Compositions and methods for the treatment and prevention of neurological disorders

Abstract

The invention provides compositions and methods for treating neurological disorders, such as amyotrophic lateral sclerosis, frontotemporal degeneration, and Alzheimer's disease, among others. Using the compositions and methods described herein, a patient having a neurological disorder, such as a neurological disorder associated with TAR-DNA binding protein (TDP)-43 aggregation, may be administered an inhibitor of cytochrome P450 (CYP450) isoform 51A1 (CYP51A1), also referred to herein as lanosterol 14-alpha demethylase, so as to treat an underlying etiology of the disorder and/or to alleviate one or more symptoms of the disease. The inhibitor of CYP51A1 may be a small molecule, anti-CYP51A1 antibody or antigen-binding fragment thereof, or a compound, such as an interfering RNA molecule, that attenuates CYP51A1 expression. Patients that may be treated using the compositions and methods described herein include those that express a mutant TDP-43 isoform containing a mutation associated with TDP-43-promoted aggregation and toxicity.

Claims

1. A method of treating a neurological disorder associated with TDP-43 aggregation in a human patient, the method comprising administering to the patient a therapeutically effective amount of a CYP51A1 inhibitor represented by formula (XLIII): ##STR00168## wherein n is 2 or 3; p is 0, 1, or 2; q is 0, 1, or 2; X is oxygen or S(O).sub.t wherein t is 0, 1, or 2; each R.sub.1 is independently halo, lower alkyl, lower alkoxy, or trifluoromethyl; each R.sub.2 is independently halo or lower alkyl; R.sub.3 is nitro or —N(R.sub.5)R.sub.6, where R.sub.5 is hydrogen or lower alkyl, and R.sub.6 is hydrogen, lower alkyl, lower alkylsulfonyl or —C(Y)R.sub.7 where Y is oxygen or sulfur and R.sub.7 is hydrogen, lower alkyl, lower alkoxy or —N(R.sub.8)R.sub.9 where R.sub.8 is hydrogen or lower alkyl and R.sub.9 is hydrogen, lower alkyl or lower alkoxycarbonyl; or R.sub.5 and R.sub.6 together with N is pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, wherein the piperazino is optionally substituted at the 4-position by —C(O)R.sub.10 where R.sub.10 is hydrogen, lower alkyl, lower alkoxy or amino; and R.sub.4 is hydrogen or optionally substituted lower alkyl; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, the method comprising: (i) determining that the patient is susceptible to developing TAR-DNA binding protein (TDP)-43 aggregation; and (ii) administering to the patient the therapeutically effective amount of the CYP51A1 inhibitor.

3. The method of claim 1, wherein the patient has previously been determined to be susceptible to developing TDP-43 aggregation.

4. The method of claim 1, the method comprising: (i) determining that the patient expresses a mutant form of TDP-43 having a mutation associated with TDP-43 aggregation; and (ii) administering to the patient the therapeutically effective amount of the CYP51A1 inhibitor.

5. The method of claim 1, wherein the patient has previously been determined to express a mutant form of TDP-43 having a mutation associated with TDP-43 aggregation.

6. The method of claim 5, wherein the mutation is selected from the group consisting of Q331K, M337V, Q343R, N345K, R361S, and N390D.

7. The method of claim 1, wherein the neuromuscular disorder is amyotrophic lateral sclerosis.

8. The method of claim 1, wherein the CYP51A1 inhibitor is azalanstat.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIGS. 1A-1C demonstrate that the viability of a yeast TDP-43 model is restored by the Erg11 inhibitor, fluconazole. (FIG. 1A) Structure of the Erg11 inhibitor and anti-fungal, fluconazole. (FIG. 1B) Fluconazole rescues viability of TDP-43-expressing yeast using a resazurin-reduction endpoint. A 2-fold serial dilution of fluconazole was applied to TDP-43-expressing yeast for 24 hours prior to analysis. (FIG. 1C) Wild-type yeast cultures were treated with fluconazole for eight hours prior to HPLC analysis for lanosterol and ergosterol. Data are expressed as the area under the curve (AUC) normalized to cell mass based on optical density of cultures at 600 nm. Fluconazole treatment reduces ergosterol, while simultaneously leading to an increase in the Erg11 substrate, lanosterol.

(2) FIG. 2 shows the structures of compounds used in primary rat cortical neuron TDP-43 wild type and Q331K mutant survival studies.

(3) FIGS. 3A and 3B demonstrate that compound (3) promotes survival in primary rat cortical neurons transfected with wild-type TDP-43. Rat primary cortical neurons were co-transfected with a red fluorescent protein (RFP) as a morphological marker and either control (empty vector) or wild-type TDP-43 expression plasmids and treated with vehicle (DMSO) or a titration of compound (3). (FIG. 3A) Risk of neuron death plots. The lifetime of each neuron was determined by either loss of RFP signal or morphological indicators of death such as loss of neurites and cell blebbing and used to generate cumulative hazard plots of risk of death over time (hrs) post-transfection. (FIG. 3B) Forest plots. Hazard ratios for each treatment group (relative to TDP-43 DMSO group) were determined by cox regression analysis and used to generate forest plots. Hazard ratios (HR)<1 in which the confidence interval (CI) does not encompass 1 represent treatments that significantly reduce probability of neuron death relative to the TDP-43 DMSO control. P, p-value.

(4) FIGS. 4A and 4B demonstrate that compound (3) promotes survival in primary rat cortical neurons transfected with Q331K Mutant TDP-43. Rat primary cortical neurons were co-transfected with a red fluorescent protein (RFP) as a morphological marker and either control (empty vector) or Q331K mutant TDP-43 expression plasmids and treated with vehicle (DMSO) or a titration of compound (3). (FIG. 4A) Risk of neuron death plots. The lifetime of each neuron was determined by either loss of RFP signal or morphological indicators of death such as loss of neurites and cell blebbing and used to generate cumulative hazard plots of risk of death over time (hrs) post-transfection. (FIG. 4B) Forest plots. Hazard ratios for each treatment group (relative to TDP-43 DMSO group) were determined by cox regression analysis and used to generate forest plots. Hazard ratios (HR)<1 in which the confidence interval (CI) does not encompass 1 represent treatments that significantly reduce probability of neuron death relative to the TDP-43 DMSO control. P, p-value.

(5) FIGS. 5A and 5B demonstrate that compound (4) promotes survival in primary rat cortical neurons transfected with wild-type TDP-43. Rat primary cortical neurons were co-transfected with a red fluorescent protein (RFP) as a morphological marker and either control (empty vector) or wild type TDP-43 expression plasmids and treated with vehicle (DMSO) or a titration of compound (4). (FIG. 5A) Risk of neuron death plots. The lifetime of each neuron was determined by either loss of RFP signal or morphological indicators of death such as loss of neurites and cell blebbing and used to generate cumulative hazard plots of risk of death over time (hrs) post-transfection. (FIG. 5B) Forest plots. Hazard ratios for each treatment group (relative to TDP-43 DMSO group) were determined by cox regression analysis and used to generate forest plots. Hazard ratios (HR)<1 in which the confidence interval (CI) does not encompass 1 represent treatments that significantly reduce probability of neuron death relative to the TDP-43 DMSO control. P, p-value.

DETAILED DESCRIPTION

(6) The present invention features compositions and methods for treating neurological disorders, such as amyotrophic lateral sclerosis and other neuromuscular disorders, as well as frontotemporal degeneration, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington's disease, Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathyamong others. Particularly, the invention provides inhibitors of cytochrome P450 isoform 51A1 (CYP51A1), also referred to herein as lanosterol 14-alpha demethylase, that may be administered to a patient (e.g., a human patient) so as to treat or prevent a neurological disorder, such as one or more of the foregoing conditions. In the context of therapeutic treatment, the CYP51A1 inhibitor may be administered to the patient to alleviate one or more symptoms of the disorder and/or to remedy an underlying molecular pathology associated with the disease, such as to suppress or prevent aggregation of TAR-DNA binding protein (TDP)-43.

(7) The disclosure herein is based, in part, on the discovery that CYP51A1 inhibition modulates TDP-43 aggregation in vivo. Suppression of TDP-43 aggregation exerts beneficial effects in patients suffering from a neurological disorder. Many pathological conditions have been correlated with TDP-43-promoted aggregation and toxicity, such as amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington's disease, IBMPFD, sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy. Without being limited by mechanism, by administering an inhibitor of CYP51A1, patients suffering from diseases associated with TDP-43 aggregation and toxicity may be treated, for example, due to the suppression of TDP-43 aggregation induced by the CYP51A1 inhibitor.

(8) Patients that are likely to respond to CYP51A1 inhibition as described herein include those that have or are at risk of developing TDP-43 aggregation, such as those that express a mutant form of TDP-43 associated with TDP-43 aggregation and toxicity in vivo. Examples of such mutations in TDP-43 that have been correlated with elevated TDP-43 aggregation and toxicity include Q331K, M337V, Q343R, N345K, R361 S, and N390D, among others. The compositions and methods described herein thus provide the additional clinical benefit of enabling the identification of patients that are likely to respond to CYP51A1 inhibitor therapy, as well as processes for treating these patients accordingly.

(9) As described in further detail below, CYP51A1 inhibitors useful in conjunction with the compositions and methods of the invention include inhibitory small molecules, such as LEK-935, CP-320626, itraconazole, posaconazole, cyproconazole, voriconazole, fluconazole, clotrimazol, fenticonazole, epoxiconazole, ketoconazole, ravuconazole, isavuconazole, holothurin A, theasaponin, capsicosine, betulafolientriol, prochloraz, propiconazole, prothioconazole, prothioconazole-desthio, tebuconazole, triadimenol, azalanstat, and variants thereof. In some embodiments, the CYP51A1 inhibitor is an anti-CYP51A1 antibody or antigen-binding fragment thereof, or a compound, such as an interfering RNA molecule, that attenuates CYP51A1 expression.

(10) The sections that follow provide a description of exemplary CYP51A1 inhibitors that may be used in conjunction with the compositions and methods disclosed herein. The sections below additionally provide a description of various exemplary routes of administration and pharmaceutical compositions that may be used for delivery of these substances for the treatment of a neurological disorder.

(11) Small Molecule CYP51A1 Inhibitors

(12) LEK-935 and Variants Thereof

(13) CYP51A1 inhibitors that may be used in conjunction with the compositions and methods described herein include small molecule antagonists of CYP51A1 activity. The CYP51A1 inhibitor may be, for example, LEK-935, represented by formula (3), herein.

(14) ##STR00084##

(15) In some embodiments, the CYP51A1 inhibitor is a variant of LEK-835 that retains CYP51A1 inhibitory activity. For example, CYP51A1 inhibitors useful in conjunction with the compositions and methods described herein include those represented by formula (I)

(16) ##STR00085##

(17) wherein n is 1 or 2;

(18) X is hydrogen, lower alkyl, lower alkoxy-lower alkyl, or a group X.sup.a of the formula:

(19) ##STR00086##

(20) Z is a group of the formula:

(21) ##STR00087##

(22) Y is a group of the formula:

(23) ##STR00088##

(24) R.sub.O is lower alkyl, COR.sub.4 or C(R.sub.5)=CHCOR.sub.4;

(25) R is R.sub.o or is OR″;

(26) R″ is hydrogen, lower-alkyl, lower alkanoyl, (CH.sub.2).sub.1-6—OH, (CH.sub.2).sub.1-6—O(CH.sub.2).sub.1-6R.sub.6, or (CH.sub.2).sub.1-6—COR.sub.4;

(27) R.sub.1 and R.sub.a are hydrogen, lower alkanoyl, benzoyl or (CH.sub.2).sub.1-6—OH;

(28) R.sub.2 and R.sub.b are hydrogen, Cl, Br or CF.sub.3;

(29) R.sub.3 and R.sub.5 are hydrogen or CH.sub.3;

(30) R.sub.4 is hydroxy, lower-alkoxy or N(R.sub.7, R.sub.8);

(31) R.sub.6 is hydrogen, R.sub.g, OH or COR.sub.4;

(32) R.sub.7 and R.sub.8 are hydrogen or lower alkyl;

(33) R.sub.c and R.sub.e are hydrogen, Cl, F, Br or CF.sub.3;

(34) R.sub.d is hydrogen or NH.sub.2;

(35) R.sub.f is hydrogen, CH.sub.3CONH—, NH.sub.2COCH.sub.2— or R.sub.9CH.sub.2CH.sub.2OCH.sub.2CH.sub.2O—;

(36) R.sub.g and R.sub.9 are phenyl or phenyl substituted by Cl, F or Br;

(37) or a pharmaceutically acceptable salt, ester, or ether thereof.

(38) In some embodiments of formula (I), n is 1, R.sub.1 is hydrogen, R.sub.2 is chlorine in the 6-position of a 2-pyridyl residue and Y is phenyl substituted in the p-position by R.

(39) In some embodiments of formula (I), X is X.sup.a; R.sup.a is hydrogen; Z is 6-chloro-2-pyridyl, and Y is phenyl substituted in the p-position by 2-ethoxyethoxy, 2-phenethoxyethoxy or methoxycarbonylmethoxy.

(40) In some embodiments of formula (I), the compound is methyl α,α′-[[[(R)-p-(2-ethoxyethoxy)-α-methylphen-ethyl]imino]dimethylene]bis[(RS)-6-chloro-2-pyridinemethanol]; (RS)-6-chloro-α-[[[(R)-p-(2-ethoxyethoxy)-α-methyl-phenethyl]amino]methyl]-2-pyridinemethanol; α,α′-[[[p-(2-ethoxyethoxy)phenethyl]imino]dimethylene]bis[(RS)-6-chloro-2-pyridinemethanol]; (R)-6-bromo-α-[[[(RS)-2-(6-bromo-2-pyridyl)-2-hydroxyethyl][(R)-p-(2-ethoxyethoxy)-α-methylphenethyl]-amino]methyl]-2-pyridimidinemethanol; (R)-6-chloro-α[[[(S)-2-(6-chloro-2-pyridyl)-2-hydroxyethyl][(R)-.alpha.-methyl-p-(2-phenethoxyethoxy)phenethyl]amino]methyl]-2-pyridinemethanol.

