z16 (TS-1-31) 0.0023 0.016

[0982] (±)-Z17 (LS-1- 0.0013 0.0053

[0983] 252)

[0984] (±)-Z18 (TS-1-30) 0.0017 0.0133

[0985] (±)-Z19 (TS-1-32) 0.00067 0.0040

[0986] (±)-Z20 (LS-1- 0.0020 0.024

[0987] 245)

[0988] (±)-Z21 (LS-1- 0.0013 0.0067

[0989] 254)

[0990] (±)-Z22 (TS-1-13) >0.032 >0.032

[0991] (±)-Z23 (TS-1-12) >0.032 >0.032

[0992] (±)-Z25 (TS-1-81) 0.0027 0.0067

[0993]

[0994] Hydrochloride salts ol 'compounds were used. MIC50 was defined by a prominent (>50%) drop in perceived turbidity. Fungi were cultured in RPMI 1640, pH 7.0 (0.2% glucose) and incubated at 37 °C for stated time. Strains for C. Albicans and C. Parapsilosis used were MYA2876 and ATCC 22019, respectively.

[0995] Table 4. Antifungal activity of certain exemplary compounds of the disclosure against C. Auris

[0996] C. Auris (ug / mL), 24 h

[0997] Cmpd

[0998] CDC381 CDC382 CDC383 CDC384 CDC385 CDC390 Z2 0.063 >4.0 >4.0 >4.0 0.50 >4.0 (±)-Z8 0.0078 0.063 0.031 0.063 0.016 0.016 (±)-Z9 0.25 0.25 0.25 0.25 0.13 0.13 (±)-Z12 0.25 0.13 0.13 0.063 0.063 0.063 (±)-Z14 0.13 2.0 0.25 1.0 0.25 0.50 (±)-Z15 0.0078 0.031 0.016 0.031 0.0039 0.0078 (±)-Z16 0.13 >4.0 0.50 1.0 0.50 1.0 (±)-Z17 0.0078 0.063 0.016 0.031 0.0078 0.0078 (±)-Z18 0.25 0.13 0.25 0.13 0.13 0.013

[0999]

[1000] (±)-Z19 0.13 0.063 0.25 0.13 0.031 0.063Attorney Docket No. 047162-7534WOl(02797)

[1001] (±)-Z20 0.25 0.25 0.25 0.13 0.063 0.013 (±)-Z21 0.13 0.13 0.25 0.13 0.063 0.063 (±)-Z25 >4.0 0.13 0.50 0.25 0.063 0.063

[1002]

[1003] Hydrochloric e salts of compounds were used.

[1004] Table 5. Antifungal activity of certain exemplary compounds of the disclosure against A. Fumigatus _

[1005] A. Fumigatus (pg / mL)

[1006] Cmpd

[1007] AF293 CEA10 DI-20-109 DI-15-110 DI-16-07 DI-15-105 Z2 0.13 >4.0 >4.0 >4.0 0.25 >4.0 (±)-Z8 0.031 >4.0 >4.0 >4.0 0.063 >4.0 (±)-Z9 >4.0 >4.0 >4.0 >4.0 >4.0 >4.0 (±)-Z12 >4.0 >4.0 >4.0 >4.0 >4.0 >4.0 (±)-Z14 0.031 >4.0 >4.0 >4.0 0.063 >4.0 (±)-Z15 0.13 >4.0 >4.0 >4.0 >4.0 >4.0 (±)-Z16 0.50 >4.0 >4.0 >4.0 >4.0 >4.0 (±)-Z17 0.50 >4.0 >4.0 >4.0 >4.0 >4.0 (±)-Z18 4.0 >4.0 >4.0 >4.0 >4.0 >4.0 (±)-Z19 1.0 >4.0 >4.0 >4.0 >4.0 >4.0 (±)-Z20 2.0 >4.0 >4.0 >4.0 >4.0 >4.0 (±)-Z21 2.0 >4.0 >4.0 >4.0 >4.0 >4.0 (±)-Z25 0.50 >4.0 >4.0 >4.0 >4.0 >4.0

[1008]

[1009] Hydrochloric e salts of compounds were used.

[1010] Additionally, the tested compounds were found to be non-toxic to human kidney cells (Table 6). Cytotoxicity test on mammalian A549 and HEK293T cells demonstrated that the bis-amidine compounds have a IC50 values over 25 ug / mL, which is at least 781 -fold higher than their MIC50 values, indicating these bis-amidine compounds are not toxic to humans.

[1011] Table 6. Cytotoxicity' of certain exemplary' compounds of the disclosure on A549 and HEK293T cells

[1012] Compound IC50(ug / mL) on A549, 48 h IC50(ug / mL) on HEK293T, 48 h (±)-Z8 (LS-1-212) >25 >25

[1013] (±)-Z9 (LS-1-214) >25 >25

[1014] (±)-Z12 (LS-1- 223) >25 >25

[1015] (±)-Z14 (LS-1- 230) >25 >25

[1016] (±)-Z15 (TS-1-29) >25 >25

[1017] (±)-Z16 (TS-1-31) >25 >25

[1018] (±)-Z17 (LS-1- 252) >25 >25

[1019]

[1020] (±)-Z19 (TS-1-32) >25 >25Attorney Docket No. 047162-7534WOl(02797)

[1021] (±)-Z20 (LS-1- 245) >25 >25

[1022] (±)-Z25 (TS-1-81) >25 >25

[1023]

[1024] Hydrochloride salts ol ' compounds were used.

