WO2021195603A1

WO2021195603A1 - Anti-malarial compounds and uses thereof

Info

Publication number: WO2021195603A1
Application number: PCT/US2021/024542
Authority: WO
Inventors: Max Totrov; Maria B. CASSERA; Paul R. Carlier; Sha DING; Jopaul MATHEW; Kevin KUNZ
Original assignee: University of Georgia Research Foundation Inc UGARF; Virginia Tech Intellectual Properties Inc; Virginia Polytechnic Institute and State University
Current assignee: University of Georgia Research Foundation Inc UGARF; Virginia Tech Intellectual Properties Inc; Virginia Polytechnic Institute and State University
Priority date: 2020-03-27
Filing date: 2021-03-27
Publication date: 2021-09-30
Anticipated expiration: 2022-09-27
Also published as: WO2021195603A4

Abstract

Described herein are compounds and formulations thereof that can be capable of treating and/or preventing malaria in a subject to which they are administered. Also described herein are methods of treating and/or preventing malaria in a subject in need thereof by administering a compound or formulation thereof described herein to the subject in need thereof.

Description

ANTI-MALARIAL COMPOUNDS AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/000,691, filed on March 27, 2020, entitled “ANTI-MALARIAL COMPOUNDS AND USES THEREOF,” and U.S. Provisional Patent Application No. 63/018,430, filed on April 30, 2020, entitled “ANTI-MALARIAL COMPOUNDS AND USES THEREOF,” the contents of which are incorporated by reference herein in their entireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under Grant No. AI128362 awarded by the National Institutes of Health. The government has certain rights in the invention.

TECHNICAL FIELD

[0003] The subject matter disclosed herein is generally directed to anti-malarial compounds and uses thereof.

BACKGROUND

[0004] Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitos and is a significant world health problem. Despite a huge effort and amount of money spent for the research and development of treatments and preventives, there are still an estimated 228 million cases worldwide. In 2018 there were about 405,000 deaths attributed to malaria worldwide. Children under 5 are the most vulnerable group and accounted for about 67 percent of all malaria deaths. As such there exists an urgent and unmet need for malaria treatments and/or preventives. [0005] Citation or identification of any document in this application is not an admission that such a document is available as prior art to the present invention. SUMMARY

[0006] Described in certain embodiments herein are compositions according to Formula I or a salt thereof,

wherein Ri, R₂, R₃, and R₄ are each individually selected from: H, a halogen, or a substituted or unsubstituted alkyl, wherein R₅ is selected from OCH₃, NH(CH₂)3Me, NHMe, NH(CH₂)₂OH, NH(CH₂)₂NHMe, NH(CH₂)₂N(Me)₂, NH(CH₂)₃NHMe, NH(CH₂)₃N(Me)₂, NH(CH₂)_nNHCH₂CH₂OH, NH(CH₂)_nN(CH₂CH₂OH)₂, NH(CH₂)_mNH₂, or NH(CH₂)_nNHCH₂C0₂H, wherein n is 2 or 3 and m is 2-6, wherein R₆ and R₇ are each individually selected from H, a halogen, or a substituted or unsubstituted alkyl, and wherein Z is C or N.

[0007] In certain example embodiments, Ri, R₂, R₃, and R₄ are all different from each other.

[0008] In certain example embodiments, Ri, R₂, R₃, and R4 are all the same.

[0009] In certain example embodiments, at least two or three of Ri, R₂, R3, and R4 are the same.

[0010] In certain example embodiments, at least two or three of Ri, R₂, R3, and R4 are different.

[0011] In certain example embodiments, R₆ and R₇ are different from each other.

[0012] In certain example embodiments, R₆ and R₇ are the same.

[0013] Described in certain embodiments herein are compositions according to Formula II or a salt thereof,

FORMULA II wherein X is selected from 7-CH3, 7-subsituted or unsubstituted alkyl or heteroalkyl, or 7-H, wherein Y is a substituent at positions 3 and 4 or positions 3, 4, and 5 of ring D, wherein each substituent at each position is individually selected from Cl, Br, F, I, Me, or H, and wherein Z is selected from, OCH3, NH(CH2)3Me, NHMe, NH(CH2)20H, NH(CH₂)₂NHMe, NH(CH₂)₂N(Me)2, NH(CH₂)3NHMe, NH(CH₂)3N(Me)₂, NH(CH₂)_nNHCH₂CH₂OH, NH(CH₂)_nN(CH₂CH₂OH)₂, NH(CH₂)_mNH₂, or NH(CH₂)_nNHCH₂C0₂H, wherein n is 2 or 3 and m is 2-6.

[0014] In certain example embodiments, Y is selected from 3’,4’-Cl₂; 4’Cl; 2’,4’-Cl₂; 3’,4’-F₂; 3’,4’-Br₂; or 3’,4’-I₂.

[0015] In certain example embodiments, X is selected from 7-CFb, 7-substituted or unsubstituted alkyl or heteroalkyl, or 7-H.

[0016] In certain example embodiments, Y is a 3’ and 4’ where the substituent at the 3’ position is selected from Cl, Br, F, Me, or H and the substituent at the 4’ position is selected from Cl, Br, F, Me, or H.

[0017] In certain example embodiments, the combination for the substituents at the 3’ and 4’ position is selected from: Cl and Cl; Br and Br; F and F; Me and Me; Cl and Br; Br and Cl; Cl and F; F and Cl; Br and F; F and Br; Cl and Me; Me and Cl; Br and Me; Me and Br; F and Me; Me and F; H and Cl; H and Br; H and F; or H and Me.

[0018] In certain example embodiments, Y is a halogen substituent at each of positions 3, 4, and 5 of ring D.

[0019] In certain example embodiments, the substituent at positions 3, 4, and 5 are each individually selected from Cl, Br, and F.

[0020] In certain example embodiments, Br, when optionally present as a substituent, is only present at one of positions 3, 4, or 5 of ring D. [0021] Described in certain example embodiments herein are compositions according to Formula III or a salt thereof,

wherein R4 is selected from: H, a halogen, or a substituted or unsubstituted alkyl, and wherein ¾ and R7 are each individually selected from H, a halogen, or a substituted or unsubstituted alkyl.

[0022] In certain example embodiments, R.6 and R7 are different from each other.

[0023] In certain example embodiments, R₆ and R7 are the same.

[0024] In certain example embodiments, R₆ is Cl, Br, F, or Me.

[0025] In certain example embodiments, R7 is Cl, Br, F, or Me.

[0026] In certain example embodiments, R4 is Me, Cl or H.

[0027] Described in certain example embodiments herein are compositions according to Formula IV or a salt thereof,

wherein R4 is selected from: H, a halogen, or a substituted or unsubstituted alkyl, and wherein R6 and R7 are each individually selected from H, a halogen, or a substituted or unsubstituted alkyl.

[0028] In certain example embodiments, R6 and R7 are different from each other.

[0029] In certain example embodiments, R6 and R7 are the same.

[0030] In certain example embodiments, R6 and R7 are both a halogen.

[0031] In certain example embodiments, R6 and R7 are both Cl.

[0032] In certain example embodiments, R4 is Me, Cl or H.

[0033] Described in certain example embodiments herein are compositions according to Formula V or a salt thereof,

FORMULA V wherein ¾ and R7 are each individually selected from H, a halogen, or a substituted or unsubstituted alkyl.

[0034] In certain example embodiments, R.₆ and R7 are different from each other.

[0035] In certain example embodiments, R6 and R7 are the same.

[0036] In certain example embodiments, R6 and R7 are both a halogen.

[0037] In certain example embodiments, R₆ and R7 are both Cl.

[0038] Described in certain example embodiments herein are compositions according to Formula VI or a salt thereof,

wherein ¾ and R7 are each individually selected from H, a halogen, or a substituted or unsubstituted alkyl.

[0039] In certain example embodiments, R.₆ and R7 are different from each other.

[0040] In certain example embodiments, R6 and R7 are the same.

[0041] In certain example embodiments, R6 and R7 are both a halogen.

[0042] In certain example embodiments, R₆ and R7 are both Cl.

[0043] In certain example embodiments, the 4’, 5’, 6’, or T position of the A ring is substituted with F.

[0044] In certain example embodiments, at least two or at least three of the 4’, 5’, 6’, or T positions of the A ring are substituted with F.

[0045] In certain example embodiments, the 4’ and 5’, 4’ and 6’, or 4’ and T positions of the A ring are substituted with F.

[0046] In certain example embodiments, the 5’ and 6’or 5’ and T positions of the A ring are substituted with F.

[0047] In certain example embodiments, the T and 6’or 5’ and T positions of the A ring are substituted with F.

[0048] In certain example embodiments, the composition is any one of compounds 1-77.

[0049] In certain example embodiments, the composition is compound 1. [0050] In certain example embodiments, the composition is effective to modulate hERG inhibition.

[0051] In certain example embodiments, Rs of Formula I or Z of Formula II is NH(CH₂)_nNHCH₂CH₂OH or NH(CH₂)nCH₂C0₂H, wherein n is 2 or 3.

[0052] In certain example embodiments, the composition is compound 1, 40, 42, 43, 44, or any combination thereof.

[0053] In certain example embodiments, the composition is compound 1-16, 7, 12, 30, 38, 40-44, 46-48, 50-51, 58-59, 72-77, or any combination thereof.

[0054] In certain example embodiments, the composition or formulation thereof is effective to kill quiescent rings formed by exposure to dihydroartemisinin (DHA).

[0055] Described in certain example embodiments herein are compositions according to Formula VII or a salt thereof,

FORMULA VII wherein Y is H or C0₂Me, wherein R is H, C(0)Ph, CO(CH ), C(0)(CH₂)₂-c-C₅H₉, C(0)-4"-methoxyphenyl, C(0)-4"- bromophenyl, C(0)-(5"-bromobenzofuran-2”-yl), or a benzyl, and wherein X is a 4’-halogen, 4’-OEt, or a 2’, 4’ -dihalogen.

[0056] In certain example embodiments, the composition is the (///-enantiomer.

[0057] In certain example embodiments, the composition is the (_<S)-enantiomer.

[0058] In certain example embodiments, the halogen is Cl, Br, or F.

[0059] In certain example embodiments, X is 4’-Cl.

[0060] In certain example embodiments, X is 4’-F.

[0061] In certain example embodiments, X is 4’-Br.

[0062] In certain example embodiments, X is 4’-OEt. [0063] In certain example embodiments, X is 2’, 4’-Cl₂.

[0064] In certain example embodiments, Y is H.

[0065] In certain example embodiments, R is C(0)-(5"-bromobenzofuran-2”-yl).

[0066] In certain example embodiments, the composition is any one of compounds Al-

A42.

[0067] In certain example embodiments, the composition is compound A7.

[0068] In certain example embodiments, the composition is compound A8.

[0069] In certain example embodiments, the composition is compound A9.

[0070] In certain example embodiments, the composition is effective to kill or inhibit an organism from the genus Plasmodium.

[0071] In certain example embodiments, the organism from the genus Plasmodium is capable of causing malaria.

[0072] In certain example embodiments, the Plasmodium is P. falciparum, P. vivax, P. ovale, P. malariae, P. knowlesi, or any combination thereof.

[0073] In certain example embodiments, the compound is effective against an asexual blood stage, sexual blood stage, liver stage, or a combination thereof of the Plasmodium organism.

[0074] Described in certain example embodiments herein are pharmaceutical formulations comprising: a composition described in any of the preceding paragraphs or elsewhere herein (including, but not limited to, any one or more of a compound according to any one or more of Formulas I, II, III, IV, V, VI, VII, VIII, and/or IX), one or more of any of compounds 1-77 and A1-A106, or a combination thereof; and a pharmaceutically acceptable carrier.

[0075] In certain example embodiments, the pharmaceutical formulation is adapted for oral administration.

[0076] In certain example embodiments, the pharmaceutical formulation is adapted for intravenous administration.

[0077] In certain example embodiments, the pharmaceutically acceptable carrier comprises and an amount of DMSO, an amount of Cremophor EL, an amount of glycerol, an amount of PEG 400 and an amount of a solution comprising Na₂HP0₄ and Tween 20.

[0078] In certain example embodiments, the pharmaceutically acceptable carrier comprises about 10% DMSO, about 10% Cremophor EL, about 10% glycerol, about 30% PEG400 and about 40% of a solution containing about 50 mM Na2HP04 and 2% Tween 20. [0079] In certain example embodiments, the pharmaceutical formulation further comprises an auxiliary active agent.

[0080] In certain example embodiments, the auxiliary active agent is another antimalarial agent or an antiparasitic agent.

[0081] Described in certain example embodiments herein are methods of treating or preventing Plasmodium infection in a subject in need thereof, the method comprising: administering a composition as in any one of the preceding paragraphs or described elsewhere herein (including, but not limited to, any one or more of a compound according to any one or more of Formulas I, II, III, IV, V, VI, VII, VII, and/or IX) or a pharmaceutical formulation thereof such as in any of the preceding paragraphs or elsewhere herein to the subject in need thereof.

[0082] In certain example embodiments, administration is oral or intravenous.

[0083] In certain example embodiments, the method further comprises administering a co therapy to the subject in need thereof.

[0084] In certain example embodiments, the composition as in any one of the preceding paragraphs or described elsewhere herein or a pharmaceutical formulation thereof such as in any of the preceding paragraphs or elsewhere herein and the co-therapy are administered simultaneously.

[0085] In certain example embodiments, the composition as in any one of the preceding paragraphs or described elsewhere herein or a pharmaceutical formulation thereof such as in any of the preceding paragraphs or elsewhere herein and the co-therapy are administered at substantially different times.

[0086] Described in certain example embodiments herein are kits comprising a composition as in any one of the preceding paragraphs or described elsewhere herein (including, but not limited to, any one or more of a compound according to any one or more of Formulas I, II, III, IV, V, VI, VII, VIII, and/or IX) or a pharmaceutical formulation thereof such as in any of the preceding paragraphs or elsewhere herein, and optionally a co-therapy. [0087] These and other aspects, objects, features, and advantages of the example embodiments will become apparent to those having ordinary skill in the art upon consideration of the following detailed description of example embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] An understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention may be utilized, and the accompanying drawings of which:

[0089] FIGS. 1A-1B - An experimental schedule of treatments for an iRBC efficacy study in mice (FIG. 1A) and a graph showing results of the experiment (FIG. IB). It was observed that PRC1584 protected mice at least as well as chloroquine.

[0090] FIG. 2 - A table demonstrating numeric results from the experiment outlined in FIG. 1A.

[0091] FIG. 3 - Image results from the oral dosing of PRC 1584 which can demonstrate that oral dosing is effective.

[0092] FIG. 4 - A graph demonstrating effect of 300 nM on growth of a Plasmodium in a washout assay.

[0093] FIG. 5 - Images from a study demonstrating asexual stage phenotyping using continuous drug exposure.

[0094] FIG. 6 - Images showing a blood stage SAR.

[0095] FIG. 7 - Shows a structure of compound 1 (PRC 1584) and summary of in vitro and physicochemical data.

[0096] FIG. 8 - Images showing results from a multi-day imaging study (see also e.g., FIG. 10) the effect of oral dosing in P. berghei -infected mice. Infection on Day 0; dosed daily (Days 3-6), imaged before dosing on Days 3 and 5.

[0097] FIG. 9 - Graphs showing the effect of Compound 1(PRC 1584) on P. berghei. [0098] FIG. 10 - Shows an experimental schedule of 4-day iRBC efficacy study. Differences between this and the study discussed with reference to FIG. 1A include the number of imaging done, but also in i) the instrument used (the instrument used in connection with the experiment described in association with FIG. 1A was lower sensitivity relative to the instrument used in this experiment), ii) the day of the first treatment was Day 3 in this experiment vs. Day 2 in the study discussed with reference to FIG. 1A, and iii) the number of daily treatments given differed with five treatment days in the experiment described in association with FIG. 1A and four treatment days in the present experiment.

[0099] FIG. 11 - Shows graphical results of the effect of different amounts of PRC1548. [0100] FIG. 12 - Shows a table of results of the effect of different amounts of PRC1548.

[0101] FIG. 13 - Shows the estimated metabolic stability of Compound 30 (PRC 1492).

[0102] FIG. 14 -Shows images that can demonstrate the effect Compound 30 (PRC1492) has on phenotype and its stage specify.

[0103] FIG. 15 - Graphs showing the results for ex vivo testing of PRC 1492 and other compounds and controls against Uganda field isolates (n=31). No significant resistance was observed.

[0104] FIGS. 16A-16B - (FIG. 16A)P. falciparum ring-stage (1-3 hours post-infection, hpi) synchronized parasites (4G strain, DHA-resistant) were treated with 0.7 mM DHA or 1 mM of 1, 10, 40, and 42 for 8 h. After drug exposure and washout, parasites were maintained in drug-free media. Percentage of proliferating parasites (% parasitemia) was assessed by microscopy counting of Giemsa-stained smears starting at Day 3 (*). (FIG. 16B) Quiescent parasites in W2 and 4G strains were induced by treating synchronous ring-stage (1-3 hpi) parasites with 0.7 mM DHA for 8 h, washout and incubated in drug-free media for 16 h (8-24 h). Quiescent parasites were subjected to 8 h-pulse (24-32 h) with 1 mM of 1 or mock. After drug exposure and washout, parasites were maintained in drug-free media. Starting at Day 3, parasitemia was assessed daily by light microscopy counting. In both experiments (FIGS. 16A and 16B), the initial parasitemia was set at 1% and cultures were terminated when reached > 6%.

[0105] FIG. 17 - Structure of 9A, and summary of in vitro efficacy, toxicity, physiochemical properties, in vitro ADME, and PK data.

[0106] FIG. 18 - Structures of MMV008138 and KAE609.

[0107] FIG. 19 - Concentration-response curve for Compounds A8 and A9.

[0108] FIG. 20 - Concentration-response curve for Compounds A14 and A15.

[0109] FIG. 21 - A structure-activity relationship diagram.

[0110] FIGS. 22A-22C - Compound A7 (racemic form of A9) is cytotoxic to liver stage P. berghei at 5-10 mM (FIGS. 22A-22B), but is not cytotoxic to HepG2 cells at or below 10 mM (FIG. 22C).

[0111] FIG. 23 - Anisotropic displacement ellipsoid drawings (50%) of the X-ray crystal structure of 9, showing (//(-configuration. [0112] FIG. 24 - Anisotropic displacement ellipsoid drawings (50%) of the X-ray crystal structure of 15A, showing (^-configuration. Note the benzofuran moiety is disordered in the crystal, and is modeled as having two confirmations.

[0113] FIG. 25 - Chiral stationary phase HPLC showing >95% enantiopurity of A8 and A9 (Daicel Chiralcel OD column, 4.6*250 mm. 40% Hexanes/60% isopropanol, 1 mL/min). [0114] FIG. 26 - Chiral stationary phase HPLC showing >95% enantiopurity of A14 and A15 (Daicel Chiralcel OD column, 4.6*250 mm. 40% Hexanes/60% isopropanol, 1 mL/min). [0115] FIG. 27 - PRC 1581 enantiomers (PRC 1590 (R) and 1589 ( S )).

[0116] FIG. 28 - Dose response curves of the racemate (PRC 1581) and enantiomers of

PCR 1581 (PRC 1590 (R) and 1589 (S)).

[0117] FIG. 29 - PRC 1581 can be effective against the liver stage of P. berghei.

[0118] FIG.30 - Ex vivo testing of PRC 1581 using field isolates. Black circles are clinical isolates; Dark gray circles = Dd2 lab strain; light gray circles = 3D7 lab strain; Medium gray circles = IC50 outliers defined by 2.5-fold above or below the cumulative geometric mean (only for standard antimalarials). PRRC1581 geometric mean IC50 = 219 nM. This was a racemic compound.

[0119] FIG. 31 - Asexual stages phenotyping to establish timing for washout experiments. Each compound was present for the entire experiment (continuous drug exposure).

[0120] FIG. 32 - Cultures in ring stage were treated with each compound for the time indicated in the x-axis when parasites were washed to remove the drug and then back to culture to complete 72 h. Growth was measured at 72 h using SYBRG assay. The amount used for each compound is indicated on the legend.

[0121] FIG. 33 - Shows additional analogs of Compound 1 or 30.

[0122] FIG. 34 - Shows a structure activity diagram for analogs of compound 1 or 30.

[0123] The figures herein are for illustrative purposes only and are not necessarily drawn to scale.

DETAILED DESCRIPTION OF THE EXAMPLE EMBODIMENTS [0124] 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. [0125] 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.

[0126] All publications and patents cited in this specification are cited to disclose and describe the methods and/or materials in connection with which the publications are cited. All such publications and patents are herein incorporated by references as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and/or materials described in the cited publications and patents and does not extend to any lexicographical definitions from the cited publications and patents. Any lexicographical definition in the publications and patents cited that is not also expressly repeated in the instant application should not be treated as such and should not be read as defining any terms appearing in the accompanying claims. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.

[0127] 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.

[0128] Where a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0129] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0130] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range. General Definitions

[0131] Unless defined otherwise, 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 pertains. Definitions of common terms and techniques in chemistry and organic chemistry can be found in Smith. Organic Synthesis, published by Academic Press. 2016; Tinoco et al. Physical Chemistry, 5^th edition (2013) published by Pearson; Brown et al., Chemistry, The Central Science 14^th ed. (2017), published by Pearson, Clayden et al., Organic Chemistry, 2^nd ed. 2012, published by Oxford University Press; Carey and Sunberg, Advanced Organic Chemistry, Part A: Structure and Mechanishms, 5^th ed. 2008, published by Springer; Carey and Sunberg, Advanced Organic Chemistry, Part B: Reactions and Synthesis, 5^th ed. 2010, published by Springer, and Vollhardt and Schore, Organic Chemistry, Structure and Function; 8^th ed. (2018) published by W.H. Freeman.

[0132] Definitions of common terms and techniques in molecular biology may be found in Molecular Cloning: A Laboratory Manual, 2^nd edition (1989) (Sambrook, Fritsch, and Maniatis); Molecular Cloning: A Laboratory Manual, 4^th edition (2012) (Green and Sambrook); Current Protocols in Molecular Biology (1987) (F.M. Ausubel et al. eds.); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (1995) (M.J. MacPherson, B.D. Hames, and G.R. Taylor eds.): Antibodies, A Laboratory Manual (1988) (Harlow and Lane, eds.): Antibodies A Laboratory Manual, 2^nd edition 2013 (E.A. Greenfield ed.); Animal Cell Culture (1987) (R.I. Freshney, ed.); Benjamin Lewin, Genes IX, published by Jones and Bartlet, 2008 (ISBN 0763752223); Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0632021829); Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 9780471185710); Singleton etal., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, N.Y. 1994), March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., John Wiley & Sons (New York, N.Y. 1992); and Marten H. Hofker and Jan van Deursen, Transgenic Mouse Methods and Protocols, 2^nd edition (2011). [0133] As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise.