(41) In some embodiments, the CYP51A1 inhibitor is a compound represented by formula (II)

(42) ##STR00089##

(43) wherein n is an integer from 1 to 4 and m is an integer from 0 to 5;

(44) R.sub.1 is a hydrogen atom, hydroxyl group, or lower C.sub.1-6 alkoxy group;

(45) R.sub.2 is a hydrogen atom or an optionally substituted straight or branched lower C.sub.1-6 alkyl group (e.g., an aryl lower alkyl group, such as a phenyl lower alkyl group); and

(46) each X is independently fluorine, chlorine, bromine, hydroxyl group, trifluoromethyl group, 3,4-di-Cl, 2,4-di-Cl or lower C.sub.1-6 alkoxy group, and wherein the phenyl ring containing the X is optionally fused (so as to form, e.g., a naphthyl ring);

(47) or a pharmaceutically acceptable salt, ester, or ether thereof.

(48) In some embodiments, the CYP51A1 inhibitor is a compound represented by formula (1), (2), (3), (13), (14), (15), or (16), or a pharmaceutically acceptable salt, ester, or ether thereof.

(49) ##STR00090## ##STR00091##

(50) In some embodiments, n is an integer 2, R.sub.1 is a hydroxyl group, R.sub.2 a methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group and X is a hydrogen atom or phenyl disubstituted with 2 chlorine atoms in the positions 3 and 4 or in the positions 2 and 4.

(51) Exemplary variants of LEK-935 that may be used in conjunction with the compositions and methods described herein are those compounds described in U.S. Pat. Nos. 4,800,206 and 7,560,474, the disclosures of each of which are incorporated herein by reference in their entirety.

(52) CP-320626 and Variants Thereof

(53) In some embodiments, the CYP51A1 inhibitor is CP-320626, represented by formula (4) herein.

(54) ##STR00092##

(55) In some embodiments, the CYP51A1 inhibitor is a variant of CP-320626 that retains CYP51A1 inhibitory activity, such as a compound represented by formula (III)

(56) ##STR00093##

(57) wherein the dotted line () is an optional bond;

(58) X is O or S;

(59) A is —C(H)═, —C((C.sub.1-C.sub.4)alkyl)═, —C(halo)═ or —N═, when the dotted line () is a bond, or A is methylene or —CH((C.sub.1-C.sub.4)alkyl)—, when the dotted line () is not a bond;

(60) R.sub.1, R.sub.10 or R.sub.11 are each independently H, halo, cyano, 4-, 6-, or 7-nitro, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, fluoromethyl, difluoromethyl or trifluoromethyl;

(61) R.sub.2 is H;

(62) R.sub.3 is H or (C.sub.1-C.sub.6)alkyl;

(63) R.sub.4 is H, methyl, ethyl, n-propyl, hydroxy(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy(C.sub.1-C.sub.3)alkyl, phenyl(C.sub.1-C.sub.4)alkyl, phenylhydroxy(C.sub.1-C.sub.4)alkyl, (phenyl)((C.sub.1-C.sub.4)-alkoxy)(C.sub.1-C.sub.4)alkyl, thien-2- or -3-yl(C.sub.1-C.sub.4)alkyl or fur-2- or 3-yl(C.sub.1-C.sub.4)alkyl wherein the R.sub.4 rings are mono-, di- or tri-substituted independently on carbon with H, halo, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino, cyano or 4,5-dihydro-1H-imidazol-2-yl; or

(64) R.sub.4 is pyrid-2-, -3- or -4-yl(C.sub.1-C.sub.4)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1-C.sub.4)alkyl, imidazol-2-, -4- or -5-yl(C.sub.1-C.sub.4)alkyl, pyrrol-2- or -3-yl(C.sub.1-C.sub.4)alkyl, oxazol-2-, -4- or -5-yl(C.sub.1-C.sub.4)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1-C.sub.4)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1-C.sub.4)alkyl, isothiazol-3-, -4- or -5-yl(C.sub.1-C.sub.4)alkyl, pyridazin-3- or -4-yl(C.sub.1-C.sub.4)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C.sub.1-C.sub.4)alkyl, pyrazin-2- or -3-yl(C.sub.1-C.sub.4)alkyl, 1,3,5-triazin-2-yl(C.sub.1-C.sub.4)alkyl; or indol-2-(C.sub.1-C.sub.4)alkyl, wherein the preceding R.sub.4 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, amino, hydroxy or cyano and the substituents are bonded to carbon; or

(65) R.sub.4 is R.sub.15-carbonyloxymethyl, wherein the R.sub.15 is phenyl, thiazolyl, imidazolyl, 1H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl and wherein the preceding R.sub.15 rings are optionally mono- or di-substituted independently with halo, amino, hydroxy, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy or trifluoromethyl and the mono- or di-substituents are bonded to carbon;

(66) R.sub.5 is H, methyl, ethyl, n-propyl, hydroxymethyl or hydroxyethyl;

(67) R.sub.6 is carboxy, (C.sub.1-C.sub.8)alkoxycarbonyl, benzyloxycarbonyl, C(O)NR.sub.8R.sub.9 or C(O)R.sub.12 wherein

(68) R.sub.8 is H, (C.sub.1-C.sub.6)alkyl, cyclo(C.sub.3-C.sub.6)alkyl, cyclo(C.sub.3-C.sub.6)alkyl(C.sub.1-C.sub.5)alkyl, hydroxy or (C.sub.1-C.sub.8)alkoxy; and

(69) R.sub.9 is H, cyclo(C.sub.3-C.sub.8)alkyl, cyclo(C.sub.3-C.sub.8)alkyl(C.sub.1-C.sub.5)alkyl, cyclo(C.sub.4-C.sub.7)alkenyl, cyclo(C.sub.3-C.sub.7)alkyl(C.sub.1-C.sub.5)alkoxy, cyclo(C.sub.3-C.sub.7)alkyloxy, hydroxy, methylene-perfluorinated(C.sub.1-C.sub.8)alkyl, phenyl, or a heterocycle wherein the heterocycle is pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, thiochromanyl or tetrahydrobenzothiazolyl wherein the heterocycle rings are carbon-nitrogen linked; or

(70) R.sub.9 is (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.8)alkoxy wherein the (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.8)alkoxy is optionally monosubstituted with cyclo(C.sub.4-C.sub.7)alken-1-yl, phenyl, thienyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl or indolyl and wherein the (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.8)alkoxy are optionally additionally independently mono- or di-substituted with halo, hydroxy, (C.sub.1-C.sub.5)alkoxy, amino, mono-N— or di-N,N—(C.sub.1-C.sub.5)alkylamino, cyano, carboxy, or (C.sub.1-C.sub.4)alkoxycarbonyl; and

(71) wherein the R.sub.9 rings are optionally mono- or di-substituted independently on carbon with halo, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, hydroxy, hydroxy(C.sub.1-C.sub.4)alkyl, amino(C.sub.1-C.sub.4)alkyl, mono-N— or di-N,N—(C.sub.1-C.sub.4)alkylamino(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl, amino, mono-N— or di-N,N—(C.sub.1-C.sub.4)alkylamino, cyano, carboxy, (C.sub.1-C.sub.5)alkoxycarbonyl, carbamoyl, formyl or trifluoromethyl and the R.sub.9 rings may optionally be additionally mono- or di-substituted independently with (C.sub.1-C.sub.5)alkyl or halo;

(72) with the proviso that no quaternized nitrogen on any R.sub.9 heterocycle is included;

(73) R.sub.12 is morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, pyrazolidin-1-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl, oxazolidin-3-yl, 3,4dihydroisoquinolin-2-yl, 1,3-dihydrolsoindol-2-yl, 3,4-dihydro-2H-quinol-1-yl, 2,3-dihydro-benzo[1,4]oxazin-4-yl, 2,3-dihydro-benzo[1,4]-thiazine-4-yl, 3,4-dihydro-2H-quinoxalin-1-yl, 3,4-dihydro-benzo[c][1,2]oxazin-1-yl, 1,4-dihydro-benzo[d][1,2]oxazin-3-yl, 3,4-dihydro-benzo[e][1,2]-oxazin-2-yl, 3H-benzo[d]isoxazol-2-yl, 3H-benzo[c]isoxazol-1-yl or azepan-1-yl,

(74) wherein the R.sub.12 rings are optionally mono-, di- or tri-substituted independently with halo, (C.sub.1-C.sub.5)alkyl, (C.sub.1-C.sub.5)alkoxy, hydroxy, amino, mono-N— or di-N,N—(C.sub.1-C.sub.5)alkylamino, formyl, carboxy, carbamoyl, mono-N— or di-N,N—(C.sub.1-C.sub.5)alkylcarbamoyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.3)alkoxy, (C.sub.1-C.sub.5)alkoxycarbonyl, benzyloxycarbonyl, (C.sub.1-C.sub.5)alkoxycarbonyl(C.sub.1C.sub.5)alkyl, (C.sub.1C.sub.4)alkoxycarbonylamino, carboxy(C.sub.1-C.sub.5)alkyl, carbamoyl(C.sub.1-C.sub.5)alkyl, mono-N— or di-N,N—(C.sub.1-C.sub.5)alkylcarbamoyl(C.sub.1-C.sub.5)alkyl, hydroxy(C.sub.1-C.sub.5)alkyl, (C.sub.1-C.sub.4)alkoxy(C.sub.1-4)alkyl, amino(C.sub.1C.sub.4)alkyl, mono-N— or di-N,N—(C.sub.1-C.sub.4)alkylamino(C.sub.1-C.sub.4)alkyl, oxo, hydroxylmino or (C.sub.1-C.sub.6)alkoxylmino and wherein no more than two substituents are selected from oxo, hydroxylmino or (C.sub.1-C.sub.6)alkoxylmino and oxo, hydroxylmino or (C.sub.1-C.sub.6)alkoxyimino are on nonaromatic carbon; and

(75) the R.sub.12 rings are optionally additionally mono- or di-substituted independently with (C.sub.1-C.sub.5)alkyl or halo.

(76) In some embodiments of formula (III), when R.sub.6 is (C.sub.1-C.sub.5)alkoxycarbonyl or benzyloxycarbonyl then R.sub.1 is 5-halo, 5-(C.sub.1-C.sub.4)alkyl or 5-cyano and R.sub.4 is (phenyl)(hydroxy)(C.sub.1-C.sub.4)alkyl, (phenyl)((C.sub.1-C.sub.4)alkoxy)(C.sub.1-C.sub.4)alkyl, hydroxymethyl or Ar(C.sub.1-C.sub.2)alkyl, wherein Ar is thien-2- or -3-yl, fur-2- or -3-yl or phenyl wherein the Ar is optionally mono- or di-substituted independently with halo; with the provisos that when R.sub.4 is benzyl and R.sub.5 is methyl, R.sub.12 is not 4-hydroxy-piperidin-1-yl or when R.sub.4 is benzyl and R.sub.5 is methyl R.sub.6 is not C(O)N(CH.sub.3).sub.2.

(77) In some embodiments of formula (III), when R.sub.1, R.sub.10, and R.sub.11 are H, R.sub.4 is not imidazol-4-ylmethyl, 2-phenylethyl or 2-hydroxy-2-phenylethyl.

(78) In some embodiments of formula (III), when both R.sub.8 and R.sub.9 are n-pentyl, none of R.sub.1 is 5-chloro, 5-bromo, 5-cyano, 5(C.sub.1-C.sub.5)alkyl, 5(C.sub.1-C.sub.5)alkoxy or trifluoromethyl.

(79) In some embodiments of formula (III), when R.sub.12 is 3,4dihydroisoquinol-2-yl, the 3,4-dihydroisoquinol-2-yl is not substituted with carboxy((C.sub.1-C.sub.4)alkyl.

(80) In some embodiments of formula (III), when R.sub.8 is H and R.sub.9 is (C.sub.1-C.sub.6)alkyl, R.sub.9 is not substituted with carboxy or (C.sub.1-C.sub.4)alkoxycarbonyl on the carbon which is attached to the nitrogen atom N of NHR.sub.9.

(81) In some embodiments of formula (III), when R.sub.6 is carboxy and R.sub.1, R.sub.10, R.sub.11 and R.sub.5 are all H, then R.sub.4 is not benzyl, H, (phenyl)(hydroxy)methyl, methyl, ethyl or n-propyl.

(82) Exemplary compounds of formula (III) are those belonging to a first group of compounds in which:

(83) R.sub.1 is 5H, 5-halo, 5-methyl, 5-cyano or 5-trifluoromethyl;

(84) R.sub.10 and R.sub.11 are each independently H or halo;

(85) A is —C(H)═;

(86) R.sub.2 and R.sub.3 are H;

(87) R.sub.4 is H, methyl, phenyl(C.sub.1C.sub.2)alkyl, wherein the phenyl groups are mono- or di-substituted independently with H, halo, (C.sub.1-C.sub.4)alkyl, (C.sub.1C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino or cyano and wherein the R.sub.4 groups are optionally additionally mono-substituted with halo; or

(88) R.sub.4 is thien-2- or -3-yl(C.sub.1-C.sub.2)alkyl, pyrid-2-, -3- or -4-yl(C.sub.1-C.sub.2)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, imidazol-2-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl, pyrrol-2- or -3-yl(C.sub.1-C.sub.2)alkyl, oxazol-2-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, isothiazol-3-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, pyridazin-3- or -4-yl(C.sub.1-C.sub.2)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C.sub.1-C.sub.2)alkyl, pyrazin-2- or -3-yl(C.sub.1-C.sub.2)alkyl or 1,3,5-triazin-2-yl(C.sub.1-C.sub.2)alkyl wherein the preceding R.sub.4 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, amino or hydroxy and the mono- or di-substituents are bonded to cabin;

(89) R.sub.5 is H; and

(90) R.sub.6 is C(O)NR.sub.8R.sub.9 or C(O)R.sub.12.

(91) For example, compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include those in which:

(92) R.sub.4 is H, phenyl(C.sub.1-C.sub.2)alkyl, thien-2- or -3-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl wherein the R.sub.4 rings are mono- or di-substituted independently with H or fluoro;

(93) R.sub.6 is C(O)R.sub.12; and

(94) R.sub.12 is morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl, 1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2oxazinan-2-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl, oxazolidin-3-yl, 1,3-dihydroisoindol-2-yl, or azepan-1-yl,

(95) the R.sub.12 rings are optionally mono- or di-substituted independently with halo, (C.sub.1-C.sub.5)alkyl, (C.sub.1-C.sub.5)alkoxy, hydroxy, amino, mono-N— or di-N,N—(C.sub.1-C.sub.5)alkylamino, formyl, carboxy, carbamoyl, mono-N— or di-N,N—(C.sub.1-C.sub.5)alkylcarbamoyl, (C.sub.1-C.sub.5)alkoxycarbonyl, hydroxy(C.sub.1-C.sub.5)alkyl, amino(C.sub.1-C.sub.4)alkyl, mono-N— or di-N,N—(C.sub.1C.sub.4)alkylamino(C.sub.1-C.sub.4)alkyl, oxo, hydroxylmino or (C.sub.1-C.sub.6)alkoxylmino with the proviso that only the R.sub.12 heterocycles thiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, isoxazolidin-2-yl, or oxazolidin-3-yl are optionally mono- or di-substituted with oxo, hydroxylmino, or (C.sub.1-C.sub.6)alkoxylmino; and

(96) the R.sub.12 rings are optionally additionally mono- or di-substituted independently with (C.sub.1-C.sub.5)alkyl.

