Veragranine analogs, pharmaceutical compositions, and uses in managing pain or inflammatory conditions

Abstract

Disclosed herein are compounds that are veragranine analogs, pharmaceutical compositions, and medical uses thereof. In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a compound as disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, this disclosure relates to methods of treating pain or other inflammatory condition comprising administering an effective amount of a compound disclosed herein to a subject in need thereof.

Description

[0001] VERAGRANINE ANALOGS, PHARMACEUTICAL COMPOSITIONS, AND USES IN MANAGING PAIN OR INFLAMMATORY CONDITIONS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 642,360 filed May 3, 2024. The entirety of this application is hereby incorporated by reference for all purposes.

[0004] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0005] This invention was made with government support under GM128570 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0006] BACKGROUND

[0007] Chronic pain affects a substantial number of people. Traditional remedies from plants, such as opium poppy-derived morphine, willow bark-based aspirin, and cannabis-origin tetrahydrocannabinol (THC) have been reported to treat various types of pain; however, these agents often have limitations and other undesirable side effects. Thus, there is a need to identify alternative therapies.

[0008] Peripheral nociceptors are specialized sensory neuron cells that undergo sensitization in response to inflammation. Peripheral nerve fibers exhibit abnormal discharges following injury or disease. Chronic pain resulting from a nervous system injury or disease, (neuropathic pain), is associated with persistent electrical hyperactivity in nociceptors. Voltage-gated sodium and calcium channels participate in transmitting noxious stimuli. Sustained stimuli or chronic diseases can alter this process leading to hyperactivity in the damaged nerves. Thus, there is a need to develop agents that block the activities of key ion channels that regulate the hyperexcitability of neurons.

[0009] Nicolaou et al. report palladium-catalyzed cross-coupling reactions in total synthesis. Angew Chem Int Ed, 2005, 44, 4442-4489.

[0010] Xie et al. report steroidal alkaloids with a potent analgesic effect based on N-type calcium channel inhibition. Org Lett, 2022, 24, 467-471. Zhu et al. report the synthesis of 5a,6-dihydroveragranines A and B. Org Lett, 2022, 24, 5825-5828.

[0011] References cited herein are not an admission of prior art.

[0012] SUMMARY

[0013] Disclosed herein are compounds that are veragranine analogs, pharmaceutical compositions, and medical uses thereof. In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a compound as disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, this disclosure relates to methods of treating pain or other inflammatory condition comprising administering an effective amount of a compound disclosed herein to a subject in need thereof.

[0014] In certain embodiments, the compounds have the following formula I, or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;

[0015] R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the same or different, R8;

[0016] R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8; R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0017] R4is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0018] R5is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0019] R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR7, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R5and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7;

[0020] R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; and

[0021] R8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfmyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0022] In certain embodiments, the compound is 6bl,9,10, 14b-tetramethyl-l,2,3,4,6,6a,6b,6bl,7, 8,8a,9,14a,14b-tetradecahydronaphtho[2',l':4,5]indeno[l,7-gh]isoquinolin-3-ol (27a), derivative or salt thereof.

[0023] In certain embodiments, the compound is methyl 3-hydroxy-6bl,9,14b-trimethyl- l,2,3,4,6,6a,6b,6bl,7,8,8a,9,14a,14b-tetradecahydronaphtho[2',l':4,5]indeno[l,7- gh]isoquinoline- 11 -carboxylate, (27eb) derivative or salt thereof. In certain embodiments, the compound is 6bl,9,l l ,14b-tetramethyl-l,2,3,4,6,6a,6b,6bl ,7, 8,8a,9,14a,14b-tetradecahydronaphtho[2',r:4,5]indeno[l,7-gh]isoquinolin-3-ol (27cb), derivative or salt thereof.

[0024] In certain embodiments, the compound is 6bl,9,16b-trimethyl- l,2,3,5,6,6a,6b,6bl,7,8,8a,9,16a,16b-tetradecahydronaphtho[2',l':4,5]indeno[7,l- ij]phenanthri din-3 -ol (27gb) derivative or salt thereof.

[0025] In certain embodiments, the compounds have the following formula IIA, or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;

[0026] R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the same or different, R8;

[0027] R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0028] R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0029] R4is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0030] R?is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8; R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR7, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R5and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7;

[0031] R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; and

[0032] R8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfmyl, ethylsulfmyl, mesyl, ethyl sulfonyl, methoxy carbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0033] In certain embodiments, the compound is 6bl,9,16b-trimethyl-l,2,3,4,6,6a,6b,6bl,7, 8,8a,9,16a,16b-tetradecahydronaphtho[2',l':4,5]indeno[7,l-ab]acridin-3-ol (27ga), derivative or salt thereof.

[0034] In certain embodiments, the compounds have the following formula IIB, or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;

[0035] R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the

[0036] 5 same or different, R8;

[0037] R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0038] R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8; fO R4is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0039] R5is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0040] R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR7, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R5and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7;

[0041] 20 R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; and

[0042] R8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-

[0043] 30 dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. In certain embodiments, the compound is 6bl,9,16b-trimethyl-l,2,3,4,6,6a,6b,6bl ,7, 8,8a,9,16a,16b-tetradecahydronaphtho[2',r:4,5]indeno[7,l-ab]phenanthridin-3-ol (27h), derivative or salt thereof.

[0044] In certain embodiments, the compounds have the following formula III or IV,

[0045] Formula III Formula IV or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;

[0046] R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the same or different, R8;

[0047] R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0048] R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0049] R5is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0050] R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR6, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R? and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7;

[0051] R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; and

[0052] R8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0053] In certain embodiments, the compound is 10,13-dimethyl-12-(4-methylpyridin-3-yl)-17- vinyl-2,3,4,7,8,9,10,13,14,15,16,17-dodecahydro-lH-cyclopenta[a]phenanthren-3-ol (26b), derivative or salt thereof.

[0054] In certain embodiments, the compound is 10,13-dimethyl-12-(6-methylpyridin-3-yl)-17- vinyl-2,3,4,7,8,9,10,13,14,15,16,17-dodecahydro-lH-cyclopenta[a]phenanthren-3-ol (26c), derivative or salt thereof.

[0055] In certain embodiments, the compound is 10,13-dimethyl-12-(quinolin-3-yl)-17-vinyl- 2,3,4,7,8,9,10,13,14,15,16,17-dodecahydro-lH-cyclopenta[a]phenanthren-3-ol (26g), derivative or salt thereof.