[0134] As used herein, "about," "approximately," “substantially,” and the like, when used in connection with a measurable variable such as a parameter, an amount, a temporal duration, and the like, encompass variations of and from the specified value including those within experimental error (which can be determined by e.g. given data set, art accepted standard, and/or with e.g. a given confidence interval (e.g. 90%, 95%, or more confidence interval from the mean), such as variations of +/-10% or less, +1-5% or less, +/-1% or less, and +/-0.1% or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0135] The term “optional” or “optionally” means that the subsequent described event, circumstance or substituent may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0136] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

[0137] As used herein, a “biological sample” can contain whole cells and/or live cells and/or cell debris. The biological sample can contain (or be derived from) a “bodily fluid”. Bodily fluids include, without limitation those fluids from amniotic fluid, aqueous humour, vitreous humour, bile, blood serum, breast milk, cerebrospinal fluid, cerumen (earwax), chyle, chyme, endolymph, perilymph, exudates, feces, female ejaculate, gastric acid, gastric juice, lymph, mucus (including nasal drainage and phlegm), pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, sebum (skin oil), semen, sputum, synovial fluid, sweat, tears, urine, vaginal secretion, vomit and mixtures of one or more thereof. Biological samples include cell cultures, bodily fluids, cell cultures from bodily fluids. Bodily fluids can be obtained from a mammal organism, for example by puncture, or other collecting or sampling procedures. [0138] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.

[0139] As used herein, “attached” refers to covalent or non-covalent interaction between two or more molecules. Non-covalent interactions include ionic bonds, electrostatic interactions, van der Walls forces, dipole-dipole interactions, dipole-induced-dipole interactions, London dispersion forces, hydrogen bonding, halogen bonding, electromagnetic interactions, p-p interactions, cation-p interactions, anion-p interactions, polar p-interactions, and hydrophobic effects.

[0140] As used herein, “substituted,” refers to all permissible substituents of the compounds or functional groups described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, preferably 1-14 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats. Representative substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C₃-C₂₀ cyclic, substituted C₃-C₂₀ cyclic, heterocyclic, substituted heterocyclic, amino acid, poly(lactic-co-glycolic acid), peptide, and polypeptide groups. Such alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C₃-C₂₀ cyclic, substituted C₃-C₂₀ cyclic, heterocyclic, substituted heterocyclic, amino acid, poly(lactic-co-gly colic acid), peptide, and polypeptide groups can be further substituted. “Substituted,” as used herein, refers to all permissible substituents of the compounds or functional groups described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, preferably 1-30 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats. Representative substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C₃-C₂₀ cyclic, substituted C₃-C₂₀ cyclic, heterocyclic, substituted heterocyclic, amino acid, poly(lactic-co-glycolic acid), peptide, and polypeptide groups. Such alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C3-C20 cyclic, substituted C3-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid, poly(lactic-co-gly colic acid), peptide, and polypeptide groups can be further substituted.

[0141] As used herein, “alkyl,” refers to the radical of saturated aliphatic groups, including straight-chain alkyl, alkenyl, or alkynyl groups, branched-chain alkyl, cycloalkyl (alicyclic), alkyl substituted cycloalkylgroups, and cycloalkyl substituted alkyl. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., Ci- C30 for straight chains, C3-C30 for branched chains), preferably 20 or fewer, more preferably 15 or fewer, most preferably 10 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure. The term “alkyl” (or “lower alkyl”) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls,” the latter of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, a hosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

[0142] Unless the number of carbons is otherwise specified, “lower alkyl” as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. In some embodiments, preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl. [0143] As used herein, “Alkyl” includes one or more substitutions at one or more carbon atoms of the hydrocarbon radical as well as heteroalkyls. Suitable substituents include, but are not limited to, halogens, such as fluorine, chlorine, bromine, or iodine; hydroxyl; — NRR', wherein R and R' are independently hydrogen, alkyl, or aryl, and wherein the nitrogen atom is optionally quatemized; — SR, wherein R is hydrogen, alkyl, or aryl; — CN; — NO2; — COOH; carboxylate; — COR, — COOR, or — CON(R)2, wherein R is hydrogen, alkyl, or aryl; azide, aralkyl, alkoxyl, imino, phosphonate, phosphinate, silyl, ether, sulfonyl, sulfonamido, heterocyclyl, aromatic or heteroaromatic moieties, haloalkyl (such as — CF₃, — CFL — CF₃, — CCL); — CN; — NCOCOCH2CH2, — NCOCOCHCH; — NCS; and combinations thereof. [0144] It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), haloalkyls, — CN and the like. Cycloalkyls can be substituted in the same manner.

[0145] As used herein, “alkenyl” and “alkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term “substituted alkenyl” refers to alkenyl moieties having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof. The term “substituted alkynyl” refers to alkynyl moieties having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0146] As used herein, “alkoxyl” or “alkoxy,” “aroxy” or “aryloxy,” generally describe compounds represented by the formula — OR^v, wherein R^v includes, but is not limited to, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, heteroalkyls, alkylaryl, alkylheteroaryl. The terms “alkoxyl” or “alkoxy” as used herein refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of — O-alkyl, — O-alkenyl, and — O-alkynyl. The term alkoxy also includes cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkenyl, and arylalkyl having an oxygen radical attached to at least one of the carbon atoms, as valency permits.

[0147] The term “substituted alkoxy” refers to an alkoxy group having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the alkoxy backbone. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxy carbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0148] The term “alkylthio” refers to an alkyl group, as defined above, having a sulfur radical attached thereto. The “alkylthio” moiety is represented by — S-alkyl. Representative alkylthio groups include methylthio, ethylthio, and the like. The term “alkylthio” also encompasses cycloalkyl groups having a sulfur radical attached thereto. The term “substituted alkylthio” refers to an alkylthio group having one or more substituents replacing one or more hydrogen atoms on one or more carbon atoms of the alkylthio backbone. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxy carbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0149] As used herein, “amino” and “amine,” are art-recognized and refer to both substituted and unsubstituted amines, e.g., a moiety that can be represented by the general formula:

[0150] wherein, R, R', and R" each independently represent a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, — (CEE — R'", or R and R' taken together with the N atom to which they are atached complete a heterocycle having from 3 to 14 atoms in the ring structure; R'" represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, or a poly cycle; and m is zero or an integer ranging from 1 to 8. In preferred embodiments, only one of R and R' can be a carbonyl, e.g., R and R' together with the nitrogen do not form an imide. In preferred embodiments, R and R' (and optionally R") each independently represent a hydrogen atom, substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or — (CEE — R'". Thus, the term ‘alkylamine’ as used herein refers to an amine group, as defined above, having a substituted or unsubstituted alkyl atached thereto (i.e., at least one of R, R', or R" is an alkyl group).

[0151] As used herein, “arylalkyl,” refers to an alkyl group that is substituted with a substituted or unsubstituted aryl or heteroaryl group.

[0152] As used herein, “alkylaryl,” as used herein, refers to an aryl group (e.g., an aromatic or hetero aromatic group), substituted with a substituted or unsubstituted alkyl group.

[0153] As used interchangeably herein, the terms “amide” or “amido” refer to both “unsubstituted amido” and “substituted amido” and are represented by the general formula:

[0154] wherein, E is absent, or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, wherein independently of

E, R and R' each independently represent a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, — (CEE — R'", or R and R' taken together with the N atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R'" represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, or a polycycle; and m is zero or an integer ranging from 1 to 8. In preferred embodiments, only one of R and R' can be a carbonyl, e.g., R and R' together with the nitrogen do not form an imide. In preferred embodiments, R and R' each independently represent a hydrogen atom, substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or — (CEh — R'". When E is oxygen, a carbamate is formed. The carbamate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art.

[0155] As used herein, “arylthio” refers to — S-aryl or — S-heteroaryl groups, wherein aryl and heteroaryl are as defined herein. The term “substituted arylthio” represents — S-aryl or — S-heteroaryl, having one or more substituents replacing a hydrogen atom on one or more ring atoms of the aryl and heteroaryl rings as defined herein. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0156] The terms “aroxy” and “aryloxy,” as used interchangeably herein, are represented by — O-aryl or — O-heteroaryl, wherein aryl and heteroaryl are as defined herein. The terms “substituted aroxy” and “substituted aryloxy,” as used interchangeably herein, represent — O- aryl or — O-heteroaryl, having one or more sub stituents replacing one or more hydrogen atoms on one or more ring atoms of the aryl and heteroaryl, as defined herein. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof. [0157] As used herein, “aryl” refers to C5-C26-membered aromatic, fused aromatic, fused heterocyclic, or biaromatic ring systems. Broadly defined, “aryl,” as used herein, includes 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered single-ring aromatic groups, for example, benzene, naphthalene, anthracene, phenanthrene, chrysene, pyrene, corannulene, coronene, etc. “Aryl” further encompasses polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e., “fused rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles. The term “substituted aryl” refers to an aryl group, wherein one or more hydrogen atoms on one or more aromatic rings are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF3, — CFh — CF3, — CCI3), — CN, aryl, heteroaryl, and combinations thereof.

[0158] As used herein, “carbonyl,” is art-recognized and includes such moieties as can be represented by the general formula:

[0159] wherein X is a bond, or represents an oxygen or a sulfur, and R represents a hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, — (CFh)_{m —} R", or a pharmaceutical acceptable salt, R' represents a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl or — (CFh)_{m —} R"; R" represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, or a polycycle; and m is zero or an integer ranging from 1 to 8. Where X is oxygen and R is defined as above, the moiety is also referred to as a carboxyl group. When X is oxygen and R is hydrogen, the formula represents a ‘carboxylic acid’. Where X is oxygen and R' is hydrogen, the formula represents a ‘formate’. Where X is oxygen and R or R' is not hydrogen, the formula represents an “ester”. In general, where the oxygen atom of the above formula is replaced by a sulfur atom, the formula represents a ‘thiocarbonyl’ group. Where X is sulfur and R or R' is not hydrogen, the formula represents a ‘thioester.’ Where X is sulfur and R is hydrogen, the formula represents a ‘thiocarboxylic acid.’ Where X is sulfur and R' is hydrogen, the formula represents a ‘thioformate.’ Where X is a bond and R is not hydrogen, the above formula represents a ‘ketone.’ Where X is a bond and R is hydrogen, the above formula represents an ‘aldehyde.’

[0160] The term “substituted carbonyl” refers to a carbonyl, as defined above, wherein one or more hydrogen atoms in R, R' or a group to which the moiety

[0161] is attached, are independently substituted. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0162] The term “carboxyl” is as defined above for the formula

[0163] and is defined more specifically by the formula — R^lvCOOH, wherein R^lvis an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylaryl, arylalkyl, aryl, or heteroaryl. In preferred embodiments, a straight chain or branched chain alkyl, alkenyl, and alkynyl have 30 or fewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straight chain alkyl, C₃-C₃₀ for branched chain alkyl, C₂-C₃₀ for straight chain alkenyl and alkynyl, C₃-C₃₀ for branched chain alkenyl and alkynyl), preferably 20 or fewer, more preferably 15 or fewer, most preferably 10 or fewer.

Likewise, preferred cycloalkyls, heterocyclyls, aryls and heteroaryls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.

The term “substituted carboxyl” refers to a carboxyl, as defined above, wherein one or more hydrogen atoms in R are substituted. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0164] As used herein, the terms “weight percent,” “wt%,” and “wt. %,” which are used interchangeably, indicate the percent by weight of a given component based on the total weight of a composition of which it is a component, unless otherwise specified. That is, unless otherwise specified, all wt% values are based on the total weight of the composition. It should be understood that the sum of wt% values for all components in a disclosed composition or formulation are equal to 100. Alternatively, if the wt% value is based on the total weight of a subset of components in a composition, it should be understood that the sum of wt% values the specified components in the disclosed composition or formulation are equal to 100.

[0165] As used herein, “administering” refers to the act of delivering a substance to a subject by any suitable methods, techniques, or routes. Administration routes, include, but are not limited to, auricular (otic), buccal, conjunctival, cutaneous, dental, electro-osmosis, endocervical, endosinusial, endotracheal, enteral, epidural, extra-amniotic, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-arterial, intra- articular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavemous, intracavitary, intracerebral, intracistemal, intracorneal, intracoronal (dental), intracoronary, intracorporus cavemosum, intradermal, intradiscal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intratubular, intratumor, intratym panic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous drip, intraventricular, intravesical, intravitreal, iontophoresis, irrigation, laryngeal, nasal, nasogastric, occlusive dressing technique, ophthalmic, oral, oropharyngeal, other, parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, urethral, and/or vaginal administration, and/or any combination of the above administration routes, which typically depends on the disease or condition to be treated/prevented, one or more characteristics of the subject, the compositions/substance being delivered, or a combination thereof. One of ordinary skill in the art, unless otherwise noted herein, will appreciate such parameters and be capable of determine a suitable delivery technique and route.

[0166] As used herein, “derivative” refers to any compound having the same or a similar core structure to the compound but having at least one structural difference, including substituting, deleting, and/or adding one or more atoms or functional groups. The term “derivative” does not mean that the derivative is synthesized from the parent compound either as a starting material or intermediate, although this may be the case. The term “derivative” includes prodrugs, or metabolites of the parent compound. Derivatives include compounds in which free amino groups in the parent compound have been derivatized to form amine hydrochlorides, p-toluene sulfoamides, benzoxycarboamides, t-butyloxycarboamides, thiourethane-type derivatives, trifluoroacetylamides, chloroacetylamides, or formamides. Derivatives include compounds in which carboxyl groups in the parent compound have been derivatized to form methyl and ethyl esters, or other types of esters or hydrazides. Derivatives include compounds in which hydroxyl groups in the parent compound have been derivatized to form O-acyl or O-alkyl derivatives. Derivatives include compounds in which a hydrogen bond donating group in the parent compound is replaced with another hydrogen bond donating group such as OH, NH, or SH. Derivatives include replacing a hydrogen bond acceptor group in the parent compound with another hydrogen bond acceptor group such as esters, ethers, ketones, carbonates, tertiary amines, imine, thiones, sulfones, tertiary amides, and sulfides. “Derivatives” also includes extensions of the replacement of the cyclopentane ring with saturated or unsaturated cyclohexane or other more complex, e.g., nitrogen-containing rings, and extensions of these rings with side various groups.

[0167] As used interchangeably herein, “heterocycle,” “heterocyclic” and “heterocyclyl” refer to a cyclic radical attached via a ring carbon or nitrogen atom of a monocyclic or bicyclic ring containing 3-10 ring atoms, and preferably from 5-6 ring atoms, consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, Ci-Cio alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents. Heterocyclyl are distinguished from heteroaryl by definition. Examples of heterocycles include, but are not limited to piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, dihydrofuro[2,3-b]tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidonyl, 4- piperidonyl, piperonyl, pyranyl, 2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, 6H-l,2,5-thiadiazinyl. Heterocyclic groups can optionally be substituted with one or more substituents as defined above for alkyl and aryl.

[0168] As used herein, “heteroaryl” refers to C5-C26-membered aromatic, fused aromatic, biaromatic ring systems, or combinations thereof, in which one or more carbon atoms on one or more aromatic ring structures have been substituted with an heteroatom. Suitable heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen. Broadly defined, “heteroaryl,” as used herein, includes 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered single ring aromatic groups that may include from one to four heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. The heteroaryl group may also be referred to as “aryl heterocycles” or “heteroaromatics”. “Heteroaryl” further encompasses polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (i.e., “fused rings”) wherein at least one of the rings is heteroaromatic, e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heterocycles, or combinations thereof. Examples of heteroaryl rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or more of the rings can be substituted as defined for “substituted heteroaryl”. The term “substituted heteroaryl” refers to a heteroaryl group in which one or more hydrogen atoms on one or more heteroaromatic rings are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF₃, — CEE — CF₃, — CCI₃), — CN, aryl, heteroaryl, and combinations thereof.

[0169] As used herein, “heteroalkyl,” refers to straight or branched chain, or cyclic carbon- containing radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quatemized. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4- pentadienyl), ethynyl, 1- and 3-propynyl, and 3-butynyl.

[0170] The term “phenyl” is art recognized, and refers to the aromatic moiety — ObEE, i.e., a benzene ring without one hydrogen atom. The term “substituted phenyl” refers to a phenyl group, as defined above, having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the phenyl ring. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0171] The term “phenoxy” is art recognized, and refers to a compound of the formula — OR' wherein R^vis (i.e., — O — C6H5). One of skill in the art recognizes that a phenoxy is a species of the aroxy genus. The term “substituted phenoxy” refers to a phenoxy group, as defined above, having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the phenyl ring. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0172] The term “phenylthio” is art recognized, and refers to — S — C6H5, i.e., a phenyl group attached to a sulfur atom. The term “substituted phenylthio” refers to a phenylthio group, as defined above, having one or more sub stituents replacing a hydrogen on one or more carbons of the phenyl ring. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0173] The term “phosphonyl” is represented by the formula

[0174] wherein E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted alkylaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocyclyl, wherein, independently of E, R" and R'" are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted cycloalkyl, a substituted or a unsubstituted heterocyclyl, a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, — (CEE — R'", or R and R' taken together with the P atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R'" represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, or a poly cycle; and m is zero or an integer ranging from 1 to 8. The term “substituted phosphonyl” represents a phosphonyl in which E, R^V1 and R^vu are independently substituted. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0175] The term “phosphoryl” defines a phoshonyl in which E is absent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined herein, and independently of E, R^V1 and R^vu are independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above. When E is oxygen, the phosphoryl cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art. When E, R^V1 and R^vu are substituted, the substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0176] As used herein, “polyaryl” refers to a chemical moiety that includes two or more aryls, heteroaryls, and combinations thereof. The aryls, heteroaryls, and combinations thereof, are fused, or linked via a single bond, ether, ester, carbonyl, amide, sulfonyl, sulfonamide, alkyl, azo, and combinations thereof. The term “substituted polyaryl” refers to a polyaryl in which one or more of the aryls, heteroaryls are substituted, with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxy carbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof. The term “C3-C20 cyclic” refers to a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl that have from three to 20 carbon atoms, as geometric constraints permit. The cyclic structures are formed from single or fused ring systems. The substituted cycloalkyls, cycloalkenyls, cycloalkynyls and heterocyclyls are substituted as defined above for the alkyls, alkenyls, alkynyls and heterocyclyls, respectively.

[0177] As used herein, “sulfonyl” is represented by the formula

[0178] wherein E is absent, or E is alkyl, alkenyl, alkynyl, aralkyl, alkylaryl, cycloalkyl, aryl, heteroaryl, heterocyclyl, wherein independently of E, R represents a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amine, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, — (CEE — R'", or E and R taken together with the S atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R'" represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, or a poly cycle; and m is zero or an integer ranging from 1 to 8. In preferred embodiments, only one of E and R can be substituted or unsubstituted amine, to form a “sulfonamide” or “sulfonamido.” The substituted or unsubstituted amine is as defined above. The term “substituted sulfonyl” represents a sulfonyl in which E, R, or both, are independently substituted. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0179] As used herein, “substituted sulfonyl” represents a sulfonyl in which E, R, or both, are independently substituted. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, — CN, aryl, heteroaryl, and combinations thereof.

[0180] As used herein, “sulfate” refers to a sulfonyl, as defined above, wherein E is absent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and R is independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above. When E is oxygen, the sulfate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art.

[0181] As used herein, the term “sulfonate” refers to a sulfonyl, as defined above, wherein E is oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amine, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, — (CEh)_{m —} R'", R'" represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, or a polycycle; and m is zero or an integer ranging from 1 to 8. When E is oxygen, sulfonate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art.

[0182] The term “sulfamoyl” refers to a sulfonamide or sulfonamide represented by the formula

[0183] where E is absent, or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, wherein independently of E, R and R' each independently represent a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, — (CEh)_{m —} R'", or R and R' taken together with the N atom to which they are atached complete a heterocycle having from 3 to 14 atoms in the ring structure; R'" represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, or a polycycle; and m is zero or an integer ranging from 1 to 8. In preferred embodiments, only one of R and R' can be a carbonyl, e.g., R and R' together with the nitrogen do not form an imide.

[0184] As used herein, “anti-infective” refers to compounds or molecules that can either kill an infectious agent or inhibit it from spreading. Anti-infectives include, but are not limited to, antibiotics, antibacterials, antifungals, antivirals, and antiprotozoans.

[0185] As used herein, “chemotherapeutic agent” or “chemotherapeutic” refers to a therapeutic agent utilized to prevent or treat cancer.

[0186] As used herein, “immunomodulator,” refers to an agent, such as a therapeutic agent, which is capable of modulating or regulating one or more immune function or response.

[0187] As used herein, “modulate” broadly denotes a qualitative and/or quantitative alteration, change or variation in that which is being modulated. Where modulation can be assessed quantitatively - for example, where modulation comprises or consists of a change in a quantifiable variable such as a quantifiable property of a cell or where a quantifiable variable provides a suitable surrogate for the modulation - modulation specifically encompasses both increase (e.g., activation) or decrease (e.g., inhibition) in the measured variable. The term encompasses any extent of such modulation, e.g., any extent of such increase or decrease, and may more particularly refer to statistically significant increase or decrease in the measured variable. By means of example, in aspects modulation may encompass an increase in the value of the measured variable by about 10 to 500 percent or more. In some embodiments, modulation can encompass an increase in the value of at least 10%, 20%, 30%, 40%, 50%, 75%, 100%, 150%, 200%, 250%, 300%, 400% to 500% or more, compared to a reference situation or suitable control without said modulation. In aspects, modulation may encompass a decrease or reduction in the value of the measured variable by about 5 to about 100%. In some embodiments, the decrease can be about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% to about 100%, compared to a reference situation or suitable control without said modulation. In some embodiments, modulation may be specific or selective, hence, one or more desired phenotypic aspects of a cell or cell population may be modulated without substantially altering other (unintended, undesired) phenotypic aspect(s). [0188] As used herein, “nucleic acid,” “nucleotide sequence,” and “polynucleotide” are used interchangeably herein and generally refer to a string of at least two base-sugar-phosphate combinations and refers to, among others, single-and double-stranded DNA, DNA that is a mixture of single-and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. In addition, polynucleotide as used herein can refer to triple- stranded regions comprising RNA or DNA or both RNA and DNA. The strands in such regions can be from the same molecule or from different molecules. The regions can include all of one or more of the molecules, but more typically involve only a region of some of the molecules. One of the molecules of a triple-helical region often is an oligonucleotide. “Polynucleotide” and “nucleic acids” also encompasses such chemically, enzymatically or metabolically modified forms of polynucleotides, as well as the chemical forms of DNA and RNA characteristic of viruses and cells, including simple and complex cells, inter alia. For instance, the term polynucleotide as used herein can include DNAs or RNAs as described herein that contain one or more modified bases. Thus, DNAs or RNAs including unusual bases, such as inosine, or modified bases, such as tritylated bases, to name just two examples, are polynucleotides as the term is used herein. “Polynucleotide”, “nucleotide sequences” and “nucleic acids” also includes PNAs (peptide nucleic acids), phosphorothioates, and other variants of the phosphate backbone of native nucleic acids. Natural nucleic acids have a phosphate backbone, artificial nucleic acids can contain other types of backbones, but contain the same bases. Thus, DNAs or RNAs with backbones modified for stability or for other reasons are “nucleic acids” or "polynucleotides" as that term is intended herein. As used herein, “nucleic acid sequence” and “oligonucleotide” also encompass a nucleic acid and polynucleotide as defined elsewhere herein.

[0189] As used herein, “aptamer” can refer to single-stranded DNA or RNA molecules that can bind to pre-selected targets including proteins with high affinity and specificity. Their specificity and characteristics are not directly determined by their primary sequence, but instead by their tertiary structure.

[0190] As used herein, “pharmaceutical formulation” refers to the combination of an active agent, compound, or ingredient with a pharmaceutically acceptable carrier or excipient, making the composition suitable for diagnostic, therapeutic, or preventive use in vitro, in vivo, or ex vivo.

[0191] As used herein, “pharmaceutically acceptable carrier or excipient” refers to a carrier or excipient that is useful in preparing a pharmaceutical formulation that is generally safe, non toxic, and is neither biologically or otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable carrier or excipient” as used in the specification and claims includes both one and more than one such carrier or excipient.