[1025] Enumerated Embodiments

[1026] The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance:

[1027] Embodiment 1: A compound of formula (I), or a salt, stereoisomer, or isotopologue thereof:

[1028] R1a-X1-L1-A— L2-X2— R1b(I)wherein:

[1029] A is selected from the group consisting of optionally substituted C2-C8 monocyclic heterocycloalkylenyl, optionally substituted C3-C12 bicyclic heterocycloalkylenyl. and optionally substituted C3-C8 aminocycloalkylenyl,

[1030] wherein the monocyclic heterocycloalkyl in A comprises at least two ringmember nitrogen atoms;

[1031] Rlaand Rlbare each independently selected from the group consisting of C6-C10 aryl and C2-C10 heteroaryl,

[1032] wherein each Ce-Cio aryl and C2-C10 heteroaryl is substituted with at least one C(=NRB)N(Rc)(RD) substituent, and

[1033] wherein each Ce-Cio aryl and C2-C10 heteroaryl is optionally further substituted;

[1034] L1and L2are each independently selected from the group consisting of Ci-Ce alkylenyl, optionally substituted C2-C6 heteroalkylenyl, and a bond;

[1035] X1and X2are each independently selected from the group consisting of -O-, -S-, and -N(RA);

[1036] each occurrence of RAis independently selected from the group consisting of H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted Ce-Cio ar l. optionally substituted C2-C8 heteroaryl. C(=NRB)N(RC)(RD), C(=O)RB, C(=O)ORB, C(=O)N(RB)(RC), S(=O)RB, S(=O)2RC, S(=O)N(RB)(RC),

[1037]

[1038] S(=O)2N(RB)(RC), and P(=O)(ORB)(ORC);Attorney Docket No. 047162-7534WOl(02797)

[1039] each occurrence of RB, RC, and RDis independently selected from the group consisting of H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heteroaryl, C(=O)(RE), C(=O)ORE, C(=O)N(RE)(RF), S(=O)RE, S(=O)2RE, S(=O)N(RE)(RF), S(=O)2N(RE)(RF), and P(=O)(ORE)(ORF). or wherein RBand one of RCand RDcan combine with the atoms to which they are bound to form an optionally substituted C2-C5 heterocycloalkyl; and each occurrence of REand RFis independently selected from the group consisting of H, optionally substituted Ci-Ce alky l, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted Ce-Cio aryl;

[1040] wherein the compound is not 4,4'-((piperidine-l,4-diylbis(propane-3,l-diyl))bis(oxy))dibenzimidamide.

[1041] Embodiment 2: The compound of Embodiment 1, wherein A is selected from the group consisting of

[1042]

[1043] wherein:

[1044] each occurrence of R2and R3is independently selected from the group consisting of halogen, optionally substituted Ci-Ce alky l, optionally substituted C i-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted Ce-Cio aryl, and optionally substituted C2-C8 heteroaryl;

[1045] each occurrence of R4is independently selected from the group consisting of halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted Ce-Cio aryl, and optionally substituted C2-C8 heteroaryl;

[1046] each occurrence of I is independently 0, 1, or 2;

[1047] each occurrence of m is independently 0, 1, 2, or 3;

[1048] each occurrence of n is independently 0, 1, 2, 3, 4, or 5;Attorney Docket No. 047162-7534WOl(02797)

[1049] each occurrence of o is independently 0, 1, 2, 3, 4. 5, or 6:

[1050] each occurrence of p is independently 0. 1, 2, 3, 4. 5, 6, or 7;

[1051] each occurrence of q is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[1052] each occurrence of r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each occurrence of 5 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

[1053] Embodiment 3: The compound of Embodiment 1 or 2, wherein A is selected from the group consisting of:

[1054] H

[1055] H

[1056]

[1057] Embodiment 4: The compound of any one of Embodiments 1-3, wherein L1and L2are each independently selected from the group consisting of a bond, -(CH2)-, -(CH2)2-, -(CH2)3-, and -C(=O)-.Attorney Docket No. 047162-7534WOl(02797)

[1058] Embodiment 5: The compound of any one of Embodiments 1 -4, wherein one of the following applies:

[1059] (a) L1and L2are both -(CHi)?-;

[1060] (b) L1is a bond and L2is -(CEE)!-;

[1061] (c) L1is -(CH2)- and L2is -(CH2)2-;

[1062] (d) L1is -(CH2)- and L2is -(CH2)3-;

[1063] (e) L1is -(CH2)2- and L2is -(CEhh-;

[1064] (f) L1is -(CH2)2- and L2is -(CH2)3-;

[1065] (g) L1is -(CH2)3- and L2is -(CH2)3-; and

[1066] (

[1067]

[1068] h) L1is -(CH2)3 and L2is -C(=O)-.