(97) Further exemplary compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include: 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-hydroxylmino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]amide, 5-Chloro-1H-indole-2-carboxylic acid [2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [2-(1,1-dioxo-thiazoildin-3-yl)-2-oxo-ethyl]amide, 5-Chloro-1H-indole-2-carboxylic acid (2-oxo-2-thiazolidin-3-yl-ethyl)-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-(4-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3RS)-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide, 5Chloro-1H-indole-2-carboxylic acid [2-oxo-2-((1RS)-oxo-1-thiazolidin-3-yl)-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-(2-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]amide, 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-hydroxyimino-azetidin-1-yl)-2-oxo-ethyl]-amide, and 5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(4-hydroxyimino-piperidin-1-yl)-2-oxo-ethyl]-amide.

(98) Further exemplary compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include those in which:

(99) R.sub.4 is H; and

(100) R.sub.12 is thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl, 1,1-dioxo-thiazolidin-3-yl or oxazolidin-3-yl or the R.sub.12 substituents optionally mono- or di-substituted independently with carboxy, (C.sub.1-C.sub.5)alkoxycarbonyl, hydroxy(C.sub.1-C.sub.3)alkyl, amino(C.sub.1-C.sub.3)alkyl, mono-N— or di-N,N—(C.sub.1-C.sub.3)alkylamino(C.sub.1-C.sub.3)alkyl or

(101) R.sub.12 is mono- or di-substituted pyrrolidin-1-yl wherein the substituents are independently carboxy, (C.sub.1-C.sub.5)alkoxycarbonyl, (C.sub.1-C.sub.5)alkoxy, hydroxy, hydroxy(C.sub.1-C.sub.3)alkyl, amino, amino(C.sub.1-C.sub.3)alkyl, mono-N— or di-N,N—(C.sub.1-C.sub.3)alkylamino(C.sub.1-C.sub.3)alkyl or mono-N— or di-N,N—(C.sub.1-C.sub.4)alkylamino; and the R.sub.12 rings are optionally additionally independently disubstituted with (C.sub.1-C.sub.5)alkyl.

(102) Further exemplary compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include those in which:

(103) (a) R.sub.1 is 5-chloro;

(104) R.sub.10 and R.sub.11 are H; and

(105) R.sub.12 is cis-3,4-dihydroxy-pyrrolidin-1-yl;

(106) (b) R.sub.1 is 5-chloro;

(107) R.sub.10 and R.sub.11 are H; and

(108) R.sub.12 is (3S,4S)-dihydroxy-pyrrolidin-1-yl;

(109) (c) R.sub.1 is 5-chloro;

(110) R.sub.10 and R.sub.11 are H; and

(111) R.sub.12 is 1,1-dioxo-thiazolidin-3-yl;

(112) (d) R.sub.1 is 5-chloro;

(113) R.sub.10 and R.sub.11 are H; and

(114) R.sub.12 is thiazolidin-3-yl; and

(115) (e) R.sub.1 is 5-chloro;

(116) R.sub.10 and R.sub.11 are H; and

(117) R.sub.12 is 1-oxo-thiazolidin-3-yl.

(118) Further exemplary compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include those in which:

(119) R.sub.4 is phenylmethyl, thien-2- or -3-ylmethyl wherein the R.sub.4 rings are optionally mono- or di-substituted with fluoro; and

(120) R.sub.12 is thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl, 1,1-dioxo-thiazolidin-3-yl or oxazolidin-3-yl or the R.sub.12 substituents optionally mono- or di-substituted independently with carboxy or (C.sub.1-C.sub.5)alkoxycarbonyl, hydroxy(C.sub.1-C.sub.3)alkyl, amino(C.sub.1-C.sub.3)alkyl or mono-N— or di-N,N—(C.sub.1-C.sub.3)alkylamino(C.sub.1-C.sub.3)alkyl or

(121) R.sub.12 is mono- or di-substituted azetidin-1-yl or mono- or di-substituted pyrrolidin-1-yl or mono- or di-substituted piperidin-1-yl wherein the substituents are independently carboxy, (C.sub.1-C.sub.5)alkoxycarbonyl, hydroxy(C.sub.1-C.sub.3)alkyl, amino(C.sub.1-C.sub.3)alkyl, mono-N— or di-N,N—(C.sub.1-C.sub.3)alkylamino(C.sub.1-C.sub.3)alkyl, hydroxy, (C.sub.1-C.sub.5)alkoxy, amino, mono-N— or di-N,N—(C.sub.1-C.sub.5)alkylamino, oxo, hydroxylmino or (C.sub.1-C.sub.5)alkoxylmino; and

(122) the R.sub.12 rings are optionally additionally mono- or di-substituted independently with (C.sub.1-C.sub.5)alkyl.

(123) Further exemplary compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include those in which:

(124) (a) R.sub.1 is 5-chloro;

(125) R.sub.10 and R.sub.11 are H;

(126) R.sub.4 is 4-fluorobenzyl;

(127) R.sub.12 is 4-hydroxypiperidin-1-yl; and

(128) the stereochemistry of carbon (a) is (S);

(129) (b) R.sub.1 is 5-chloro;

(130) R.sub.10 and R.sub.11 are H;

(131) R.sub.4 is benzyl;

(132) R.sub.12 is 3-hydroxypiperidin-1-yl; and

(133) the stereochemistry of carbon (a) is (S);

(134) (c) R.sub.1 is 5-chloro;

(135) R.sub.10 and R.sub.11 are H;

(136) R.sub.4 is benzyl;

(137) R.sub.12 is cis-3,4-dihydroxy-pyrrolidin-1-yl; and

(138) the stereochemistry of carbon (a) is S;

(139) (d) R.sub.1 is 5-chloro;

(140) R.sub.10 and R.sub.11 are H; R.sub.4 is benzyl;

(141) R.sub.12 is 3-hydroxyimino-pyrrolidin-1-yl; and

(142) the stereochemistry of carbon (a) is (S);

(143) (e) R.sub.1 is 5-chloro;

(144) R.sub.10 and R.sub.11 are H;

(145) R.sub.4 is 2-fluorobenzyl;

(146) R.sub.12 is 4-hydroxypiperidin-1-yl; and

(147) the stereochemistry of carbon (a) is (S);

(148) (f) R.sub.1 is 5-chloro;

(149) R.sub.10 and R.sub.11 are H;

(150) R.sub.4 is benzyl;

(151) R.sub.12 is (3S,4S)-dihydroxy-pyrrolidin-1-yl; and

(152) the stereochemistry of carbon (a) is (S);

(153) (g) R.sub.1 is 5-chloro;

(154) R.sub.10 and R.sub.11 are H;

(155) R.sub.4 is benzyl;

(156) R.sub.12 is 3-hydroxy-azetidin-1-yl; and

(157) the stereochemistry of carbon (a) is (S);

(158) (h) R.sub.1 is 5-chloro;

(159) R.sub.10 and R.sub.11 are H;

(160) R.sub.4 is benzyl;

(161) R.sub.12 is 3-hydroxyimino-azetidin-1-yl; and

(162) the stereochemistry of carbon (a) is (S); and

(163) (i) R.sub.1 is 5chloro;

(164) R.sub.10 and R.sub.11 are H;

(165) R.sub.4 is benzyl;

(166) R.sub.12 is 4-hydroxyimino-piperidin-1-yl; and

(167) the stereochemistry of carbon (a) is (S).

(168) Additionally, exemplary compounds of formula (III) are those belonging to a second group of compounds in which:

(169) R.sub.4 is H, phenyl(C.sub.1-C.sub.2)alkyl, thien-2- or -3-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl wherein the R.sub.4 rings are mono- or di-substituted independently with H or fluoro;

(170) R.sub.6 is C(O)NR.sub.8R.sub.9; and

(171) R.sub.8 is H, (C.sub.1-C.sub.5)alkyl, hydroxy or (C.sub.1-C.sub.4)alkoxy; and

(172) R.sub.9 is H, cyclo(C.sub.4-C.sub.6)alkyl, cyclo(C.sub.3-C.sub.6)alkyl(C.sub.1-C.sub.5)alkyl, methylene-perfluorinated(C.sub.1-C.sub.3)alkyl, pyridyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, piperidinyl, benzothiazolyl or thiochromanyl; or R.sub.9 is (C.sub.1-C.sub.5)alkyl wherein the (C.sub.1-C.sub.5)alkyl is optionally substituted with cyclo(C.sub.4-C.sub.6)alkenyl, phenyl, thienyl, pyridyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, or 1,1-dioxothiomorpholinyl and wherein the (C.sub.1-C.sub.5)alkyl or (C.sub.1-C.sub.4)alkoxy is optionally additionally independently mono- or di-substituted with halo, hydroxy, (C.sub.1-C.sub.5)alkoxy, amino, mono-N— or di-N,N—(C.sub.1-C.sub.5)alkylamino, cyano, carboxy, or (C.sub.1-C.sub.4)alkoxycarbonyl; wherein the R.sub.9 rings are optionally mono- or di-substituted independently on carbon with halo, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, hydroxy, amino, mono-N— or di-N,N—(C.sub.1-C.sub.4)alkylamino, carbamoyl, (C.sub.1-C.sub.5)alkoxycarbonyl or carbamoyl.

(173) Further exemplary compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include those in which:

(174) (a) R.sub.1 is 5-chloro;

(175) R.sub.10 and R.sub.11 are H;

(176) R.sub.4 is benzyl;

(177) R.sub.8 is methyl; and

(178) R.sub.9 is 3-(dimethylamino)propyl;

(179) (b) the stereochemistry of carbon (a) is (S);

(180) R.sub.1 is 5-chloro;

(181) R.sub.10 and R.sub.11 are H;

(182) R.sub.4 is benzyl;

(183) R.sub.8 is methyl; and

(184) R.sub.9 is 3-pyridyl;

(185) (c) the stereochemistry of carbon (a) is (S);

(186) R.sub.1 is 5-chloro;

(187) R.sub.10 and R.sub.11 are H;

(188) R.sub.4 is benzyl;

(189) R.sub.8 is methyl; and

(190) R.sub.9 is 2-hydroxyethyl; and

(191) (d) the stereochemistry of carbon (a) is (S);

(192) R.sub.1 is 5-fluoro;

(193) R.sub.10 and R.sub.11 are H;

(194) R.sub.4 is 4-fluorophenylmethyl;

(195) R.sub.8 is methyl; and

(196) R.sub.9 is 2-morpholinoethyl.

(197) Additionally, exemplary compounds of formula (III) are those belonging to a third group of compounds in which:

(198) R.sub.4 is H, phenyl(C.sub.1-C.sub.2)alkyl, thien-2- or -3-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl wherein the R.sub.4 rings are mono- or di-substituted independently with H or fluoro;

(199) R.sub.6 is C(O)NR.sub.8R.sub.9; and

(200) R.sub.8 is H, (C.sub.1-C.sub.5)alkyl, hydroxy or (C.sub.1-C.sub.4)alkoxy; and

(201) R.sub.9 is (C.sub.1-C.sub.4)alkoxy wherein the (C.sub.1-C.sub.4)alkoxy is optionally substituted with cyclo(C.sub.4-C.sub.6)alkenyl, phenyl, thienyl, pyridyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, or 1,1-dioxothiomorpholinyl and wherein the (C.sub.1-C.sub.5)alkyl or (C.sub.1-C.sub.4)alkoxy is optionally additionally independently mono- or di-substituted with halo, hydroxy, (C.sub.1-C.sub.5)alkoxy, amino, mono-N— or di-N,N—(C.sub.1-C.sub.5)alkylamino, cyano, carboxy, or (C.sub.1-C.sub.4)alkoxycarbonyl; wherein the R.sub.9 rings are optionally mono- or di-substituted independently on carbon with halo, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, hydroxy, amino, mono-N— or di-N,N—(C.sub.1-C.sub.4)alkylamino, carbamoyl, (C.sub.1-C.sub.5)alkoxycarbonyl or carbamoyl.

(202) Further exemplary compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include those in which:

(203) (a) R.sub.1 is 5-chloro;

(204) R.sub.10 and R.sub.11 are H;

(205) R.sub.4 is benzyl;

(206) R.sub.8 is methyl; and

(207) R.sub.9 is 2-hydroxyethoxy;

(208) (b) the stereochemistry of carbon (a) is (S);

(209) R.sub.1 is 5-chloro;

(210) R.sub.10 and R.sub.11 are H;

(211) R.sub.4 is 4-fluorophenylmethyl;

(212) R.sub.8 is methyl; and

(213) R.sub.9 is methoxy;

(214) (c) the stereochemistry of carbon (a) is (S);

(215) R.sub.1 is 5-chloro;

(216) R.sub.10 and R.sub.11 are H;

(217) R.sub.4 is benzyl;

(218) R.sub.8 is methyl; and

(219) R.sub.9 is methoxy;

(220) Further exemplary compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include those in which:

(221) R.sub.1 is 5-halo, 5-methyl, 5-cyano or trifluoromethyl;

(222) R.sub.10 and R.sub.11 are each independently H or halo;

(223) A is —C(H)═;

(224) R.sub.2 and R.sub.3 are H;

(225) R.sub.4 is H, phenyl(C.sub.1-C.sub.2)alkyl, thien-2- or -3-yl(C.sub.1-C.sub.2)alkyl, fur-2- or 3-yl(C.sub.1-C.sub.2)alkyl wherein the rings are mono- or di-substituted Independently with H or fluoro;

(226) R.sub.5 is H; and

(227) R.sub.6 is (C.sub.1-C.sub.5)alkoxycarbonyl.