[0056] In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a compound as disclosed herein and a pharmaceutically acceptable excipient.

[0057] In certain embodiments, this disclosure relates to methods of treating or preventing pain or other a disease or condition reported herein by administering an effective amount of a compound as reported herein or pharmaceutical composition as provided herein to a subject in need thereof.

[0058] In certain embodiments, this disclosure relates to making a medicament having compounds herein for uses in therapies disclosed herein. In certain embodiments, this disclosure relates to methods of making compounds disclosed herein comprising contacting the starting materials with reagents providing the products reported herein.

[0059] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0060] Figure 1 illustrates retro- synthetic methods for synthesizing veragranine analogs.

[0061] Figure 2A illustrates methods used to make the steroidal core of veragranine analogs.

[0062] Figure 2B illustrates methods used to produce variant polycyclic pyridine analogs.

[0063] Figure 3 A illustrates a general strategy for synthesizing polycyclic pyridine analogs.

[0064] Figure 3B illustrates the yields of specific pyridine ortho and meta substituted and quinoline analogs using methods reported herein.

[0065] Figure 3C illustrates the yields of specific pyridine analogs with para and meta substitutions and quinoline analogs using methods reported herein.

[0066] Figure 4A illustrates TIPSO substituted analogs of veragranine and the alternative 4-methyl pyridine cyclization product.

[0067] Figure 4B shows the yields of veragranine analogs using alternative reactions reagents and conditions.

[0068] Figure 5A shows data using veragranine A analogs on depolarization-induced calcium influx in rat DRG neurons. Bar graphs show data of normalized average peak response of rat DRG neurons incubated overnight with 20 pM veragranine A analogs or 0.1% DMSO as a control in response to a 40 mM KC1 trigger. TTA-P2 (1 pM) was used as positive control.

[0069] Figure 5B shows data using 90 mM KC1. Omega-conotoxin GVIA (500 nM) was used as positive control.

[0070] Figure 5C shows bar graphs data on the normalized average peak response of rat DRG neurons incubated overnight with 10 pM 27a and 27eb or 0.1% DMSO as a control in response to 40 mM KC1, 90 mM KC1, and 30 pM veratridine trigger.

[0071] Figure 5D shows bar graphs on the normalized average peak response of rat DRG neurons incubated 30 min with 10 pM 27a and 27eb or 0.1% DMSO as a control in response to 40 mM KC1, 90 mM KC1, and 30 pM veratridine trigger. Fig. 6A illustrates experiments and treatment conditions using intrathecal administration of veragranine A analogs 27a and 27eb to show reversal of mechanical and cold allodynia induced in the mono-iodoacetate (MIA) model of osteoarthritis pain.

[0072] Figure 6B shows data on baseline paw-withdrawal thresholds measured before (pre-MIA) and after (post-MIA) in both male and female rats. The response paw-withdrawal threshold was then assessed every hour following a single administration of vehicle, 27a or 27eb (20 pg / 5 pL, i.t.) for up to 4 h after administration. Quantification of the paw-withdrawal threshold is reported in the panel from post-MIA to 4 h post administration indicating 27a and 27eb significantly improved MIA induced mechanical allodynia, when compared with vehicle.

[0073] Figure 6C shows data on baseline response duration that was measured before (pre-MIA) and after (post-MIA) to an application of an acetone drop in male and female rats. The response duration was then assessed every hour following a single administration of vehicle, 27a or 27eb (20 pg / 5 pL, i.t.) for up to 4 h after administration.

[0074] DETAILED DISCUSSION

[0075] Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims or as amended during prosecution.

[0076] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

[0077] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

[0078] Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

[0079] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent.

[0080] Prior to describing the various embodiments, the following definitions are provided and should be used unless otherwise indicated.

[0081] To the extent that structures provided herein are compounds with tautomers by hydrogen migration, a skilled artisan would understand the formula to cover all tautomeric forms.

[0082] As used herein, "alkyl" means a noncyclic straight chain or branched, unsaturated or saturated hydrocarbon such as those containing from 1 to 10 carbon atoms, typically 1 to 4 otherwise designated Ci-4alkyl. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl" or "alkynyl", respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1 -pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2- butynyl, 1-pentynyl, 2-pentynyl, 3- methyl- 1-butynyl, and the like.

[0083] Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles" or "carbocyclyl" groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like.

[0084] "Heterocarbocycles" or heterocarbocyclyl" groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0085] The term "aryl" refers to aromatic homocyclic (i.e., hydrocarbon) mono-, bi- or tricyclic ring-containing groups preferably having 6 to 12 members such as phenyl, naphthyl and biphenyl. Phenyl is a preferred aryl group. The term "substituted aryl" refers to aryl groups substituted with one or more groups, preferably selected from alkyl, substituted alkyl, alkenyl (optionally substituted), aryl (optionally substituted), heterocyclo (optionally substituted), halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), aroyl, (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl, and, the like, where optionally one or more pair of substituents together with the atoms to which they are bonded form a 3 to 7 member ring.

[0086] As used herein, "heteroaryl" or “heteroaromatic” refers an aromatic heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and containing at least 1 carbon atom, including both mono- and polycyclic ring systems. Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that the use of the term "heteroaryl" includes N-alkylated derivatives such as a 1-methylimidazol- 5-yl substituent. As used herein, "heterocycle" or "heterocyclyl" refers to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and containing at least 1 carbon atom. The mono- and polycyclic ring systems may be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings. Heterocycle includes heterocarbocycles, heteroaryls, and the like.

[0087] "Alkylthio" refers to an alkyl group as defined herein attached through a sulfur bridge. An example of an alkylthio is methylthio, (i.e., -S-CH3).

[0088] "Alkoxy" refers to an alkyl group as defined herein attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, s-butoxy, t-butoxy, n- pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, t-butoxy.

[0089] "Alkylamino" refers an alkyl group as defined herein attached through an amino bridge. An example of an alkylamino is methylamino, (i.e., -NH-CH3). An example of a dialkylamino is dimethylamino (i.e., -N(CH3)2).

[0090] “Aminoalkyl” refers to an amino group attached through an alkyl bridge as defined herein (i.e., NH2-alkyl-).

[0091] "Alkanoyl" refers to an alkyl as defined herein attached through a carbonyl bridge (i.e., - (C=O)alkyl).

[0092] The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, and iodine.