[1069] Embodiment 6: The compound of any one of Embodiments 1-5, wherein X1and X2are each independently selected from the group consisting of -O-, -S-, and -NH-.

[1070] Embodiment 7: The compound of any one of Embodiments 1-6, wherein Rlaand Rlbare each independently selected from the group consisting of:

[1071]

[1072] wherein:

[1073] each occurrence of R3and R6, if present, is independently selected from

[1074] R7is C(=NR8)NH2;

[1075] R8is selected from the group consisting of H and S(=O)2(optionally substituted Ci-Ce alkyl);

[1076] each occurrence of t is independently 0, 1, 2, or 3;

[1077] each occurrence of u is independently 0, 1, 2, 3, or 4.

[1078] Embodiment 8: The compound of Embodiment 7, wherein R8is selected from the group consisting of IT and S(=O)2CEl3.

[1079] Embodiment 9: The compound of Embodiment 7 or 8, wherein R7is selected from the group consisting of C(=N[S(=O)2CI43])NH2 and C(=NI4)NH2.

[1080] Embodiment 10: The compound of any one of Embodiments wherein Rlaand Rlbare each independently selected from the group consisting of:Attorney Docket No. 047162-7534WOl(02797)

[1081]

[1082] Embodiment 11: The compound of any one of Embodiments 1-10, which is selected from the group consisting of:

[1083] 4,4'-(((2,7-diazaspiro[4.4]nonane-2,7-diyl)bis(propane-3,l-diyl))bis(oxy))dibenzimidamide; 4-(3-(5-(2-(4-carbamimidoylphenoxy)ethyl)hexahydrocyclopenta|c]pyrrol-2(lH)-yl)propoxy)benzimidamide;

[1084] 4-(3-((3aR,5r,6aS)-5-(2-(4-carbamimidoylphenoxy)ethyl)hexahydrocyclopenta[c]pyrrol- 2(lH)-yl)propoxy)benzimidamide;

[1085] 4-(3-((3aR.5s,6aS)-5-(2-(4-carbamimidoylphenoxy)ethyl)hexahydrocyclopenta|c]pyrrol- 2(l I)-yl)propoxy)benzimidamide;

[1086] 4,4'-(((3-azabicyclo[3.1.0]hexane-3,6-diyl)bis(propane-3,l-diyl))bis(oxy))dibenzimidamide; 4,4'-((((lR,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-diyl)bis(propane-3,l- diyl))bis(oxy))dibenzimidamide:

[1087] 4,4'-((((lR,5S,6s)-3-azabicyclo[3.1.0]hexane-3,6-diyl)bis(propane-3,l- diyl))bis(oxy))dibenzimidamide;

[1088] 4-(3-(6-((4-carbamimidoylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide;

[1089] 4-(3-((lR,5S,6s)-6-((4-carbamimidoylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide;

[1090] 4-(3-((lR,5S,6r)-6-((4-carbamimidoylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide;

[1091] 4-(3-(2-((4-carbamimidoylphenoxy)methyl)-7-azaspiro[3.5]nonan-7-yl)propoxy)benzimidamide;

[1092] 3-((7-(3-(4-carbamimidoylphenoxy)propyl)-7-azaspiro[3.5]nonan-2-yl)methoxy)benzimidamide;Attorney Docket No. 047162-7534WOl(02797)

[1093] 4-(3-(6-((4-carbamimidoylphenoxy)methyl)-3,4-dihydroisoquinolin-2(lH)-yl)propoxy)benzimidamide;

[1094] 4-(3-(9-(4-carbamimidoylphenoxy)-3-azaspiro[5.5]undecan-3-yl)propoxy)-N'- (methylsulfonyl)benzimidamide;

[1095] (E)-4-(3-(9-(4-carbamimidoylphenoxy)-3-azaspiro[5.5]undecan-3-yl)propoxy)-N'- (methylsulfonyl)benzimidamide;

[1096] (Z)-4-(3-(9-(4-carbamimidoylphenoxy)-3-azaspiro[5.5]undecan-3-yl)propoxy)-N'- (methylsulfonyl)benzimidamide;

[1097] 4-(3-(4-(2-(4-carbamimidoylphenoxy)ethyl)azepan-l-yl)propoxy)benzimidamide;

[1098] (S)-4-(3-(4-(2-(4-carbamimidoylphenoxy)ethyl)azepan-1-yl)propoxy)benzimidamide; (R)-4-(3-(4-(2-(4-carbamimidoylphenoxy)ethyl)azepan-1-yl)propoxy)benzimidamide; 4-(3-(l-(4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)guanidino)propoxy)benzimidamide;

[1099] 4-(3-(l-((ls,4s)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)guanidino)propoxy)benzimidamide;