(228) Further exemplary compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include those in which:

(229) R.sub.1 is 5-halo, 5-methyl, 5-cyano or trifluoromethyl;

(230) R.sub.10 and R.sub.11 are each independently H or halo;

(231) A is —C(H)═;

(232) R.sub.2 and R.sub.3 are H;

(233) R.sub.4 is H, methyl or phenyl(C.sub.1-C.sub.2)alkyl, wherein the phenyl groups are mono- or di-substituted independently with H, halo, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, trifluoromethyl, hydroxy, amino or cyano and wherein the phenyl groups are additionally mono- or di-substituted independently H or halo; or

(234) R.sub.4 is thien-2- or -3yl(C.sub.1-C.sub.2)alkyl, pyrid-2-, -3- or -4-yl(C.sub.1-C.sub.2)alkyl, thiazol-2-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, imidazol-2-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, fur-2- or -3-yl(C.sub.1-C.sub.2)alkyl, pyrrol-2- or -3-yl(C.sub.1-C.sub.2)alkyl, oxazol-2-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, pyrazol-3-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, isoxazol-3-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, isothiazol-3-, -4- or -5-yl(C.sub.1-C.sub.2)alkyl, pyridazin-3- or -4yl(C.sub.1-C.sub.2)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C.sub.1-C.sub.2)alkyl, pyrazin-2- or -3-yl(C.sub.1-C.sub.2)alkyl or 1,3,5-triazin-2-yl(C.sub.1-C.sub.2)alkyl wherein the preceding R.sub.4 heterocycles are optionally mono- or di-substituted independently with halo, trifluoromethyl, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, amino or hydroxy and the mono- or di-substituents are bonded to carbon;

(235) R.sub.5 is H; and

(236) R.sub.6 is carboxy.

(237) Further exemplary compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include those in which:

(238) R.sub.10 and R.sub.11 are H; and

(239) R.sub.4 is H.

(240) Further exemplary compounds of formula (III) that may be used in conjunction with the compositions and methods described herein include those in which R.sub.1 is 5-chloro.

(241) Exemplary variants of CP-320606 that may be used in conjunction with the compositions and methods described herein are those compounds described in U.S. Pat. No. 6,277,877, the disclosure of which is incorporated herein by reference in its entirety.

(242) Itraconazole, Posaconazole, and Variants Thereof

(243) In some embodiments, the CYP51A1 inhibitor itraconazole, posaconazole, or a variant thereof that retains CYP51A1 inhibitory activity. For example, the CYP51A1 inhibitor may be a compound represented by formula (IV)

(244) ##STR00094##

(245) wherein Ar is thienyl, pyridyl, biphenyl, phenyl or phenyl substituted by one or more of halo, nitro, cyano, lower alkyl, lower alkoxy or perhalo(lower)alkyl;

(246) Y is CH or N;

(247) either one of A, B and C is oxygen and the remaining two of A, B and C are CH.sub.2; or A is oxygen, B is CH.sub.2, and C is a direct bond;

(248) Q is:

(249) ##STR00095##

(250) W is —NR.sub.5—, —O—, or —S(O).sub.n—;

(251) X is —NO.sub.2, —P—NR.sub.6R.sub.7,

(252) ##STR00096##
Ar, OR.sub.3 or halogen;

(253) P is a direct bond, —CHR.sub.11— or —CHR.sub.11CHR.sub.12—;

(254) R.sub.1, R.sub.8, R.sub.9 and R.sub.10 are independently hydrogen, lower alkyl or lower alkyl substituted by one or more hydroxy groups;

(255) R.sub.2, R.sub.4, R.sub.11, R.sub.12 and R.sub.14 are hydrogen, hydroxy, lower alkyl or lower alkyl substituted by one or more hydroxy groups;

(256) R.sub.3 and R.sub.13 are independently hydrogen, lower alkyl, (C.sub.2-C.sub.8) perhaloalkanoyl or (C.sub.2-C.sub.8) alkanoyl;

(257) R.sub.6 and R.sub.7 are independently hydrogen, lower alkyl, phenyl or phenyl substituted by one or more of halo, perhalo(lower)alkyl, (C.sub.2-C.sub.8)alkanoyl, lower alkyl, lower alkyl substituted by one or more hydroxy groups, lower alkoxy, or 2-(lower)alkyl-3-oxo-1,2,4-triazol-4-yl, or R.sub.6 and R.sub.7 taken together with the nitrogen atom in NR.sub.6 R.sub.7 form unsubstituted or substituted 5- or 6-membered heterocyclyl ring systems containing carbon and one to four heteroatoms chosen from N, O and S, the heterocyclyl substituents being (C.sub.1-C.sub.8)alkanoyl, lower alkyl, lower alkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N,N-di(lower alkyl)amino carbonyl, aminothiocarbonyl, N-lower alkylaminothiocarbonyl, N,N-di(lower alkyl)aminothiocarbonyl, lower alkyl sulfonyl, phenyl-substituted lower alkyl sulfonyl, N-lower alkylamino, N,N-di(lower alkyl)amino, 1,3-imidazol-1-yl, 2-loweralkylsulfenyl-1,3-imidazol-1-yl, 2-pyridinyl, 2-thiazolyl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, 1-lower alkylbenzimidazol-2-yl, phenyl or phenyl substituted by one or more of halo, perhalo lower alkyl, (C.sub.2-C.sub.8) alkanoyl, lower alkyl, lower alkyl substituted by one or more hydroxy group, lower alkoxy, 1H,2,4-triazol-1-yl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, or a substituent represented by the formula:

(258) ##STR00097##

(259) R.sub.5 is a lower alkyl, lower alkoxy, amino, N,N-dilower alkylamino, phenyl or phenyl substituted by one or more of halo, perhalo lower alkyl, lower alkoxy, nitro, cyano, (C.sub.2-C.sub.8)alkanoyl;

(260) p is 0, 1, 2, 3, 4 or 5;

(261) n is 0, 1 or 2;

(262) r is 1 or 2; and

(263) t is 0, 1, 2 or 3;

(264) or a pharmaceutically acceptable salt, ester, or ether thereof.

(265) In some embodiments of formula (IV), when R.sub.2, R.sub.11, or R.sub.12 is attached to a carbon atom adjacent to —NR.sub.5, —S(O).sub.n or —O—, the R.sub.2, R.sub.11, or R.sub.12 is not hydroxy.

(266) In some embodiments, the CYP51A1 inhibitor is represented by formula (V)

(267) ##STR00098##

(268) Wherein Y and Ar are as defined for formula (IV) herein;

(269) one of A, B or C is oxygen and the remaining two of A, B, or C are —CH.sub.2—;

(270) T is ═O, ═NOR.sub.1, ═NNR.sub.1 R.sub.2 or

(271) ##STR00099##

(272) wherein R.sub.1 is hydrogen, lower alkyl or lower alkyl substituted by one or more hydroxy groups; and

(273) R.sub.2 is hydrogen, hydroxy, lower alkyl or lower alkyl substituted by one or more hydroxy groups.

(274) In some embodiments, the CYP51A1 inhibitor is represented by formula (VI)

(275) ##STR00100##

(276) wherein Y, Ar, R.sub.1, R.sub.2, R.sub.6 and R.sub.7 are as previously defined for formula (IV) herein, and either one of A, B and C is oxygen and the remaining two of A, B and C are CH.sub.2, or A is oxygen, B is CH.sub.2, and C is a direct bond.

(277) Exemplary compound of formula (VI) for use in conjunction with the compositions and methods described herein are those in which NR.sub.6 R.sub.7 form unsubstituted or substituted 5- or 6-membered heterocyclyl ring systems containing carbon and one to four heteroatoms chosen from N, O and S, the heterocyclyl substituents being (C.sub.1-C.sub.8) alkanoyl, lower alkyl, lower alkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N,N-di(lower alkyl)aminocarbonyl, aminothiocarbonyl, N-lower alkylaminothiocarbonyl, N,N-di(lower alkyl)aminothiocarbonyl, lower alkyl sulfonyl, phenyl-substituted lower alkyl sulfonyl, N-lower alkyl-amino, N,N-di(lower alkyl)amino, 1,3-imidazol-1-yl, 2-loweralkylsulfenyl-1,3-imidazol-1-yl, 2-pyridinyl, 2-thiazolyl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, 1-lower alkylbenzimidazol-2-yl, phenyl, phenyl substituted by one or more of halo, perhalo lower alkyl, (C.sub.2-C.sub.8)alkanoyl, lower alkyl, lower alkyl substituted by one or more hydroxy groups, lower alkoxy, 1H,2,4-triazol-1-yl or 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl; R.sub.5 is a lower alkyl, amino, N,N-dilower alkylamino, or

(278) ##STR00101##

(279) In some embodiments of formula (VI), the NR.sub.6R.sub.7 is:

(280) ##STR00102##

(281) wherein Z is hydrogen, (C.sub.1-C.sub.8) alkanoyl, lower alkyl, (C.sub.1-C.sub.8) perhaloalkanoyl or phenyl substituted by 2-loweralkyl-3-oxo-1,2,4-triazol-4-yl.

(282) In some embodiments, the CYP51A1 inhibitor is represented by formula (VII)

(283) ##STR00103##

(284) wherein one of A, B and C is oxygen and the remaining two of A, B and C are —CH.sub.2—, or two of A, B and C are —CH.sub.2—;

(285) each Hal is independently a halogen, such as Cl or F; and

(286) Z is lower alkyl, (C.sub.2-C.sub.8)alkanoyl, or phenyl substituted by 2-loweralkyl-3-oxo-1,2,4triazol-4-yl.

(287) In some embodiments of formula (VII), the compound is selected from:

(288) ##STR00104##

(289) In some embodiments, the CYP51A1 inhibitor is represented by formula (VIII)

(290) ##STR00105##

(291) wherein Ar is thienyl, pyridyl, biphenyl, phenyl or phenyl substituted by one or more of halo, nitro, cyano, lower alkyl, lower alkoxy or perhalo(lower)alkyl;

(292) Q is:

(293) ##STR00106##

(294) W is —NR.sub.5—, —O—, or —S(O).sub.n—;

(295) X is —NO.sub.2, —P—NR.sub.6R.sub.7,

(296) ##STR00107##
Ar, OR.sub.3 or halogen;

(297) P is a direct bond, —CHR.sub.11— or —CHR.sub.11CHR.sub.12—;

(298) R.sub.8, R.sub.9 and R.sub.10 are independently hydrogen, lower alkyl or lower alkyl substituted by one or more hydroxy groups;

(299) R.sub.4, R.sub.11, R.sub.12 and R.sub.14 are hydrogen, hydroxy, lower alkyl or lower alkyl substituted by one or more hydroxy groups;

(300) R.sub.3 and R.sub.13 are independently hydrogen, lower alkyl, (C.sub.2-C.sub.8) perhaloalkanoyl or (C.sub.2-C.sub.8) alkanoyl;

(301) R.sub.6 and R.sub.7 are independently hydrogen, lower alkyl, phenyl or phenyl substituted by one or more of halo, perhalo(lower)alkyl, (C.sub.2-C.sub.8)alkanoyl, lower alkyl, lower alkyl substituted by one or more hydroxy groups, lower alkoxy, or 2-(lower)alkyl-3-oxo-1,2,4-triazol-4-yl, or R.sub.6 and R.sub.7 taken together with the nitrogen atom in NR.sub.6 R.sub.7 form unsubstituted or substituted 5- or 6-membered heterocyclyl ring systems containing carbon and one to four heteroatoms chosen from N, O and S, the heterocyclyl substituents being (C.sub.1-C.sub.8)alkanoyl, lower alkyl, lower alkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N,N-di(lower alkyl)amino carbonyl, aminothiocarbonyl, N-lower alkylaminothiocarbonyl, N,N-di(lower alkyl)aminothiocarbonyl, lower alkyl sulfonyl, phenyl-substituted lower alkyl sulfonyl, N-lower alkylamino, N,N-di(lower alkyl)amino, 1,3-imidazol-1-yl, 2-loweralkylsulfenyl-1,3-imidazol-1-yl, 2-pyridinyl, 2-thiazolyl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, 1-lower alkylbenzimidazol-2-yl, phenyl or phenyl substituted by one or more of halo, perhalo lower alkyl, (C.sub.2-C.sub.8) alkanoyl, lower alkyl, lower alkyl substituted by one or more hydroxy group, lower alkoxy, 1H,2,4-triazol-1-yl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, or a substituent represented by the formula:

(302) ##STR00108##

(303) R.sub.5 is a lower alkyl, lower alkoxy, amino, N,N-dilower alkylamino, phenyl or phenyl substituted by one or more of halo, perhalo lower alkyl, lower alkoxy, nitro, cyano, (C.sub.2-C.sub.8)alkanoyl;

(304) p is 0, 1, 2, 3, 4 or 5;

(305) n is 0, 1 or 2;

(306) r is 1 or 2; and

(307) t is 0, 1, 2 or 3;

(308) R.sub.1 is hydrogen, lower alkyl or lower alkyl substituted by one or more hydroxy groups; and

(309) R.sub.2 is hydrogen, hydroxy, lower alkyl or lower alkyl substituted by one or more hydroxy groups.

(310) In some embodiments, the CYP51A1 inhibitor is a compound represented by formula (IX)

(311) ##STR00109##

(312) wherein each X is independently a halogen, such as F or Cl; and

(313) R.sub.1 is a straight or branched chain (C.sub.3 to C.sub.8) alkyl group optionally substituted by one or two hydroxy moieties or by one or two groups convertible in vivo into hydroxy moieties;

(314) or a pharmaceutically acceptable salt, ester, or ether thereof.

(315) In some embodiments of formula (IX), the compound is represented by formula (X)

(316) ##STR00110##

(317) wherein each X is independently a halogen, such as F or Cl; and

(318) R.sub.2 is H or (C.sub.1-C.sub.3) alkyl and R.sub.3 is (C.sub.1-C.sub.3) alkyl optionally substituted by one hydroxy moiety or by a group convertible in vivo into a hydroxy moiety;

(319) or a pharmaceutically acceptable salt, ester, or ether thereof.

(320) In some embodiments of formula (X), the compound is represented by formula (XI)

(321) ##STR00111##

(322) wherein R.sub.5 is:

(323) ##STR00112##

(324) or a pharmaceutically acceptable salt, ester, or ether thereof.

(325) In some embodiments of formula (XI), the compound is represented by formula (XII)

(326) ##STR00113##

(327) wherein R.sub.9 is —H(C.sub.2H.sub.5)CH(R.sub.6)CH.sub.3 or —H(CH.sub.3)CH(R.sub.6)CH.sub.3;

(328) R.sub.6 is OH or a group convertible in vivo into OH;

(329) or a pharmaceutically acceptable salt, ester, or ether thereof.