[0093] The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents." The molecule may be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Example substituents within this context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarb ocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, - NRaSChRb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, -S(=O)2Ra, -OS(=O)2Ra and -S(=O)2ORa. Ra and Rb in this context may be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl. The term "optionally substituted," as used herein, means that substitution is optional and therefore it is possible for the designated atom to be unsubstituted.

[0094] The term “protected” or “protecting group” as used herein and unless otherwise defined refers to a chemical group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes, i.e., chemical moi eties that are introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis, and are described, for example, in Greene et al., Protective Groups in Organic Synthesis, supra. Examples include, but are not limited to, 4-methoxy-2,3,6- trimethylphenyl)sulfonyl (Mtr), 2,2,5,7,8-pentamethyl-chroman-6-sulphonyl (Pmc), tosyl (Tos), mesitylenesulfonyl (Mts), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob), tripheylmethyl (Trt), 9-fluorenylmethyloxycarbonyl (fmoc), tert-buty (tBu), benzyl (Bzl), t- butoxymethyl ether (Bum), (2,4-dinitrophenol) Dnp, benzyloxymethyl (Bom), benzyloxycarbonyl (Z), 2-chloro-benzyloxycarbonyl (CIZ), t-butyloxycarbonyl (Boc), formyl (CHO), 2- bromobenzyloxycarbonyl (BrZ), trimethylsilyl, dimethylhexyl silyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, trityl, substituted trityl, alkyl, alkoxy, or polyalkoxy groups, acyl groups, acetyl, propionyl, methanesulfonyl, p-toluenel sulfonyl, and heterocycles such as succinimide, maleimide, and phthalimide.

[0095] As used herein, "salts" refer to derivatives of the disclosed compounds where the parent compound is modified making acid or base salts thereof. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkylamines, or dialkylamines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. In preferred embodiment the salts are conventional nontoxic pharmaceutically acceptable salts including the quaternary ammonium salts of the parent compound formed, and non-toxic inorganic or organic acids. Preferred salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

[0096] A "subject" refers any animal, preferably a human patient, livestock, or domestic pet. The term "prodrug" refers to an agent that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in compositions over the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Typical prodrugs are esters. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of an alcohol, i.e., hydroxy group.

[0097] As used herein, the term “derivative” refers to a structurally similar compound that retains sufficient functional attributes of the identified analogue. The derivative may be structurally similar because it is lacking one or more atoms, substituted, a salt, in different hydration / oxidation states, or because one or more atoms within the molecule are switched, such as, but not limited to, replacing an oxygen atom with a sulfur atom or replacing an amino group with a hydroxyl group or vice versa. The derivative may be a prodrug. Derivatives may be prepared by any variety of synthetic methods or appropriate adaptations presented in synthetic or organic chemistry textbooks, such as those provide in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze hereby incorporated by reference.

[0098] In certain embodiments, this disclosure contemplates compositions comprising a compound herein having greater than 60%, 70%, 80%, 90%, or 95% enantiomeric excess or diastereomeric excess. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportion can be known as a "racemic" mixture. The term "(+-)" is used to designate a racemic mixture where appropriate. "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry can be specified according to the Cahn- Ingold-Prelog R-S system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0099] The "enantiomeric excess" or "% enantiomeric excess" of a composition can be calculated using the equation shown below. In the example shown below, a composition contains 90% of one enantiomer, e.g., an S enantiomer, and 10% of the other enantiomer, e.g., an R enantiomer. Thus ee = (90-10) / 100 = 80%. Enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), the formation and crystallization of chiral salts, or prepared by asymmetric syntheses.

[0100] In certain embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" is a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a double bond, or a triple bond to a single bond, or vice versa). "Tautomerization" includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton accompanied by changes in bond order.

[0101] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement or enrichment of a hydrogen by deuterium or tritium at one or more atoms in the molecule. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by deuterium. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium.

[0102] The disclosure also embraces isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, e.g.,2H,3H,13C,14C,15N,18O,31P,35S, and18F.

[0103] As used herein, the terms "prevent" and "preventing" include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

[0104] As used herein, the terms "treat" and "treating" are not limited to the case where the subject (e g. patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and / or delays disease progression.

[0105] Synthetic veragranine analogs

[0106] In certain embodiments, this disclosure relates to veragranine, analog compounds, and compositions as reported herein. In certain embodiments, the veragranine analogs are any of the compounds reported herein, e.g., specification or in the figures. In certain embodiments, for any of the formula reported herein, it is contemplated that embodiments exclude natural products such as naturally occurring veragranine or naturally occurring derivative.

[0107] In certain embodiments, the veragranine analogs are compounds having the following chemical formula I,

[0108] Formula I or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;

[0109] R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the same or different, R8;

[0110] R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0111] R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0112] R4is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0113] R5is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0114] R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR7, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R5and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7;

[0115] R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; and

[0116] R8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfmyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. In certain embodiments the veragranine analog is 6bl ,9,10,14b-tetramethyl- l,2,3,4,6,6a,6b,6bl,7,8,8a,9,14a,14b-tetradecahydronaphtho[2',l':4,5]indeno[l,7-gh]isoquinolin- 3-ol, (27a) derivative or salt thereof.

[0117] In certain embodiments the veragranine analogs is methyl 3-hydroxy-6bl,9,14b-trimethyl- l,2,3,4,6,6a,6b,6bl,7,8,8a,9,14a,14b-tetradecahydronaphtho[2',l':4,5]indeno[l,7- gh]isoquinoline-l 1 -carboxylate, (27eb) derivative or salt thereof.

[0118] In certain embodiments the veragranine analogs is 6bl,9,ll,14b-tetramethyl- 1,2, 3, 4, 6, 6a, 6b, 6b 1,7, 8, 8a, 9, 14a, 14b-tetradecahydronaphtho[2',l':4,5]indeno[l,7-gh]isoquinolin- 3-oL (27cb), derivative or salt thereof. In certain embodiments the veragranine analog is 6b 1 ,9,16b-trimethyl- l,2,3,5,6,6a,6b,6bl,7,8,8a,9,16a,16b-tetradecahydronaphtho[2',l':4,5]indeno[7,l- ij]phenanthri din-3 -ol derivative or salt thereof.

[0119] In certain embodiments the veragranine analog is compound having the following formula or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;

[0120] R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the same or different, R8; R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0121] R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0122] R4is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0123] R5is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0124] R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR7, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R5and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7;

[0125] R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; and

[0126] R8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-di ethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. In certain embodiments the veragranine analog is 6bl ,9,16b-trimethyl- 1,2, 3, 4, 6, 6a, 6b, 6b 1,7, 8,8a,9,16a,16b-tetradecahydronaphtho[2',1:4,5]indeno[7,l-ab]acridin-3-ol

[0127] (27ga) derivative or salt thereof.