[1100] 4-(3-(l-((lr,4r)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)guanidino)propoxy)benzimidamide;

[1101] 4-(3-((4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)amino)propoxy)benzimidamide; 4-(3-(((ls,4s)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)amino)propoxy)benzimidamide;

[1102] 4-(3-(((lr,4r)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)amino)propoxy)benzimidamide;

[1103] 3-(3-(3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)propoxy)benzimidamide;

[1104] 3-(3-((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)propoxy)benzimidamide;

[1105] 3-(3-((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)propoxy)benzimidamide;

[1106] 3-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[1107] 3-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[1108] 3-(((1R,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;Attorney Docket No. 047162-7534WOl(02797)

[1109] 6-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2-naphthimidamide;

[1110] 6-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2-naphthimidamide;

[1111] 6-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2-naphthimidamide;

[1112] 6-((4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)methyl)-3-(3-(4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)propyl)-3-azabicyclo[3.1.0]hexane;

[1113] (lR,5S,6r)-6-((4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)methyl)-3-(3-(4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)propyl)-3-azabicyclo[3.1.0]hexane;

[1114] (lR,5S,6s)-6-((4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)methyl)-3-(3-(4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)propyl)-3-azabicyclo[3.1.0]hexane;

[1115] 4-((3-(2-(4-carbamimidoylphenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[1116] 4-(((1R,5S,6r)-3-(2-(4-carbamimidoylphenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[1117] 4-(((lR,5S,6s)-3-(2-(4-carbamimidoylphenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[1118] 4-(2-(4-((2-(4-carbamimidoylphenoxy)ethyl)(methyl)amino)cyclohexyl)ethoxy)benzimidamide 4-(2- ((lr,4r)-4-((2-(4-carbamimidoylphenoxy)ethyl)(methyl)amino)cyclohexyl)ethoxy)benzi midamide;

[1119] 4-(2-((1r,4s)-4-((2-(4-carbamimidoylphenoxy)ethyl)(methyl)amino)cyclohexyl)ethoxy)benzimidamide;

[1120] 4-(3-((4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzimidamide;

[1121] 4-(3-(((lr,4r)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzimidamide;

[1122] 4-(3-(((lr,4s)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzimidamide;

[1123] 4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-fluorobenzimidamide;

[1124] 4-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-fluorobenzimidamide;Attorney Docket No. 047162-7534WOl(02797)

[1125] 4-(((1R,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-fluorobenzimidamide;

[1126] 3-(3-(4-carbamimidoylphenoxy)propyl)-N-(4-carbamimidoylphenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

[1127] (1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-N-(4-carbamimidoylphenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

[1128] (1R,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-N-(4-carbamimidoylphenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

[1129] 5-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)picolinimidamide;

[1130] 5-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)picolinimidamide;

[1131] 5-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)picolinimidamide;

[1132] 4-(((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzimidamide;

[1133] 4-((((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzimidamide;

[1134] 4-((((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzimidamide;

[1135] 4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methylbenzimidamide;

[1136] 4-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methylbenzimidamide;

[1137] 4-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methylbenzimidamide;

[1138] 4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methoxybenzimidamide;

[1139] 4-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methoxybenzimidamide;

[1140] 4-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methoxybenzimidamide;

[1141] 3-bromo-4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;Attorney Docket No. 047162-7534WOl(02797)

[1142] 3-bromo-4-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[1143] 3-bromo-4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;

[1144] 4-(2-(l-(3-(4-carbamimidoylphenoxy)propyl)azepan-4-yl)ethoxy)-3-fluorobenzimidamide.

[1145] Embodiment 12: The compound of any one of Embodiments 1-11, wherein the compound is a salt of the compound of Formula (I).

[1146] Embodiment 13: The compound of Embodiment 12, wherein the compound is selected from the group consisting of a hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, benzenesulfonate, citrate, acetate, maleate, and fumarate salt.

[1147] Embodiment 14: A pharmaceutical composition comprising the compound of any one of Embodiments 1-13 and at least one pharmaceutically acceptable excipient.

[1148] Embodiment 15: A method of treating, preventing, and / or ameliorating a microbial infection in a subject, the method comprising administering to the subject at a therapeutically effective amount of at least one compound selected from the group consisting of: (a) the compound of any one of Embodiments 1-11 and / or the pharmaceutical composition of Embodiment 12; and (b) 4,4'-((piperidine-l,4-diylbis(propane-3,l-diyl))bis(oxy))dibenzimidamide or a pharmaceutical composition thereof.

[1149] Embodiment 16: The method of Embodiment 15, wherein the microbial infection comprises a fungal infection.