(330) In some embodiments of formula (XII), the compound is:

(331) ##STR00114##

(332) or a pharmaceutically acceptable salt, ester, or ether thereof.

(333) In some embodiments of formulas (IX)-(XII), the compound is an ester of the corresponding structural formula, such as a phosphate ester. The phosphate ester may be, for example, a phosphate ester selected from

(334) ##STR00115##

(335) wherein z is 0 or 1, R.sub.7 is a (C.sub.1-C.sub.6) straight or branched chain alkyl group or H, f and n are independently an integer from 0 to 6, m is zero or 1 and W is H, CH.sub.2 Ar or and Ar is phenyl, phenyl substituted by halo, nitro, cyano or trihalomethyl.

(336) Exemplary variants of itraconazole and posaconazole useful in conjunction with the compositions and methods described herein are described in U.S. Pat. Nos. 5,039,676, and 5,661,151, the disclosures of each of which are incorporated herein by reference in their entirety.

(337) Cyproconazole and Variants Thereof

(338) In some embodiments, the CYP51A1 inhibitor cyproconazole or a variant thereof that retains CYP51A1 inhibitory activity, such as a compound represented by formula (XIII)

(339) ##STR00116##

(340) wherein R.sub.O is alkyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl-alkyl in which the cycloalkyl is of 3 to 6 carbon atoms and the alkyl portion of 1 to 3 carbon atoms, the cycloalkyl and cycloalkyl-alkyl being optionally ring substituted by one or two alkyl groups of 1 to 3 carbon atoms;

(341) R is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or nitro;

(342) R′ is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, —CF.sub.3 in the 3-position of Ring A, nitro, —CN, —COOR″, an optionally substituted phenyl group of the formula:

(343) ##STR00117##
or an optionally substituted phenoxy group in the 4-position of Ring A and having the formula:

(344) ##STR00118##

(345) R″ is hydrogen, alkyl of 1 to 4 carbon atoms or a cation, preferably an agriculturally acceptable cation, or R and R′ together represent alkylenedioxy of 1 or 2 carbon atoms substituted onto adjacent carbon atoms of the phenyl Ring A; and

(346) Y.sub.O and Y are independently hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.

(347) In some embodiments of formula (XIII), when R.sub.O is n-butyl: (a) at least one of R and R′ is other than hydrogen and (b) R and R′ are not both halo.

(348) In some embodiments, the CYP51A1 inhibitor is an α-[aryl(alkylene).sub.m]-α-[CR.sub.1R.sub.2—(CHR.sub.3).sub.n—R.sub.4]1H-1,2,4-triazole-1-ethanol (formula (XIV-A)) or an α-[aryl(alkylene).sub.m]-α-[CR.sub.1R.sub.2—(CHR.sub.3).sub.n—R.sub.4]1H-imidazole-1-ethanol (formula (XIV-B)), or a pharmaceutically acceptable salt or ester thereof, wherein:

(349) R.sub.1 is C.sub.1-5 alkyl, unsubstituted or substituted by halogen, by C.sub.1-5-alkoxy, by phenyl-C.sub.1-3 alkoxy, by phenoxy, by C.sub.1-5 alkylthio, by phenyl-C.sub.1-3 alkylthio or by phenylthio, whereby optional phenyl groups may be substituted by C.sub.1-5 alkyl, halogen, halogen substituted C.sub.1-5 alkyl, C.sub.1-5 alkoxy or halogen substituted C.sub.1-5 alkoxy; or

(350) is C.sub.2-5 alkenyl or C.sub.2-5 alkynyl, unsubstituted or substituted by halogen; or

(351) is cycloalkyl, unsubstituted or substituted by C.sub.1-5 alkyl; or

(352) is phenyl, unsubstituted or substituted by substituents selected from the group consisting of halogen and C.sub.1-5 alkyl;

(353) R.sub.2 and R.sub.3, independently, are H or have an R.sub.1 significance, whereby R.sub.1 and R.sub.2 may be linked together to form a C.sub.3-7 cycloalkyl group;

(354) m is 0 or 1;

(355) n is 0, 1 or 2; and

(356) R.sub.4 is C.sub.3-7 cycloalkyl, unsubstituted or substituted by C.sub.1-5 alkyl.

(357) The aryl portion in the α-[aryl(alkylen).sub.m] moiety of formula (XIV) may be an aromatic hydrocarbon (e.g. naphthyl, preferably phenyl) unsubstituted or substituted, or a heteroaromatic ring linked by one of its ring carbon atoms (e.g. a 5- or 6-membered ring with 1 or 2 heteroatoms from the group O, N and S, preferably furyl, thienyl or pyridyl), and may be unsubstituted or substituted.

(358) Examples of suitable α-[aryl(alkylene).sub.m] groups that may be present in formula (XIV) are phenyl, benzyl and α-C.sub.1-5 alkylbenzyl (e.g., unsubstituted, mono- or multiple-substituted in the phenyl moiety by NO.sub.2, halogen, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, or C.sub.1-5 alkoxy (unsubstituted or halogenated), phenyl, or phenoxy, unsubstituted or substituted). Further examples of suitable α-aryl groups are the heteroaromatic 3-pyridyl group and 2-thienyl and 2-furyl, which may be, for example, unsubstituted or singly substituted by halogen or lower alkyl (e.g. 5-Cl-2-thienyl and 5-tert.butyl-2-furyl).

(359) For example, the α-[aryl(alkylene).sub.m] group may be phenyl, benzyl, or α-C.sub.1-5 alkylbenzyl substituted in the phenyl moiety by R.sub.5, R.sub.6 and/or R.sub.7, wherein:

(360) R.sub.5 and R.sub.6, independently, are H; halogen, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, or C.sub.1-5 alkoxy, (e.g., unsubstituted or halogenated), phenyl or phenoxy (e.g., unsubstituted or substituted), or NO.sub.2; and

(361) R.sub.7 is H, C.sub.1-5 alkyl or halogen.

(362) In some embodiments, the compound represented by formula (XIV) is a compound represented by formula (XV)

(363) ##STR00119##

(364) wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, m and n are as defined for formula (XIV) herein, R.sub.8 is H or C.sub.1-5 alkyl, and Y is CH or N;

(365) or a pharmaceutically acceptable salt, ester, or ether thereof.

(366) In some embodiments, the compound represented by formula (XV) is a compound represented by formula (XVI)

(367) ##STR00120##

(368) wherein R.sub.2 is hydrogen or optionally substituted alkyl, such as optionally substituted lower alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or the like); and

(369) R.sub.5 and R.sub.6 are each independently hydrogen or a halogen atom, such as chloro;

(370) or a pharmaceutically acceptable salt, ester, or ether thereof.

(371) In some embodiments, the CYP51A1 inhibitor is 2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol, 2-(4-chlorophenyl)-3-cyclopropyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol, 2-(2,4-diclorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl) butan-2-ol, or 2-(2,4-dichlorophenyl-3-cyclopropyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

(372) Exemplary variants of cyproconazole useful in conjunction with the compositions and methods described herein are described in U.S. Pat. Nos. 4,432,989 and 4,664,696, the disclosures of each of which are incorporated herein by reference in their entirety.

(373) Voriconazole and Variants Thereof

(374) In some embodiments, the CYP51A1 inhibitor is voriconazole or a variant thereof that retains CYP51A1 inhibitory activity, such as a compound represented by formula (XVII)

(375) ##STR00121##

(376) wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from halo and CF.sub.3;

(377) R.sup.1 is C.sub.1-C.sub.4alkyl;

(378) R.sub.2 is H or C.sub.1-C.sub.4 alkyl; and

(379) “Het”, which is attached to the adjacent carbon atom by a ring carbon atom, is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. “Het” may be optionally substituted by C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halo, CF.sub.3, CN, NO.sub.2, NH.sub.2, —NH(C.sub.1-C.sub.4 alkanoyl) or —NHCO.sub.2 (C.sub.1-C.sub.4alkyl);

(380) or a pharmaceutically acceptable salt, ester, or ether thereof.

(381) In some embodiments of formula (XVII), “Het” is selected from 2- and 4-pyridinyl, pyridazinyl, 2- and 4-pyrimidinyl, pyrazinyl and triazinyl, and may be optionally substituted by C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halo, CF.sub.3, CN, NO.sub.2, NH.sub.2, —NH(C.sub.1-C.sub.4 alkanoyl) or —NHCO.sub.2 (C.sub.1-C.sub.4 alkyl). In some embodiments, “Het” is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and may be optionally substituted by C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halo, CF.sub.3, NO.sub.2, NH.sub.2 or —NH(C.sub.1-C.sub.4 alkanoyl).

(382) In some embodiments of formula (XVII), R is a substituted phenyl moiety, such as 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-iodophenyl, 2-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl, or 4-bromo-2,5-difluorophenyl. In some embodiments, R is a phenyl group substituted by from 1 to 3 halo (preferably F or Cl) substituents. In some embodiments, R is a phenyl group substituted by from 1 or 2 halo (preferably F or Cl) substituents. In some embodiments, R is 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-fluorophenyl or 2-chlorophenyl.

(383) In some embodiments, the CYP51A1 inhibitor is 2-(2,4-difluorophenyl)-3-(pyridin-2-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, 2-(2,4-difluorophenyl)-3-(pyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, or 2-(2,4-difluorophenyl)-3-(pyrimidin-4-yl)-1H,1,2,4-triazol-1-yl)butan-2-ol.

(384) In some embodiments, the CYP51A1 inhibitor is a compound represented by formula (XVIII)

(385) ##STR00122##

(386) wherein R is optionally substituted phenyl (e.g., substituted by from 1 to 3 substituents each independently selected from halo, —CF.sub.3 and —OCF.sub.3);

(387) R.sup.1 is optionally substituted alkyl, such as optionally substituted lower alkyl (e.g., C.sub.1-C.sub.4 alkyl);

(388) R.sub.2 is H or optionally substituted alkyl, such as optionally substituted lower alkyl (e.g., C.sub.1-C.sub.4 alkyl);

(389) X is CH or N; and

(390) Y is a halogen, such as F or Cl;

(391) or a pharmaceutically acceptable salt, ester, or ether thereof.

(392) Examples of R in formula (XVIII) are 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 2-iodophenyl, 2-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl, 4-bromo-2,5-difluorophenyl, and 2-trifluoromethoxyphhenyl.

(393) In some embodiments of formula (XVIII), the compound is represented by formula (XIX)

(394) ##STR00123##

(395) wherein R, R.sub.1, R.sub.2, X, and Y are as defined for formula (XVIII).

(396) In some embodiments of formula (XVIII), the compound is represented by formula (XX)

(397) ##STR00124##

(398) wherein R, R.sub.1, R.sub.2, X, and Y are as defined for formula (XVIII).

(399) In some embodiments of formula (XVIII), the compound is represented by formula (XXI)

(400) ##STR00125##

(401) wherein R, R.sub.1, R.sub.2, X, and Y are as defined for formula (XVIII).

(402) In some embodiments, the CYP51A1 inhibitor is 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, or a pharmaceutically acceptable salt, ester, or ether thereof. In some embodiments, the CYP51A1 inhibitor is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, or a pharmaceutically acceptable salt, ester, or ether thereof.

(403) Exemplary variants of voriconazole that may be used in conjunction with the compositions and methods described herein are described, for example, in U.S. Pat. No. 5,116,844, the disclosure of which is incorporated herein by reference in its entirety.

(404) Fluconazole and Variants Thereof

(405) In some embodiments, the CYP51A1 inhibitor is fluconazole or a variant thereof that retains CYP51A1 inhibitory activity, such as a compound represented by formula (XXII)

(406) ##STR00126##

(407) wherein R.sub.1 is an optionally substituted alkyl, cycloalkyl (e.g. cyclopentyl or cyclohexyl), aryl (e.g. phenyl) or arylalkyl (e.g. benzyl) group; and

(408) Y.sub.1 and Y.sub.2 are each independently ═CH— or ═N—;

(409) or a pharmaceutically acceptable salt, ester, or ether thereof.

(410) In some embodiments of formula (XXII), R.sub.1 is alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; and Y.sup.1 and Y.sup.2 are either both ═CH— or both ═N—.

(411) In some embodiments of formula (XXII), R.sub.1 is phenyl or benzyl, optionally substituted with one or more of halogen, alkyl or haloalkyl each containing from 1 to 5 carbon atoms, alkoxy or haloalkoxy each containing from 1 to 4 carbon atoms, nitro, cyano, hydroxy, alkylthio containing from 1 to 40 carbon atoms, vinyl, phenyl or phenoxy. In some embodiments, the alkyl moiety of the benzyl is unsubstituted, or substituted with alkyl containing from 1 to 4 carbon atoms, phenyl or chlorophenyl.

(412) In some embodiments, the CYP51A1 inhibitor is selected from:

(413) ##STR00127##

(414) Exemplary variants of fluconazole that may be used in conjunction with the compositions and methods described herein are described, for example, in U.S. Pat. Nos. 4,416,682 and 4,404,216, the disclosures of each of which are incorporated herein by reference in their entirety.

(415) Clotrimazole and Variants Thereof

(416) In some embodiments, the CYP51A1 inhibitor is clotrimazole or a variant thereof that retains CYP51A1 inhibitory activity, such as a compound represented by formula (XXIII)

(417) ##STR00128##

(418) wherein each of R.sub.1, R.sub.2, and R.sub.3 is independently an aryl group represented by the formula:

(419) ##STR00129##

(420) n is an integer of from 0 to 5 (e.g., an integer of from 0 to 2) and each R′ is independently halogen or optionally substituted alkyl (e.g., optionally substituted lower alkyl); and

(421) each X is independently selected from hydrogen, optionally substituted alkyl (e.g., optionally substituted lower alkyl), or optionally substituted aryl (e.g., optionally substituted phenyl);

(422) or a pharmaceutically acceptable salt thereof. In some embodiments, the total number of carbon atoms in all X substituents is an integer of from 0 to 15.

(423) In some embodiments, the CYP51A1 inhibitor is a compound selected from I-(tris(m-tert-butylphenyl)methyl) imidazole, 1-(tris(p-tert-butylphenyl methyl) imidazole, 1-(his (2,4-difiourophenyl)methyl)-2,4,5-trimethylimidazole, 1-(tris(p-chlorophenyl)methyl)-2-methyl-4,5-diphenylimidazone, 1-(tris(m-tolyl)methyl)-2-n-propylimidaz-ole, and 1-trityl-2-methylimidazole.