[0192] As used herein, “pharmaceutically acceptable salt” refers to any acid or base addition salt whose counter-ions are non-toxic to the subject to which they are administered in pharmaceutical doses of the salts.

[0193] As used herein, “substantial” and “substantially,” specify an amount of between 95% and 100%, inclusive, between 96% and 100%, inclusive, between 97% and 100%, inclusive, between 98% 100%, inclusive, or between 99% 100%, inclusive.

[0194] As used herein, "substantially free" can mean an object species is present at non- detectable or trace levels so as not to interfere with the properties of a composition or process. [0195] As used herein, "substantially pure" means that an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition), and preferably a substantially purified fraction is a composition wherein the object species comprises about 50 percent of all species present. Generally, a substantially pure composition is composed of more than about 80 percent of all species present in the composition, more preferably more than about 85%, 90%, 95%, and 99%. In some embodiments, the object species is purified to essential homogeneity (i.e., contaminant species cannot be detected in the composition by conventional detection methods) whereby the composition is substantially only composed of a single species.

[0196] As used interchangeably herein, the terms “sufficient” and “effective,” refer to an amount (e.g., mass, volume, dosage, concentration, and/or time period) needed to achieve one or more desired result(s). For example, a therapeutically effective amount refers to an amount needed to achieve one or more therapeutic effects.

[0197] As used herein, “therapeutic” refers to treating, healing, and/or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect. A “therapeutically effective amount” therefore refers to an amount of a compound that can yield a therapeutic effect.

[0198] As used herein, the terms "treating" and "treatment" refers generally to obtaining a desired pharmacological and/or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein covers any treatment of a disease in a subject, particularly a human, and includes any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and/or its symptoms or conditions. The term "treatment" as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and/or those in which the disorder is to be prevented. As used herein, the term "treating", includes inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain. [0199] As used herein, “water-soluble”, as used herein, generally means at least about 10 g of a substance is soluble in 1 L of water, i.e., at neutral pH, at 25° C.

[0200] Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment(s). Reference throughout this specification to “one embodiment”, “an embodiment,” “an example embodiment,” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” or “an example embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention. For example, in the appended claims, any of the claimed embodiments can be used in any combination.

[0201] All publications, published patent documents, and patent applications cited herein are hereby incorporated by reference to the same extent as though each individual publication, published patent document, or patent application was specifically and individually indicated as being incorporated by reference.

OVERVIEW

[0202] Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitos and is a significant world health problem. Despite a huge effort and amount of money spent for the research and development of treatments and preventives, there are still an estimated 228 million cases worldwide. In 2018 there were about 405,000 deaths attributed to malaria worldwide. Children under 5 are the most vulnerable group and accounted for about 67 percent of all malaria deaths. As such there exists an urgent and unmet need for malaria treatments and/or preventives. [0203] There are about 400 different species of Anopheles mosquito, of which about 30 are malaria vectors of major importance. Transmission is more prevalent in places where the mosquito vector lifespan is longer, which is a major reason why about 90% of the world’s malaria cases are in Africa. When a mosquito bites an infected person, a small amount of blood is taken in which contains microscopic malaria parasites. About 1 week later, when the mosquito takes its next blood meal, these parasites mix with the mosquito’s saliva and are injected into the person being bitten. The malaria parasite can be found in the red blood cells of an infected person, and thus can also be transmitted through blood transfusion, organ transplant, or through the shared use of needles and syringes contaminated with infected blood. Transmission can also occur from a mother to her unborn infant before or during delivery, a condition also referred to as “congenital” malaria.

[0204] Malaria is caused by parasites of the genus Plasmodium, and more specifically P. vivax, P. ovale, P. malariae, and P. falciparum. P. falciparum causes the most severe form. The parasite life cycle involves two hosts. During a blood meal, malaria-infected female Anopheles mosquito inoculates sporozoites into the human host. Sporozoites infect liver cells and mature into schizonts , which rupture and release merozoites. Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver (if untreated) and cause relapses by invading the bloodstream weeks, or even years later. After this initial replication in the liver (exo-erythrocytic schizogony), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony). Merozoites infect red blood cells. The ring stage trophozoites mature into schizonts, which rupture releasing merozoites. Some parasites differentiate into sexual erythrocytic stages (gametocytes). Blood stage parasites are responsible for the clinical manifestations of the disease. The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal. The parasites’ multiplication in the mosquito is known as the sporogonic cycle. While in the mosquito’s stomach, the microgametes penetrate the macrogametes generating zygotes. The zygotes in turn become motile and elongated (ookinetes) which invade the midgut wall of the mosquito where they develop into oocysts. The oocysts grow, rupture, and release sporozoites, which make their way to the mosquito’s salivary glands. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle.

[0205] Many modalities including vector control via insecticide spraying and use of mosquito nets along with antimalarial pharmaceuticals and one vaccine have been used to fight malaria. However, insecticide and drug resistance has been a recurring problem limiting the efficacy of past and current treatment and preventions. [0206] With that said, embodiments disclosed herein can provide various compounds and formulations thereof that can be effective against one or more stages of a parasite of the Plasmodium genus, such as those that are a vector for malaria e.g., P. falciparum, vivax, P. ovale, P. malariae, and/or P. knowlesi. Other compositions, compounds, methods, features, and advantages of the present disclosure will be or become apparent to one having ordinary skill in the art upon examination of the following drawings, detailed description, and examples. It is intended that all such additional compositions, compounds, methods, features, and advantages be included within this description, and be within the scope of the present disclosure. ANTI-MALARIAL COMPOUNDS

[0207] Described herein are tetracyclic compounds that, in some embodiments, can be effective to treat and/or prevent malaria in a subject in need thereof. In some embodiments, the compound(s) described herein can be effective to inhibit the growth, infectivity, transmission, and/or can kill a parasite of the species Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) in one or more stages of its life cycle (e.g., in the asexual and/or one or more of the sexual blood stages and/or liver stage) or a symptom thereof. In some embodiments, the compounds can be any one or more of Formulas I, II, III, IV, V, VI, VII, VIII, including but not necessarily limited to, compounds 1-77 and A1-A78, salts thereof, analogs thereof and/or derivatives thereof.

[0208] In some embodiments, the compound can be according to Formula I or a salt thereof,

where Ri, R₂, R₃, and R₄ are each individually selected from: H, a halogen, or a substituted or unsubstituted alkyl, where R5 is selected from OCH3, NH(CH2)3Me, NHMe, NH(CH₂)₂OH, NH(CH₂)₂NHMe, NH(CH₂)₂N(Me)₂, NH(CH₂)₃NHMe, NH(CH₂)₃N(Me)₂, NH(CH₂)_nNHCH₂CH₂OH, NH(CH₂)_nN(CH₂CH₂OH)₂, NH(CH₂)_mNH₂, or NH(CH₂)_nNHCH₂C0₂H, wherein n is 2 or 3 and m is 2-6, where ¾ and R7 are each individually selected from H, a halogen, or a substituted or unsubstituted alkyl, and where Z is C or N.

[0209] In some embodiments, Ri, R₂, R₃, and R4 are all different from each other. In some embodiments, Ri, R₂, R₃, and R4 are all the same. In some embodiments, at least two or three of Ri, R₂, R₃, and R4 are the same. In some embodiments, at least two or three of Ri, R₂, R₃, and R4 are different. In some embodiments, Rr, and R7 are different from each other. In some embodiments, R₆ and R7 are the same.

[0210] In some embodiments, the compound can be according to Formula II or a salt thereof,

where X is selected from 7-CH₃, 7-subsituted or unsubstituted alkyl or heteroalkyl, or 7-H, where Y is a substituent at positions 3 and 4 or positions 3, 4, and 5 of ring D, wherein each substituent at each position is individually selected from Cl, Br, F, I, Me, or H, and where Z is selected from, OCH₃, NH(CH₂)₃Me, NHMe, NH(CH₂)₂OH, NH(CH₂)₂NHMe, NH(CH₂)₂N(Me)₂, NH(CH₂)₃NHMe, NH(CH₂)₃N(Me)₂, NH(CH₂)_nNHCH₂CH₂OH, NH(CH₂)_nN(CH₂CH₂OH)₂, NH(CH₂)_mNH₂, or NH(CH₂)_nNHCH₂C0₂H, wherein n is 2 or 3 and m is 2-6.

[0211] In some embodiments, Y can be selected from 3’,4’-Cl₂, 4’Cl, 2’,4’-Cl₂, 3’,4’-F₂, 3’,4’-Br₂, or 3’,4’-I₂.

[0212] In some embodiments, where X can be selected from 7-CH₃, 7-substituted or unsubstituted alkyl or heteroalkyl, or 7-H.

[0213] In some embodiments, Y can be a 3’ and 4’ where the substituent at the 3’ position can be selected from Cl, Br, F, Me, or H and the substituent at the 4’ position can be selected from Cl, Br, F, Me, or H. In some of these embodiments, the following combinations for the substituents at the 3’ and 4’ position can be as follows: Cl and Cl; Br and Br; F and F; Me and Me; Cl and Br; Br and Cl; Cl and F; F and Cl; Br and F; F and Br; Cl and Me; Me and Cl; Br and Me; Me and Br; F and Me; Me and F; H and Cl; H and Br; H and F; and H and Me.

[0214] In some embodiments, Y is a halogen substituent at each of positions 3, 4, and 5 of ring D. In some embodiments, the substituent at positions 3, 4, and 5 are each individually selected from Cl, Br, and F. In some embodiments, wherein Br, when optionally present as a substituent, is only present at one of positions 3, 4, or 5 of ring D.

[0215] In some embodiments, the compound can be according to Formula III or a salt thereof,

where R4 is selected from: H, a halogen, or a substituted or unsubstituted alkyl, and where R.₆ and R7 are each individually selected from H, a halogen, or a substituted or unsubstituted alkyl.

[0216] In some embodiments, ¾ and R7 are different from each other. In some embodiments, R6 and R7 are the same. In some embodiments, R6 is Cl, Br, F, or Me. In some embodiments, R7 is Cl, Br, F, or Me. In some embodiments, R4 is Me, Cl or H.

[0217] In some embodiments, the compound can be according to Formula IV or a salt thereof,

[0218] In some embodiments, ¾ and R7 are different from each other. In some embodiments, Rr, and R7 are the same. In some embodiments, R₆ and R7 are both a halogen. In certain example embodiments, R6 and R7 are both Cl. In certain example embodiments, R4 is Me, Cl or H.

[0219] In some embodiments, the compound can be according to Formula V or a salt thereof,

where R.6 and R7 are each individually selected from H, a halogen, or a substituted or unsubstituted alkyl.

[0220] In some embodiments, ¾ and R7 are different from each other. In some embodiments, Rr, and R7 are the same. In some embodiments, R₆ and R7 are both a halogen In some embodiments, R₆ and R7 are both Cl.

[0221] In some embodiments, the compound can be according to Formula VI or a salt thereof,

where R₆ and R7 are each individually selected from H, a halogen, or a substituted or unsubstituted alkyl.

[0222] In some embodiments, Rr, and R7 are different from each other. In some embodiments, Rr, and R7 are the same. In some embodiments, R₆ and R7 are both a halogen In some embodiments, R6 and R7 are both Cl. In some embodiments, the 4’, 5’, 6’, or T position of the A ring is substituted with F. In some embodiments, at least two of the 4’, 5’, 6’, or T positions of the A ring are substituted with F.

[0223] In some embodiments, at least three of the 4’, 5’, 6’, or T positions of the A ring are substituted with F.

[0224] In some embodiments, 4’ and 5’, 4’ and 6’, or 4’ and T positions of the A ring are substituted with F. [0225] In some embodiments, 5’ and 6’or 5’ and T positions of the A ring are substituted with F.

[0226] In some embodiments, T and 6’or 5’ and T positions of the A ring are substituted with F.

[0227] In some embodiments, the antimalarial compound can be any one of compounds 1-

29, 30, 38, or 40-77 as shown in e.g., Table 1 and as shown in the Working Examples (e.g., Example 1) below. In some embodiments, the antimalarial compound is Compound 1 (also referred to herein in as PRC 1584), which is a salt.

[0228] The free-base form of Compound 1 is referred to herein as PRC 1492 or Compound

30.

[0229] Compound 30 is not generally cytotoxic (E. coli MIC > 250 micromolar (>2, 700- fold selectivity), HEK-293 growth IC50 ~32 micromolar (345-fold selectivity), appears to be effective against P. falciparum and can have efficacy against artemisin-resistant parasites. The free-base form of Compound 1 (Compound 30) did not demonstrate significant resistance in ex vivo studies using field isolates. These and other attributes of Compound 30 are at least demonstrated in the Working Examples below.

[0230] Also described and encompassed by the present disclosure herein are derivatives and analogs of a compound according to Formula I, II, III, IV, V or VI described herein. Also described and encompassed by the present disclosure herein are derivatives and analogs of any one of compounds 1-77, such as 1-30, 38, and/or 40-77 described herein.

[0231] In some embodiments, the compound according to any one of Formulas I, II, III, IV, V or VI is effective to modulate (e.g., reduce) hERG inhibition. In some embodiments, the compound that is effective to modulate hERG inhibition is a compound according to Formula I or II, where R5 of Formula I or Z of Formula II is NF^CFy_nNFlCFhCFhOFl or NH(CH2)_nNHCH2CC)2H, wherein n is 2 or 3. In some embodiments, the compound effective to modulate hERG inhibition is compound 1, 40, 42, 43, or 44. In some embodiments, modulation of hERG inhibition is to reduce inhibition by 1-100%, such as 1, to/or 2, 3, 4, 5, 6,

7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,

33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,

58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,

83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 percent. In some embodiments, the compound(s) is/are capable of increasing the IC50 of hERG inhibition by 1-

50 fold or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,

22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,

47, 48, 49, to/or 50 fold or more. See e.g., the Working Examples herein, particularly at Table

4.

[0232] In some embodiments, the compound of any one of Formulas I, II, III, IV, V or VI is effective is effective to kill quiescent rings formed by exposure to dihydroartemisinin (DHA). In some embodiments, the compound can be according to Formula VII or a salt thereof,

where Y can be H or C0₂Me, where R can be H, C(0)Ph, CO(CFb), C(0)(CH₂)₂- C-C5H9, C(0)-4"-methoxyphenyl, C(0)-4"-bromophenyl, C(0)-(5"-bromobenzofuran-2”-yl), or a benzyl, and where X can be a 4’-halogen, a 4’-OEt, or a 2’,4’-dihalogen.

[0233] In some embodiments the halogen is Cl. In some embodiments the halogen is Br. In some embodiments, the halogen is F. In some embodiments, X can be 4’-Cl. In some embodiments, X can be 4’-F. In some embodiments, X can be 4’-Br. In some embodiments, X can be 2’, 4’-Cl₂. [0234] In some embodiments, the antimalarial compound can be any one of compounds A1-A43, A49-A78as shown in Table 2 as shown in the Working Examples below (e.g., Example 5). In some embodiments, the antimalarial compound can be any one of compounds A1-A16. In some embodiments, the antimalarial compound is Compound A7 (also referred to herein in as PRC 1581), which is a racemate. In some embodiments, the antimalarial compound is Compound A8 (also referred to herein in as PRC 1589). In some embodiments, the antimalarial compound is Compound A9 (also referred to herein in as PRC 1590).

[0235] In other embodiments, the composition of Formula VII is any compound except for any of compounds A7, A8, A9, or any combination thereof.

[0236] Also described herein are derivatives and analogs of a compound according to Formula VII described herein. Also described herein are derivatives and analogs of any one of compounds A1-A43, A49-A78 described herein.

[0237] Where the composition is the pure enantiomer, the pure enantiomer can be separated out from a racemic mix. In some embodiments, a method described in LI, X.; Branum, S.; Russell, R. K.; Jiang, W.; Sui, Z. Org. Proc. Res. Dev. 2005, 9, 640-645, which is incorporated by reference as if expressed in its entirety herein, can be use to generate the pure enantiomer compound. In some embodiments, a method described in Klaussen, R. S.; Jacobsen, E. N. Org. Lett. 2009, 11, 887-890, which is incorporated by reference as if expressed in its entirety herein, can be use to generate the pure enantiomer compound. In further embodiments, enantiomerically pure analogs can be prepared as they were for compounds A9 and A15 as shown in the Working Examples herein, namely resolution of the corresponding tetrahydro- -carboline with /V-acetyl-D-leucine (Li et ak, 2005) salt break, and acylation with 5-bromobenzofuran-2-yl carbonyl chloride. In the event that resolution with this reagent is not successful, other V- acetyl. N- Boc and /V-CBz amino acids, or other conventional resolving agents could be employed. Finally catalytic asymmetric Pictet-Spengler reaction could also be used to prepare the required enantioenriched tetrahydro- -carboline (Klaussen et al. 2009). In all cases, X-ray crystallography can be used to establish absolute configuration. PHARMACEUTICAL FORMULATIONS

[0238] Also described herein are pharmaceutical formulations that can contain an amount, effective amount, and/or least effective amount, and/or therapeutically effective amount of one or more compounds, molecules, compositions, vectors, vector systems, cells, or a combination thereof (which are also referred to as the primary active agent or ingredient elsewhere herein) described in greater detail elsewhere herein a pharmaceutically acceptable carrier. When present, the compound can optionally be present in the pharmaceutical formulation as a pharmaceutically acceptable salt. In some embodiments, the pharmaceutical formulation can include, such as an active ingredient, an anti-malarial compound described herein.

[0239] Also described herein are pharmaceutical formulations that can contain an amount, effective amount, and/or least effective amount, and/or therapeutically effective amount of one or more compounds (e.g. a compound of any one of Formulas I, II, III, IV, V, VI, VII, VIII and/or VIX (including but not limited to any one or more of compounds 1-77 and A1-A106, particularly, 1-30, 38, 40-77, A1-A16, A17-43, A49-A78, A79-A106, a salt thereof, analog thereof, or a derivative thereof)), molecules, compositions, or a combination thereof (which are also referred to as the primary active agent or ingredient elsewhere herein) described in greater detail elsewhere herein a pharmaceutically acceptable carrier. In some embodiments, the formulation contains a racemic mix of any one or more of a compound of Formulas I, II, III, IV, V, VI, VII, and/or VIII, such as, but not limited to, 1-30, 38, 40-77, A1-A16, A17-43, A49-A78, A79-A106, an analogue of or a derivative thereof. In some embodiments, the formulation is entantiomerically pure as to any one or more compounds of Formulas I, II, III, IV, V, VI, VII, and/or VIII, such as, but not limited to, 1-30, 38, 40-77, A1-A16, A17-43, A49-A78, A79-A106, an analogue of or a derivative thereof. In some embodiments, the formulation contains only the R-enantiomer. In some embodiments, the formulation contains only the S-enantiomer. When present, the compound can optionally be present in the pharmaceutical formulation as a pharmaceutically acceptable salt. In some embodiments, the pharmaceutical formulation can include, such as an active ingredient, an anti-malarial compound described herein.

[0240] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of a compound(s) of Formulas I, II, III, IV, V, VI, VII, and/or VIII, such as, but not limited to, 1-30, 38, 40-77, A1-A16, A17-43, A49-A78, A79-A106, an analogue of or a derivative thereof is effective to treat and/or prevent malaria or a symptom thereof in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of any one or more of a compound(s) of Formulas I, II, III, IV, V, VI, VII, and/or VIII, such as, but not limited to, 1-30, 38, 40-77, A1-A16, A17-43, A49-A78, A79-A106, an analogue of or a derivative thereof is effective to kill and/or inhibit the growth of an organism of the genus Plasmodium in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of any one or more of a compound(s) of Formulas I, II, III, IV, V, VI, VII, and/or VIII, such as, but not limited to, 1-30, 38, 40-77, A1-A16, A17- 43, A49-A78, A79-A106, an analogue of or a derivative thereof is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both.

[0241] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of any one or more of compounds 1-30, an analogue of or a derivative thereof is effective to treat and/or prevent malaria or a symptom thereof in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of any one or more of compounds 1-30, an analogue of or a derivative thereof is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both.

[0242] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of any one or more of compounds 1, 46, 58, 69, and/or 74, an analogue of or a derivative thereof is effective to treat and/or prevent malaria or a symptom thereof in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of any one or more of compounds 1, 46, 58, 69, and/or 74, an analogue of or a derivative thereof is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both. [0243] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of compounds 11, 47, 59, 72, 75, and/or 77, an analogue of or a derivative thereof is effective to treat and/or prevent malaria or a symptom thereof in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of any one or more of compounds 11, 47, 59, 72, 75, and/or 77, an analogue of or a derivative thereof is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both.

[0244] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of compounds 7, 12, 48 and/or 76, an analogue of or a derivative thereof is effective to treat and/or prevent malaria or a symptom thereof in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of any one or more of compounds 7, 12, 48 and/or 76, an analogue of or a derivative thereof is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both.

[0245] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of compounds 50, 73, 43, 51, and/or 71, an analogue of or a derivative thereof is effective to treat and/or prevent malaria or a symptom thereof in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of any one or more of compounds 50, 73, 43, 51, and/or 71, an analogue of or a derivative thereof is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both.

[0246] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of compounds having a D ring substitution of any of Formulas I, II, III, IV, V or VI that is a 3’ and/or 4’ halogen (including, but not limited to, a 3’- Cl, 4’-Cl; 3’-F, 4’-F) is effective to treat and/or prevent malaria or a symptom thereof in a subject. Exemplary compounds include, but are not limited to, 1, 11, 47, 50, 51, 71, 72, and 77. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of compounds having a D ring substitution of any of Formulas I, II, III, IV, V or VI that is a 3’ and/or 4’ halogen is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both.

[0247] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of compounds having a D ring substitution of any of Formulas I, II, III, IV, V or VI that is a 3’ 4’, and 4’ halogen (including, but not limited to, a 3’, 4’, 5’ - Cl) is effective to treat and/or prevent malaria or a symptom thereof in a subject. Exemplary compounds include, but are not limited to, 73, 74, 75, and 76. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of compounds having a D ring substitution of any of Formulas I, II, III, IV, V or VI that is that is a 3’ 4’, and 5’ halogen is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both.

[0248] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of one or more compounds having a D ring substitution of any of Formulas I, II, III, IV, V or VI that is a 4’ halogen (including, but not limited to, a 4’ - Br) is effective to treat and/or prevent malaria or a symptom thereof in a subject. Exemplary compounds include, but are not limited to, 58 and 59. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of compounds having a D ring substitution of any of Formulas I,

II, III, IV, V or VI that is that is a 4’halogen is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both.

[0249] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of compounds of any of Formulas I, II,

III, IV, V or VI is effective to reduce hERG blockade. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of compounds of any of Formulas I, II, III, IV, V or VI effective to reduce hERG blockade contains one or more alkyl substitutions on the pendant basic amine of the compound of any one of Formulas I, II, III, IV, V or VI. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any one or more of compounds of any of Formulas I, II, III, IV, V or VI effective to reduce hERG blockade contains is any one or more compounds 1, 40, 44, 43, or 44.

[0250] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds A8, A9, A1-A78, or a combination thereof is effective to treat and/or prevent malaria or a symptom thereof in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds A8, A9, A1-A78, or a combination thereof is effective to kill and/or inhibit the growth of an organism of the genus Plasmodium in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds A8, A9, A1-A78, or a combination thereof is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both. In some embodiments, the enantiomerically pure form of the (///-enantiomer (///-enantiomer, or both (not contained in the same formulation) are therapeutically effective where the racemic mix is not.