[1150] Embodiment 17: The method of Embodiment 16, wherein the fungal infection is caused by a fungal pathogen selected from the group consisting of Cryptococcus neoformans, Blastomyces dermatitidis, Cryptococcus gattii, Candida albicans, Candida auris, Candida krusei, Candida glabrata, Candida dubliniensis, 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, Fusarium solani, Absidia corymbifera, Lichtheimia corymbifera, Mucor racemosus, Trichosporo nasahii, Malassezia furfur, Rhizopus spp., Histoplasma capsulatum, Coccidioides spp., Paecilomyces variotii, Pneumocystis murina, Pneumocystis jiroveci, Scedosporium spp., Sporotrix spp., and Aspergillus spp., or a combination thereof.

[1151] Embodiment 18: The method of Embodiment 15, wherein the microbial infection comprises a stramenopile infection.Attorney Docket No. 047162-7534WOl(02797)

[1152] Embodiment 19: The method of Embodiment 18, wherein the stramenopile infection is caused by a stramenopile selected from the group consisting of Albugo laibachii. Albugo Candida, Bremia lactucae, Hyaloperonospora arabidopsidis, Hyaloperonospora parasitica, Phytophthora cactorum, Phytophthora capsica, Phytophthora cinnamomic, Phytophthora infestans, Phytophthora ipomoeae, Phytophthora fragariae var. fragariae, Phytophthora mirabilis, Phytophthora palmivora, Phytophthora parasitica, Phytophthora phaseoli, Phytophthora ramorum, Phytophthora sojae, Plasmopara halstedii, Phytophthora agathidicida, Plasmopara viticola, Pseudoperonospora cubensis, Pythium ultimum, Pythium aphanidermatum, Pythium arrhenomanes, Pythium irregulare, Pythium iwayamai, Pythium ultimum var. sporangiiferum, Pythium vexans, Aphanomyces euteiches, and Peronospora manshurica.

[1153] Embodiment 20: The method of any one of Embodiments 15-19, wherein the subject is a mammal.

[1154] Embodiment 21: The method of Embodiment 20, wherein the mammal is a human. Embodiment 22: The method of any one of Embodiments 15-17 and 20-21. wherein the microbial infection is a fungal infection 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), and seborrhoeic dermatitis, or a combination thereof.

[1155] Embodiment 23: The method of any one of Embodiments 15-19, wherein the subject is a crop.

[1156] Embodiment 24: The method of Embodiment 23, wherein the crop is selected from the group consisting of almonds, apples, avocados, barley, bananas, beans, blueberries, broccoli, cabbage, carrots, cassava, cherries, chickpeas, citrus fruits, coffee, com, 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.

[1157] Embodiment 25: The method of Embodiment 23 or 24, wherein the microbial infection is selected from the group consisting of Magnaporthe grisea, Magnaporthe spp. (blast diseases), Plasmopara viticola (dow ny mildew), Erysiphe necator (powdery mildew),Attorney Docket No. 047162-7534WOl(02797)

[1158] Botrytis cinerea (grey mold), Guignardia bidwellii (black rot), Venturia inaequalis (apple scab), Venturia pirina (pear scab), Ustilago maydis (com 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), and Phytophthora blight.

[1159] Embodiment 26: The method of any one of Embodiments 15-25, wherein the compound is administered by a route selected from the group consisting of foliar spray, agroinfiltration, oral, topical, inhalation, aerosol, intravenous injection, intramuscular injection, and subcutaneous injection.

[1160] Embodiment 27: The method of any one of Embodiments 15-26, wherein the compound is coadministered with at least one additional antifungal compound.

[1161] Embodiment 28: The method of Embodiment 27, wherein the at least one additional fungal compound is selected from the group consisting of amphotericin B, amphotericin B liposomal, anidulafungin, bifonazole, carbendazim, caspofungin, clotrimazole, econazole, fenticonazole, fluconazole, fluopyran, ibrexafungrep, isavuconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, nystatin, olorofim, oxiconazole, posaconazole, rezafungin, sertaconazole, sulconazole, terbinafine, terconazole, thioconazole, and voriconazole.

[1162] 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 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.

Claims

Attomey Docket No. 047162-7534WOl(02797)CLAIMSWhat is claimed is:

1. A compound of formula (I), or a salt, stereoisomer, or isotopologue thereof:R1a-X1-L1-A— L2-X2— R1b(I)wherein:A is selected from the group consisting of optionally substituted C2-C8 monocyclic heterocycloalkylenyl, optionally substituted C3-C12 bicyclic heterocycloalkylenyl, and optionally substituted C3-C8 aminocycloalkylenyl,wherein the monocyclic heterocycloalkyl in A comprises at least two ringmember nitrogen atoms;Rlaand Rlbare each independently selected from the group consisting of C6-C10 aryl and C2-C10 heteroaryl,wherein each C6-C10 aryl and C2-C10 heteroaryl is substituted with at least one C(=NRB)N(RC)(RD) substituent, andwherein each Ce-Cio aryl and C2-C10 heteroaryl is optionally further substituted;L1and L2are each independently selected from the group consisting of Ci-Ce alkylenyl, optionally substituted C2-C6 heteroalkylenyl, and a bond;X1and X2are each independently selected from the group consisting of -O-, -S-, and -N(RA);each occurrence of RAis independently selected from the group consisting of H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyd, optionally substituted C2-C8 heterocycloalkyl, optionally substituted Ce-Cio ary l, optionally substituted C2-C8 heteroaryl, C(=NRB)N(RC)(RD), C(=O)RB, C(=O)ORB, C(=O)N(RB)(RC), S(=O)RB, S(=O)2RC, S(=O)N(RB)(RC),S(=O)2N(RB)(RC), and P(=O)(ORB)(ORC);each occurrence of RB, RC, and RD is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heteroaryl, C(=O)(RE), C(=O)ORE, C(=O)N(RE)(RF), S(=O)RE, S(=O)2RE, S(=O)N(RE)(RF), S(=O)2N(RE)(RF), and P(=O)(ORE)(ORF), or wherein RBand one of RCand RDcan combine with the atoms to which they are bound to form an optionally substituted C2-C5 heterocycloalkyl; andAttorney Docket No. 047162-7534WOl(02797)each occurrence of REand RFis independently selected from the group consisting of H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl;wherein the compound is not 4,4'-((piperidine-l,4-diylbis(propane-3,l-diyl))bis(oxy))dibenzimidamide.

2. The compound of claim 1, wherein A is selected from the group consisting of:wherein:each occurrence of R2and R3is independently selected from the group consisting of halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted Ce-Cio aryl, and optionally substituted C2-C8 heteroaryl:each occurrence of R4is independently selected from the group consisting of halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted Ce-Cio aryl, and optionally substituted C2-C8 heteroaryl;each occurrence of I is independently 0, 1, or 2;each occurrence ofm is independently 0, 1, 2, or 3;each occurrence of n is independently 0. 1, 2, 3, 4. or 5;each occurrence of o is independently 0, 1, 2, 3, 4, 5, or 6;each occurrence of p is independently 0, 1, 2, 3, 4, 5, 6, or 7;each occurrence of q is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;each occurrence ofr is independently 0, 1. 2, 3, 4. 5, 6, 7, 8. 9, or 10; andeach occurrence of s is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

3. The compound of claim 1 or 2, wherein A is selected from the group consisting of:Attorney Docket No. 047162-7534WOl(02797)4. The compound of any one of claims 1-3, wherein L1and L2are each independently selected from the group consisting of a bond, -(CH2)-. -(CH2)2-, -(CH2)3-, and -C(=O)-.

5. The compound of any one of claims 1-4, wherein one of the following applies:(a) L1and L2are both -(CH2)3-;(b) L1 is a bond and L2 is -(CH2)3-;(c) L1is -(CH2)- and L2is -(CH2)2-;(d) L1is -(CH2)- and L2is -(CH2)3-;(e) L1is -(CH2)2- and L2is -(CH2)2-;(f) L1is -(CH2)2- and L2is -(CH2)3-;Attomey Docket No. 047162-7534WOl(02797)(g) L1is -(CH2)3- and L2is -(CH2)3-; and(h) L1is -(CH2)3 and L2is -C(=0)-.

6. The compound of any one of claims 1-5, wherein X1and X2are each independently selected from the group consisting of -O-, -S-, and -NH-.

7. The compound of any one of claims 1-6. wherein Rlaand Rlbare each independently selected from the group consisting of:wherein:each occurrence of R5 and R6, if present, is independently selected fromR7is C(=NR8)NH2;R8is selected from the group consisting of H and S(=O)2(optionally substituted Ci-Ce alkyd);each occurrence of t is independently 0, 1, 2, or 3;each occurrence of u is independently 0. 1, 2, 3, or 4.