[0128] In certain embodiments the veragranine analog is compound having the following formula

[0129] I IB, or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;

[0130] R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the same or different, R8; R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0131] R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8; R4is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0132] R?is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0133] R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR7, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R5and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7;

[0134] R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; and

[0135] R8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfmyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0136] In certain embodiments the veragranine analog is 6bl,9,16b-trimethyl- 1,2, 3, 4, 6, 6a, 6b, 6b 1,7, 8,8a,9,16a,16b-tetradecahydronaphtho[2',l':4,5]indeno[7,l- ab]phenanthridin-3 -ol,

[0137] (27h) derivative or salt thereof. In certain embodiments the veragranine analog is compound having the following formula III or IV, or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;

[0138] R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the same or different, R8;

[0139] R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0140] R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0141] R5is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;

[0142] R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR7, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R5and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7; R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; and

[0143] R8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0144] In certain embodiments the veragranine analog is 10,13-dimethyl-12-(4-methylpyridin-3- yl)-17-vinyl-2,3,4,7,8,9,10,13,14, 15,16,17-dodecahydro-lH-cyclopenta[a]phenanthren-3-ol

[0145] (26b) derivative or salt thereof.

[0146] In certain embodiments the veragranine analog is 10,13-dimethyl-12-(6-methylpyridin-3- yl)-17-vinyl-2,3,4,7,8,9,10,13,14,15,16,17-dodecahydro-lH-cyclopenta[a]phenanthren-3-ol,

[0147] (26c) derivative or salt thereof. In certain embodiments the veragranine analog is 10,13-dimethyl-12-(quinolin-3-yl)-17- vinyl-2,3,4,7,8,9,10,13,14,15,16,17-dodecahydro-lH-cyclopenta[a]phenanthren-3-ol,

[0148] (26g) derivative or salt thereof. In certain embodiments, this disclosure relates to methods of making a compound as provided herein comprising contacting / mixing a starting material reported herein with reagent reported herein under conditions such that the compound is formed. In certain embodiments, methods further comprise isolating or purifying the compound from one or more reagents or side products produced therefrom. In certain embodiments, this disclosure relates to methods of making a veragranine analog comprising, contacting a compound: wherein,

[0149] R-N is an optionally substituted heteroaryl comprising a nitrogen heteroatom, and Prot is a triisopropylsilyl, tri(branched)alkylsilyl, trialkyl silyl, or other hydroxy protecting group; with reagents disclosed herein providing a compound

[0150] wherein

[0151] R-N is an optionally substituted heteroaryl comprising a nitrogen heteroatom, and Prot is a triisopropylsilyl, tri(branched)alkylsilyl, trialkyl silyl, or other hydroxy protecting group.

[0152] In certain embodiments, this disclosure relates to methods a veragranine analog comprising, contacting a compound having the formula:

[0153] Prof - wherein,

[0154] R-N is an optionally substituted heteroaryl comprising a nitrogen heteroatom, and Prot is a triisopropylsilyl, tri(branched)alkylsilyl, trialkyl silyl, or other hydroxy protecting group; with a metal acetyl acet onate complex and / or metal acetate complex, and titanium alkoxide, and a silane reducing reagent, providing a compound wherein

[0155] R-N is an optionally substituted heteroaryl comprising a nitrogen heteroatom, and Prot is a triisopropylsilyl, tri(branched)alkylsilyl, trialkyl silyl, or other hydroxy protecting group.

[0156] In certain embodiments, the metal acetate is Mn(OAc)a.

[0157] In certain embodiments, the titanium alkoxide is Ti(0Me)4.

[0158] In certain embodiments, the silane reducing reagent is PhSiHs.

[0159] Pharmaceutical Compositions

[0160] In certain embodiments, this disclosure relates to pharmaceutical composition comprising veragranine analogs as reported herein and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is in the form or a tablet, pill, capsule, micronized particle, powder, gel, gel capsule, saline solution, isotonic solution, and / or pH buffered solution, a sterilized pH buffered aqueous salt solution or a saline phosphate buffer between a pH of 6 to 8.

[0161] In certain embodiments, the pharmaceutically acceptable excipient is a saccharide, polysaccharide, lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose sodium, polyvinyl N-pyrrolidone, crospovidone, ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, corn starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, content of enteric coatings such as methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, salts, or combinations thereof.

[0162] In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a compound as disclosed herein or salt thereof and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, gel, gel capsule, or cream. In certain embodiments, the pharmaceutical composition is in the form of a sterilized pH buffered aqueous salt solution or a saline phosphate buffer between a pH of 6 to 8, optionally comprising a saccharide or polysaccharide. In certain embodiments, the pharmaceutical composition is in the form of a saline, citrate buffer or phosphate buffer, optionally comprising a saccharide or polysaccharide.

[0163] In certain embodiments, the pharmaceutical composition is in solid form surrounded by an enteric coating. In certain embodiments, the enteric coatings comprises a component such as methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hypromellose (hydroxypropyl methylcellulose), hypromellose phthalate (hydroxypropyl methyl cellulose phthalate), hypromellose acetate succinate (hydroxypropyl methyl cellulose acetate succinate), diethyl phthalate, polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, or combinations thereof.

[0164] In certain embodiments, the pharmaceutically acceptable excipient is selected from lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose sodium, polyvinyl N-pyrrolidone (crospovidone), ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, corn starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, or salts thereof.

[0165] In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a compound disclosed herein or pharmaceutically acceptable salt, and a pharmaceutically acceptable vehicle, adjuvant, or carrier.

[0166] In certain embodiments, the pharmaceutical compositions may additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.

[0167] Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

[0168] The pharmaceutical compositions containing compounds reported herein may further comprise one or more additional therapeutic agent(s) such as an anti-inflammatory agent or antibiotic agent.

[0169] Methods of Use

[0170] Compounds disclosed herein are contemplated forbroad applications for treating pain, e.g., due to the hyperexcitability of neurons, arthritic pain, etc. The ability of compounds disclosed herein to block sodium and calcium channels suggests potential efficacy in treating various types of neuropathic pain, inflammatory pain, and other associated neurological dysfunction.