[0251] In some embodiments the pharmaceutical formulation contains a compound according to Formula IX

where Xi, X₂, and X₃ are each independently selected H, CH₃, OCH₃, a halogen (e.g., Cl, Br, F), OCH₂CH₃, NO₂, CF₃, where optionally Xi and X₂ together form a 3, 4, 5, or 6 member heterocycle (e.g., X₂ and X₃ are substituted such that 5’-0CH₂CH-0-4’ and form a 5 member heterocycle), where B is CH where Y is substituted at the 5”, the 6”, or both where each are selected from a halogen or H, where the halogen is Br, Cl, or F, and where R is H or (CH₂)2N(CH₃)2, or a salt thereof, analog thereof, or derivative thereof.

[0252] In some embodiments, the composition contained in the pharmaceutical formulation such as active ingredient is according to Formula IX is any one of compounds A49-A78, and any of those provided in Appendix A to U.S. Provisional Application Serial No. 63/018,430, which is incorporated by reference as if expressed in its entirety herein. In some embodiments, the pharmaceutical formulation contains the enantiomerically pure form of the (//(-enantiomer. (///-enantiomer of a composition of Formula IX, including but not limited to any one of compounds A49-A78 or a salt thereof, analog thereof, or derivative thereof. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds A8, A9, A1-A78, or a combination thereof is effective to treat and/or prevent malaria or a symptom thereof in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of a composition of Formula IX, including but not limited to any one of compounds A49-A78, is effective to kill and/or inhibit the growth of an organism of the genus Plasmodium in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of Formula IX, including but not limited to any one of compounds A49-A78, is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both. In some embodiments, the enantiomerically pure form of the (//(-enantiomer. CS')-enantiomer. or both (not contained in the same formulation) are therapeutically effective where the racemic mix is not.

[0253] Also described herein are pharmaceutical formulations that can contain an effective amount, least effective amount, and/or therapeutically effective amount, of any one of compounds described or set forth in International Patent Application Publications WO 2004092123 A2 or WO 2001087038 A2, which are incorporated by reference as if expressed in their entirety herein. For example, in some of these embodiments, in some embodiments the pharmaceutical formulation can contain an effective amount, least effective amount, and/or therapeutically effective amount of a compound of Formula A from W02004092123

[0254] wherein each of R¹, R²,R³, and R⁴ is, independently selected from, hydrogen, or C1-C6 alkyl ; A is NR⁵R⁶ ; B is C⁷CR⁸ ; or is absent; C is NR⁹R¹⁰ ; the dashed lines between A and B and between B and C are bonds when B is present, or unshared electron pairs on A and C when B is absent; R⁵ is hydrogen; or R⁶ and R⁷ together are a bond when B is present; R⁶ is RaC(O)-, or is absent; R7 and RS together are a bond when B is present; R8 is C₁-C₄ alkyl, optionally substituted with NR^bR^c or R^aC(0)-; R⁹ is C₆-C₁₀ aryl, optionally substituted with hydrogen, halo, or C₁-C₄ alkyl ; R¹⁰ is hydrogen, or is absent; R^a is C₁-C₄ alkyl, optionally substituted with halo, NR^bR^c or -C(O) NHNHC(O) R^d; each of R^b and R^c is, independently, C₁-C₆ alkyl, C₂-C₆ aminoalkyl, C₂-C₆ alkylaminoalkyl, C₂-C₆ dialkylaminoalkyl, C₇-C₁₁ aralkyl, or R^eC(0)-; or R^b and R^c together are a heterocyclyl, or heterocycloalkenyl, optionally substituted with 1-3 R^f; R^d is C6-C10 aryl or 3-10 membered heteroaryl, optionally substituted with 1-3 R^g ; R^e is C1-C6 alkyl, C7-C11 aralkyl, C6-C10 aryl, or C₆-C₁₀ arylamino, each of which may be substituted with C₁-C₄ alkyl, halo or C₁-C₄ alkoxy; R^f is oxo or C₁-C₆ alkyl; R^g is hydrogen, halo, hydroxy, alkoxy, nitro, amino, cyano, carboxy, Ci- C₆ alkyl, C₆-C₁₀ aryl, or 5-8 membered heteroaryl; and X is O or S. In some embodiments when B is present, R5 and R7 together can be a bond, and R8 can be substituted with NR^bR^c, e.g., CH (NR^bR^c)CH₃ or CH(NR^bR^c)CH₂CH₃. R^b can be (CH3)₂NCH₂CH₂, benzyl, or Ci-C₆ alkyl and W can be R^eC(0)-, in which R^e can be C₅- Cn alkyl or substituted or unsubstituted C₆-C₁₀ arylamino ; preferred substituents include CH₃ or OCH₃. R^c can be R^eC(0)-. R^e can be C5-C11 alkyl or substituted or unsubstituted C6-C10 arylamino, wherein the substituents are selected from CH₃ or OCH₃. R₉ can be a substituted or unsubstituted phenyl, wherein the substituents are selected from halo or C₁-C₄ alkyl (e. g., CH³ or chloro). Other compounds are described in W02004092123.

[0255] Also by way of example, in some embodiments the pharmaceutical formulation can contain an effective amount, least effective amount, and/or therapeutically effective amount of a compound in WO 2001087038 such as a compound of the general formula I of WO 2001087038

[0256] where R¹ is independently selected from the group consisting of halogen, nitro, hydroxy, Ci -Cs alkyl, Ci -Cs alkoxy, - NH2, -NHR^A -N(R^a)₂, -0-R^A -C(0)NH², -C(0)NHR^A -C(0)N(R^a)₂, -NC(0)-R^A -SO₂NHR^A - S0₂N(R^a)₂, phenyl (optionally substituted with 1 to 3 R^B) and heteroaryl (optionally substituted with 1 to 3 R^B); where each R^A is independently is independently selected from the group consisting of Cl -Cs alkyl, aryl (optionally substituted with 1 to 3 RB), Cl-Cs aralkyl (optionally substituted with 1 to 3 RB) and heteroaryl (optionally substituted with 1 to 3 R^B); where each R^B is independently selected from the group consisting of halogen, hydroxy, nitro, cyano, Ci -Cs alkyl, Ci -Cs alkoxy, Ci-Cs alkoxycarbonyl, carboxy Ci-Cs alkyl, Ci-Cs alkylsulfonyl, trifluoromethyl, trifluoromethoxy, amino, acetylamino, di(Ci-Cs alkyl)amino, di(Ci-C8 alkyl)aminoCl -Cs alkoxy, di(Ci-C8alkyl)aminoacetylCi-C8alkyl, di(Ci- C₈alkyl)aminoacetylamino, carboxyCi-C₈)alkylcarbonylamino, hydroxyCi-Csalkylamino, NHR^a, N(R^a)₂ and heterocycloalkylCi-Csalkoxy: n is an integer from O to 4; X is selected from the group consisting of 0, S and NR^D; where R^D is selected from the group consisting of hydrogen, hydroxy, -OR^A Ci-Csalkyl (wherein the alkyl is optionally substituted with one to three substituent independently selected from halogen, carboxy, amino, Ci-Csalkylamino. di(Ci-c_8aikyi)amino, Ci-Csalkoxycarbonyl, heteroaryl or heterocycloalkyl), heteroaryl and heteroarylcarbonyl (wherein the heteroaryl may be optionally substituted with phenyl or substituted phenyl, where the phenyl substituents are one to three R^B);

R² is selected from the group consisting of Cs-Cioalkyl (optionally substituted with 1 to 3 R^c), aryl (optionally substituted with 1 to 3 R^B), heteroaryl (optionally substituted with 1 to 3 R^B) and heterocycloalkyl (optionally substituted with 1 to 3 R^B); where each Re is independently selected from the group consisting of halogen, hydroxy, nitro, NH₂, NHR^A and N(R^A)₂; Z is selected from the group of CH₂, CHOH and C(O); provided that when Z is CHOH or C(O), then X is NH; R⁴ is selected from the group consisting of hydrogen, hydroxy, carboxy, Cl- CV.alkylcarbonyk Ci-Csalkoxylcarbonyl, di(Ci-C5alkyl)aminoalkoxycarbonyl, di(Ci- C8alkyl)aminoCi-C8alkylaminocarbonyl, and -COR^F; where R^F is selected from the group of Ci-Csalkyl, NH₂, NHR^A, NR^A ₂, -Ci-C₈alkyl-NH₂, -Ci-C₅alkyl-NHR^A -Ci-C₅alkyl-NR^A ₂ and - NH-Ci-C₈alkyl-NR^A; a is an integer from O to 1 ; Y is selected from the group of CH₂, C(O),

C(0)0, C(0)-NH and ' is selected from the group consisting of naphthyl, heteroaryl and a heterocycloalkyl; m is an integer from O to 2; R³ is independently selected from the group consisting of halogen, nitro, Ci- Csalkyl, Ci-Csalkoxy, trifluoromethyl, trifluoromethoxy, phenyl (optionally substituted with 1 to 3 R^B), phenylsulfonyl, naphthyl, Ci-Csaralkyl, heteroaryl (optionally 30 substituted with 1 to 3 R^B), NH2, NHR^A and N(R^A)2; provided that when

2-furyl or 2-thienyl, then m is an integer from 1 to 2. Other compounds are described in WO 2001087038.

[0257] In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds of WO 2001087038, W02004092123, or a combination thereof is effective to treat and/or prevent malaria or a symptom thereof in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds of WO 2001087038, W02004092123, or a combination thereof is effective to kill and/or inhibit the growth of an organism of the genus Plasmodium in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds of WO 2001087038, W02004092123, or a combination thereof is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both.

[0258] Also described herein are pharmaceutical formulations that can contain an effective amount, least effective amount, and/or therapeutically effective amount, of any one of compounds A43 and A9-A78, which is incorporated by reference as if expressed in its entirety herein, or an (R)- or fSj-enantiomer thereof. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds of A43 and A49-A78 or a combination thereof is effective to treat and/or prevent malaria or a symptom thereof in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds of A43 and A49-A78or a combination thereof is effective to kill and/or inhibit the growth of an organism of the genus Plasmodium in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds of A43 and A49-A78or a combination thereof is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both.

[0259] Also described herein are pharmaceutical formulations containing an effective amount, least effective amount, and/or a therapeutically effective amount of a compound of

Formula VIII

Formula VIII where X and Z can be as shown in Table 3 below (compounds A79-A106) or the ( R )- or ( S ) enantiomer thereof:

and where 3’4’-methylenedioxy is . In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds of A79- A106 or a combination thereof is effective to treat and/or prevent malaria or a symptom thereof in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds of A79-A106or a combination thereof is effective to kill and/or inhibit the growth of an organism of the genus Plasmodium in a subject. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of any of compounds of A79-A106or a combination thereof is effective to kill and/or inhibit one or more stages of the Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the liver stage, a blood stage, or both. In some embodiments, the blood stage is the asexual blood stage, the sexual blood stage, or both. [0260] The pharmaceutical formulations described herein can be administered via any suitable method or route to a subject in need thereof. Suitable administration routes can include, but are not limited to auricular (otic), buccal, conjunctival, cutaneous, dental, electro-osmosis, endocervical, endosinusial, endotracheal, enteral, epidural, extra-amniotic, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-arterial, intra- articular, intrabibary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavemous, intracavitary, intracerebral, intracistemal, intracorneal, intracoronal (dental), intracoronary, intracorporus cavemosum, intradermal, intradiscal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intratubular, intratumor, intratym panic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous drip, intraventricular, intravesical, intravitreal, iontophoresis, irrigation, laryngeal, nasal, nasogastric, occlusive dressing technique, ophthalmic, oral, oropharyngeal, other, parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, urethral, and/or vaginal administration, and/or any combination of the above administration routes, which typically depends on the disease to be treated and/or the active ingredient(s).

[0261] Where appropriate, compounds, molecules, compositions, vectors, vector systems, cells, or a combination thereof described in greater detail elsewhere herein can be provided to a subject in need thereof as an ingredient, such as an active ingredient or agent, in a pharmaceutical formulation. As such, also described are pharmaceutical formulations containing one or more of the compounds and salts thereof, or pharmaceutically acceptable salts thereof described herein. Suitable salts include, hydrobromide, iodide, nitrate, bisulfate, phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, napthalenesulfonate, propionate, malonate, mandelate, malate, phthalate, and pamoate. [0262] In some embodiments, the subject in need thereof has or is suspected of having malaria, suspected of having malaria, infected with a species of the genus Plasmodium, (e.g., P. falciparum, vivax, P. ovale, P. malariae, and/or P. knowlesi), at-risk of being infected with a parasite of the species of the genus Plasmodium (e.g., P. falciparum, vivax, P. ovale, P. malariae, and/or P. knowlesi) or a symptom thereof. As used herein, “agent” refers to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a biological and/or physiological effect on a subject to which it is administered to. An agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. An agent can be a secondary agent, or in other words, the component(s) of a composition to which an additional part and/or other effect of the composition is attributed.

Pharmaceutically Acceptable Carriers and Auxiliary Ingredients and Agents [0263] The pharmaceutical formulation can include a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include, but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxy methylcellulose, and polyvinyl pyrrolidone, which do not deleteriously react with the active composition.

[0264] The pharmaceutical formulations can be sterilized, and if desired, mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances, and the like which do not deleteriously react with the active compound.

[0265] In some embodiments, the pharmaceutical formulation can also include an effective amount of auxiliary active agents, including but not limited to, biologic agents or molecules (including but not limited to (e.g. polypeptides, polynucleotides, antibodies and fragments thereof, aptamers, and the like), chemotherapeutics, antineoplasic agents, hormones, antibiotics, antivirals, immunomodulating agents, antinausea, pain modifying compounds (such as opiates), anti-inflammatory agents, antipyretics, antibiotics, and combinations thereof.

Effective Amounts

[0266] In some embodiments, the amount of the primary active agent and/or optional auxiliary active agent can be an effective amount, least effective amount, and/or therapeutically effective amount. The effective amount, least effective amount, and/or therapeutically effective amount of the primary and optional auxiliary active agent described elsewhere herein contained in the pharmaceutical formulation can range from about 0 to 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280,

290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470,

480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660,

670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850,

860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 pg, ng, pg, mg, or g or be any numerical value with any of these ranges. In some embodiments, the effective amount, least effective amount, and/or therapeutically effective amount can be an effective concentration, least effective concentration, and/or therapeutically effective concentration, which can each range from about 0 to 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320,

330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510,

520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700,

710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890,

900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 pM, nM, pM, mM, or M or be any numerical value with any of these ranges.

[0267] In other embodiments, the effective amount, least effective amount, and/or therapeutically effective amount of the auxiliary active agent can range from about 0 to 10, 20,

30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420,

430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610,

620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800,

810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990,

1000 IU or be any numerical value with any of these ranges.

[0268] In some embodiments, a primary active agent can be present in the pharmaceutical formulation can range from about 0 to 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008,

0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.9, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,

82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5,

99.6, 99.7, 99.8, 99.9 % w/w, v/v, or w/v of the pharmaceutical formulation.

[0269] In some embodiments, the auxiliary active agent, when optionally present, can range from about 0 to 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87,

0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.9, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,

11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,

36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,

61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,

86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7,

99.8, 99.9 % w/w, v/v, or w/v of the pharmaceutical formulation.

[0270] In some embodiments where a cell population is delivered, the effective amount of cells can range from about lXIOVmL to lX10²⁰/mL or more, such as about lXlOVmL, lX10²/mL, lX10³/mL, lXIOVmL, lX10⁵/mL, lX10⁶/mL, lX10⁷/mL, lX10⁸/mL, lX10⁹/mL, lX10¹⁰/mL, lX10ⁿ/mL, lX10¹²/mL, lX10¹³/mL, lX10¹⁴/mL, lX10¹⁵/mL, lX10¹⁶/mL, lX10¹⁷/mL, lX10¹⁸/mL, lX10¹⁹/mL, to/or about lX10²°/mL.

[0271] In embodiments where there is an auxiliary active agent contained in the pharmaceutical formulation, the effective amount of the auxiliary active agent will vary depending on the auxiliary active agent.

[0272] When optionally present in the pharmaceutical formulation, the auxiliary active agent can be included in the pharmaceutical formulation or can exist as a stand-alone compound or pharmaceutical formulation that can be administered contemporaneously or sequentially with the compound, derivative thereof, or pharmaceutical formulation thereof. In some embodiments, the auxiliary active agent can be an anti-parasitic, immunomodulator, anti pyretic, other antimalarial or other compound effective to treat malaria or a symptom thereof in a subject. In some embodiments the auxiliary active agent can be an endectocide. In some embodiments the auxiliary active agent can be ivermectin. In yet other embodiments, the effective amount of the auxiliary active agent can range from about 0 to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,

35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,

60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,

85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7,

99.8, 99.9 % w/w, v/v, or w/v of the total auxiliary active agent pharmaceutical formulation. In additional embodiments, the effective amount of the auxiliary active agent can range from about 0 to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,

51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,

76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1,

99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 % w/w, v/v, or w/v of the total pharmaceutical formulation.

Dosage Forms

[0273] In some embodiments, the pharmaceutical formulations described herein can be in a dosage form. The dosage form can be administered to a subject in need thereof. The dosage form can be effective generate specific concentration, such as an effective concentration, at a given site in the subject in need thereof. In some cases, the dosage form contains a greater amount of the active ingredient than the final intended amount needed to reach a specific region or location within the subject to account for loss of the active components such as via first and second pass metabolism.

[0274] The dosage forms can be adapted for administration by any appropriate route. Appropriate routes include, but are not limited to, oral (including buccal or sublingual), rectal, intraocular, inhaled, intranasal, topical (including buccal, sublingual, or transdermal), vaginal, parenteral, subcutaneous, intramuscular, intravenous, intemasal, and intradermal. Other appropriate routes are described elsewhere herein. Such formulations can be prepared by any method known in the art. [0275] Dosage forms adapted for oral administration can discrete dosage units such as capsules, pellets or tablets, powders or granules, solutions, or suspensions in aqueous or non- aqueous liquids; edible foams or whips, or in oil-in-water liquid emulsions or water-in-oil liquid emulsions. In some embodiments, the pharmaceutical formulations adapted for oral administration also include one or more agents which flavor, preserve, color, or help disperse the pharmaceutical formulation. Dosage forms prepared for oral administration can also be in the form of a liquid solution that can be delivered as a foam, spray, or liquid solution. The oral dosage form can be administered to a subject in need thereof. Where appropriate, the dosage forms described herein can be microencapsulated.

[0276] The dosage form can also be prepared to prolong or sustain the release of any ingredient. In some embodiments, compounds, molecules, compositions, vectors, vector systems, cells, or a combination thereof described herein can be the ingredient whose release is delayed. In some embodiments the primary active agent is the ingredient whose release is delayed. In some embodiments, an optional auxiliary agent can be the ingredient whose release is delayed. Suitable methods for delaying the release of an ingredient include, but are not limited to, coating or embedding the ingredients in material in polymers, wax, gels, and the like. Delayed release dosage formulations can be prepared as described in standard references such as "Pharmaceutical dosage form tablets," eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989), "Remington - The science and practice of pharmacy", 20th ed., Lippincott Williams & Wlkins, Baltimore, MD, 2000, and "Pharmaceutical dosage forms and drug delivery systems", 6th Edition, Ansel et al., (Media, PA: Wiliams and Wlkins, 1995). These references provide information on excipients, materials, equipment, and processes for preparing tablets and capsules and delayed release dosage forms of tablets and pellets, capsules, and granules. The delayed release can be anywhere from about an hour to about 3 months or more.

[0277] Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name EUDRAGIT® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides. [0278] Coatings may be formed with a different ratio of water-soluble polymer, water insoluble polymers, and/or pH dependent polymers, with or without water insoluble/water soluble non-polymeric excipient, to produce the desired release profile. The coating is either performed on the dosage form (matrix or simple) which includes, but is not limited to, tablets (compressed with or without coated beads), capsules (with or without coated beads), beads, particle compositions, "ingredient as is" formulated as, but not limited to, suspension form or as a sprinkle dosage form.

[0279] Where appropriate, the dosage forms described herein can be a liposome. In these embodiments, primary active ingredient(s), and/or optional auxiliary active ingredient(s), and/or pharmaceutically acceptable salt thereof where appropriate are incorporated into a liposome. In embodiments where the dosage form is a liposome, the pharmaceutical formulation is thus a liposomal formulation. The liposomal formulation can be administered to a subject in need thereof.

[0280] Dosage forms adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. In some embodiments for treatments of the eye or other external tissues, for example the mouth or the skin, the pharmaceutical formulations are applied as a topical ointment or cream. When formulated in an ointment, a primary active ingredient, optional auxiliary active ingredient, and/or pharmaceutically acceptable salt thereof where appropriate can be formulated with a paraffinic or water-miscible ointment base. In other embodiments, the primary and/or auxiliary active ingredient can be formulated in a cream with an oil-in-water cream base or a water-in- oil base. Dosage forms adapted for topical administration in the mouth include lozenges, pastilles, and mouth washes.

[0281] Dosage forms adapted for nasal or inhalation administration include aerosols, solutions, suspension drops, gels, or dry powders. In some embodiments, a primary active ingredient, optional auxiliary active ingredient, and/or pharmaceutically acceptable salt thereof where appropriate can be in a dosage form adapted for inhalation is in a particle-size-reduced form that is obtained or obtainable by micronization. In some embodiments, the particle size of the size reduced (e.g. micronized) compound or salt or solvate thereof, is defined by a D50 value of about 0.5 to about 10 microns as measured by an appropriate method known in the art. Dosage forms adapted for administration by inhalation also include particle dusts or mists. Suitable dosage forms wherein the carrier or excipient is a liquid for administration as a nasal spray or drops include aqueous or oil solutions/suspensions of an active (primary and/or auxiliary) ingredient, which may be generated by various types of metered dose pressurized aerosols, nebulizers, or insufflators. The nasal/inhalation formulations can be administered to a subject in need thereof.

[0282] In some embodiments, the dosage forms are aerosol formulations suitable for administration by inhalation. In some of these embodiments, the aerosol formulation contains a solution or fine suspension of a primary active ingredient, auxiliary active ingredient, and/or pharmaceutically acceptable salt thereof where appropriate and a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations can be presented in single or multi-dose quantities in sterile form in a sealed container. For some of these embodiments, the sealed container is a single dose or multi-dose nasal or an aerosol dispenser fitted with a metering valve (e.g., metered dose inhaler), which is intended for disposal once the contents of the container have been exhausted.

[0283] Where the aerosol dosage form is contained in an aerosol dispenser, the dispenser contains a suitable propellant under pressure, such as compressed air, carbon dioxide, or an organic propellant, including but not limited to a hydrofluorocarbon. The aerosol formulation dosage forms in other embodiments are contained in a pump-atomizer. The pressurized aerosol formulation can also contain a solution or a suspension of a primary active ingredient, optional auxiliary active ingredient, and/or pharmaceutically acceptable salt thereof. In further embodiments, the aerosol formulation also contains co-solvents and/or modifiers incorporated to improve, for example, the stability and/or taste and/or fine particle mass characteristics (amount and/or profile) of the formulation. Administration of the aerosol formulation can be once daily or several times daily, for example 2, 3, 4, or 8 times daily, in which 1, 2, or 3 doses are delivered each time. The aerosol formulations can be administered to a subject in need thereof.