8. The compound of claim 7, wherein R8is selected from the group consisting of H and S(=O)2CH3.

9. The compound of claim 7 or 8, wherein R7is selected from the group consisting of C(=N[S(=O)2CH3])NH2and C(=NH)NH2.

10. The compound of any one of claims wherein Rlaand Rlbare each independently selected from the group consisting of:Attorney Docket No. 047162-7534WOl(02797)NH, and NH11. The compound of any one of claims 1-10, which is selected from the group consisting of:4,4'-(((2,7-diazaspiro[4.4]nonane-2,7-diyl)bis(propane-3,l- diyl))bis(oxy))dibenzimidamide;4-(3-(5-(2-(4-carbamimidoylphenoxy)ethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)propoxy)benzimidamide;4-(3-((3aR.5r,6aS)-5-(2-(4- carbamimidoylphenoxy)ethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)propoxy)benzimidamide;4-(3-((3aR,5s,6aS)-5-(2-(4- carbamimidoylphenoxy)ethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)propoxy)benzimidamide;4,4'-(((3-azabicyclo[3.1.0]hexane-3,6-diyl)bis(propane-3,l- diyl))bis(oxy))dibenzimidamide;4.4'-((((lR,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-diyl)bis(propane-3,l- diyl))bis(oxy))dibenzimidamide;4,4'-((((lR,5S,6s)-3-azabicyclo[3.1.0]hexane-3,6-diyl)bis(propane-3,l- diyl))bis(oxy))dibenzimidamide;4-(3-(6-((4-carbamimidoylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide;4-(3-((lR,5S,6s)-6-((4-carbamimidoylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide;4-(3-((lR,5S,6r)-6-((4-carbamimidoylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)benzimidamide;Attomey Docket No. 047162-7534WOl(02797)4-(3-(2-((4-carbamimidoylphenoxy)methyl)-7-azaspiro[3.5]nonan-7-yl)propoxy)benzimidamide;3-((7-(3-(4-carbamimidoylphenoxy)propyl)-7-azaspiro[3.5]nonan-2-yl)methoxy)benzimidamide;4-(3-(6-((4-carbamimidoylphenoxy)methyl)-3,4-dihydroisoquinolin-2(lH)-yl)propoxy)benzimidamide;4-(3-(9-(4-carbamimidoylphenoxy)-3-azaspiro[5.5]undecan-3-yl)propoxy)-N'-(methylsulfonyl)benzimidamide;(E)-4-(3-(9-(4-carbamimidoylphenoxy)-3-azaspiro[5.5]undecan-3-yl)propoxy)-N'-(methylsulfonyl)benzimidamide;(Z)-4-(3-(9-(4-carbamimidoylphenoxy)-3-azaspiro[5.5]undecan-3-yl)propoxy)-N'-(methylsulfonyl)benzimidamide;4-(3-(4-(2-(4-carbamimidoylphenoxy)ethyl)azepan-l-yl)propoxy)benzimidamide; (< S’)-4-(3-(4-(2-(4-carbamimidoylphenoxy)ethyl)azepan-l-yl)propoxy)benzi midamide; (R)-4-(3-(4-(2-(4-carbamimidoylphenoxy)ethyl)azepan-1-yl)propoxy)benzimidamide; 4-(3-(l-(4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)guanidino)propoxy)benzimidamide;4-(3-(l-((ls,4s)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)guanidino)propoxy)benzimidamide;4-(3-(l-((lr,4r)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)guanidino)propoxy)benzimidamide;4-(3-((4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)amino)propoxy)benzimidamide;4-(3-(((ls,4s)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)amino)propoxy)benzimidamide;4-(3-(((lr,4r)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)amino)propoxy)benzimidamide;3-(3-(3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)propoxy)benzimidamide;3-(3-((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)propoxy)benzimidamide;3-(3-((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)propoxy)benzimidamide;Attorney Docket No. 047162-7534WOl(02797)3-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;3-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;3-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;6-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2-naphthimidamide;6-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2-naphthimidamide;6-(((1R,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-2-naphthimidamide;6-((4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)methyl)-3-(3-(4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)propyl)-3-azabicyclo[3.1.0]hexane;(1R,5S,6r)-6-((4-(4,5-dihydro-1H-imidazol-2-yl)phenoxy)methyl)-3-(3-(4-(4,5-dihydro-1H-imidazol-2-yl)phenoxy)propyl)-3-azabicyclo[3.1.0]hexane;(lR,5S,6s)-6-((4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)methyl)-3-(3-(4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy)propyl)-3-azabicyclo[3.1.0]hexane;4-((3-(2-(4-carbamimidoylphenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;4-(((lR,5S,6r)-3-(2-(4-carbamimidoylphenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;4-(((lR,5S,6s)-3-(2-(4-carbamimidoylphenoxy)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;4-(2-(4-((2-(4-carbamimidoylphenoxy)ethyl)(methyl)amino)cyclohexyl)ethoxy)benzimidamide 4-(2-((lr,4r)-4-((2-(4-carbamimidoylphenoxy)ethyl)(methyl)amino)cyclohexyl)ethoxy)benzi midamide;4-(2-((1r,4s)-4-((2-(4-carbamimidoylphenoxy)ethyl)(methyl)amino)cyclohexyl)ethoxy)benzimidamide;4-(3-((4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzimidamide;4-(3-(((lr,4r)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzimidamide;Attomey Docket No. 047162-7534WOl(02797)4-(3-(((lr,4s)-4-(2-(4-carbamimidoylphenoxy)ethyl)cyclohexyl)(methyl)amino)propoxy)benzimidamide;4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)- 3-fluorobenzimidamide;4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-fluorobenzimidamide;4-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-fluorobenzimidamide;3-(3-(4-carbamimidoylphenoxy)propyl)-N-(4-carbamimidoylphenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;(1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-N-(4-carbamimidoylphenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;(lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-N-(4-carbamimidoylphenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;5-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)picolinimidamide;5-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)picolinimidamide;5-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)picolinimidamide;4-(((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzimidamide;4-((((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzimidamide;4-((((1R,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)thio)benzimidamide;4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)- 3-methylbenzimidamide;4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methylbenzimidamide;4-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-y l)methoxy )-3 -methylbenzimidamide;4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)- 3-methoxybenzimidamide;Attorney Docket No. 047162-7534WOl(02797)4-(((lR,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methoxybenzimidamide;4-(((lR,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)-3-methoxybenzimidamide;3-bromo-4-((3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;3-bromo-4-(((1R,5S,6r)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;3-bromo-4-(((1R,5S,6s)-3-(3-(4-carbamimidoylphenoxy)propyl)-3-azabicyclo[3.1.0]hexan-6-yl)methoxy)benzimidamide;4-(2-(l-(3-(4-carbamimidoylphenoxy)propyl)azepan-4-yl)ethoxy)-3-fluorobenzimidamide.