[0171] In certain embodiments, this disclosure relates to methods of treating or preventing a disease or condition reported herein by administering an effective amount of a compound as reported herein or pharmaceutical composition as provided herein to a subject in need thereof. In certain embodiments, this disclosure relates to methods of treating pain or other inflammatory condition comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain embodiments, this disclosure relates to methods of treating nociceptive pain that arises from tissues damaged by physical or chemical agents such as trauma, surgery, or chemical bums, or neuropathic pain that arises from diseases or damage mediated directly to sensory nerves, such as diabetic neuropathy, shingles, or postherpetic neuralgia comprising administering an effective amount of a compound disclosed herein to a subject in need thereof.

[0172] In certain embodiments, this disclosure relates to methods of treating a neurological disorder, or pain associated therewith, comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain embodiments, the neurological disorder is a patient diagnosed with acute spinal cord injury, Alzheimer's Disease, amyotrophic lateral sclerosis, ataxia, Bell's palsy, brain tumors, cerebral aneurysm, epilepsy, seizures Guillain- Barre syndrome, headaches, migraines, head injury, hydrocephalus, herniated disk, meningitis, multiple sclerosis, muscular dystrophy, a neurocutaneous syndrome, Parkinson's disease, stroke, encephalitis, septicemia, or myasthenia gravis.

[0173] In certain embodiments, this disclosure relates to methods of treating type I diabetes or type II diabetes comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain embodiments, this disclosure relates to methods of treating obesity-related insulin resistance comprising administering an effective amount of a compound disclosed herein to a subject in need thereof.

[0174] In certain embodiments, this disclosure relates to methods of treating cancer or prostate cancer comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain embodiments the compound disclosed herein is administered in combination another anticancer agent.

[0175] "Cancer" refers any of various cellular diseases with malignant neoplasms characterized by the proliferation of cells. It is not intended that the diseased cells must actually invade surrounding tissue and metastasize to new body sites. Cancer can involve any tissue of the body and have many different forms in each body area. Within the context of certain embodiments, whether "cancer is reduced" may be identified by a variety of diagnostic manners known to one skill in the art including, but not limited to, observation the reduction in size or number of tumor masses or if an increase of apoptosis of cancer cells observed, e.g., if more than a 5 % increase in apoptosis of cancer cells is observed for a sample compound compared to a control without the compound. It may also be identified by a change in relevant biomarker or gene expression profile, such as PSA for prostate cancer, HER2 for breast cancer, or others. The cancer to be treated in the context of the present disclosure may be any type of cancer or tumor. These tumors or cancer include, and are not limited to, tumors of the hematopoietic and lymphoid tissues or hematopoietic and lymphoid malignancies, tumors that affect the blood, bone marrow, lymph, and lymphatic system. Hematological malignancies may derive from either of the two major blood cell lineages: myeloid and lymphoid cell lines. The myeloid cell line normally produces granulocytes, erythrocytes, thrombocytes, macrophages and mast cells; the lymphoid cell line produces B, T, NK and plasma cells. Lymphomas, lymphocytic leukemias, and myeloma are from the lymphoid line, while acute and chronic myelogenous leukemia, myelodysplastic syndromes and myeloproliferative diseases are myeloid in origin.

[0176] Also contemplated are malignancies located in the colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, hypophysis, testicles, ovaries, thymus, thyroid), eye, head and neck, nervous system (central and peripheral), lymphatic system, pelvis, skin, soft tissue, spleen, thorax and genito-urinary apparatus and, more particularly, childhood acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, adult (primary) hepatocellular cancer, adult (primary) liver cancer, adult acute lymphocytic leukemia, adult acute myeloid leukemia, adult Hodgkin's disease, adult Hodgkin's lymphoma, adult lymphocytic leukemia, adult non-Hodgkin's lymphoma, adult primary liver cancer, adult soft tissue sarcoma, AIDS-related lymphoma, AIDS-related malignant tumors, anal cancer, astrocytoma, cancer of the biliary tract, cancer of the bladder, bone cancer, brain stem glioma, brain tumors, breast cancer, cancer of the renal pelvis and ureter, primary central nervous system lymphoma, central nervous system lymphoma, cerebellar astrocytoma, brain astrocytoma, cancer of the cervix, childhood (primary) hepatocellular cancer, childhood (primary) liver cancer, childhood acute lymphoblastic leukemia, childhood acute myeloid leukemia, childhood brain stem glioma, childhood cerebellar astrocytoma, childhood brain astrocytoma, childhood extracranial germ cell tumors, childhood Hodgkin's disease, childhood Hodgkin's lymphoma, childhood visual pathway and hypothalamic glioma, childhood lymphoblastic leukemia, childhood medulloblastoma, childhood non-Hodgkin's lymphoma, childhood supratentorial primitive neuroectodermal and pineal tumors, childhood primary liver cancer, childhood rhabdomyosarcoma, childhood soft tissue sarcoma, childhood visual pathway and hypothalamic glioma, chronic lymphocytic leukemia, chronic myeloid leukemia, cancer of the colon, cutaneous T-cell lymphoma, endocrine pancreatic islet cells carcinoma, endometrial cancer, ependymoma, epithelial cancer, cancer of the esophagus, Ewing's sarcoma and related tumors, cancer of the exocrine pancreas, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic biliary tract cancer, cancer of the eye, breast cancer in women, Gaucher's disease, cancer of the gallbladder, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal tumors, germ cell tumors, gestational trophoblastic tumor, tricoleucemia, head and neck cancer, hepatocellular cancer, Hodgkin's disease, Hodgkin's lymphoma, hypergammaglobulinemia, hypopharyngeal cancer, intestinal cancers, intraocular melanoma, islet cell carcinoma, islet cell pancreatic cancer, Kaposi's sarcoma, cancer of kidney, cancer of the larynx, cancer of the lip and mouth, cancer of the liver, cancer of the lung, lymphoproliferative disorders, macroglobulinemia, breast cancer in men, malignant mesothelioma, malignant thymoma, medulloblastoma, melanoma, mesothelioma, occult primary metastatic squamous neck cancer, primary metastatic squamous neck cancer, metastatic squamous neck cancer, multiple myeloma, multiple myeloma / plasmatic cell neoplasia, myelodysplastic syndrome, myelogenous leukemia, myeloid leukemia, myeloproliferative disorders, paranasal sinus and nasal cavity cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma during pregnancy, nonmelanoma skin cancer, non-small cell lung cancer, metastatic squamous neck cancer with occult primary, buccopharyngeal cancer, malignant fibrous histiocytoma, malignant fibrous osteosarcoma / histiocytoma of the bone, epithelial ovarian cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, paraproteinemias, purpura, parathyroid cancer, cancer of the penis, phaeochromocytoma, hypophysis tumor, neoplasia of plasmatic cells / multiple myeloma, primary central nervous system lymphoma, primary liver cancer, prostate cancer, rectal cancer, renal cell cancer, cancer of the renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma, cancer of the salivary glands, sarcoidosis, sarcomas, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous neck cancer, stomach cancer, pineal and supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, transitional renal pelvis and ureter cancer, trophoblastic tumors, cell cancer of the renal pelvis and ureter, cancer of the urethra, cancer of the uterus, uterine sarcoma, vaginal cancer, optic pathway and hypothalamic glioma, cancer of the vulva, Waldenstrom's macroglobulinemia, Wilms' tumor and any other hyperproliferative disease, as well as neoplasia, located in the system of a previously mentioned organ. Synthetic veragranine derivatives, synthesis, purified enantiomers, characterization and uses in treating osteoarthritis-related pain