[0284] For some dosage forms suitable and/or adapted for inhaled administration, the pharmaceutical formulation is a dry powder inhalable-formulations. In addition to a primary active agent, optional auxiliary active ingredient, and/or pharmaceutically acceptable salt thereof where appropriate, such a dosage form can contain a powder base such as lactose, glucose, trehalose, manitol, and/or starch. In some of these embodiments, a primary active agent, auxiliary active ingredient, and/or pharmaceutically acceptable salt thereof where appropriate is in a particle-size reduced form. In further embodiments, a performance modifier, such as L-leucine or another amino acid, cellobiose octaacetate, and/or metals salts of stearic acid, such as magnesium or calcium stearate. In some embodiments, the aerosol formulations are arranged so that each metered dose of aerosol contains a predetermined amount of an active ingredient, such as the one or more of the compositions, compounds, vector(s), molecules, cells, and combinations thereof described herein.

[0285] Dosage forms adapted for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations. Dosage forms adapted for rectal administration include suppositories or enemas. The vaginal formulations can be administered to a subject in need thereof.

[0286] Dosage forms adapted for parenteral administration and/or adapted for injection can include aqueous and/or non-aqueous sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, solutes that render the composition isotonic with the blood of the subject, and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents. The dosage forms adapted for parenteral administration can be presented in a single-unit dose or multi-unit dose containers, including but not limited to sealed ampoules or vials. The doses can be lyophilized and re-suspended in a sterile carrier to reconstitute the dose prior to administration. Extemporaneous injection solutions and suspensions can be prepared in some embodiments, from sterile powders, granules, and tablets. The parenteral formulations can be administered to a subject in need thereof.

[0287] For some embodiments, the dosage form contains a predetermined amount of a primary active agent, auxiliary active ingredient, and/or pharmaceutically acceptable salt thereof where appropriate per unit dose. In an embodiment, the predetermined amount of primary active agent, auxiliary active ingredient, and/or pharmaceutically acceptable salt thereof where appropriate can be an effective amount, a least effect amount, and/or a therapeutically effective amount. In some embodiments, the predetermined amount can be effective to inhibit one or more stages of the Plasmodium (e.g., P. falciparum, vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite and/or kill a Plasmodium (e.g., P. falciparum, vivax, P. ovale, P. malariae, and/or P. knowlesi) parasite in one or more stages. In some embodiments, the one or more stages is the asexual and/or sexual blood stages.

[0288] In other embodiments, the predetermined amount of a primary active agent, auxiliary active agent, and/or pharmaceutically acceptable salt thereof where appropriate, can be an appropriate fraction of the effective amount of the active ingredient. Such unit doses may therefore be administered once or more than once a day, month, or year (e.g., 1, 2, 3, 4, 5, 6, or more times per day, month, or year). Such pharmaceutical formulations may be prepared by any of the methods well known in the art.

[0289] In some embodiments, the pharmaceutical formulation can, include an amount of an anti-malarial compound described herein (such as any one or more of Formulas I, II, III, IV, V, VI, VII, VIII and/or IX), and 40:10:50 PEG400: Ethanol: PBS. In some of these embodiments, the anti-malarial compound described herein is present in the formulation at up to about 5 mg/mL. In some of these embodiments, such a formulation is suitable for intravenous administration.

[0290] In some embodiments, the pharmaceutical formulation can, particularly in the case of Compound 1, include an amount of an anti-malarial compound described herein (such as one of Formula I), and 40:10:50 PEG400: Ethanol: PBS. In some of these embodiments, the anti-malarial compound described herein is present in the formulation at up to about 5 mg/mL. In some of these embodiments, such a formulation is suitable for intravenous administration. [0291] In some embodiments, the pharmaceutical formulation can include an amount of an anti-malarial compound described herein (e.g., any of those of Formulas I, II, III, IV, V, VI, VII, VIII and/or IX, particularly Formula VII) and a carrier containing an amount of DMSO, an amount of Cremophor EL, an amount of glycerol, an amount of PEG 400 and an amount of a solution containing Na₂HP0₄ and Tween 20. In some embodiments, the pharmaceutical formulation can include an amount of an anti-malarial compound described herein (such as one of Formulas I, II, III, IV, V, VI, VII, VIII, and/or IX, particularly Formula VII), and a carrier containing about 10% DMSO, about 10% Cremophor EL, about 10% glycerol, about 30% PEG400 and about 40% of a solution containing about 50 mM Na₂HP0₄ and 2% Tween 20. In some of these embodiments, the anti-malarial compound described herein is present in the formulation at up to about 5 mg/mL. In some of these embodiments, such a formulation is suitable for intravenous administration.

KITS

[0292] The compounds and/or pharmaceutical formulations provided herein (including but not necessarily limited to any amount of the antimalarial compounds and pharmaceutical formulations described herein (e.g., one or more compounds of any one or more of Formulas I, II, III, IV, V, VI, VII, VIII, and/or IX such as, but not limited to, 1-177 and A1-A106, particularly 1-30, 38, 40-77, A1-A16, A17-43, A49-A78, A79-A106) and any optional co- therapy can be presented as a combination kit. As used herein, the terms “combination kit” or “kit of parts” refers to the compounds, or pharmaceutical formulations and additional components that are used to package, sell, market, deliver, and/or administer the combination of elements or a single element, such as the active ingredient, contained therein. Such additional components include but are not limited to, packaging, syringes, blister packages, bottles, and the like. When one or more of the components (e.g., active agents) contained in the kit are administered simultaneously, the combination kit can contain the active agents in a single pharmaceutical formulation (e.g., a tablet) or in separate pharmaceutical formulations. [0293] When the agents are not administered simultaneously, the combination kit can contain each agent in separate pharmaceutical formulations. The separate pharmaceutical formulations can be contained in a single package or in separate packages within the kit. [0294] In some embodiments, the combination kit also includes instructions printed on or otherwise contained in a tangible medium of expression. The instructions can provide information regarding the content of the compound or pharmaceutical formulations contained therein, safety information regarding the content of the compound(s) or pharmaceutical formulation(s) contained therein, information regarding the dosages, indications for use, and/or recommended treatment regimen(s) for the compound(s) and/or pharmaceutical formulations contained therein. In some embodiments, the instructions can provide directions for administering the compounds, pharmaceutical formulations, or salts thereof to a subject having or suspected of having malaria, suspected of having malaria, infected with a species of the genus Plasmodium, (e.g. P. falciparum, vivax, P. ovale, P. malariae, and/or P. knowlesi), at- risk of being infected with a parasite of the species of the genus Plasmodium (e.g. P. falciparum, vivax, P. ovale, P. malariae, and/or P. knowlesi) or a symptom thereof. In some embodiments, the instructions can provide directions for administering the compound or formulations thereof described herein to someone who has or is suspected of having a blood stage (e.g., asexual blood stage and/or sexual blood stage) infection of a parasite from the genus Plasmodium (e.g., P. falciparum, vivax, P. ovale, P. malariae, and/or P. knowlesi) or a symptom thereof. In some aspects, the instructions can provide directions for administering the compounds, pharmaceutical formulations, or salts thereof to a subject having or suspected of having malaria, suspected of having malaria, infected with a species of the genus Plasmodium, (e.g. P. falciparum, vivax, P. ovale, P. malariae, and/or P. knowlesi), at-risk of being infected with a parasite of the species of the genus Plasmodium (e.g. P. falciparum, vivax, P. ovale, P. malariae, and/or P. knowlesi) or a symptom thereof. In some embodiments, the kit provides a co-therapeutic, such as a separate auxiliary active ingredient. Such auxiliary active ingredients are described elsewhere herein. In some embodiments, the instructions include information and recommended treatment regimens for these auxiliary active agents and any combination effect these may have on the efficacy of the anti-malarial compound, pharmaceutical formulations or ingredient thereof, and/or any changes to dosing of the antimalarial compound or formulation thereof and/or auxiliary ingredient when the two are used in combination. In some embodiments, the kit further includes an auxiliary active agent. Exemplary auxiliary active agents are discussed in greater detail elsewhere herein.

METHODS OF TREATING AND/OR PREVENTING MALARIA [0295] Any amount of the antimalarial compounds and pharmaceutical formulations described herein can be administered to a subject in need thereof one or more times per day, week, month, or year. In some embodiments, the pharmaceutical formulation administered contains an effective amount, a least effective amount, biased effective amount and/or a pharmaceutically effective amount of the compound of any one of the anti-malarial compounds described herein or any other compound described herein or a structural analogue thereof. For example, the pharmaceutical formulations can be administered in a daily dose. This amount may be given in a single dose per day. In other embodiments, the daily dose may be administered over multiple doses per day, in which each containing a fraction of the total daily dose to be administered (sub- doses). In some embodiments, the number of doses delivered per day is 2, 3, 4, 5, or 6. In further embodiments, the compounds, formulations, or salts thereof are administered one or more times per week, such as 1, 2, 3, 4, 5, or 6 times per week. In other embodiments, the compounds, formulations, or salts thereof are administered one or more times per month, such as 1 to 5 times per month. In still further embodiments, the compounds, formulations, or salts thereof are administered one or more times per year, such as 1 to 11 times per year.

[0296] Any amount of the antimalarial compounds and pharmaceutical formulations described herein (e.g. one or more compounds of any one or more of Formulas I, II, III, IV, V, VI, VII, VIII, and/or IX, such as, but not limited to, 1-77 and A1-A106, particularly 1-30, 38, 40-77, A1-A16, A17-43, A49-A78, A79-A106, any compound in WO 2001087038, WO 2004092123, a R- or S- enantiomer of any of the aforementioned compounds, or any combination thereof, particularly compounds 1, 30, 38, 40, 42, 43, 44, A7, A8, and/or A9, a salt thereof, analog thereof, or a derivative thereof and any pharmaceutical formulation thereof) can be administered to a subject in need thereof one or more times per day, week, month, or year. In some embodiments, the method can include administering one or more compounds, pharmaceutical formulations, or salts thereof to a subject having or suspected of having malaria, suspected of having malaria, infected with a species of the genus Plasmodium, (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi). In some embodiments, the method can include administering one or more one or more compounds, pharmaceutical formulations, or salts thereof to a subject in need thereof at-risk of being infected with a parasite of the species of the genus Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) or a symptom thereof. In some embodiments, the method can include administering one or more compounds, pharmaceutical formulations, or salts thereof to a subject who has or is suspected of having a liver stage and/or a blood stage (e.g., sexual or asexual blood stage) infection of a parasite from the genus Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) or a symptom thereof. In some embodiments, the method can include administering one or more compounds, pharmaceutical formulations, or salts thereof to a subject having or suspected of having malaria, suspected of having malaria, infected with a species of the genus Plasmodium, (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi), at-risk of being infected with a parasite of the species of the genus Plasmodium (e.g., P. falciparum, P. vivax, P. ovale, P. malariae, and/or P. knowlesi) or a symptom thereof.

[0297] In some embodiments, administration can occur prior to infection, during infection, after infection, or a combination thereof.

[0298] In some embodiments, the method can include a co-therapy approach where an antimalarial compound or formulation thereof of the present disclosure is one of the therapies. Additional preventions and therapies that can be co-administered with an antimalarial compound or formulation thereof of the present disclosure can be a vector control measure (e.g. insecticides, mosquito nets) and/or administration of another pharmaceutically effective compound or formulation thereof, including, but not limited to, aniti-parasitic, immunomodulator, anti-pyretic, other antimalarial or other compound effective to treat malaria or a symptom thereof in a subject. In some embodiments, the co-therapeutic or preventative can be an endectocide. In some embodiments, the co-therapeutic or preventative can be ivermectin. The co-therapies can be administered substantially at the same time (e.g. simultaneously) or at different times. In some embodiments, co-therapeutic agents can be contained in the same formulation.

[0299] Further embodiments are illustrated in the following Examples which are given for illustrative purposes only and are not intended to limit the scope of the invention.

EXAMPLES

[0300] Now having described the embodiments of the present disclosure, in general, the following Examples describe some additional embodiments of the present disclosure. While embodiments of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit embodiments of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of embodiments of the present disclosure. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to perform the methods and use the probes disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C, and pressure is at or near atmospheric. Standard temperature and pressure are defined as 20 °C and 1 atmosphere.

Example 1-Efficacy of PRC 1584 against P. berghei Blood Stage Infection [0301] PRC 1584 can protect mice against blood stage plasmodium infection as is demonstrated by at least FIGS. 1A-1B, 2-3, and 9. Mice were infected with 10³ iRBC (about 5 x 10⁵ percent infection). The infection was P. berghei infection. Treatments (vehicle, chloroquine, PRC 1582, and PRC 1584) were started 48 hours after infection and continued for 5 days. Amounts of each treatment are shown in FIG. 1A. Images were taken 7 days after infection, which is after 5 treatments. Results are shown in FIGS. IB-3. A screen against stage IV-V P. falciparum gametocytes in in vitro culture demonstrated that PRC 1584 was effective to eliminate P. falciparum gametocytes at all stages IV-V.

[0302] A similar experiment was completed but with some differences. Experiment details are further described and demonstrated in e.g., FIGS. 8, 10-12 and Example 3 below. FIG. 10 shows an experimental schedule of 4-day iRBC efficacy study. Differences between this and the study discussed with reference to FIG. 1A include the number of imagings done, but also in i) the instrument used (the instrument used in connection with the experiment described in association with FIG. 1A was lower sensitivity relative to the instrument used in this experiment), ii) the day of the first treatment was Day 3 in this experiment vs. Day 2 in the study discussed with reference to FIG. 1A, and iii) the number of daily treatments given differed with five treatment days in the experiment described in association with FIG. 1A and four treatment days in the present experiment. FIG. 11 shows graphical results of the effect of different amounts of PRC 1548. FIG. 12 shows a table of results of the effect of different amounts of PRC1548. FIG. 8 shows imaging results. These results are also further discussed in Example 3 below.

Example 2-Asexual stages phenotyping

[0303] As shown in FIG. 5 each compound was present for the entire experiment (i.e., continuous drug exposure for 72 hours). As shown in FIG. 4, cultures in the ring stage were treated with each compound (PRC 1584 or untreated) for the time indicated in the x-axis of FIG. 4 when parasites were washed to remove the compound or other treatment and then back to culture to complete 72 h. Growth was measured at 72 h using SYBRG assay. The amount used for each compound is indicated in the legend. PRC1584 was observed to be cytocidal and acts within 12 h of treatment.

Example 3- Orally-Active Tetracyclic Antimalarial

[0304] Compound 1 is Rule of Five-compliant and is prepared in five steps from commercial starting materials. It emerged from research optimization of the Malaria Box compound MMV008138. Unlike MMV008138 which is a tetrahydro- -carboline acid, 1 is a b-carboline amide, and its P. falciparum growth inhibition is not reversed by co-application of isopentenyl diphosphate (IPP). As shown in FIG. 7, 1 has excellent potency in vitro against four strains of blood-stage P. falciparum. Stage-specific exposure (8 h) and wash-out studies¹ indicate that 1 is cytocidal to late rings (EC₅o^8h=350 nM) and early trophozoites (EC5o^8h=200 nM). Also, 1 shows excellent selectivity against three mammalian cell lines (EC50/CC50 OO) and against a major component of the gut microbiome ( E . coli MIC > 250 mM). Courtesy of Roland Cooper and Phil Rosenthal, 1 was tested ex vivo against 31 Ugandan clinical isolates and an average EC50 of 70 nM was observed, with no isolate showing greater than 3 x average EC50 value. Two independent tests showed that 1 was orally efficacious at 40 mg/kg/day in P. berghei- infected mice (performed by NYU Anti-infectives Core, FIG. 8). Compound 1 killed Stage V gametocytes with an EC50 value of 750 nM (microscopy). Thus, dosing with 1 or analogs can provide transmission-blocking activity in addition to clearing blood stage parasitemia. So far, continuous exposure of blood stage at 3 x EC50 (14 days) and 1 x EC50 (5 days) failed to yield resistant or viable parasites after 60 day follow up of cultures. Up to now, 28 analogs of 1 have been prepared and assayed against blood stage P. falciparum, and a clear SAR picture has emerged, especially for the amide substituent and the D-ring (FIG. 6). Although its mechanism of action is currently unknown, it is distinct from that of i) chloroquine (morphology), ii) KAE-609 (Dd2-KAE609^Resistant strain is susceptible), and iii) methylerythritol phosphate (MEP) pathway inhibitors (no reversal of growth inhibition by isopentenyl diphosphate supplementation). Compound 1 (PRC 1584) demonstrated good potency against Dd2/3D7 strains and shows no resistance in ex vivo assays (31 isolates, Uganda). It further demonstrated excellent selectivity against HEK-293 and E.coli. It is orally efficacious at about 40 mg/kg/day in . berghei- infected mice as previously demonstrated. Blood Stage Structure-Activity Relationship Data.

Structure-Activity Relationship.

[0305] Only -carboline-3 -carboxamides with a pendant basic amine were observed to have in vitro blood-stage P. falciparum growth inhibition values EC50 £ 200 nM: Compounds 1 (108 ± 7 nM), 10 (173 ± 2 nM), 46 (227 ± 33 nM), 58 (188 ± 21 nM), 69 (80-160 nM) and 74 (< 40 nM) all have 2-(methylamino)ethyl amides; compounds 11 (132 ± 27 nM), 47 (158 ± 23 nM), 59 (146 ± 12 nM), 72 (40-80 nM), 75 (< 40 nM), and 77 (40-80 nM) have 2- (dimethylamino)ethyl groups; compounds 7 (217 ± 28 nM), 12 (207 ± 21 nM), 48 (96 ± 11 nM) and 76 (<40 nM) haves 3-(methylamino)propyl group; compounds 50 (230 ± 32 nM), and 73 (<40 nM) have 2-aminoethyl groups; 43 (211 ± 41 nM) and 51 (123 ± 21 nM) have 2- ((2-hydroxyethyl)amino)ethyl groups, and 71 (80-160 nM) has a 3-((2- hydroxyethyl)amino)propyl groups; 42 (141 ± 7 nM) has a 2-(pyrrolidin-l-yl)ethyl group. In contrast (a) Acids 3 and 21 have EC50 > 10,000 nM; (b) Methyl esters 2 and 20) have EC50 > 10,000 nM; (c) Methyl amide 6 and butyl amides 5 and 14 have EC50 > 1,000 nM and >1,250 nM, respectively; and (d) 2-hydroxy ethyl amides 9 and 15 both have EC50 > 1,250 nM.

D-rins substitution effect (Ύ substituent).

[0306] For -carboline-3 -carboxamides with the pendant basic amines described above, the lowest EC50 values are observed when the D-ring bears halogen substitution at 3'- and 4'-. For example, the following D-ring substitution patterns exhibit high potency against P. falciparum : Y = 3',4'-dichloro: compounds 1, 11, 47, 50, 51, and 71; Y = 3'-fluoro,4'-chloro: compound 72; Y = 3',4'-difluoro: 77; and 3',4',5'-trichloro: 73, 74, 75, 76. Good potency is also observed when Y = 4'-bromo (compounds 58, 59), and when the D-ring comprises 5- bromothiophen-3-yl. In contrast, poor potency against P. falciparum is seen for compounds bearing the following D-ring substitution patterns: Y = H (compounds 26-29), Y = 2', 4'- dichloro (compounds 22-25), 3'-chloro (compounds 53-56), 4'-fluoro (compound 57), 4'- methyl (compounds 60-63), 3',4'-dimethoxy (compounds 64-66), or when the aromatic D-ring is replaced with a cycloalkyl (cyclohexyl, compound 67) or alkyl group (i-Pr, compound 68). hERG Inhibition

[0307] Blockade of the hERG channel is a common liability of hydrophobic basic amines. It was observed that that modulation of alkyl substitution on the pendant basic amine can reduce hERG block (Table 4). FIG. 33 shows additional analogs that can be effective at modulating hERG block, such as inhibiting the hERG block. FIG. 34 shows a structure activity diagram for analogs that can be effective at hERG block, such as inhibiting the hERG block.

Table 4. Effect of amine substitution on hERG block and potency against P. falciparum

Cpd# PRC# R¹ R² Salt hERG EC₅₀₇ ^2h

IC₅₀ (nM) Dd2 Strain (nM)

1 1584 H Me HC1 510 108 ± 7

40 1645 H H HC1 2,100 263 ± 25

43 1664 H CH2CH2OH None 4,920 211 ± 41

44 1656 Me CH2CO2H None 7,800 889 ± 103

[0308] Note that for compounds 40 and 43, the hERG IC50 values are significantly raised, while only moderately increasing the P. falciparum growth inhibition EC50 values.

[0309] Compound 1 was submitted to an Ames mini-panel (TA98 and TA100 strains of

Salmonella typhimurium Sequani, UK). Up to the doses at which 1 reduces bacterial growth

(150 pg/plate in the presence of S9-mix, 50 pg/plate in its absence), 1 does not increase revertant numbers, indicating it is not mutagenic under these conditions.

[0310] Short exposure to 1 kills both proliferating and DHA-induced quiescent P. falciparum ring stages. Since it is known that about 6 h exposure to dihydroartemisinin (DHA) induces a quiescent (dormant) state in P. falciparum rings, we performed experiments to determine if short exposures (0-8 h) of 1 also induces quiescence or kills the proliferating ring stage. DHA-induced quiescence is characterized phenotypically by small parasites showing condensed chromatin and reduced cytoplasm within 24 h of DHA treatment. As shown in FIG.

16A, parasites exposed for 8 h to 1, 10, 40, and 42 and followed by washout showed a quiescent-like morphology similar to those of DHA on Day 3. As expected, following 8 h treatment with DHA and washout, parasitemia increased (recrudescence) after Day 3. In contrast, P. falciparum 4G strain (DHA-resistant) cultures similarly treated with 1 or its analogs did not recrudesce by Day 14 (FIG. 16A). It is worth noting that quiescent-like parasites were no longer observed in the Giemsa-stained smears from cultures treated with 1 or its analogs after Day 10. These results indicate that 8 h exposure to 1 or its analogs kills the proliferating ring stage of P. falciparum. It was then assessed whether 1 has activity against DHA-induced quiescent ring stage in the presence (4G) or absence (W2) of DHA-resistance. Following DHA treatment (0-8 h) and washout, recrudescence was observed in both 4G and W2 strains (DHA/mock) on Day 4 (FIG. 16B). Remarkably, when 4G and W2 DHA-induced quiescent rings were treated with 1 from 24 to 32 h, followed by washout, no proliferating parasites were observed out to Day 9 indicating that 1 kills DHA-induced quiescent rings independently of the presence of DHA-resistance (FIG. 16B). As recently stated by Reyser et al, activity against artemisinin derivative-induced quiescent rings should be the “gold standard” for a partner drug, as it could enable novel artemisinin combination therapies (ACTs) even in the context of artemisinin resistance.³ Experimental Description P. falciparum growth inhibition assay P. falciparum Culture.

[0311] Parasites Dd2 (MRA-150) strain were maintained in 0⁺ human erythrocytes at 4% hematocrit in RPMI 1640 media supplemented with 2 g/L glucose (Sigma- Aldrich), 2.3 g/L sodium bicarbonate (Sigma-Aldrich), 50 mg/L hypoxanthine (Sigma-Aldrich), 5.94 g/L HEPES, 20 mg/L gentamycin (GIBCO Life Technologies), and 5 g/L Albumax I (GIBCO Life Technologies). Parasites were kept at 37 °C under reduced oxygen conditions (5% CO2, 5% O2, and 90% N2). Synchronous cultures in ring stage (>95%) were obtained by two cycles of 5% sorbitol treatment.