12. The compound of any one of claims 1-11, wherein the compound is a salt of the compound of Formula (I).

13. The compound of claim 12, wherein the compound is selected from the group consisting of a hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, benzenesulfonate, citrate, acetate, maleate, and fumarate salt.

14. A pharmaceutical composition comprising the compound of any one of claims 1-13 and at least one pharmaceutically acceptable excipient.

15. A method of treating, preventing, and / or ameliorating a microbial infection in a subject, the method comprising administering to the subject at a therapeutically effective amount of at least one compound selected from the group consisting of:(a) the compound of any one of claims 1-11 and / or the pharmaceutical composition of claim 12; and(b) 4,4'-((piperidine-l,4-diylbis(propane-3,l-diyl))bis(oxy))dibenzimidamide or a pharmaceutical composition thereof.

16. The method of claim 15, wherein the microbial infection comprises a fungal infection.Attomey Docket No. 047162-7534WOl(02797)17. The method of claim 16, wherein the fungal infection is caused by a fungal pathogen selected from the group consisting of Cryptococcus neoformans, Blastomyces dermatitidis, Cryptococcus gattii, Candida albicans, Candida auris. Candida krusei, Candida glabrata, Candida dubliniensis, 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, Fusarium solani, Absidia corymbifera, Lichtheimia corymbifera, Mucor racemosus. Trichosporo nasahii, Malassezia furfur, Rhizopus spp., Histoplasma capsulatum, Coccidioides spp., Paecilomyces variotii, Pneumocystis murina, Pneumocystis jiroveci, Scedosporium spp., Sporotrix spp., and Aspergillus spp.. or a combination thereof.

18. The method of claim 15, wherein the microbial infection comprises a stramenopile infection.

19. The method of claim 18, wherein the stramenopile infection is caused by a stramenopile selected from the group consisting of Albugo laibachii, Albugo Candida, Bremia lactucae, Hyaloperonospora arabidopsidis, Hyaloperonospora parasitica, Phytophthora cactorum, Phytophthora capsica, Phytophthora cinnamomic, Phytophthora infestans, Phytophthora ipomoeae. Phytophthora fragariae var. fragariae, Phytophthora mirabilis, Phytophthora palmivora, Phytophthora parasitica, Phytophthora phaseoli, Phytophthora ramorum, Phytophthora sojae, Plasmopara halstedii, Phytophthora agathidicida, Plasmopara viticola, Pseudoper onospora cubensis, Pythium ultimum, Pythium aphanidermatum, Pythium arrhenomanes. Pythium irregulare, Pythium iwayamai. Pythium ultimum var. sporangiiferum, Pythium vexans, Aphanomyces euteiches, and Peronospora manshurica.

20. The method of any one of claims 15-19, wherein the subject is a mammal.

21. The method of claim 20, wherein the mammal is a human.

22. The method of any one of claims 15-17 and 20-21, wherein the microbial infection is a fungal infection selected from the group consisting of aspergillosis, blastomycosis, candidemia (Candida bloodstream infection), Candida intertrigo, candidiasis (yeastAttorney Docket No. 047162-7534WOl(02797)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), and seborrhoeic dermatitis, or a combination thereof.

23. The method of any one of claims 15-19, wherein the subject is a crop.

24. The method of claim 23, wherein the crop is selected from the group consisting of almonds, apples, avocados, barley, bananas, beans, blueberries, broccoli, cabbage, carrots, cassava, cherries, chickpeas, citrus fruits, coffee, com, 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.

25. The method of claim 23 or 24, wherein the microbial 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 (com 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), and Phytophthora blight.

26. The method of any one of claims 15-25, wherein the compound is administered by a route selected from the group consisting of foliar spray, agroinfiltration, oral, topical, inhalation, aerosol, intravenous injection, intramuscular injection, and subcutaneous injection.

27. The method of any one of claims 15-26, wherein the compound is coadministered with at least one additional antifungal compound.

28. The method of claim 27, wherein the at least one additional fungal compound is selected from the group consisting of amphotericin B, amphotericin B liposomal,Attorney Docket No. 047162-7534WOl(02797)anidulafungin, bifonazole, carbendazim, caspofungin, clotrimazole, econazole, fenticonazole, fluconazole, fluopyran, ibrexafungrep, isavuconazole. isoconazole, itraconazole, ketoconazole, micafungin, miconazole, nystatin, olorofim, oxiconazole, posaconazole, rezafungin, sertaconazole, sulconazole, terbinafine, terconazole, thioconazole, and voriconazole.

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