[0177] Veragranines are cholestane steroidal alkaloids isolated from Veratrum grandiflorum, a traditional herbal medicine. Veragranines block N-type calcium channels. The isolation yields of veragranines from V grandiflorum are extremely low. Thus, experiments on the syntheses of the veragranines were performed. Naturally occurring veragranines feature a complex hexacyclic ring system, a unique C12-C23 linkage, and a pyridine ring. Disclosed herein is a scalable semisynthesis of veragranine A from dehydroepiandrosterone. Synthetic analogs were evaluated in sensory neurons in vitro and in an in vivo model of arthritic pain.

[0178] Biosynthetically, veragranines A and B may be derived from veramiline, a major steroidal alkaloid of V. grandiflorum. Veramiline could be converted to vermitaline via an enzymatic C-H hydroxylation at C12 and dehydrogenation of the piperidine ring. Retrosynthetically (See Figure 1), it was contemplated that the C20-C22 bond could be formed by a Minisci-type radical C-H cyclization. A hydrogen atom transfer (HAT)-initiated C-H cyclization strategy was contemplated. From experiments, it was determined that compound 7 could be synthesized from vinyltriflate via a transition-metal-catalyzed cross-coupling reaction with a pyridyl nucleophile. Compound 8 could be synthesized from 10 via an oxidation adjustment at C12 and the introduction of a vinyl group at C17. To access 10, a Schbnecker-Baran C-H oxidation at the C12 would result in a protected form of dehydroepiandrosterone.

[0179] The synthesis started from dehydroepiandrosterone (11) (Figure 2A). Its C3 alcohol was first protected as a TIPS ether. In the same reaction pot, a subsequent condensation of the C17 ketone with 2-picolylamine (12) gave imine 13 for the next Schbnecker-Baran C- H oxidation with a combination of Cu(NO3)2 and H2O2. Product 14 was obtained in 78% yield from 11 on a gram scale. To introduce a vinyl group at Cl 7, two Wittig one-carbon homologations were employed. First, Wittig olefination of 14 with the phosphonium ylide derived from treating (methoxymethyl)triphenylphosphonium chloride with NaHMDS gave methyl enol ether 15 in 53% yield on a multigram scale with 21% recycled 14. Compound 15 was then converted to ketoaldehyde 16 in 80% yield on a gram scale via a one-pot DMP oxidation of the C12 alcohol followed by methyl enol ether hydrolysis with p-toluenesulfonic acid (p-TsOH). The second chemosei ective Wittig olefination occurred on the aldehyde to convert 16 to 17 in 83% yield on a gram scale. Compound 17 was then advanced to vinyltriflate 18 in 95% yield on a gram scale with triflic anhydride (TfzO) in the presence of 2,6-di-tert-butyl-4-methylpyridine (DTBMP). For the subsequent transition-metal-catalyzed cross-coupling reaction to introduce the pyridine functionality, Suzuki-Miyaura cross-coupling with boronate 19 was explored. The cross-coupling product 20 could be produced in 96% yield with Pd(PPha)4 as a catalyst and aqueous Na2CCh as a base in THF at an elevated temperature (80 °C). With compound 20 in hand, a combination of Mn(0Ac)3, PhSiHa, and Ti(OMe)4 in mixed THF / MeOH was identified as the optimal conditions to deliver the desired product 21 in 60% yield together with its isomer 22 in 15% yield on 3 * 80 mg scale (22% yield of 20 was recovered as well). Notably, the use of titanium tetra-alkoxide such as Ti(OMe)4 as a Lewis acid to activate the pyridine optimized the cyclization. The desired stereochemistry at C20 was obtained, consistent with a cyclization transition state that minimizes 1,3-diaxial interactions between C21 and the axial C18 methyl groups. To complete the synthesis, the TIPS group was removed with TBAF to give (-)-veragranine A in 91% yield. Its structure was confirmed by an X-ray crystallographic analysis. Overall, (neg)-veragranine A was prepared in 11 steps and over a 200 mg scale.

[0180] Whether the HAT-initiated Minisci C-H cyclization is general and can be used to prepare veragranine analogs was investigated. Substrates 24b-h were prepared in 71-97% yields using the Suzuki-Miyaura cross-coupling (Figures 3A and 3B). Notably, a mixture of inseparable rotamers was obtained for the cases of 24b (2 / 1), 24d (3 / 1), and 24h (3 / 1) as well as the corresponding TIPS removal products 26b (2 / 1), 26d (3 / 1), and 26h (3 / 1). While 24b-h all underwent the HAT-initiated Minisci C-H cyclization, different results were obtained. For 24b and 24d, since the para position is blocked by a methyl group, 25b and 25d were obtained in 60% and 49% yields, respectively, with about 40% of the starting material recycled. For 24c and 24e with a methyl or ester group at the ortho position, a 1.7 / 1 or 1 / 2.2 mixture of 25ca and 25cb or 25ea and 25eb was obtained, albeit in 19% or 32% yield, respectively. The low yields for these two cases were presumably due to the steric hindrance generated by the methyl or ester group, which could negatively influence coordination of the pyridine nitrogen with Ti-(OMe)4. For 24f with an ester at the meta position, regioisomer 25f was obtained in 50% yield with 34% of starting material recycled. In addition, both quinoline (24g)- and isoquinoline (24h)-containing substrates are effective for the HAT-initiated Minisci C-H cyclization. Notably, for 24g, the para cyclization product (25gb) turned out to be major and a 1 / 7.4 mixture of 25ga and 25gb was obtained in 59% yield. For 24h, product 25h was obtained in 30% yield with a 34% yield of starting material recycled. For biological evaluations, the TIPS group of the Suzuki-Miyaura cross-coupling products and the HAT cyclization products were removed with TBAF.