(424) In some embodiments, the CYP51A1 inhibitor is a compound represented by formula (XXIV)

(425) ##STR00130##

(426) wherein each of R, R.sub.1, and R.sub.2 is independently hydrogen, optionally substituted alkyl (e.g., optionally substituted lower alkyl), or optionally substituted and optionally fused aryl (e.g., optionally substituted phenyl);

(427) each of X, X′, and X′″ is independently hydrogen, halogen, optionally substituted alkyl (e.g., optionally substituted lower alkyl), or optionally substituted and optionally fused aryl (e.g., optionally substituted phenyl); and

(428) each of n, n′, and n″ is independently 1, 2, 3, 4, or 5 (e.g., 1, 2, or 3).

(429) In some embodiments of formula (XXIV), the compound is represented by formula (XXV)

(430) ##STR00131##

(431) wherein X, X′, X″′, n, n′, and n″ are as defined for formula (XXIV).

(432) In some embodiments of formula (XXIV), the compound is represented by formula (XXVI)

(433) ##STR00132##

(434) wherein X, X′, X″′, n, n′, and n″ are as defined for formula (XXIV).

(435) In some embodiments, the CYP51A1 inhibitor is 1-(3,4-Dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole, 1-(2,4-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole, 1-(2,6-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole, 1-(2,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole, 1-(3,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole, 1-(2,5-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole, 1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole, 1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole, 1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole, 1-(2,3-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole, 1-(3,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole, or a pharmaceutically acceptable salt thereof, such as the 1,5-naphthalene-disulphonate salt thereof or the hydrochloride salt thereof.

(436) Exemplary variants of clotrimazole that may be used in conjunction with the compositions and methods described herein are described, for example, in U.S. Pat. No. 3,321,366, the disclosure of which is incorporated herein by reference in its entirety.

(437) Epoxiconazole and Variants Thereof

(438) In some embodiments, the CYP51A1 inhibitor is epoxiconazole or a variant thereof that retains CYP51A1 inhibitory activity, such as a compound represented by formula (XXVII)

(439) ##STR00133##

(440) wherein A and B are independently selected from optionally substituted alkyl (e.g., optionally substituted lower alkyl, such as alkyl of 1 to 4 carbon atoms), optionally substituted naphthyl, optionally substituted biphenyl, and optionally substituted phenyl, and Z is CH or N. In some embodiments, A and/or B is an optionally substituted phenyl group, such as a phenyl group substituted by one or more of halogen, nitro, alkyl (e.g., of from 1 to 4 carbon atoms), alkoxy (e.g., of from 1 to 4 carbon atoms), haloalkyl (e.g., of from 1 to 4 carbon atoms), phenoxy, or phenylsulyfonyl.

(441) In some embodiments, the CYP51A1 inhibitor is a compound represented by formula (XXVIII)

(442) ##STR00134##

(443) wherein R is optionally substituted aryl, such as phenyl, pyridyl, tetrahydropyranyl, norbornyl, C.sub.3-C.sub.12 cycloalkyl or C.sub.5-C.sub.8 cycloalkenyl, each of which may be unsubstituted or monosubstituted to trisubstituted by halogen, nitro, phenoxy, alkyl, amino, alkoxy (e.g., of from 1 to 4 carbon atoms), haloalkoxy (e.g., of from 1 to 4 carbon atoms), or haloalkyl (e.g., of from 1 to 4 carbon atoms);

(444) each X is independently fluorine, chlorine, bromine, or iodine; and

(445) each n is independently an integer of from 1 to 5 (e.g., an integer of from 1 to 3).

(446) In some embodiments of formula (XXVIII), the compound is represented by formula (XXIX)

(447) ##STR00135##

(448) wherein R and X are as defined for formula (XXVIII).

(449) In some embodiments of formula (XXVIII), the compound is represented by formula (XXX)

(450) ##STR00136##

(451) wherein R is as defined for formula (XXVIII).

(452) Exemplary variants of epoxiconazole that may be used in conjunction with the compositions and methods described herein are described, for example, in U.S. Pat. Nos. 4,464,381 and 4,940,717, the disclosures of each of which are incorporated herein by reference in their entirety.

(453) VNI, VNF, and Variants Thereof

(454) In some embodiments, the CYP51A1 inhibitor is VNI, represented by formula (5), herein, or VNF, represented by formula (6), herein.

(455) ##STR00137##

(456) In some embodiments, the CYP51A1 inhibitor is a variant of VNI or VNF that retains CYP51A1 inhibitory activity. For example, the CYP51A1 inhibitor may be a compound represented by formula (XXXI)

(457) ##STR00138##

(458) wherein each of rings A and B are independently optionally substituted and optionally fused aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

(459) each X is independently halogen or optionally substituted alkyl (e.g., optionally substituted lower alkyl); and

(460) n is an integer of from 1 to 5 (e.g., an integer of from 1 to 3).

(461) In some embodiments of formula (XXXI), the compound is represented by formula (XXXII)

(462) ##STR00139##

(463) wherein each X is independently halogen or optionally substituted alkyl (e.g., optionally substituted lower alkyl); and

(464) each n is independently an integer of from 1 to 5 (e.g., an integer of from 1 to 3).

(465) In some embodiments of formula (XXXII), the compound is represented by formula (XXXIII)

(466) ##STR00140##

(467) wherein each X and n are as defined for formula (XXXII).

(468) In some embodiments, the CYP51A1 inhibitor is a compound represented by formula (XXXIV)

(469) ##STR00141##

(470) wherein each X is independently halogen or optionally substituted alkyl (e.g., optionally substituted lower alkyl); and

(471) each n is independently an integer of from 1 to 5 (e.g., an integer of from 1 to 3).

(472) In some embodiments of formula (XXXIV), the compound is represented by formula (XXXV)

(473) ##STR00142##

(474) wherein each X and n are as defined for formula (XXXIV).

(475) Ketoconazole and Variants Thereof

(476) In some embodiments, the CYP51A1 inhibitor is ketoconazole or a variant thereof that retains CYP51A1 inhibitory activity, such as a compound represented by formula(XXXVI)

(477) ##STR00143##

(478) wherein Q is selected from the group consisting of CH and N;

(479) Ar is an optionally substituted, optionally fused aryl group, such as an optionally fused, optionally substituted phenyl group, for example, a phenyl group having from 1 to 3 substituents, such as from 1 to 3 substituents independently selected from the group consisting of halo, lower alkyl and lower alkyloxy;

(480) A is selected from the group consisting of: (a) an isothiocyanato group —N═C═S; (b) an amino group of the formula

(481) ##STR00144## wherein R.sub.1 and R.sub.2 are each independently selected from the group consisting of hydrogen and lower alkyl; (c) a group of the formula

(482) ##STR00145## wherein X is selected from the group consisting of O and S, Y is selected from the group consisting of O and NH, m is the integer 0 or 1, and R.sub.3 is selected from the group consisting of hydrogen, lower alkyl, mono- and dihalo-(lower alkyl), phenyl and substituted phenyl, said substituted phenyl having from 1 to 2 substituents independently selected from the group consisting of halo, lower alkyl and lower alkyloxy, optionally provided that: i) when said X is S, then said Y is NH and said m is 1; and ii) when said Y is O and said m is 1, then said R.sub.3 is other than hydrogen; and (d) a group of the formula

(483) ##STR00146## wherein Z is selected from the group consisting of a direct bond, CH.sub.2, O and N—R.sub.4, wherein R.sub.4 is selected from the group consisting of hydrogen, lower alkyl, hydroxy-(lower alkyl), (lower alkyloxy)-lower alkyl, lower alkanoyl, lower alkylsulfonyl, phenylmethylsulfonyl, lower alkyloxycarbonyl, lower alkyloxycarbonylmethyl, phenoxycarbonyl, aminocarbonyl, mono- and di(lower alkyl)aminocarbonyl, aminocarbonylmethyl, (lower alkyl)aminocarbonylmethyl, (lower alkyl)aminothioxomethyl, (lower alkylthio)thioxomethyl, phenyl, phenylmethyl, benzoyl and substituted benzoyl, said substituted benzoyl being benzoyl having from 1 to 2 substituents independently selected from the group consisting of halo, lower alkyl and lower alkyloxy; and R is selected from the group consisting of hydrogen and nitro, optionally provided that when said R is nitro, then said A is amino.

(484) In some embodiments, the CYP51A1 inhibitor is a compound represented by formula (XXXVII)

(485) ##STR00147##

(486) wherein Q is selected from the group consisting of N and CH;

(487) Ar is selected from the group consisting of phenyl, thienyl, halothienyl and substituted phenyl, the substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of halo, lower alkyl, lower alkyloxy and trifluoromethyl; and the group Y is selected from the group consisting of: a group of the formula —SO.sub.2R.sub.1, wherein R.sub.1 is selected from the group consisting of trifluoromethyl and aryl; a group of formula -alk-R.sub.2, wherein alk is selected from the group consisting of lower alkylene and lower alkenylene and R.sub.2 is selected from the group consisting of cyano, amino, mono- and di(lower alkyl)amino, arylamino, mono- and di(aryllower alkyl)amino, 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl, aryloxy and aryl, provided that alk is other than methylene when R.sub.2 is phenyl; a group of formula

(488) ##STR00148## wherein n is an integer of from 0 to 6 inclusive, X is O or S and R.sub.3 is selected from the group consisting of hydrogen, mono-, di- and trihalolower alkyl, amino, mono- and di(lower alkyl)amino, arylamino, mono- and di(aryllower alkyl)amino, amino lower alkyl, mono- and di(lower alkyl)amino lower alkyl, (1-pyrrolidinyl)lower alkyl, (1-morpholinyl)lower alkyl, (1-piperidinyl)lower alkyl, aryl, aryllower alkyl, aryllower alkenyl and lower alkyloxycarbonyl lower alkyloxy, optionally provided that: (i) said n is other than 0 or 1 when said R.sub.3 is amino or lower alkylamino; and (ii) said n is other than 0 when said R.sub.3 is di(lower alkyl)amino or aryl; and a group of formula

(489) ##STR00149## wherein m is an integer of from 1 to 6 inclusive, A is O or NH, X is O or S and R.sub.4 is selected from the group consisting of hydrogen, lower alkyl, lower alkyloxy, aryl, aryloxy, aryllower alkyl, amino, mono- and di(lower alkyl)amino, arylamino, mono- and di(aryllower alkyl)amino, 1-pyrrolidinyl, 1-morpholinyl and 1-piperidinyl;
wherein said aryl, as used in the foregoing definitions, is selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, lower alkylthienyl and pyridinyl, said substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of lower alkyl, lower alkyloxy, halo, amino, mono- and di(lower alkyl)amino, lower alkylcarbonylamino, nitro and trifluoromethyl.

(490) Exemplary variants of ketoconazole that may be used in conjunction with the compositions and methods described herein are described, for example, in U.S. Pat. Nos. 4,144,346 and 4,503,055, the disclosures of each of which are incorporated herein by reference in their entirety.

(491) Prochloraz and Variants Thereof

(492) In some embodiments, the CYP51A1 inhibitor is prochloraz, represented by formula (7), below.

(493) ##STR00150##

(494) In some embodiments, the CYP51A1 inhibitor is a variant of prochloraz that retains CYP51A1 inhibitory activity, such as a compound represented by formula (XXXVIII)

(495) ##STR00151##

(496) wherein X is oxygen or sulfur, R.sub.1 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, phenylalkyl, phenylalkenyl, phenoxyalkyl or phenylthioalkyl and R.sub.2 is optionally substituted phenyl, phenylalkyl, phenylalkenyl, phenoxyalkyl or phenylthioalkyl, provided that when R.sub.1 is methyl or phenyl R.sub.2 is substituted phenyl or optionally substituted phenylalkyl, phenylalkenyl, phenoxyalkyl or phenylthioalkyl.

(497) In some embodiments of formula (XXXVIII), X is selected from the group consisting of oxygen and sulfur, R.sub.1 is selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkenyl of 3 or 4 carbon atoms, alkynyl of 3 to 5 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, optionally substituted phenyl, phenylalkyl, of the formula Ph(CH.sub.2).sub.n where n is 1 to 5, phenylalkenyl of 9 to 11 carbon atoms, phenoxyalkyl of the formula PhO(CH.sub.2).sub.n where n is 2 to 5 and phenylthioalkyl of the formula PhS(CH.sub.2).sub.n where n is 2 to 5, wherein the substituted phenyl nucleus has at least one substituent selected from the group consisting of halo, alkoxy of 1 or 2 carbon atoms, alkyl of 1 to 4 carbon atoms, trihalomethyl, cyano, methylthio, nitro and methylsulphonyl, and R.sub.2 is selected from the group consisting of optionally substituted phenylalkyl, of the formula Ph(CH.sub.2).sub.n where n is 1 to 5, phenylalkenyl of 9 to 11 carbon atoms, phenoxyalkyl of the formula PhO(CH.sub.2).sub.n where n is 2 to 5 and phenylthioalkyl of the formula PhS(CH.sub.2).sub.n where n is 2 to 5, wherein the substituted phenyl nucleus has at least one substituent selected from the group consisting of halo, alkoxy of 1 or 2 carbon atoms, alkyl of 1 to 4 carbon atoms, trihalomethyl, cyano, methylthio, nitro and methylsulphonyl.

(498) Exemplary variants of prochloraz that may be used in conjunction with the compositions and methods described herein are described, for example, in U.S. Pat. No. 4,080,462, the disclosure of which is incorporated herein by reference in its entirety.

(499) Propiconazole and Variants Thereof

(500) In some embodiments, the CYP51A1 inhibitor is propiconazole, represented by formula (8), below.

(501) ##STR00152##

(502) In some embodiments, the CYP51A1 inhibitor is a variant of propiconazole that retains CYP51A1 inhibitory activity, such as a compound represented by formula (XXXIX)

(503) ##STR00153##

(504) wherein Z is an alkylene selected from the group consisting of —CH.sub.2CH.sub.2—, —CH.sub.2—CH.sub.2CH.sub.2—, —CH(CH.sub.3)CH(CH.sub.3)—, and —CH.sub.2CH(alkyl)-, wherein the alkyl has from 1 to about 10 carbon atoms; and

(505) Ar is an optionally fused, optionally substituted aryl group, such as an optionally fused, optionally substituted phenyl, thienyl, naphthyl, or fluorenyl, for example, phenyl, thienyl, halothienyl, naphthyl and fluorenyl, each optionally containing one or more (e.g., from 1 to 3) substituents selected independently from the group consisting of halo, lower alkyl, lower alkyloxy, cyano, and nitro.