P. falciparum Growth Effective (EC50) and isopentenyl diphosphate (IPP) Reversal of Growth Assays.

[0312] The effects of 1 and analogs were evaluated against P. falciparum, Dd2 strain, by SYBR Green assay as described previously in a 72 h assay since we previously reported that this class of apicoplast-targeting compounds do not present a delayed death phenotype.⁴ Briefly, ring stage parasite cultures (100 pL per well, with 1% hematocrit and 1% parasitemia) were grown for 72 h in the presence of increasing concentrations of the inhibitor under reduced oxygen conditions (5% CO2, 5% O2, and 90% N2) at 37 °C. After 72 h in culture, parasite viability was determined by DNA quantitation using SYBR Green I as described previously.⁵ The half-maximum effective concentration (EC50) values were calculated with GraphPad Prism (GraphPad Software, Inc.) using nonlinear regression curve fitting. The reported values represent averages of at least three independent experiments performed in triplicate, using 10- point serial dilutions, with standard errors of the mean (S.E.M.). The range for serial dilutions was adjusted accordingly for each analog after the first screening to set the IC50 value in the middle of the concentration range. To establish reversal of growth inhibition by IPP, ring stage parasite cultures were grown for 72 h in the presence of increasing concentrations of drug, and in the presence or absence of 200 mM IPP. The reported values represent averages of at least two independent experiments. S.E.M. values are only indicated for mean values below 100%. The parasite’s growth inhibition and recovery was assessed by SYBR Green as described previously.⁴ As discussed, 1 was not reversed by supplementation with IPP.

Synthesis Procedures and Analytical Data

l-( 34-dichlorophenyl)-8-methyl-N-(2-(methylamino)ethyl)-9H-pyrido[34-b lindole-3- carboxamide hydrochloride (1) (PRC 1584)

[0313] To an oven-dried 25 mL RBF were added methyl l-(3,4-dichlorophenyl)-8-methyl- 9//-pyrido| 3.4-/ |indole-3-carbo\ylate 2 (250 mg, 0.649 mmol) and a magnetic stirbar. The flask was sealed with a rubber septum and purged with N2 for 5 minutes. /Y-methylethane- 1,2- diamine (0.283 mL, d = 0.85 g/mL, 0.25 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 2. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~3 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 1 (240 mg, 87% yield). A portion of this material (204 mg) was dissolved in 0.1 M HC1 in methanol (4.8 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (5 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 1 (as the depicted HC1 salt ,185 mg, 86% yield).

[0314] ¾ NMR (400 MHz, DMSO-ri₆) d 11.52 (s, 1H), 9.00 (t, J= 6.1 Hz, 1H), 8.86 (s,

1H), 8.55 (br s, 2H), 8.34 (d, .7= 2.1 Hz, 1H), 8.26 (d, J= 7.9 Hz, 1H), 8.12 (dd, J= 8.3, 2.1 Hz, 1H), 7.90 (d, J= 8.3 Hz, 1H), 7.43 (dt, J= 7.2, 1.1 Hz, 1H), 7.26 (app t , J= 7.6 Hz, 1H), 3.69 (quintet, J= 6.0 Hz, 2H), 3.14 (t, J= 6.1 Hz, 2H), 2.64 (s, 2H), 2.59 (s, 3H).

[0315] ¹³C NMR (101 MHz, DMSO-r/e) d 165.6, 141.1, 139.7, 138.7, 138.1, 134.8, 131.6,

131.5, 131.0, 131.0, 130.8, 129.6, 129.4, 122.4, 121.2, 120.8, 119.5, 113.9, 48.4, 35.6, 32.8, 17.4.

[0316] HRMS (ESI+) calculated for C₂₂H₂₀CI₂N₄O [M+H]⁺: 427.1087, found 427.1081

methyl l-(34-dichlorophenyl)-8-methyl-9H-pyrido[34-b lindole-3-carboxylate (2)

( PRC1526 )

[0317] To an oven-dried 100 mL RBF were added methyl l-(3,4-dichlorophenyl)-8- methyl-2,3,4,9-tetrahydro- 1 H -pyrido[3,4-Z>]indole-3-carboxylate 34 (1.0 g, 2.57 mmol), iodobenzene diacetate (1.65 g, 5.14 mmol, 2.0 equiv) and DMF (5.5 mL). The mixture was stirred at r.t. under N2 for 6 h until completion was indicated by TLC. After completion, the reaction mixture was neutralized with aq. sodium bicarbonate (~15 mL). The mixture was extracted with EtOAc (3 x 20 mL), the combined organic phases washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude product was triturated with toluene (3 x 4 mL), vacuum filtered, and air dried to give 2 (616 mg, 62%) as a pale brown solid.

[0318] ¾ NMR (400 MHz, DMSO-ri₆) d 11.62 (s, 1H), 8.94 (s, 1H), 8.28 (d, J= 7.9 Hz,

1H), 8.15 (d, J= 2.0 Hz, 1H), 7.96 (dd, J= 8.3, 2.0 Hz, 1H), 7.89 (d, J= 8.3, 1H), 7.43 (dt, J = 7.2, 1.1 Hz, 1H), 7.26 (app t, J= 7.6 Hz 1H), 3.93 (s, 3H), 2.63 (s, 3H).

[0319] ¹³C NMR (101 MHz, DMSO-ri₆) d 165.9, 140.9, 140.1, 138.2, 136.8, 135.1, 131.6,

131.4, 130.9, 130.3, 129.6, 129.3, 122.5, 121.1, 120.9, 119.5, 117.2, 52.2, 17.5. (19 resonances found). [0320] HRMS (ESI+) calculated for C20H14CI2N2O2 [M+H]⁺: 385.0505, found 385.0500

l-(3,4-dichlorophenyl)-8-methyl-9H-pyrido[3,4-blindole-3-carboxylic acid (3) (PRC1603)

[0321] To a 6 dram vial were added methyl l-(3.4-dichlorophenyl)-8-methyl-9 /- pyridol 3.4-/? |indole-3-carbo\ylate 2 (30 mg, 0.078 mmol) and a magnetic stirbar. To this ethanol (3 mL) and aq. KOH (20%, 2 mL) was added, the mixture was stirred at rt for 5 minutes, and then heated to 95 °C for 4 h, at which point TLC indicated complete consumption of 2. The reaction was allowed to cool to rt, then added aq. HC1 (3 mL, 6 M) to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain 3 (22 mg, 76% yield) as an off-white solid.

[0322] ¾NMR (500 MHz, DMSO-i¾ d 11.59 (s, 1H), 8.92 (s, 1H), 8.27 - 8.25 (m, 2H), 8.03 (dd, J= 8.3, 2.1 Hz, 1H), 7.89 (d, J= 8.3 Hz, 1H), 7.42 (dt,J= 7.2, 1.2 Hz, 1H), 7.26 (app t, J= 7.5 Hz, 1H), 2.64 (s, 3H).

[0323] ¹³C NMR (126 MHz, DMSO-fik) d 166.6, 141.0, 139.6, 138.1, 137.5, 135.0, 131.5,

131.4, 131.0, 130.7, 130.6, 129.6, 129.3, 122.4, 121.1, 120.8, 119.5, 116.8, 17.4.

[0324] HRMS (ESI+) calculated for C19H12CI2N2O2 [M+H]⁺: 371.0349, found 371.0341

l-( 34-dichlorophenyl)-N-(2-(dimethylamino)ethyl)-8-methyl-9H-pyrido[3 4-b lindole-3- carboxamide hydrochloride (4) (PRC1619)

[0325] To a 1 dram vial were added methyl l-(3.4-dichlorophenyl)-8-methyl-9//- pyridol 3.4-6 |indole-3-carbo\ylate 2 (40 mg, 0.103 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. /V^;,/V^;-dimethylethane-l,2- diamine (0.06 mL, d = 0.807 g/mL, 0.52 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 2. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 4 (43 mg, 93% yield). A portion of this material (20 mg) was dissolved in 0.1 M HC1 in methanol (0.44 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 4 (as the depicted HC1 salt ,20.9 mg, 96% yield) as bright yellow solid. [0326] ¾ NMR (500 MHz, CD3OD) d 8.83 (s, 1H), 8.27 (d, J= 2.1 Hz, 1H), 8.09 (d, J =

7.9 Hz, 1H), 8.04 (dd, J= 8.3, 2.1 Hz, 1H), 7.78 (d, J= 8.3 Hz, 1H), 7.42 (d, J= 7.2 Hz, 1H), 7.27 (app t ,J= 7.6 Hz, 1H), 3.90 (t, J= 5.8 Hz, 2H), 3.46 (t, J= 5.8 Hz, 2H), 3.01 (s, 6H), 2.65 (s, 3H).

[0327] ¹³C NMR (126 MHz, CD3OD) d 169.2, 142.7, 141.0, 140.2, 139.6, 136.7, 134.0,

133.8, 132.8, 132.1, 131.9, 130.9, 129.8, 123.8, 122.8, 122.3, 120.0, 115.1, 59.0, 44.0, 36.1, 17.5.

[0328] HRMS (ESI+) calculated for C23H22CI2N4O [M+H]⁺: 441.1243, found 441.1245

N-butyl-l-f 3.4-dichlorophenyl)-8-methyl-9H-pyrido[34-b lindole-3-carboxamide (5)

( PRC1553 )

[0329] To a 1 dram vial were added methyl l-(3.4-dichlorophenyl)-8-methyl-9//- pyridol 3.4-6 |indole-3-carbo\ylate 2 (40 mg, 0.103 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. Butylamine (0.08 mL, d = 0.74 g/mL, 0.82 mmol, 8 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 60 °C for 36 h, at which point TLC indicated complete consumption of 2. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air- dried obtain 5 (19 mg, 43% yield) as an off-white solid.

[0330] ¾ NMR (400 MHz, DMSO-ri,;) d 8.81 (s, 1H), 8.71 (t, J= 6.2 Hz, 1H), 8.35 (d, J

= 2.1 Hz, 1H), 8.24 (dt, .7= 7.8, 1.0 Hz, 1H), 8.13 (dd, J= 8.3, 2.1 Hz, 1H), 7.89 (d, .7= 8.3 Hz, 1H), 7.41 (dt, J= 7.1, 1.1 Hz, 1H), 7.24 (app t, J= 7.5 Hz, 1H), 3.44 - 3.35 (m, 2H), 2.63 (s, 3H), 1.57 (app quin, J= 7.3 Hz, 2H), 1.36 (app h , J= 7.4 Hz, 2H), 0.93 (t, J= 7.4 Hz, 3H). [0331] ¹³C NMR (126 MHz, DMSO-ri,;) d 164.5, 141.2, 140.3, 138.6, 138.2, 134.8, 131.5,

131.5, 131.1, 131.0, 130.7, 129.5, 129.4, 122.4, 121.3, 120.6, 119.5, 113.5, 38.6, 31.7, 19.8, 17.4, 13.8.

[0332] HRMS (ESI+) calculated for C23H21CI2N3O [M+H]⁺: 426.1134, found 426.1124

l-( 34-dichlorophenyl)-N 8-dimethyl-9H-pyrido[34-b lindole-3-carboxamide ( 6) (PRC 1555)

[0333] To a sealed tube were added methyl l-(3.4-dichlorophenyl)-8-methyl-9//- pyrido[3,4-Z>]indole-3-carboxylate 2 (30 mg, 0.078 mmol), ethanol (1.5 mL), methylamine (0.2 mL, d = 0.7 g/mL, 3.86 mmol, 50 equiv), and a magnetic stirbar. The tube was purged with N2, and sealed with its cap. The mixture was stirred at rt for 5 minutes, and then heated to 65 °C for 67 h, at which point TLC indicated complete consumption of 2. The reaction was allowed to cool to rt, then concentrated in vacuo to obtain 6 (17 mg, 62% yield) as an off-white solid. [0334] ¾ NMR (500 MHz, DMSO) d 11.47 (s, 1H), 8.81 (s, 1H), 8.73 (q, .7= 4.8 Hz, 1H),

8.37 (d, J= 2.1 Hz, 1H), 8.25 (d, J= 7.8 Hz, 1H), 8.13 (dd, J= 8.3, 2.1 Hz, 1H), 7.88 (app t, J = 7.5 Hz, 1H), 2.91 (d, J= 4.8 Hz, 3H), 2.63 (s, 3H).

[0335] ¹³C NMR (126 MHz, DMSO) d 165.2, 141.1, 140.3, 138.6, 138.2, 134.6, 131.5,

131.1, 131.0, 130.7, 129.5, 129.3, 122.3, 121.3, 120.7, 119.5, 113.4, 26.1, 17.4. (19 resonances found)

[0336] HRMS (ESI+) calculated for C20H15CI2N3O [M+H]⁺: 384.0665, found-pending.

l-(34-dichlorophenyl)-8-methyl-N-(3-(methylamino)propyl)-9H-pyrido[34-blindole-3- carboxamide hydrochloride (7) (PRC1606)

[0337] To a 1 dram vial were added methyl l-(3.4-dichlorophenyl)-8-methyl-9//- pyrido[3,4-Z>]indole-3-carboxylate 2 (30 mg, 0.078 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. L^-methyl propane- 1.3-diamine (0.04 mL, d = 0.84 g/mL, 0.39 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 2. The reaction was allowed to cool to rt, then placed in an ice bath, and ice- cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 7 (27 mg, 77% yield). A portion of this material (14.3 mg) was dissolved in 0.1 M HC1 in methanol (0.33 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 7 (as the depicted HC1 salt 9.0 mg, 58% yield) as a bright yellow solid.

[0338] ¾ NMR (400 MHz, CD3OD) d 8.84 (s, 1H), 8.27 (d, .7= 2.1 Hz, 1H), 8.11 (ddd, J

= 7.9, 1.2, 0.7 Hz, 1H), 8.04 (dd, J= 8.3, 2.1 Hz, 1H), 7.78 (d, J= 8.3 Hz, 1H), 7.43 (dt, J = 7.2, 1.0 Hz, 1H), 7.28 (app t , J= 7.5 Hz, 1H), 3.62 (t, J= 6.5 Hz, 2H), 3.08 (t, J= 7.2 Hz, 2H), 2.74 (s, 3H), 2.65 (s, 3H), 2.04 (app quin, J= 6.9 Hz, 2H).

[0339] ¹³C NMR (126 MHz, CD3OD) d 168.1, 142.7, 140.80, 140.76, 139.7, 136.5, 133.88,

133.77, 132.8, 132.0, 131.8, 130.8, 129.7, 123.7, 122.9, 122.1, 120.0, 114.6, 49.8, 38.2, 35.8, 30.0, 17.5.

[0340] HRMS (ESI+) calculated for C23H22CI2N4O [M+H]⁺: 441.1243, found 441.1238

l-(34-dichlorophenyl)-N-(3-(dimethylamino)propyl)-8-methyl-9H-pyrido[34-blindole-3- carboxamide hydrochloride (8) (PRC 1609)

[0341] To a 1 dram vial were added methyl l-(3.4-dichlorophenyl)-8-methyl-9//- pyridol 3.4-/? |indole-3-carbo\ylate 2 (50 mg, 0.13 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N₂ for 5 minutes. A^.A^-di methyl propane- 1.3- diamine (0.11 mL, d = 0.81 g/mL, 0.91 mmol, 7 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 70 °C for 30 h, at which point TLC indicated complete consumption of 2. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 8 (23 mg, 39% yield). A portion of this material (10 mg) was dissolved in 0.1 M HC1 in methanol (0.22 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 8 (as the depicted HC1 salt 9.0 mg, 84% yield) as a bright yellow solid. [0342] ¾ NMR (400 MHz, CD OD) d 8.89 (s, 1H), 8.27 (d, J= 2.1 Hz 1H), 8.13 (ddd, J

= 7.9, 1.1, 0.7 Hz, 1H), 8.03 (dd, J= 8.3, 2.1 Hz, 1H), Ί.Ί9 (d, J= 8.3 Hz, 1H), 7.45 (dt, J =

7.2, 1.1 Hz, 1H), 7.30 (app t , J= 7.6 Hz, 1H), 3.63 (t, J= 6.5 Hz, 2H), 3.24 (t, J= 7.6 Hz, 2H), 2.94 (s, 6H), 2.66 (s, 3H), 2.11 (app quin, J= 7.1 Hz, 3H)

[0343] ¹³C NMR (101 MHz, CD3OD) 167.8, 142.6, 140.9, 140.6, 139.7, 136.4, 133.8,

133.7, 132.8, 131.9, 131.7, 130.7, 129.7, 123.6, 122.8, 122.0, 120.0, 114.5, 58.5, 45.5, 39.0,

28.2, 17.4 (free base form).

[0344] HRMS (ESI+) calculated for C24H24CI2N4O [M+H]⁺: 455.1400, found 455.1395

l-( 34-dichlorophenyl)-N-(2-hvdroxyethyl)-8-methyl-9H-pyrido[34-b lindole-3-carboxamide (9) (PRC 1604)

[0345] To a 1 dram vial were added methyl l-(3.4-dichlorophenyl)-8-methyl-9//- pyrido[3,4-Z>]indole-3-carboxylate 2 (30.0 mg, 0.078 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes ethanolamine (0.03 mL, d = 1.01 g/mL, 0.39 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 2. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain 9 (24 mg, 74% yield) as an off-white solid.

[0346] ¾ NMR (400 MHz, DMSO-fifc) d 11.48 (s, 1H), 8.84 (s, 1H), 8.71 (t, J = 6.0 Hz,

1H), 8.32 (d, J = 2.1 Hz, 1H), 8.25 (ddd, J= 7.9, 1.2, 0.7 Hz, 1H), 8.09 (dd, J= 8.3, 2.1 Hz, 1H), 7.89 (d, J= 8.3 Hz, 1H), 7.41 (dt, J= 7.2, 1.2 Hz, 1H), 7.24 (app t , J= 7.6 Hz, 1H), 4.83 (t, J= 5.4 Hz, 1H), 3.60 - 3.54 (m, 2H), 3.50 - 3.44 (m, 2H), 2.63 (s, 3H).

[0347] ¹³C NMR (126 MHz, DMSO-ri^) d 164.7, 141.1, 140.1, 138.7, 138.2, 134.7, 131.6,

131.5, 131.03, 130.98, 130.8, 129.5, 129.3, 122.4, 121.2, 120.7, 119.5, 113.6, 60.0, 41.7, 17.4. [0348] HRMS (ESI+) calculated for C21H17CI2N3O2 [M+H]⁺: 414.0771, found 414.0768.

l-( 3, 4-dichlorophenyl)-N-(2-(methylamino)ethyl)-9H-pyrido[3, 4-b lindole-3-carboxamide (10) ( PRC1572 )

[0349] To a 1 dram vial were added methyl 1 -(3.4-dichlorophenyl)-9//-pyrido|3.4- Z>]indole-3-carboxylate 31 (30.0 mg, 0.081 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. A^-methylethane- 1.2-diamine (0.03 mL, d = 0.85 g/mL, 0.32 mmol, 4 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 80 °C for 23 h, at which point TLC indicated complete consumption of 31. The reaction was allowed to cool to rt, then placed in an ice bath, and ice- cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water and hexane, and air-dried to obtain 10 (30 mg, 90% yield) as an off-white solid. [0350] ¾NMR (400 MHz, CD3OD) d 8.83 (s, 1H), 8.30 (d, J= 2.1 Hz, 1H), 8.27 (dt, J = 8.0, 1.1 Hz, 1H), 8.05 (dd, J= 8.3, 2.1 Hz, 1H), 7.77 (d, J= 8.3 Hz, 1H), 7.67 (dt, J= 8.3, 1.1, Hz, 1H), 7.61 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.35 (ddd, J= 8.0, 7.0, 1.1 Hz, 1H), 3.67 (t , J = 6.2 Hz, 2H), 2.92 (t, J= 6.2 Hz, 2H), 2.49 (s, 3H).

[0351] ¹³C NMR (126 MHz, CD3OD) d 168.2, 143.3, 140.7, 140.2, 139.5, 136.1, 134.0,

132.2, 131.9, 131.7, 130.1, 129.5, 122.9, 122.7, 121.8, 114.7, 113.5, 51.9, 39.7, 35.8 (20 resonances found only).

[0352] HRMS (ESI+) calculated for C21H18CI2N4O [M+H]⁺: 413.0930, found 413.0935

l-( 34-dichlorophenyl)-N-(2-(dimethylamino)ethyl)-9H-pyrido[34-b lindole-3-carboxamide (11) (PRC 1574)

[0353] To a 1 dram vial added methyl 1 -(3.4-dichlorophenyl)-9//-pyrido| 3.4-6 |indole-3- carboxylate 31 (30.0 mg, 0.081 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. /V^/V imethylethane- 1,2-diamine (0.04 mL, d = 0.807 g/mL, 0.32 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 80 °C for 23 h, at which point TLC indicated complete consumption of 31. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water and hexane, and air-dried to obtain 11 (25 mg, 72% yield) as off-white solid.

[0354] ¾NMR (400 MHz, CD OD) d 8.81 (s, 1H), 8.29 (d, J= 2.1 Hz, 1H), 8.26 (dt, J = 8.0, 1.0 Hz, 1H), 8.05 (dd, J= 8.3, 2.1 Hz, 1H), 7.77 (d, = 8.3 Hz, 1H), 7.66 (dt, = 8.3, 1.1 Hz, 1H), 7.60 (ddd, J = 8.3, 7.0, 1.0 Hz, 1H), 7.34 (ddd, J= 8.0, 7.0, 1.1 Hz, 1H), 3.65 (t , J = 6.6 Hz, 2H), 2.66 (t, J= 6.6 Hz, 2H), 2.36 (s, 6H).

[0355] ¹³C NMR (126 MHz, CD3OD) d 167.9, 143.3, 140.7, 140.1, 139.6, 136.1, 133.98,

133.97, 132.2, 131.9, 131.7, 130.1, 129.4, 122.9, 122.7, 121.8, 114.6, 113.5, 59.5, 45.6, 38.1. [0356] HRMS (ESI+) calculated for C22H20CI2N4O [M+H]⁺: 427.1087, found 427.1093.

[0357]

l-(3,4-dichlorophenyl)-N-(3-(methylamino)propyl)-9H-pyrido[3,4-blindole-3-carboxamide

(12) (PRC 1575)

[0358] To a 1 dram vial were added methyl 1 -(3.4-dichlorophenyl)-9//-pyrido|3.4- Z>]indole-3-carboxylate 31 (30.0 mg, 0.081 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. /V'-methylpropane- 1.3-diamine (0.033 mL, d = 0.84 g/mL, 0.32 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 80 °C for 23 h, at which point TLC indicated complete consumption of 31. The reaction was allowed to cool to rt, then placed in an ice bath, and ice- cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water and hexane, and air-dried to obtain 12 (27 mg, 78% yield) as an off-white solid. [0359] ¾ NMR (500 MHz, CD3OD) d 8.81 (s, 1H), 8.29 - 8.23 (m, 2H), 8.03 (dd, J= 8.3,

2.1 Hz, 1H), 7.77 (d, .7= 8.3 Hz, 1H), 7.66 (d, J= 8.2 Hz, 1H), 7.60 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H), 7.34 (ddd , J= 8.0, 7.0, 1.1 Hz, 1H), 3.57 (t, .7= 6.8 Hz, 2H), 2.72 (t, J= 7.1 Hz, 2H), 2.44 (s, 3H), 1.90 (app quin, J= 7.0 Hz, 2H).

[0360] ¹³C NMR (126 MHz, CD30D) d 168.1, 143.3, 140.7, 140.2, 139.6, 136.1, 134.0,

132.2, 132.0, 131.7, 130.1, 129.4, 122.9, 122.7, 121.8, 114.7, 113.5, 49.7, 38.2, 35.8, 30.0 (21 resonances found).