[0181] Reaction optimization of the HAT-cyclization

[0182] The combination of Fe(acac)3 and PhSiHa with trifluoroacetic acid (TFA) as additive to activate the pyridine was first examined, but only a trace amount of 21 was detected and most of the starting material 20 was recycled (entry 1), Fig. 4B. The combination of Fe(NO3)3 and NaBH4 gave a trace amount of 21 as well, but with a mixture of over reduction byproducts (entry 2). Little product was obtained with the combination of Co(acac)3and tert-butyl hydroperoxide (TBHP) conditions (entry 3) while most of the starting material was consumed. When BF3*OEt2 was used to activate the pyridine, about 10% of 21 was obtained with 52% of 20 recovered (entry 4). Using BF3ºOEt2 as an activator and different transition metal complexes (entry 5-10) were evaluated. With Mn(OAc)3 (entry 10), 36% yield of desired product 21 was obtained together with 4% yield of the para cyclization isomer 22. While lower the reaction temperature from 60 °C to 23 °C (entry 11) or 0 °C (entry 12) did not substantially change the yield of 21, more starting material was recovered. Other silane reducing reagents including Ph2SiH2, PhMeSiH2, n-BuSiHs, and (i- PrO)PhSiH2 were then investigated (entry 13-17). PhSiHs remained to be the optimal choice. Various Lewis acids such as BCI3, TMSOTf, TFA, B(OMe)3, BiFs, Ti(OMe)4, Ti(Oi-Pr)4, Ti(OEt)4, and TiCh (entry 18-26) were then examined as the pyridine activators. The use of titanium(IV) alkoxides (entry 23-25) gave above 50% yield of 21 and around 10% yield of 22. Ti(OMe)4 was selected as the optimal activator. Notably, reducing the reaction time has beneficial effect (entry 27-29), but increasing the scale of the starting material decreased the reaction yields, which can be countered by increasing the amount of Mn(OAc)s (entry 30-35). With the optimal reaction conditions (entry 35), 60% yield of 21 and 15% yield of 22 can be obtained with 22% yield of 20 recycled at 3 x 80 mg scale. HAT Reaction for the Synthesis of TIPS-Protected Veragranine A Analogs Synthesis of 25 (0.04 mmol scale): to a solution of Mn(OAc)3.2H2O (26.5 mg, 96.0 μmol, 2.4 equiv), compound 24 (40.0 pmol), and Lewis acid Ti(OMe)4 (29.0 mg, 160 pmol, 4.0 equiv) in THF / MeOH (4: 1, 2.0 mL) was added PhSiHs (22 pL, 160 pmol, 4.0 equiv) at room temperature under argon. The reaction was stirred at the same temperature for 16 h. The reaction mixture was quenched with saturated NaHCO3aqueous solution (2 mL) and brine (2 mL), extracted with EtOAc (3 x 4 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by preparative thin layer chromatography (4 plates, hexanes / EtOAc) or flash chromatography on silica gel using EtOAc in hexanes as eluent to give TIPS-protected Veragranine A analog (25) and the recovered starting material 24.

[0183] Synthesis of 26 Synthesis of 26: To a solution of compounds 20 or 24 in THF (1 mL) at 0 °C was added TBAF (1 M in THF, 2 equiv). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel using EtOAc in hexanes as eluent to give secondary alcohol 26.

[0184] Synthesis of 27

[0185] Synthesis of 27: To a solution of compounds 25 in THF (1.0 mL) at 0 °C was added TBAF (1 M in THF, 2 equiv). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel using EtOAc in hexanes as eluent to give secondary alcohol 27.

[0186] Biological Evaluations To evaluate the functional effects of veragranine A and its analogs on voltage-gated ion channels, calcium imaging was used to measure changes in depolarization evoked Ca2+influx. Primary cultures of rat dorsal root ganglia (DRG) neurons were seeded on coverslips and treated overnight with 20 pM corresponding compounds or 0.1% DMSO as a vehicle (negative) control. The next day, DRG neurons were loaded with fura-2-acetoxymethyl ester (Fura2-AM) for 30 min before being mounted in a perfusion chamber for the imaging assay. To test the inhibitory effects of the compounds on voltage-gated calcium channels, which are associated with pain sensation, KC1 was used as a trigger. Peak calcium influx was recorded within 15s of stimulation with two concentrations of KC1; 40 mM KC1 trigger to test low-voltage-activated (LVA) and 90 mM KC1 trigger to test high-voltage-activated (HVA) calcium channels. When compared with 0.1% DMSO, veragranine A at 20 pM inhibited calcium influx by about 30%. Analogs 26b, 26c, 26g, 27a, and 27eb inhibited calcium influx by more than 50% when challenged with 40 mM KC1. Three of these analogs, 26g, 27a, and 27eb, also exhibited inhibition of approximately 12-25% when challenged with 90 mM KC1.

[0187] At this stage, compounds 27a and 27eb were selected for further investigation. Overnight incubation with 10 pM compounds 27a and 27eb did not inhibit calcium influx via LVA channels. Both analogs produced a significant decrease in KC1 triggered calcium channel activity when neurons were challenged with 90 mM KC1. To evaluate the effect of overnight incubation with 10 pM compounds 27a and 27eb on voltage-gated sodium channels, a general sodium channel activator, veratridine (30 pM), was used as a depolarizing agent. Compound 27a had no significant effect on calcium influx, whereas compound 27eb inhibited veratridine-evoked calcium influx compared with the control condition (0.1% DMSO).

[0188] The effects of acute application (30 min) of 27a and 27eb on the calcium influx were examined. When compared with control conditions (0.1% DMSO), both analogs significantly suppressed the average peak response when neurons were challenged with 40 and 90 mM KC1. Analog 27eb had reduced veratridine-evoked calcium influx. Together, these data suggest that these veragranine A analogs inhibit calcium influx in rat DRG sensory neurons: compound 27a by blocking voltage-gated calcium channels, and compound 27eb by blocking voltage-gated calcium and sodium channels.