(506) Exemplary variants of propiconazole that may be used in conjunction with the compositions and methods described herein are described, for example, in U.S. Pat. No. 4,079,062, the disclosure of which is incorporated herein by reference in its entirety.

(507) Prothioconazole, Prothioconazole-desthio, and Variants Thereof

(508) In some embodiments, the CYP51A1 inhibitor is prothioconazole, represented by formula (8), below.

(509) ##STR00154##

(510) In some embodiments, the CYP51A1 inhibitor is prothioconazole-desthio, represented by formula (9), below.

(511) ##STR00155##

(512) In some embodiments, the CYP51A1 inhibitor is a variant of prothioconazole or prothioconazole-desthio that retains CYP51A1 inhibitory activity, such as a compound represented by formula (XL)

(513) ##STR00156##

(514) wherein R.sub.1 and R.sub.2 are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aroxyalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

(515) X is —SH, —SR.sub.3, —SO—R.sub.3, —SO.sub.2—R.sub.3, or —SO.sub.3H, wherein R.sub.3 is alkyl which is optionally substituted by one or more halogen moieties (e.g., fluorine and/or chlorine), alkenyl which is optionally substituted by one or more halogen moieties (e.g., fluorine and/or chlorine), optionally substituted aralkyl or optionally substituted aryl.

(516) Exemplary variants of prothioconazole and prothioconazole-desthio that may be used in conjunction with the compositions and methods described herein are described, for example, in U.S. Pat. No. 5,789,430, the disclosure of which is incorporated herein by reference in its entirety.

(517) Tebuconazole and Variants Thereof

(518) In some embodiments, the CYP51A1 inhibitor is tebuconazole, represented by formula (10), below.

(519) ##STR00157##

(520) In some embodiments, the CYP51A1 inhibitor is a variant of tebuconazole that retains CYP51A1 inhibitory activity, such as a compound represented by formula (XLI)

(521) ##STR00158##

(522) wherein R.sub.1 is —CH═CH—X, —C≡C—X, or —CH.sub.2—CH.sub.2—X, wherein X is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or optionally substituted aryl, aralkyl, aryloxy alkyl, or heterocycle;

(523) R.sub.2 is alkyl, cycloalkyl (e.g. cyclopropyl, cyclopentyl, or cyclohexyl) or optionally substituted aryl;

(524) Z is Cl, CN, or OR.sub.3, wherein R.sub.3 is hydrogen, acetyl, alkyl, alkenyl or aralkyl; and

(525) Y is ═N— or ═CH—,

(526) or a pharmaceutically acceptable salt, ester, or ether thereof.

(527) Exemplary variants of tebuconazole that may be used in conjunction with the compositions and methods described herein are described, for example, in U.S. Pat. No. 4,507,140, the disclosure of which is incorporated herein by reference in its entirety.

(528) Triadimenol and Variants Thereof

(529) In some embodiments, the CYP51A1 inhibitor is triadimenol, represented by formula (11), below.

(530) ##STR00159##

(531) In some embodiments, the CYP51A1 inhibitor is a variant of triadimenol that retains CYP51A1 inhibitory activity, such as a compound represented by formula (XLII)

(532) ##STR00160##

(533) wherein X.sub.1 is hydrogen or an alkyl group,

(534) X.sub.2 is hydrogen or an alkyl group,

(535) R.sub.1 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or optionally substituted aryl or aralkyl group,

(536) R.sub.2 is hydrogen or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or optionally substituted aryl or aralkyl group,

(537) R.sub.3 is hydrogen or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or optionally substituted aryl or aralkyl group, and

(538) Y is a keto group or a functional keto derivative.

(539) or a pharmaceutically acceptable salt, ester, or ether thereof.

(540) Exemplary variants of triadimenol that may be used in conjunction with the compositions and methods described herein are described, for example, in U.S. Pat. No. 3,912,752, the disclosure of which is incorporated herein by reference in its entirety.

(541) Azalanstat and Variants Thereof

(542) In some embodiments, the CYP51A1 inhibitor is azalanstat, represented by formula (12), below.

(543) ##STR00161##

(544) In some embodiments, the CYP51A1 inhibitor is a variant of azalanstat that retains CYP51A1 inhibitory activity, such as a compound represented by formula (XLIII)

(545) ##STR00162##

(546) wherein n is 2 or 3;

(547) p is 0, 1 or 2;

(548) q is 0, 1 or 2;

(549) X is oxygen or S(O).sub.t wherein t is 0, 1, or 2;

(550) each R.sub.1 is independently halo, lower alkyl, lower alkoxy, or trifluoromethyl;

(551) each R.sub.2 is independently halo or lower alkyl;

(552) R.sub.3 is nitro or —N(R.sub.5)R.sub.6 where

(553) R.sub.5 is hydrogen or lower alkyl;

(554) R.sub.6 is hydrogen, lower alkyl, lower alkylsulfonyl or —C(Y)R.sub.7 where Y is oxygen or sulfur and R.sub.7 is hydrogen, lower alkyl, lower alkoxy or —N(R.sub.8)R.sub.9 where R.sub.8 is hydrogen or lower alkyl and R.sub.9 is hydrogen, lower alkyl or lower alkoxycarbonyl; or

(555) R.sub.5 and R.sub.6 together with N is pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, wherein the piperazino is optionally substituted at the 4-position by —C(O)R.sub.10 where R.sub.10 is hydrogen, lower alkyl, lower alkoxy or amino; and

(556) R.sub.4 is hydrogen or optionally substituted lower alkyl;

(557) or a pharmaceutically acceptable salt, ester, or ether thereof.

(558) In some embodiments of formula (XLIII), the compound is represented by formula (XLIV)

(559) ##STR00163##

(560) wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, X, n, p, and q are as defined for formula (XLIII).

(561) In some embodiments of formula (XLIII), the compound is represented by formula (XLV)

(562) ##STR00164##

(563) wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, X, n, p, and q are as defined for formula (XLIII).

(564) In some embodiments of formula (XLIII), the compound is represented by formula (XLVI)

(565) ##STR00165##

(566) wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, X, n, p, and q are as defined for formula (XLIII).

(567) In some embodiments of formula (XLIII), the compound is represented by formula (XLVII)

(568) ##STR00166##

(569) wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, X, n, p, and q are as defined for formula (XLIII).

(570) In some embodiments of formula (XLIII), the compound is represented by formula (XLVIII)

(571) ##STR00167##

(572) wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, X, n, p, and q are as defined for formula (XLIII).

(573) Exemplary variants of azalanstat that may be used in conjunction with the compositions and methods described herein are described, for example, in U.S. Pat. No. 5,158,949, the disclosure of which is incorporated herein by reference in its entirety.

(574) Antibody Inhibitors of CYP51A1

(575) CYP51A1 inhibitors useful in conjunction with the compositions and methods described herein include antibodies and antigen-binding fragments thereof, such as those that specifically bind to CYP51A1 and/or inhibit CYP51A1 catalytic activity. In some embodiments, the antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a dual-variable immunoglobulin domain, a single-chain Fv molecule (scFv), a diabody, a triabody, a nanobody, an antibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab′).sub.2 molecule, and a tandem di-scFv. In some embodiments, the antibody has an isotype selected from IgG, IgA, IgM, IgD, and IgE.

(576) Interfering RNA Inhibitors of CYP51A1

(577) CYP51A1 inhibitors useful in conjunction with the compositions and methods described herein include interfering RNA molecules, such as short interfering RNA (siRNA) molecules, micro RNA (miRNA) molecules, or short hairpin RNA (shRNA) molecules. The interfering RNA may suppress expression of a CYP51A1 mRNA transcript, for example, by way of (i) annealing to a CYP51A1 mRNA or pre-mRNA transcript, thereby forming a nucleic acid duplex; and (ii) promoting nuclease-mediated degradation of the CYP51A1 mRNA or pre-mRNA transcript and/or (iii) slowing, inhibiting, or preventing the translation of a CP51A1 mRNA transcript, such as by sterically precluding the formation of a functional ribosome-RNA transcript complex or otherwise attenuating formation of a functional protein product from the target RNA transcript.

(578) In some embodiments, the interfering RNA molecule, such as the siRNA, miRNA, or shRNA, contains an antisense portion that anneals to a segment of a CYP51A1 RNA transcript (e.g., mRNA or pre-mRNA transcript), such as a portion that anneals to a segment of a CYP51A1 RNA transcript having a nucleic acid sequence that is at least 85% identical to the nucleic acid sequence of SEQ ID NO: 2 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%<96%, 97%, 98%, 99%, 99.9%, or 100% identical to the nucleic acid sequence of SEQ ID NO: 2).

(579) In some embodiments, the interfering RNA molecule, such as the siRNA, miRNA, or shRNA, contains a sense portion having at least 85% sequence identity to the nucleic acid sequence of a segment of SEQ ID NO: 2 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%<96%, 97%, 98%, 99%, 99.9%, or 100% identical to the nucleic acid sequence of a segment of SEQ ID NO: 2).

(580) Interfering RNAs as described herein may be provided to a patient, such as a human patient having a neurological disorder described herein, in the form of, for example, a single- or double-stranded oligonucleotide, or in the form of a vector (e.g., a viral vector) containing a transgene encoding the interfering RNA. Exemplary interfering RNA platforms are described, for example, in Lam et al., Molecular Therapy -Nucleic Acids 4:e252 (2015); Rao et al., Advanced Drug Delivery Reviews 61:746-769 (2009); and Borel et al., Molecular Therapy 22:692-701 (2014), the disclosures of each of which are incorporated herein by reference in their entirety.

(581) Methods of Treatment

(582) Suppression of CYP51A1 Activity and TDP-43 Aggregation to Treat Neurological Disorders

(583) Using the compositions and methods described herein, a patient suffering from a neurological disorder may be administered a CYP51A1 inhibitor, such as a small molecule, antibody, antigen-binding fragment thereof, or interfering RNA molecule described herein, so as to treat the disorder and/or to suppress one or more symptoms associated with the disorder. Exemplary neurological disorders that may be treated using the compositions and methods described herein are, without limitation, amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington's disease, IBMPFD, sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, and hereditary inclusion body myopathy, as well as neuromuscular diseases such as congenital myasthenic syndrome, congenital myopathy, cramp fasciculation syndrome, Duchenne muscular dystrophy, glycogen storage disease type II, hereditary spastic paraplegia, inclusion body myositis, Isaac's Syndrome, Kearns-Sayre syndrome, Lambert-Eaton myasthenic syndrome, mitochondrial myopathy, muscular dystrophy, myasthenia gravis, myotonic dystrophy, peripheral neuropathy, spinal and bulbar muscular atrophy, spinal muscular atrophy, Stiff person syndrome, Troyer syndrome, and Guillain-Barré syndrome.

(584) The present disclosure is based, in part, on the discovery that CYP51A1 inhibitors, such as the agents described herein, are capable of attenuating TDP-43 aggregation in vivo. TDP-43-promoted aggregation and toxicity have been associated with various neurological diseases. The discovery that CYP51A1 inhibitors modulate TDP-43 aggregation provides an important therapeutic benefit. Using a CYP51A1 inhibitor, such as a CYP51A1 inhibitor described herein, a patient suffering from a neurological disorder or at risk of developing such a condition may be treated in a manner that remedies an underlying molecular etiology of the disease. Without being limited by mechanism, the compositions and methods described herein can be used to treat or prevent such neurological conditions, for example, by suppressing the TDP-43 aggregation that promotes pathology.

(585) Additionally, the compositions and methods described herein provide the beneficial feature of enabling the identification and treatment of patients that are likely to respond to CYP51A1 inhibitor therapy. For example, in some embodiments, a patient (e.g., a human patient suffering from or at risk of developing a neurological disease described herein, such as amyotrophic lateral sclerosis) is administered a CYP51A1 inhibitor if the patient is identified as likely to respond to this form of treatment. Patients may be identified as such on the basis, for example, of susceptibility to TDP-43 aggregation. In some embodiments, the patient is identified is likely to respond to CYP51A1 inhibitor treatment based on the isoform of TDP-43 expressed by the patient. For example, patients expressing TDP-43 isoforms having a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D, among others, are more likely to develop TDP-43-promoted aggregation and toxicity relative to patients that do not express such isoforms of TDP-43. Using the compositions and methods described herein, a patient may be identified as likely to respond to CYP51A1 inhibitor therapy on the basis of expressing such an isoform of TDP-43, and may subsequently be administered a CYP51A1 inhibitor so as to treat or prevent one or more neurological disorders, such as one or more of the neurological disorders described herein.

(586) Assessing Patient Response

(587) A variety of methods known in the art and described herein can be used to determine whether a patient having a neurological disorder (e.g., a patient at risk of developing TDP-43 aggregation, such as a patient expressing a mutant form of TDP-43 having a mutation associated with elevated TDP-43 aggregation and toxicity, for example, a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D) is responding favorably to CYP51A1 inhibition. For example, successful treatment of a patient having a neurological disease, such as amyotrophic lateral sclerosis, with a CYP51A1 inhibitor described herein may be signaled by:

(588) (i) an improvement in condition as assessed using the amyotrophic lateral sclerosis functional rating scale (ALSFRS) or the revised ALSFRS (ALSFRS-R), such as an improvement in the patient's ALSFRS or ALSFRS-R score within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement in the patient's ALSFRS or ALSFRS-R score within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient);

(589) (ii) an increase in slow vital capacity, such as an increase in the patient's slow vital capacity within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an increase in the patient's slow vital capacity within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient);

(590) (iii) a reduction in decremental responses exhibited by the patient upon repetitive nerve stimulation, such as a reduction that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., a reduction that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient);

(591) (iv) an improvement in muscle strength, as assessed, for example, by way of the Medical Research Council muscle testing scale (as described, e.g., in Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339 (2014), the disclosure of which is incorporated herein by reference as it pertains to measuring patient response to neurological disease treatment), such as an improvement that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient);

(592) (v) an improvement in quality of life, as assessed, for example, using the amyotrophic lateral sclerosis-specific quality of life (ALS-specific QOL) questionnaire, such as an improvement in the patient's quality of life that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., an improvement in the subject's quality of life that is observed within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient);

(593) (vi) a decrease in the frequency and/or severity of muscle cramps, such as a decrease in cramp frequency and/or severity within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., a decrease in cramp frequency and/or severity within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient); and/or

(594) (vii) a decrease in TDP-43 aggregation, such as a decrease in TDP-43 aggregation within one or more days, weeks, or months following administration of the CYP51A1 inhibitor (e.g., a decrease in TDP-43 aggregation within from about 1 day to about 48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), or more, following the initial administration of the CYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following the initial administration of the CYP51A1 inhibitor to the patient.