[0361] HRMS (ESI+) calculated for C22H20CI2N4O [M+H]⁺: 427.1087, found 427.1090

l-(34-dichlorophenyl)-N-(3-(dimethylamino)propyl)-9H-pyrido[34-blindole-3-carboxamide (13) ( PRC1576 )

[0362] To a 1 dram vial were added methyl 1 -(3.4-dichlorophenyl)-9//-pyrido|3.4- Z>]indole-3-carboxylate 31 (30.0 mg, 0.081 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N₂ for 5 minutes. A^ A^-dimethylpropane- 1.3-diamine (0.041 mL, d = 0.812 g/mL, 0.32 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 80 °C for 23 h, at which point TLC indicated complete consumption of 31. The reaction was allowed to cool to rt, then placed in an ice bath, and ice- cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration and washed with cold water and air-dried to obtain 13 (22 mg, 62% yield) as an off-white solid.

[0363] ¾ NMR (500 MHz, CD3OD) d 8.81 (s, 1H), 8.30 - 8.24 (m, 2H), 8.04 (dd, J= 8.3,

2.1 Hz, 1H), 7.77 (d, J= 8.3 Hz, 1H), 7.66 (dt, J= 8.3, 1.1 Hz, 1H), 7.60 (ddd, J= 8.3, 7.0, 1.2 Hz, 1H), 7.34 (ddd, J= 7.9, 7.0, 1.1 Hz, 1H), 3.55 (t, J= 6.8 Hz, 2H), 2.51 (t, J= 7.5 Hz, 2H), 2.31 (s, 6H), 1.89 (app quin, J= 6.9 Hz, 2H).

[0364] ¹³C NMR (126 MHz, CD₃OD) d 167.9, 143.3, 140.8, 140.2, 139.6, 136.1, 134.0,

132.2, 132.0, 131.7, 130.1, 129.4, 122.9, 122.7, 121.8, 114.7, 113.5, 58.4, 45.4, 39.0, 28.2 (21 resonances found).

[0365] HRMS (ESI+) calculated for C23H22CI2N4O [M+H]⁺: 441.1243, found 441.1246

N-butyl-l-f 34-dichlorophenyl)-9H-pyrido[34-b lindole-3-carboxamide (14) (PRC 1573)

[0366] To a 1 dram vial were added methyl 1 -(3.4-dichlorophenyl)-9//-pyrido|3.4- Z>]indole-3-carboxylate 31 (30.0 mg, 0.081 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. Butylamine (0.04 mL, d = 0.74 g/mL, 0.32 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 80 °C for 23 h, at which point TLC indicated complete consumption of 31. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration and washed with cold water and hexane, and air-dried to obtain 14 (25 mg, 76% yield) as an off-white solid.

[0367] ¾ NMR (400 MHz, DMSO-r/₆) d 11.94 (s, 1H), 8.85 (s, 1H), 8.75 (t, J= 6.2 Hz,

1H), 8.42 (dt, J= 7.9, 1.1 Hz, 1H), 8.38 (d, J= 2.1 Hz, 1H), 8.15 (dd, J= 8.4, 2.1 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.69 (dt, J= 8.2, 1.1 Hz, 1H), 7.62 (ddd, J= 8.2, 7.0, 1.1 Hz, 1H), 7.33 (ddd, J= 7.9, 7.0, 1.1 Hz, 1H), 3.48 - 3.37 (m, 2H), 1.58 (app quin, J= 7.3 Hz, 2H), 1.36 (app h, J = 7.4 Hz, 2H), 0.93 (t, J= 7.3 Hz, 3H).

[0368] ¹³C NMR (126 MHz, DMSO-r/e) d 164.5, 141.7, 140.2, 138.0, 137.9, 134.2, 131.72,

131.66, 130.9, 130.6, 130.4, 129.0, 128.9, 122.2, 121.2, 120.4, 113.7, 112.6, 38.6, 31.7, 19.8, 13.8.

[0369] HRMS (ESI+) calculated for C22H19CI2N3O [M+H]⁺: 412.0978, found 412.0981.

l-( 3, 4-dichlorophenyl)-N-(2-hvdroxyethyl)-9H-pyrido[3, 4-b lindole-3-carboxamide (15)

(PRC 1577)

[0370] To a 1 dram vial were added methyl 1 -(3.4-dichlorophenyl)-9//-pyrido|3.4- Z>]indole-3-carboxylate 31 (30.0 mg, 0.081 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. Ethanolamine (0.02 mL, d = 1.01 g/mL, 0.32 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 80 °C for 23 h, at which point TLC indicated complete consumption of 31. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration and washed with cold water, and air- dried to obtain 15 (25 mg, 77% yield) as an off-white solid.

[0371] ¾ NMR (500 MHz, CD3OD) d 8.80 (s, 1H), 8.27 - 8.21 (m, 2H), 8.02 (dd, J= 8.3,

2.1 Hz, 1H), 7.76 (d, .7= 8.3 Hz, 1H), 7.65 (d, .7= 8.3 Hz, 1H), 7.59 (ddd, J= 8.3, 7.0, 1.2 Hz, 1H), 7.33 (ddd, J= 8.0, 7.0, 1.0 Hz, 1H), 3.78 (t, J= 5.6 Hz, 2H), 3.64 (t, J= 5.7 Hz, 2H). [0372] ¹³C NMR (126 MHz, CD3OD) d 168.0, 143.3, 140.6, 140.2, 139.5, 136.1, 134.0,

132.2, 132.0, 131.6, 130.1, 129.4, 122.9, 122.7, 121.8, 114.7, 113.5, 61.9, 43.0.

[0373] HRMS (ESI+) calculated for C20H15CI2N3O2 [M+H]⁺: 400.0614, found 400.0619

l-(4-chlorophenyl)-8-methyl-N-(2-(methylamino)ethyl)-9H-pyrido[34-blindole-3- carboxamide hydrochloride (16) (PRC 1594)

[0374] To a 1 dram vial were added methyl l-(4-chlorophenyl)-8-methyl-9//-pyrido|3.4- Z>]indole-3-carboxylate 30 (50 mg, 0.143 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. A^-methylethane- 1.2-diamine (0.06 mL, d = 0.85 g/mL, 0.71 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 30. The reaction was allowed to cool to rt, then placed in an ice bath, and ice- cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 16 (38 mg, 68% yield). A portion of this material (36 mg) was dissolved in 0.1 M HC1 in methanol (1.0 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 16 (as the depicted HC1 salt, 25 mg, 64% yield) as bright yellow solid. [0375] ¾ NMR (400 MHz, CDsOD) d 8.82 (s, 1H), 8.15 - 8.05 (m, 3H), 7.67 - 7.60 (m,

2H), 7.41 (dt, J= 7.2, 1.1 Hz, 1H), 7.27 (ddd, J= 7.7, 7.2, 0.4 Hz, 1H), 3.85 - 3.78 (m, 2H), 3.31 - 3.24 (m, 2H), 2.76 (s, 3H), 2.64 (s, 3H).

[0376] ¹³C NMR (126 MHz, MeOD) d 169.3, 142.6, 142.3, 140.2, 137.9, 136.7, 136.1,

132.5, 131.6, 130.7, 130.0, 123.8, 122.9, 122.1, 120.0, 114.6, 51.0, 37.4, 34.0, 17.4.

[0377] HRMS (ESI+) calculated for C22H21CIN4O [M+H]⁺: 393.1477, found 393.1472

l-( 4-chlorophenyl)-N-(2-(dimethylamino)ethyl)-8-methyl-9H-pyrido[34-b lindole-3- carboxamide hydrochloride (17) (PRC 1595)

[0378] To a 1 dram vial were added methyl l-(4-chlorophenyl)-8-methyl-9//-pyrido|3.4- Z>]indole-3-carboxylate 30 (30 mg, 0.086 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. /V^/V imethylethane- 1,2-diamine (0.05 mL, d = 0.807 g/mL, 0.43 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 30. The reaction was allowed to cool to rt, then placed in an ice bath, and ice- cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 17 (31 mg, 89% yield). A portion of this material (15 mg) was dissolved in 0.1 M HC1 in methanol (0.4 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 17 (as the depicted HC1 salt, 16 mg, 98% yield) as bright yellow solid. [0379] ¾ NMR (400 MHz, CD OD) d 8.88 (s, 1H), 8.17 - 8.07 (m, 3H), 7.70 - 7.62 (m,

2H), 7.44 (dt, J= 7.2, 1.0 Hz, 1H), 7.29 (ddd, J = 7.8, 7.2, 0.4 Hz, 1H), 3.90 (t, J= 5.7 Hz, 2H), 3.46 (t, J= 5.7 Hz, 2H), 3.02 (s, 6H), 2.65 (s, 3H).

[0380] ¹³C NMR (126 MHz, CD3OD) d 168.3, 142.6, 142.3, 140.7, 138.1, 136.6, 136.0,

132.6, 131.6, 130.6, 129.9, 123.7, 123.0, 122.0, 120.0, 114.2, 38.1, 35.7, 29.9, 17.4 (free base form).

[0381] HRMS (ESI+) calculated for C23H23CIN4O [M+H]⁺: 407.1633, found 407.1628

l-( 4-chlorophenyl)-8-methyl-N-( 3-(methylamino)propyl)-9H-pyrido[3 4-b lindole-3- carboxamide hydrochloride (18) (PRC 1596)

[0382] To a 1 dram vial were added methyl l-(4-chlorophenyl)-8-methyl-9//-pyrido|3.4- |indole-3-carbo\ylate 30 (30 mg, 0.086 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. A^-methyl propane- 1.3-diamine (0.05 mL, d = 0.844 g/mL, 0.43 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 30. The reaction was allowed to cool to rt, then placed in an ice bath, and ice- cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 18 (20 mg, 57% yield). A portion of this material (15 mg) was dissolved in 0.1 M HC1 in methanol (0.4 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 18 (as the depicted HC1 salt, 14.3 mg, 87% yield) as bright yellow solid. [0383] ¾ NMR (500 MHz, CD OD) d 8.86 (s, 1H), 8.14-8.11 (m, 3H), 7.69 - 7.64 (m,

2H), 7.45 (dt, J= 7.2, 1.1 Hz, 1H), 7.30 (app t , J= 7.5 Hz, 1H), 3.64 (t, J= 6.5 Hz, 2H), 3.12 (t, J= 7.3 Hz, 2H), 2.77 (s, 3H), 2.67 (s, 3H), 2.07 (app quin, J= 6.9 Hz, 2H).

[0384] ¹³C NMR (126 MHz, MeOD) d 168.3, 142.6, 142.3, 140.7, 138.1, 136.6, 136.0,

132.6, 131.6, 130.6, 129.9, 123.7, 123.0, 122.0, 120.0, 114.2, 49.6, 38.1, 35.7, 29.9, 17.4. [0385] HRMS (ESI+) calculated for C23H23CIN4O [M+H]⁺: 407.1633, found 407.1615

l-(4-chlorophenyl)-N-(3-(dimethylamino)propyl)-8-methyl-9H-pyrido[34-blindole-3- carboxamide hydrochloride (19) (PRC1597)

[0386] To a 1 dram vial were added methyl l-(4-chlorophenyl)-8-methyl-9//-pyrido|3.4- Z>]indole-3-carboxylate 30 (30 mg, 0.086 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. /V^;,/V^;-dimethylpropane-l, 3-diamine (0.06 mL, d = 0.812 g/mL, 0.43 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 30. The reaction was allowed to cool to rt, then placed in an ice bath, and ice- cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 19 (27 mg, 75% yield). A portion of this material (15 mg) was dissolved in 0.1 M HC1 in methanol (0.4 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 18 (as the depicted HC1 salt, 12 mg, 73% yield) as bright yellow solid. [0387] ¾ NMR (400 MHz, CD3OD) d 8.81 (s, 1H), 8.16 - 8.07 (m, 3H), 7.67 - 7.60 (m,

2H), 7.41 (dt, J= 7.2, 1.0 Hz, 1H), 7.27 (t, J= 7.9 Hz, 1H), 3.62 (t, J= 6.5 Hz, 2H), 3.20 (t, J = 7.50 Hz, 2H), 2.91 (s, 6H), 2.65 (s, 3H), (app quin, J= 7.1 Hz, 2H)

[0388] ¹³C NMR (126 MHz, CD3OD) d 167.6, 141.2, 141.0, 138.9, 136.6, 135.3, 134.7,

131.2, 130.2, 129.3, 128.6, 122.4, 121.5, 120.7, 118.6, 113.1, 55.4, 42.2, 35.7, 25.2, 16.0. [0389] HRMS (ESI+) calculated for C24H25CIN4O [M+H]⁺: 421.1790, found 421.1784.

l-(24-dichlorophenyl)-8-methyl-N-(2-(methylamino)ethyl)-9H-pyrido[34-b lindole-3- carboxamide hydrochloride (22) (PRC1607)

[0390] To a 1 dram vial were added methyl l-(2.4-dichlorophenyl)-8-methyl-9//- pyridol 3.4-/? |indole-3-carbo\ylate 32 (30 mg, 0.078 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. /V^;-methylethane- 1,2- diamine (0.04 mL, d = 0.85 g/mL, 0.39 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 32. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 22 (28 mg, 84% yield). A portion of this material (14.8 mg) was dissolved in 0.1 M HC1 in methanol (0.4 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 22 (as the depicted HC1 salt, 15 mg, 93% yield) as a bright yellow solid. [0391] ¾NMR (500 MHz, CD OD) d 8.94 (s, 1H), 8.13 (dt, J= 8.0, 0.9 Hz, 1H), 7.74 (d, .7 = 2.1 Hz, 1H), 7.66 (d, J= 8.2 Hz, 1H), 7.58 (dd, J= 8.2, 2.1 Hz, 1H), 7.42 (dt, J= 7.2, 1.1 Hz, 1H), 7.28 (app t , J= 7.6 Hz, 1H), 3.79 (t, J= 5.6 Hz, 2H), 3.28 (t, J= 5.6 Hz, 2H), 2.75 (s, 3H), 2.58 (s, 3H).

[0392] ¹³C NMR (126 MHz, CD3OD) d 168.9, 142.7, 140.8, 139.3, 137.4, 136.9, 136.6,

135.9, 134.2, 131.8, 131.0, 130.7, 128.7, 123.6, 122.5, 122.1, 120.2, 115.4, 50.9, 37.2, 33.8, 17.4.

[0393] HRMS (ESI+) calculated for C22H20CI2N4O [M+H]⁺: 427.1087, found 427.1089

l-(24-dichlorophenyl)-N-(2-(dimethylamino)ethyl)-8-methyl-9H-pyrido[3 4-b lindole-3- carboxamide hydrochloride (23) (PRC1610)

[0394] To a 1 dram vial were added methyl l-(2.4-dichlorophenyl)-8-methyl-9//- pyrido[3,4-Z>]indole-3-carboxylate 32 (30 mg, 0.078 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. /V^;,/V^;-dimethylethane-l,2- diamine (0.04 mL, d = 0.807 g/mL, 0.39 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 32. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 23 (30 mg, 87% yield). A portion of this material (14.5 mg) was dissolved in 0.1 M HC1 in methanol (0.3 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 23 (as the depicted HC1 salt, 15.2 mg, 97% yield) as a bright yellow solid. [0395] ¾ NMR (500 MHz, CD₃OD) 5 8.87 (s, 1H), 8.11 (d, J= 7.9 Hz, 1H), 7.72 (d, J =

2.1 Hz, 1H), 7.65 (d, J= 8.2 Hz, 1H), 7.57 (dd, J= 8.2, 2.1 Hz, 1H), 7.41 (d, J= 7.2 Hz, 1H), 7.26 (app t ,J= 7.6 Hz, 1H), 3.84 (t, J= 5.8 Hz, 2H), 3.40 (t, J= 5.8 Hz, 2H), 2.97 (s, 6H), 2.58 (s, 3H).

[0396] ¹³C NMR (126 MHz, CD3OD) 5 169.2, 142.5, 141.0, 139.7, 137.5, 137.2, 136.7,

135.9, 134.2, 131.6, 130.8, 130.6, 128.6, 123.5, 122.6, 122.0, 120.1, 115.3, 59.0, 44.0, 36.1, 17.4.

[0397] HRMS (ESI+) calculated for C23H22CI2N4O [M+H]⁺: 441.1243, found 441.1247

l-(2, 4-dichlorophenyl)-8-methyl-N-(3-(methylamino)propyl)-9H-pyrido[3, 4-b lindole-3- carboxamide hydrochloride (24) (PRC 1608)

[0398] To a 1 dram vial were added methyl l-(2.4-dichlorophenyl)-8-methyl-9//- pyridol 3.4- |indole-3-carbo\ylate 32 (30 mg, 0.078 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N₂ for 5 minutes. /V'-methyl propane- 1.3- diamine (0.04 mL, d = 0.844 g/mL, 0.39 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 32. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 24 (26 mg, 76% yield). A portion of this material (15.6 mg) was dissolved in 0.1 M HC1 in methanol (0.4 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 24 (as the depicted HC1 salt, 16.5 mg, 98% yield) as a bright yellow solid. [0399] ¾ NMR (500 MHz, CD₃OD) 5 8.96 (s, 1H), 8.16 (d, J= 7.9 Hz, 1H), 7.76 (d, J =

2.1 Hz, 1H), 7.69 (d, = 8.2 Hz, 1H), 7.60 (dd, .7= 8.2, 2.1 Hz, 1H), 7.45 (dt, = 7.2, 1.1 Hz, 1H), 7.30 (t, J= 7.6 Hz, 1H), 3.61 (t, J= 6.5 Hz, 2H), 3.11 (t, = 7.3 Hz, 2H), 2.76 (s, 3H), 2.60 (s, 3H), 2.1 (app quin, J= 6.9 Hz, 2H).

[0400] ¹³C NMR (126 MHz, CD₃OD) 5 168.2, 142.9, 140.6, 139.1, 137.3, 137.0, 135.9,

134.2, 132.1, 131.2, 130.7, 128.7, 123.7, 122.5, 122.2, 120.2, 115.3, 48.0, 37.1, 33.7, 27.8, 17.4. (21 resonances found only).

[0401] HRMS (ESI+) calculated for C23H22CI2N4O [M+H]⁺: 441.1243, found 441.1247

l-(24-dichlorophenyl)-N-(3-(dimethylamino)propyl)-8-methyl-9H-pyrido[34-b lindole-3- carboxamide hydrochloride (25) {PRC 1620)

[0402] To a 1 dram vial were added methyl l-(2.4-dichlorophenyl)-8-methyl-9//- pyridol 3.4-6 |indole-3-carbo\ylate 32 (40 mg, 0.104 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. A^.A^-di methyl propane- 1, 3-diamine (0.07 mL, d = 0.812 g/mL, 0.52 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 32. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 25 (40 mg, 85% yield). A portion of this material (20.3 mg) was dissolved in 0.1 M HC1 in methanol (0.5 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 25 (as the depicted HC1 salt, 20 mg, 91% yield) as bright yellow solid.

[0403] ¾ NMR (500 MHz, CD3OD) 5 8.88 (s, 1H), 8.11 (d, J= 7.9 Hz, 1H), 7.72 (d, J =

2.1 Hz, 1H), 7.65 (d, J= 8.2 Hz, 1H), 7.57 (dd, J= 8.2, 2.1 Hz, 1H), 7.40 (d, = 7.2 Hz, 1H), 7.26 (app t ,J= 7.6 Hz, 1H), 3.58 (t, J= 6.5 Hz, 2H), 3.21 (t, J= 7.7 Hz, 1H), 2.92 (s, 6H), 2.58 (s, 3H), 2.07 (app quin, J= 7.0 Hz, 2H).

[0404] ¹³C NMR (126 MHz, CD OD) d 168.9, 142.5, 141.0, 139.8, 137.4, 137.2, 136.6,

135.9, 134.2, 131.6, 130.8, 130.6, 128.6, 123.5, 122.6, 121.9, 120.1, 115.1, 56.7, 43.5, 37.0, 26.5, 17.4.

[0405] HRMS (ESI+) calculated for C24H24CI2N4O [M+H]⁺: 455.1400, found 455.1406

N-(2-(methylamino)ethyl)-l-phenyl-9H-pyrido[3 4-b lindole-3-carboxamide hydrochloride (26) (PRC 1611)

[0406] To a 1 dram vial were added methyl 1 -phenyl-9//-pyrido| 3.4-6 |indole-3- carboxylate 33 (30 mg, 0.099 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. Anethylethane- 1.2-diamine (0.05 mL, d = 0.85 g/mL, 0.50 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 33. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air- dried obtain the free base of 26 (25 mg, 73% yield). A portion of this material (15.3 mg) was dissolved in 0.1 M HC1 in methanol (0.45 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 26 (as the depicted HC1 salt, 15.7 mg, 93% yield) as bright yellow solid.

[0407] ¾ NMR (500 MHz, CD3OD) d 8.83 (s, 1H), 8.27 (d, J= 7.9 Hz, 1H), 8.10 (d, J =

8.7 Hz, 1H), 7.70 - 7.53 (m, 5H), 7.34 (t, J= 7.5 Hz, 1H), 3.83 (t, J= 5.6 Hz, 2H), 3.29 (t, J = 5.3 Hz, 2H), 2.76 (s, 3H).

[0408] ¹³C NMR (126 MHz, CD3OD) d 169.5, 143.3, 143.3, 140.1, 139.1, 136.4, 131.6,

130.2, 130.02, 129.96, 129.8, 122.9, 122.6, 121.7, 114.4, 113.6, 51.1, 37.3, 33.9. [0409] HRMS (ESI+) calculated for C21H20N4O [M+H]⁺: 345.1710, found 345.1720

N-(2-(dimethylamino)ethyl)-l-phenyl-9H-pwido[3, 4-b lindole-3-carboxamide hydrochloride (27) (PRC1612)

[0410] To a 1 dram vial were added methyl 1 -phenyl-9//-pyrido| 3.4-6 |indole-3- carboxylate 33 (30 mg, 0.099 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. /V^/V imethylethane- 1,2-diamine (0.06 mL, d = 0.807 g/mL, 0.5 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 33. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 27 (28 mg, 79% yield). A portion of this material (15.3 mg) was dissolved in 0.1 M HC1 in methanol (0.45 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 27 (as the depicted HC1 salt, 13.7 mg, 81% yield) as bright yellow solid.

[0411] ¾ NMR (500 MHz, CD3OD) 5 8.86 (s, 1H), 8.28 (dt, J= 8.0, 1.1 Hz, 1H), 8.11 -

8.09 (m, 2H), 7.71 - 7.54 (m, 5H), 7.35 (ddd, J= 8.0, 7.1, 1.0 Hz, 1H), 3.90 (t, J= 5.7 Hz, 2H), 3.46 (t, J= 5.7 Hz, 2H), 3.02 (s, 6H).

[0412] ¹³C NMR (126 MHz, CD3OD) 5 167.4, 142.0, 141.9, 138.4, 137.4, 135.0, 130.3,

128.9, 128.7, 128.6, 128.4, 121.5, 121.2, 120.4, 113.2, 112.2, 57.6, 41.0, 33.6.

[0413] HRMS (ESI+) calculated for C22H22N4O [M+H]⁺: 359.1866, found 359.1877

N-(3-(methylamino)propyl)-l-phenyl-9H-pyrido[34-b ]indole-3-carboxamide hydrochloride (28) (PRC 1613)

[0414] To a 1 dram vial were added methyl 1 -phenyl-9//-pyrido| 3.4-/? |indole-3- carboxylate 33 (30 mg, 0.099 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N2 for 5 minutes. /V'-methyl propane- 1.3-diamine (0.05 mL, d = 0.844 g/mL, 0.5 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 33. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air- dried obtain the free base of 28 (26 mg, 73% yield). A portion of this material (14.5 mg) was dissolved in 0.1 M HC1 in methanol (0.41 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 28 (as the depicted HC1 salt, 14.5 mg, 91% yield) as bright yellow solid.