[0189] To assess the potential effects of these compounds on pain related to osteoarthritis, the antinociceptive effects of 27a and 27eb were tested for mechanical and cold allodynia using monoiodoacetate (MIA). MIA was injection into the left knee joint in male and female rats. Four weeks after injury, they were injected with 27a and 27eb (20 pg / 5 pL, i.t.), or vehicle, and assessed hourly over a 4 h period. MIA induced a marked increase in mechanical sensitivity on the plantar surface of the paw in both male and female rats, which was significantly improved by administration of 27a and 27eb across males and females. Statistical analysis showed no significant effects of sex on the results. In addition, MIA induced clear cold allodynia in both males and females, which was seen as an increase in the duration of aversive response following the application of a drop of acetone to the plantar surface of the ipsilateral paw (post-MIA time point). Administration of 27eb significantly improved the cold allodynia in both genders, while 27a showed robust effects in males (45.4 ± 9.5%), but not significantly in females (33.7 ± 11.1%). This compares with 72.8 ± 8.2% for Gabapentin across sex. These results suggest the overall beneficial effects of the two compounds in improving pain-like behavioral symptoms from an osteoarthritis model.

Claims

CLAIMS1. A compound having the following formula I,or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the same or different, R8;R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R4is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R5is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR7, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R5and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7;R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; andR8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

2. The compound of claim 1 which is 6bl,9,10, 14b-tetramethyl-l,2,3,4,6,6a,6b,6bl,7, 8,8a,9,14a,14b-tetradecahydronaphtho[2',T:4,5]indeno[l,7-gh]isoquinolin-3-ol,(27a) derivative or salt thereof.

3. The compound of claim 1 which is methyl 3-hydroxy-6bl,9,14b-trimethyl- l,2,3,4,6,6a,6b,6bl,7,8,8a,9,14a,14b-tetradecahydronaphtho[2',T:4,5]indeno[l,7- gh] i soqui noli ne- 11 -carb oxy 1 ate,(27eb) derivative or salt thereof.

4. The compound of claim 1 which is 6bl,9,ll,14b-tetramethyl-l,2,3,4,6,6a,6b,6bl,7,8,8a,9,14a,14b-tetradecahydronaphtho[2',T:4,5]indeno[l,7-gh]isoquinolin-3-ol.(27cb), derivative or salt thereof.

5. The compound of claim 1 which is 6b 1,9,16b-trimethyl- l,2,3,5,6,6a,6b,6bl,7,8,8a,9,16a,16b-tetradecahydronaphtho[2',l':4,5]indeno[7,l-derivative or salt thereof.

6. A compound having the following formula IIA,Formula II A or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the same or different, R8;R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R4is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R5is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR7, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R5and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7;R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; andR8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

7. The compound of claim 6 which is 6bl,9, 16b-trimethyl-l,2,3,4,6,6a,6b,6bl,7,8, 8a, 9, 16a, 16b-tetradecahydronaphtho[2', 1 ' :4,5]indeno[7, 1 -ab]acridin-3-ol(27ga) derivative or salt thereof.

8. A compound having the following formula IIB,Formula IIB or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the same or different, R8;R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R4is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R?is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR7, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R5and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7;R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; andR8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfmyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

9. The compound of claim 8 which is 6bl,9,16b-trimethyl-l,2,3,4,6,6a,6b,6bl,7,8,8a,9,16a,16b-tetradecahydronaphtho[2',r:4,5]indeno[7,l-ab]phenanthridin-3-ol,(27h) derivative or salt thereof.

10. A compound having the following formula III or IV,or salts, esters, or prodrugs thereof wherein, each dotted line, individually and independently at each occurrence, represent a double or single bond between the attached carbons;R1is H, OH, O-R7, SH, S-R7, NH2, NH-R7, optionally substituted with one or more, the same or different, R8;R2is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R3is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R5is H, alkyl, OH, SH, or NH2 optionally substituted with one or more, the same or different, R8;R6is alkyl, CN, halogen, NO2, (C=O)R7, (C=O)OR7, (C=O)NHR7, (C=O)SR7, OH, O-R7, SH, S-R7, NH2, NH-R7, alkoxy, alkylamino, dialkylamino, aminoalkyl, alkylthio, thioalkyl, carbocyclyl, heterocyclyl, or aryl, wherein R6is optionally substituted with one or more, the same or different, R7; or R5and R6and the attached atoms come together to from a heterocyclyl, or heteroaryl optionally substituted with one or more, the same or different, R7;R7is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkanoyl, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R7is optionally substituted with one or more, the same or different, R8; andR8is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N- methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfmyl, ethylsulfmyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

11. A pharmaceutical composition comprising a compound as in any of the claims 1-9 and a pharmaceutically acceptable excipient.

12. The pharmaceutical composition of claim 11 in the form or a tablet, pill, capsule, micronized particle, powder, gel, gel capsule, saline solution, isotonic solution, and / or pH buffered solution, a sterilized pH buffered aqueous salt solution or a saline phosphate buffer between a pH of 6 to 8.

13. The pharmaceutical composition of claim 11, wherein the pharmaceutically acceptable excipient is a saccharide, polysaccharide, lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose sodium, polyvinyl N-pyrrolidone, crospovidone, ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, corn starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, content of enteric coatings such as methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetatesuccinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, salts, or combinations thereof.

14. A method of treating or preventing pain comprising administering an effective amount of a compound as in any of claims 1-9 or salt thereof to a subject in need thereof15. The method of claim 14 wherein the compound isor salt thereof, to a subject in need thereof. wherein the compound isor salt thereof, to a subject in need thereof.

17. A method of making a veragranine analog comprising, contacting a compound having the formula:wherein,R-N is an optionally substituted heteroaryl comprising a nitrogen heteroatom, and Prot is a triisopropylsilyl, tri(branched)alkylsilyl, trialkyl silyl, or other hydroxy protecting group; with a metal acetylacetonate complex and / or metal acetate complex, and titanium alkoxide, and a silane reducing reagent, providing a compoundwhereinR-N is an optionally substituted heteroaryl comprising a nitrogen heteroatom, and Prot is a triisopropylsilyl, tri(branched)alkylsilyl, trialkyl silyl, or other hydroxy protecting group.

18. The method of claim 17, wherein the metal acetate is Mn(0Ac).3.

19. The method of claim 17, wherein the titanium alkoxide is Ti(0Me)4.

20. The method of claim 17, wherein the silane reducing reagent is PhSiHs.

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