(595) Routes of Administration and Dosing

(596) CYP51A1 inhibitors (e.g., inhibitory small molecules, antibodies, antigen-binding fragments thereof, and interfering RNA molecules) described herein may be administered to a patient (e.g., a human patient having one or more neurological disorders described herein) by a variety of routes. Exemplary routes of administration are oral, transdermal, subcutaneous, intranasal, intravenous, intramuscular, intraocular, parenteral, topical, intrathecal, and intracerebroventricular administration. The most suitable route for administration in any given case will depend on the particular agent being administered, the patient, pharmaceutical formulation methods, administration methods (e.g., administration kinetics), the patient's age, body weight, sex, severity of the diseases being treated, the patient's diet, and the patient's excretion rate, among other factors.

(597) Therapeutic compositions can be administered with medical devices known in the art. For example, therapeutic compositions described herein can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Pat. Nos. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556. Examples of implants and modules useful in conjunction with the routes of administration described herein are those described in U.S. Pat. No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Pat. No. 4,486,194, which discloses a therapeutic device for administering medicaments through the skin; U.S. Pat. No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Pat. No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Pat. No. 4,475,196, which discloses an osmotic drug delivery system. These patents are incorporated herein by reference as they pertain to devices suitable for administration of a therapeutic agent to a patient (e.g., a human patient). Various other such implants, delivery systems, and modules are known to those skilled in the art.

(598) Pharmaceutical Compositions

(599) The CYP51A1 inhibitors (e.g., small molecules, antibodies, antigen-binding fragments thereof, and interfering RNA molecules described herein) suitable for use with the compositions and methods described herein can be formulated into pharmaceutical compositions for administration to a patient, such as a human patient exhibiting or at risk of developing TDP-43 aggregation, in a biologically compatible form suitable for administration in vivo. A pharmaceutical composition containing, for example, a CYP51A1 inhibitor described herein, such as LEK-935, CP-320626, itraconazole, posaconazole, cyproconazole, voriconazole, fluconazole, clotrimazol, fenticonazole, epoxiconazole, ketoconazole, ravuconazole, isavuconazole, holothurin A, theasaponin, capsicosine, betulafolientriol, prochloraz, propiconazole, prothioconazole, prothioconazole-desthio, tebuconazole, triadimenol, azalanstat, or a variant thereof, or an antibody, antigen-binding fragment thereof, or interfering RNA molecule described herein, may additionally contain a suitable diluent, carrier, or excipient. CYP51A1 inhibitors can be formulated for administration to a subject, for example, by way of any one or more of the routes of administration described above. Under ordinary conditions of storage and use, a pharmaceutical composition may contain a preservative, e.g., to prevent the growth of microorganisms. Procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy (2012, 22.sup.nd ed.) and in The United States Pharmacopeia: The National Formulary (2015, USP 38 NF 33).

(600) Pharmaceutical compositions may include sterile aqueous solutions, dispersions, or powders, e.g., for the extemporaneous preparation of sterile solutions or dispersions. In all cases the form may be sterilized using techniques known in the art and may be fluidized to the extent that may be easily administered to a patient in need of treatment.

(601) A pharmaceutical composition may be administered to a patient, e.g., a human patient, alone or in combination with one or more pharmaceutically acceptable carriers, e.g., as described herein, the proportion of which may be determined by the solubility of the compound, the chemical nature of the compound, and/or the chosen route of administration, among other factors.

EXAMPLES

(602) The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regards as their invention.

Example 1. Inhibition of CYP51A1 Modulates TDP-43 Aggregation

Introduction

(603) Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an aggressive, debilitating disease in which affected patients succumb within two to five years after diagnosis. ALS presents with heterogeneous clinical features but has a common underlying pathology of motor neuron loss that limits the central nervous system's ability to effectively regulate voluntary and involuntary muscle activity. Additionally, without neuronal trophic support muscles being to atrophy, further exacerbating motor deterioration. Cellular and tissue degeneration results in motor impairment such as fasciculations and weakening in the arms, legs and neck, difficulty swallowing, slurred speech and ultimately failure of the diaphragm muscles that control breathing.

(604) At the cellular level, 97% of all ALS cases have the common pathological feature of misfolded and aggregated TAR-DNA binding protein (TDP)-43 in spinal motor neuron inclusions. TDP-43 is a DNA/RNA binding protein involved in RNA splicing and is typically localized to the nucleus but can be translocated to the cytoplasm under conditions of cell stress. Nuclear clearing and cytoplasmic accumulation of misfolded and aggregated TDP-43 are hallmarks of degenerating motor neurons in ALS, but it remains unclear if mechanism of toxicity is due to aggregation-dependent loss of TDP-43 function or if the aggregates acquire toxic gain of function. Aggregates of TDP-43 accumulate in discrete cellular domains known as stress granules, which are also enriched with translationally inactive mRNAs. Stress granules are observed in multiple cellular types and are thought to be directly related to TDP-43-dependent toxicity in ALS and FTD. Dysfunction in DNA/RNA binding protein activity plays a crucial role in susceptible motor neurons in ALS, as familial cases have also been traced to mutations in the protein Fused in Sarcoma (FUS), a DNA/RNA binding protein that recently has been shown to be involved in gene silencing. Preclinical studies suggest that FUS mutations promote a toxic gain of function that may be causative in motor neuron degeneration.

(605) Mutations in the TDP-43 gene (TARDBP) have also been causally linked to familial forms of ALS. A common TDP-43 mutation is known as Q331K, in which glutamine (Q) 331 has been mutated to a lysine (K). This mutation results in a TDP-43 protein that is more aggregation prone and exhibits enhanced toxicity. A recent study has also demonstrated that the Q331K mutation can confer a toxic gain of function in a TDP-43 knock-in mouse, which exhibits cognitive deficits and histological abnormalities similar to that which occurs in frontotemporal dementia (FTD). FTD refers to a group of degenerative disorders that are characterized by atrophy in the frontal and temporal cortices due to progressive neuron loss. Due to the functional nature of the brain regions impacted in FTD, the most common symptoms involve noticeable alterations in personality, behavior and linguistic ability and can also present with loss of speech. The pathological basis of FTD appears to be multifactorial involving mutations in genes such as C9orf72, progranulin (GRN) and MAPT, but intracellular inclusions of aggregated TDP-43, FUS and tau have been observed. Although ALS and FTD may have different genetic and molecular triggers and occur in different cell types, similar protein misfolding and degenerative mechanisms may operate in multiple diseases.

(606) The toxic gain of function features of TDP-43 can be faithfully recapitulated in the simple model organism, budding yeast, where the protein also localizes to stress granules. Human disease mutations in TDP-43 enhance toxicity and yeast genetic screens have revealed key connections that are conserved to humans. The yeast model thus provides a robust cell-based screening platform for small molecules capable of ameliorating toxicity. To validate compounds from such phenotypic screens, it is imperative to test compounds in a mammalian neuronal context. In an effort to develop TDP-43-related mammalian models of neuron loss that occurs in ALS and FTD, primary cultures of rat cortical neurons were transfected with human wild type or Q331K mutant TDP-43. These cells were compared to cells which received an empty expression vector control. Validation studies have demonstrated that cells expressing either wild type or Q331K TDP-43 have are more susceptible to dying over time in culture. In the experiments described in this example, this model system is used to interrogate new therapeutic approaches to ameliorate TDP-43 toxicity.

Results

(607) From the TDP-43 yeast model, a compound with known mode of action was identified that restored viability to TDP-43-expressing yeast (FIG. 1A). Fluconazole is an antifungal known to inhibit Erg11, the yeast lanosterol 14-alpha demethylase (FIG. 1B). Inhibition of Erg11 reduces ergosterol synthesis (yeast equivalent of cholesterol), while increasing lanosterol levels, the substrate of Erg11 (FIG. 1C). The human homolog of Erg11 is Cyp51A1, a member of the cytochrome P450 superfamily of enzymes but does not appear to have a role in detoxification of xenobiotics. CYP51A1 has also been known as lanosterol 14-alpha demethylase, which describes its function in removing the 14-alpha-methyl group from lanosterol to generate 4,4-dimethylcholesta-8(9),14,24-trien-3β-ol, which is a critical step in the cholesterol biosynthetic pathway.

(608) To evaluate the potential role of CYP51A1 in TDP-43 pathology, the aforementioned primary rat cortical neuron TDP-43 models were utilized to test the efficacy of published inhibitors (FIG. 2). Rat cortical neurons transfected with wild type human TDP-43 exhibited a significant reduction in survival compared to neurons transfected with empty vector control, and this reduction in survival was partially alleviated by treatment with compound (3) (FIGS. 3A and 3B). A similar survival befit was conferred by compound (3) when applied to cells transfected with Q331K mutant TDP-43 (FIGS. 4A and 4B). A similar effect in rescuing a survival deficit was observed for a structurally differentiated compound (4) when applied to cells transfected with wild type TDP-43 (FIGS. 5A and 5B). These studies demonstrate that inhibition of Erg11 in yeast and inhibition of Cyp51A1 has a beneficial effect of rescuing cells from wild type and mutant TDP-43 toxicity and promotes cell survival. This is the first demonstration that inhibition of CYP51A1 is beneficial in treating and preventing TDP-43 pathological processes and represents a novel therapeutic approach for the treatment of ALS.

Example 2. Use of a CYP51A1 Inhibitor for the Treatment or Prevention of a Neurological Disorder in a Human Patient

(609) Using the compositions and methods described herein, a patient suffering from or at risk of developing a neurological disorder, such as amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, corticobasal degeneration, progressive supranuclear palsy, dementia parkinsonism ALS complex of Guam, Huntington's disease, Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy, dementia pugilistica, chronic traumatic encephalopathy, Alexander disease, or hereditary inclusion body myopathy, may be administered a CYP51A1 inhibitor so as to treat the disease, alleviate one or more symptoms of the disease, or slow or prevent the onset of the disease. The CYP51A1 inhibitor may be, for example, a small molecule that specifically binds to an/or inhibits the enzymatic activity of CYP51A1, an antibody or antigen-binding fragment thereof that specifically binds to and/or inhibits the activity of CYP51A1, or substance that reduces expression of functional CYP51A1, such as an interfering RNA molecule (for example, a siRNA, miRNA, or shRNA molecule described herein).

(610) Prior to treatment, the patient may be subjected to one or more analytical tests in order to determine their initial quality of life, muscle strength, muscle function, slow vital capacity, decremental responses exhibited upon repetitive nerve stimulation, among other parameters that describe the patient's initial disease state. The patient may then be administered a CYP51A1 inhibitor, such as by way of oral, transdermal, subcutaneous, intranasal, intravenous, intramuscular, intraocular, parenteral, topical, intrathecal, and/or intracerebroventricular administration. The CYP51A1 inhibitor may be administered to the patient in combination with one or more pharmaceutically acceptable excipients, carriers, or diluents. The CYP51A1 inhibitor may be administered to the patient once or a plurality of times, such as periodically over the course of a treatment period of one or more days, weeks, months, or years.

(611) To determine the responsiveness of the patient to CYP51A1 inhibitor therapy, a physician may perform one or more tests in order to evaluate whether the patient exhibits any of the following indications of clinical benefit:

(612) (i) an improvement in condition as assessed using the amyotrophic lateral sclerosis functional rating scale (ALSFRS) or the revised ALSFRS (ALSFRS-R);

(613) (ii) an increase in slow vital capacity, such as an increase in the patient's slow vital capacity within one or more days, weeks, or months following administration of the CYP51A1 inhibitor;

(614) (iii) a reduction in decremental responses exhibited by the patient upon repetitive nerve stimulation, such as a reduction that is observed within one or more days, weeks, or months following administration of the CYP51A1 inhibitor;

(615) (iv) an improvement in muscle strength, as assessed, for example, by way of the Medical Research Council muscle testing scale (as described, e.g., in Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339 (2014), the disclosure of which is incorporated herein by reference as it pertains to measuring patient response to neurological disease treatment);

(616) (v) an improvement in quality of life, as assessed, for example, using the amyotrophic lateral sclerosis-specific quality of life (ALS-specific QOL) questionnaire;

(617) (vi) a decrease in the frequency and/or severity of muscle cramps, such as a decrease in cramp frequency and/or severity within one or more days, weeks, or months following administration of the CYP51A1 inhibitor; and/or

(618) (vii) a decrease in TDP-43 aggregation, such as a decrease in TDP-43 aggregation within one or more days, weeks, or months following administration of the CYP51A1 inhibitor.

Example 3. Determining the Likelihood of a Patient to Respond to CYP51A1 Inhibitor Therapy

(619) Using the compositions and methods described herein, one may determine the propensity of a patient (e.g., a human patient) suffering from a neurological disease to respond to CYP51A1 inhibitor therapy. For example, a physician may obtain a sample from a patient having a neurological disease, such as amyotrophic lateral sclerosis or another neurological disorder described herein. The physician may then determine whether the patient expresses an isoform of TDP-43 having a mutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D, among others, as these mutations are associated with elevated TDP-43 aggregation and toxicity. This may be done, for example, by determining the patient's genotype at the TDP-43 locus and/or by isolating TDP-43 protein from a biological sample obtained from the patient and sequencing the protein using molecular biology techniques known in the art. A finding that the patient exhibits TDP-43 aggregation and/or expresses a mutant TDP-43 protein having a Q331K, M337V, Q343R, N345K, R361S, or N390D mutation may be taken as an indication that the patient is likely to respond to CYP51A1 inhibitor therapy.

(620) Upon determining that the patient is likely to respond to treatment with a CYP51A1 inhibitor, the patient may be administered one or more CYP51A1 inhibitors, for example, as described in Example Two, above. The inhibitor of CYP51A1 may be a small molecule, such as LEK-935, CP-320626, itraconazole, posaconazole, cyproconazole, voriconazole, fluconazole, clotrimazol, fenticonazole, epoxiconazole, ketoconazole, ravuconazole, isavuconazole, holothurin A, theasaponin, capsicosine, betulafolientriol, prochloraz, propiconazole, prothioconazole, prothioconazole-desthio, tebuconazole, triadimenol, azalanstat, or a variant thereof. In some embodiments, the CYP51A1 inhibitor is an anti-CYP51A1 antibody or antigen-binding fragment thereof, or a compound, such as an interfering RNA molecule, that attenuates CYP51A1 expression.

OTHER EMBODIMENTS

(621) All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

(622) While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

(623) Other embodiments are within the claims.