[0415] ¾ NMR (500 MHz, CD3OD) 5 8.85 (s, 1H), 8.28 (dt, J= 8.0, 1.0 Hz, 1H), 8.12 -

8.06 (m, 2H), 7.71 - 7.54 (m, 5H), 7.35 (ddd, J= 8.0, 7.0, 1.0 Hz, 1H), 3.63 (t, J= 6.5 Hz, 2H), 3.10 (t, J= 7.3 Hz, 2H), 2.75 (s, 3H), 2.0 (app quin, J= 6.9 Hz, 2H).

[0416] ¹³C NMR (126 MHz, CD3OD) 5 169.5, 143.4, 143.2, 139.8, 138.7, 136.3, 131.7,

130.3, 130.02, 130.04, 129.8, 122.9, 122.6, 121.8, 114.4, 113.6, 48.0, 37.8, 33.2, 27.9.

[0417] HRMS (ESI+) calculated for C22H22N4O [M+H]⁺: 359.1866, found 359.1878

N-( 3-fdimethylamino)propyl)-l -phenyl-9H-pyrido[3 4-b ]indole-3-carboxamide hydrochloride (29) (PRC 1621)

[0418] To a 1 dram vial were added methyl 1 -phenyl-9//-pyrido| 3.4-/? |indole-3- carboxylate 33 (40 mg, 0.132 mmol) and a magnetic stirbar. The vial was sealed with a rubber septum and purged with N₂for 5 minutes. /V^/V imethylpropane-l, 3-diamine (0.09 mL, d = 0.812 g/mL,0.66 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 33. The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 29 (43 mg, 88% yield). A portion of this material (20.8 mg) was dissolved in 0.1 M HC1 in methanol (0.55 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (~1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 29 (as the depicted HC1 salt, 20 mg, 90% yield) as bright yellow solid.

[0419] ¾ NMR (500 MHz, CD OD) d 8.83 (s, 1H), 8.27 (d, J= 7.9 Hz, 1H), 8.10 (d, J =

6.9 Hz, 2H), 7.70 - 7.53 (m, 5H), 7.34 (app t , J= 7.5 Hz, 1H), 3.63 (t, J= 6.5 Hz, 2H), 3.24 (t, J= 7.5 Hz, 2H), 2.93 (s, 6H), 2.10 (app quin, J= 7.0 Hz, 2H).

[0420] ¹³C NMR (126 MHz, CD₃OD) d 169.1, 143.3, 143.2, 140.1, 139.2, 136.4, 131.6,

130.2, 130.0, 129.9, 129.8, 123.0, 122.5, 121.7, 114.3, 113.6, 56.7, 43.5, 37.0, 26.5.

[0421] HRMS (ESI+) calculated for C₂₃H₂₄N₄O [M+H]⁺: 373.2023, found 373.2023

methyl l-(4-chlorophenyl)-8-methyl-9H-pyrido[3 4-b lindole-3-carboxylate (30)

methyl l-(34-dichlorophenyl)-9H-pyrido[34-blindole-3-carboxylate (31)

[0422] To an oven-dried 100 mL RBF were added cis isomer of methyl l-(3,4- dichlorophenyl)-2.3.4.9-tetrahydro- 1 /-pyrido| 3.4-/? |indole-3-carbo\ylate 37 (280 mg, 0.75 mmol), DMF(4 mL). Using a syringe added 0.7 mL of DMF solution of trichloroisocynauric acid (121 mg, 0.522 mmol, 0.7 equiv) followed by addition of triethylamine (0.215 mL, 0.73 g/mL, 1.49 mmol). The mixture was stirred at r.t. under N2 for 20 h until completion was indicated by TLC. After completion, placed in an ice bath, and ice-cold water (~15 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain a solid. The crude product was triturated with dichloromethane (3 x 4 mL) and diethyl ether (3 x 4 mL), vacuum filtered, and air dried to give 31 (180 mg, 65%) as a pale brown solid. [0423] To an oven-dried 100 mL RBF were added trans isomer of methyl l-(3,4- dichlorophenyl)-2.3.4.9-tetrahydro- 1 //-pyrido| 3.4- |indole-3-carbo\ylate 37 (250 mg, 0.67 mmol), DMF(4 mL). Using a syringe added 0.7 mL of DMF solution of trichloroisocyanuric acid (108 mg, 0.47 mmol, 0.7 equiv) followed by addition of triethylamine (0.192 mL, 0.73 g/mL, 1.33 mmol). The mixture was stirred at r.t. under N2 for 2.5 h until completion was indicated by TLC. After completion, placed in an ice bath, and ice-cold water (~15 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain a solid. The crude product was triturated with dichloromethane (3 x 4 mL) and diethyl ether (3 x 4 mL), vacuum filtered, and air dried to give 31 (180 mg, 44%) as a pale brown solid. [0424] ¾NMR (400 MHz, DMSO-ri,;) d 12.07 (s, 1H), 8.97 (s, 1H), 8.45 (dt, J= 8.0, 1.1 Hz, 1H), 8.21 (d,J = 2.1 Hz, 1H), 8.01 (dd, J= 8.3, 2.1 Hz, 1H), 7.90 (d, J= 8.3 Hz, 1H), 7.70 (dt, J= 8.2, 1.1 Hz, 1H), 7.63 (ddd, J= 8.2, 7.0, 1.1 Hz, 1H), 7.35 (ddd, J= 8.0, 7.0, 1.1 Hz, 1H), 3.94 (s, 3H).

[0425] HRMS (ESI+) calculated for C19H12CI2N2O2 [M+H]⁺: 371.0349, found 371.0349

methyl l-(24-dichlorophenyl)-8-methyl-9H-pyrido[34-b lindole-3-carboxylate ( 32)

[0426] To an oven-dried 100 mL RBF were added cis isomer of methyl l-(2,4- dichlorophenyl)-8-methyl-2.3.4.9-tetrahydro- l//-pyrido|3.4-/ |indole-3-carbo\ylate 38 (580 mg, 1.48 mmol), iodobenzene diacetate (959 mg, 2.98 mmol, 2.0 equiv) and DMF (3 mL). The mixture was stirred at r.t. under N2 for 6 h until completion was indicated by TLC. After completion, the reaction mixture was neutralized with aq. sodium bicarbonate (~12 mL). The mixture was extracted with EtOAc (3 x 15 mL), the combined organic phases washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude product was triturated with toluene (3 x 2 mL), vacuum filtered, and air dried to give 32 (326 mg, 57%) as a pale brown solid.

[0427] ¾ NMR (400 MHz, DMSO-ri,;) d 11.51 (s, 1H), 8.98 (s, 1H), 8.27 (d, J= 7.9 Hz,

1H), 7.86 (dd, J= 1.5, 0.9 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.41 (dt, J= 7.2, 1.0 Hz, 1H), 7.25 (dd, J= 7.9, 7.2 Hz, 1H), 3.91 (s, 3H), 2.56 (s, 3H).

[0428] ¹³C NMR (101 MHz, DMSO-ri,;) d 165.9, 140.6, 140.3, 136.2, 135.7, 135.7, 134.3,

134.1, 133.2, 129.5, 129.1, 129.0, 127.5, 122.1, 120.9, 120.7, 119.5, 117.5, 52.1, 17.4.

[0429] HRMS (ESI+) calculated for C20H14CI2N2O2 [M+H]⁺: 385.0505, found 385.0508

methyl 1 -phenyl-9H-pyrido[34-blindole-3-carboxylate (33) [0430] Was synthesized as described in the literature.⁶

methyl l-(34-dichlorophenyl)-8-methyl-2349-tetrahvdro-lH-pyrido[3 4-b lindole-3- carboxylate (34)

[0431] A 150 mL RBF was charged with 39 (2.0 g, 7.4 mmol), 4 A molecular sieves (4.5 g, powder form), 3,4-dichlorobenzaldehyde (1.32 g, 7.5 mmol, 1.0 equiv), and CH2CI2 (20 mL), capped with a septum and purged with nitrogen. After stirring at rt for 36 h, the reaction was cooled to 0 °C, and TFA (1.2 mL, 1.7 g, 14.9 mmol, 2 equiv) was added dropwise. After stirring for an additional 48 h TLC indicated complete consumption of imine intermediate, and the reaction mixture was basified with saturated aq. sodium bicarbonate (20 mL). The molecular sieves were removed by filtration, and the remaining mixture was extracted with EtOAc (3 x 40 mL). The combined organic phases were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by silica plug wash (5:5:1 Hexanes/DCM/EtOAc) to give mixture of cis- and trans- diastereomers of 34 in 1:2 ratio (yield 1.9 g, 66%).

[0432] ¾ NMR (500 MHz, CDCL) d 7.52 (d, J = 2.0 Hz, 1H), 7.47 - 7.44 (m, 3H), 7.43

- 7.40 (m, 8H), 7.26-7.24 (m, 1H), 7.15 (dd, J= 8.3, 2.0 Hz, 2H), 7.10 - 7.06 (m, 3H), 7.02 - 6.98 (m, 4H), 5.39 (s, 2H), 5.23 (s, 1H), 3.98 - 3.90 (m, 3H), 3.83 (s, 3H), 3.72 (s, 6H), 3.29- 3.21 (m, 3H), 3.12 (ddd,J= 15.5, 6.8, 1.6 Hz, 2H), 3.01 (ddd, J= 15.2, 11.2, 2.6 Hz, 1H), 2.50 (br s, 3H), 2.40 (s, 6H), 2.38 (s, 3H).

[0433] ¹³C NMR (126 MHz, CDCL) d 174.16, 173.09, 142.54, 141.32, 135.95, 135.91,

133.22, 133.15, 133.02, 132.83, 132.30, 131.85, 131.07, 130.83, 130.79, 130.52, 128.14, 127.95, 126.62, 126.52, 123.18, 120.42, 120.37, 120.26, 120.13, 116.22, 116.17, 110.24, 109.56, 57.92, 56.78, 54.15, 52.62, 52.50, 52.33, 25.77, 24.84, 16.83, 16.81.

[0434] HRMS (ESI+) calculated for C20H18CI2N2O2 [M+H]⁺: 389.0818, found 389.0816

methyl l-(2, 4-dichlorophenyl)-8-methyl-2, 3, 4, 9-tetrahydro-lH-pyrido[3, 4-b lindole-3- carboxylate (38)

[0438] A 150 mL RBF was charged with 39 (3.0 g, 11.16 mmol), 4 A molecular sieves (7 g, powder form), 2,4-dichlorobenzaldehyde (1.97 g, 11.27 mmol, 1.0 equiv), and CH2CI2 (30 mL), capped with a septum and purged with nitrogen. After stirring at rt for 36 h, the reaction was cooled to 0 °C, and TFA (1.79 mL, 2.6 g, 22.3 mmol, 2 equiv) was added dropwise. After stirring for an additional 48 h TLC indicated complete consumption of imine intermediate, and the reaction mixture was basified with saturated aq. sodium bicarbonate (30 mL). The molecular sieves were removed by filtration, and the remaining mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by silica column chromatography using 5:5:1 Hexanes/DCM/EtOAc to give cis- and trans- diastereomers of 38 in 2:1 ratio (yield cis- 1.3 g, 30%, trans- 580 mg, 14%) as bright yellow solids.

Cis- diastereomer

[0439] ¾ NMR (400 MHz, CDCL) d 7.49 (d, J = 2.1 Hz, 1H), 7.44 - 7.37 (m, 3H), 7.21

(dd, .7= 8.4, 2.1 Hz, 1H), 7.07 (dd, J= 7.9, 7.1 Hz, 1H), 6.98 (dt, J= 7.1, 1.0 Hz, 1H), 5.81 (s, 1H), 3.98 (dd, J= 11.0, 4.1 Hz, 1H), 3.82 (s, 3H), 3.23 (ddd, J= 15.1, 4.1, 1.8 Hz, 1H), 3.01 (ddd, ./= 15.1, 11.0, 2.5 Hz, 1H), 2.62 (br s, 1H), 2.39 (s, 3H).

[0440] ¹³C NMR (101 MHz, CDCL) d 173.1, 135.9, 134.8, 134.4, 132.9, 131.6, 129.6,

128.2, 126.6, 123.1, 120.3, 120.2, 116.1, 110.3, 56.7, 52.5, 25.7, 16.8.

Trans- diastereomer

[0441] ¾ NMR (400 MHz, CDCL) d 7.55 (s, 1H), 7.49 (d, J= 2.2 Hz, 1H), 7.42 (ddt, J =

7.8, 1.3, 0.7 Hz, 1H), 7.12 (ddd, J= 8.4, 2.2, 0.5 Hz, 1H), 7.08 (d, J= 7.8 Hz, 1H), 7.01 (dt, J = 7.1, 1.1 Hz, 1H), 6.90 (d, J= 8.4 Hz, 1H), 5.87 (d, .7= 1.3 Hz, 1H), 3.83 (dd, J= 8.1, 4.9 Hz, 1H), 3.74 (s, 3H), 3.25 (ddd, J= 15.3, 4.9, 1.3 Hz, 1H), 3.08 (ddd, J= 15.3, 8.1, 1.3 Hz, 1H), 2.77 (br s, 1H), 2.41 (s, 3H).

[0442] HRMS (ESI+) calculated for C20H18CI2N2O2 [M+H]⁺: 389.0818, found— pending.

7-methyltryptophan methyl ester (39)

[0443] To a 0.2 M methanol solution of acylated tryptophan (1.63g, 6.26 mmol) at 0 °C, were added thionyl chloride (2.49 mL, 4.09 g, 34.43 mmol, 5.5 equiv) dropwise. The mixture was warmed up to room temperature and then heated to 70 °C under reflux for 52 h. The mixture was cooled down and concentrated in vacuo. Et20 (30 mL) were added and the mixture were stirred for 30 min. The emulsion was filtered and washed numerous times with Et20 until the solid was not sticky. The solid was air dried to afford tryptophan methyl ester hydrochloride salt 39 (1.38g, 82% yield) as a dark red solid.

[0444] ¾NMR (400 MHz, CD OD) d 7.37 (dd, J= 7.7, 1.4 Hz, 1H), 7.19 (s, 1H), 7.04 - 6.90 (m, 2H), 4.32 (dd, J= 7.5, 5.5 Hz, 1H), 3.80 (s, 3H), 3.45 (ddd, J= 15.1, 5.5, 0.8 Hz, 1H), 3.35 (ddd, J= 15.1, 7.3, 0.7 Hz, 1H), 2.49 (s, 3H).

[0445] ¹³C NMR (101 MHz, CD3OD) d 170.8, 137.7, 127.8, 125.4, 123.4, 122.2, 120.6,

116.5, 107.8, 54.6, 53.6, 27.7, 16.9.

[0446] HRMS (ESI+) calculated for C13H16N2O2 [M+H]⁺: 233.1285, found 233.1318

hydrochloride 40 (PRC 1645).

[0447] Free base of compound 40 was prepared similarly to 1 described above, using methyl 1 -(3.4-dichlorophenyl)-8-methyl-9//-pyrido| 3.4- |indole-3-carbo\ylate 2 (50 mg, 0.130 mmol), ethane- 1,2-diamine (0.05 mL, d = 0.9 g/mL, 0.650 mmol, 5 equiv) affording 47 mg, 87% yield as an off-white powder. A portion of this material (19.6 mg) was dissolved in 0.1 M HC1 in methanol (0.48 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 40 (as the depicted HC1 salt, 19 mg, 90% yield) as bright yellow solid. [0448] ¾ NMR (500 MHz, DMSO-c/₆) d 11.53 (s, 1H), 9.00 (t , J = 6.2 Hz, 1H), 8.86 (s,

1H), 8.35 (d, .7= 2.1 Hz, 1H), 8.26 (d, J= 7.8 Hz, 1H), 8.14 (dd, J= 8.4, 2.1 Hz, 1H), 8.09 - 8.03 (br m, 2H), 7.89 (d, J= 8.4 Hz, 1H), 7.42 (d, J= 7.2 Hz, 1H), 7.25 (app t ,J= 7.6 Hz, 1H), 3.65 (q, J= 6.3 Hz, 2H), 3.04 (q, J= 6.0 Hz, 2H), 2.64 (s, 3H).

[0449] ¹³C NMR (126 MHz, DMSO-fife) d 165.4, 141.0, 139.7, 138.6, 138.0, 134.8, 131.5,

131.5, 131.0, 131.0, 130.7, 129.5, 129.3, 122.3, 121.2, 120.7, 119.4, 113.7, 38.8, 36.9, 17.4. [0450] HRMS (ESI+) calculated for C21H18CI2N4O [M+H]⁺: 413.0930, found 413.0911.

hydrochloride 41 (PRC 1646).

[0451] Free base of compound 41 was prepared similarly to 1 described above, using methyl 1 -(3.4-dichlorophenyl)-8-methyl-9//-pyrido| 3.4- |indole-3-carbo\ylate 2 (50 mg, 0.130 mmol), propane- 1,3-diamine (0.06 mL, d = 0.89 g/mL, 0.650 mmol, 5 equiv) affording 46 mg, 83% yield as an off-white powder. A portion of this material (21.2 mg) was dissolved in 0.1 M HC1 in methanol (0.49 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 41 (as the depicted HC1 salt, 18 mg, 78% yield) as bright yellow solid.

[0452] ¾ NMR (500 MHz, DMSO-fife) d 11.5 (s, 1H), 9.0 (t, J= 6.3 Hz, 1H), 8.8 (s, 1H),

8.3 (d,J= 2.0 Hz, 1H), 8.2 (d, J= 7.8 Hz, 1H), 8.1 (dd, J= 8.3, 2.0 Hz, 1H), 8.0 (br app s, 3H), 7.9 (d, J= 8.3 Hz, 1H), 7.4 (d, J= 7.1 Hz, 1H), 7.2 (t, J= 7.5 Hz, 1H), 3.5 (q, J= 6.5 Hz, 2H), 2.8 (q, J= 6.7 Hz, 2H), 2.6 (s, 3H), 1.9 (app quin, J= 7.0 Hz, 2H).

[0453] ¹³C NMR (126 MHz, DMSO-fife) d 165.2, 141.0, 139.9, 138.7, 138.0, 134.7, 131.5,

131.4, 131.0, 131.0, 130.7, 129.5, 129.3, 122.3, 121.2, 120.6, 119.4, 113.6, 36.8, 35.9, 27.6, 17.3.

HRMS (ESI+) calculated for C22H20CI2N4O [M+H]⁺: 427.1087, found 427.1061.

Ill

carboxamide hydrochloride 42 (PRC1647).

[0454] Free base of compound 42 was prepared similarly to 1 described above, using methyl 1 -(3.4-dichlorophenyl)-8-methyl-9 /-pyrido| 3.4-6 |indole-3-carbo\ylate 2 (50 mg, 0.130 mmol), 2-(pyrrolidin-l-yl)ethan-l -amine (0.09 mL, d = 0.9 g/mL, 0.650 mmol, 5 equiv) affording 47 mg, 77% yield as a pale brown powder. A portion of this material (21.2 mg) was dissolved in 0.1 M HC1 in methanol (0.45 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 42 (as the depicted HC1 salt, 20 mg, 88% yield) as a pale brown solid.

[0455] ¾ NMR (500 MHz, CD OD) 5 8.8 (s, 1H), 8.3 (d, J= 2.0 Hz, 1H), 8.1 (d, .7= 7.9

Hz, 1H), 8.0 (dd, J= 8.3, 2.0 Hz, 1H), 7.8 (d, J= 8.3 Hz, 1H), 7.42 (d, J= 7.5 Hz, 1H), 7.3 (t, J= 7.6 Hz, 1H), 3.9 (t, J= 5.8 Hz, 2H), 3.9 - 3.8 (br m, 2H), 3.5 (t, J= 5.8 Hz, 2H), 3.2-3.1 (br m, 2H), 2.6 (s, 3H), 2.2 (br m, 2H), 2.0 (br m, 2H).

[0456] ¹³C NMR (126 MHz, CD3OD) 5 169.1, 142.8, 141.0, 140.4, 139.6, 136.8, 134.1,

133.9, 132.9, 132.1, 131.9, 130.9, 129.8, 123.8, 122.9, 122.3, 120.0, 115.0, 56.3, 55.7, 37.2, 24.0, 17.4.

[0457] HRMS (ESI+) calculated for C25H24CI2N4O [M+H]⁺: 467.1400, found 467.1381.

blindole-3-carboxamide 43 (PRC 1664).

[0458] Compound 43 was prepared similarly to free base of 1 described above, using methyl 1 -(3.4-dichlorophenyl)-8-methyl-9 /-pyrido| 3.4-6 |indole-3-carbo\ylate 2 (50 mg, 0.130 mmol), 2-((2-aminoethyl)amino)ethan-l-ol (0.07 mL, d = 1.03 g/mL, 0.650 mmol, 5 equiv) affording 56 mg, 93% yield as a pale brown powder.

[0459] ¾ NMR (500 MHz, DMSO-iife) 5 11.5 (s, 1H), 8.8 (s, 1H), 8.8 (t, J= 5.9 Hz, 1H),

8.3 (d, J = 2.0 Hz, 1H), 8.2 (d, J = 7.8 Hz, 1H), 8.1 (dd, J= 8.3, 2.0 Hz, 1H), 7.9 (d, J = 8.3 Hz, 1H), 7.4 (d, J= 7.2 Hz, 1H), 7.2 (app t, J= 7.5 Hz, 1H), 4.5 (s, 1H), 3.5 (m, 4H), 2.8 (t, J = 6.5 Hz, 2H), 2.6 (m, 5H).

[0460] ¹³C NMR (126 MHz, DMSO-fife) d 164.5, 141.1, 140.2, 138.5, 138.2, 134.7, 131.5,

131.5, 131.1, 130.9, 130.7, 129.5, 129.3, 122.4, 121.2, 120.7, 119.5, 113.5, 60.5, 51.5, 48.7, 17.4. Note that one carbon is obscured by the d6-DMSO septet at 39.8 ppm.

[0461] HRMS (ESI+) calculated for C23H22CI2N4O2 [M+H]⁺: 457.1193, found 457.1185.

N-(2-( 1 -( 3, 4-dichlorophenyl)-8-methyl-9H-pyrido[3, 4-b ]indole-3-carboxamido)ethyl)-N- methylglvcine 44 (PRC1656).

[0462] To a 6-dram vial were added methyl N-(2-( 1 -(3.4-dichlorophenyl)-8-methyl-9//- pyrido[3,4-Z>]indole-3-carboxamido)ethyl)-/V-methylglycinate 45 (30 mg, 0.060 mmol) and a magnetic stir bar. To this Amberlyt hydroxide resin (214 mg, 0.901 mmol, 15.0 equiv, Aldrich, loading 4.2 mmoles/g) was added, sealed with a rubber septum, added THF/MeOHTLO (0.8 mL/0.8 mL/0.8 mL). The mixture was stirred for 24 hours at rt. after which the resin was filtered and washed with MeOH and DCM alternatively (4 x 2 mL). An aqueous solution of AcOH (50%, 2 mL) was added to release the product from the resin, and the solution containing the product was collected by filtration. The resin beads were rinsed another 4 times with aq. AcOH (50%, 2 mL). The combined filtrates were concentrated in vacuo. The residue was suspended in a minimum amount of MeOH, and the desired product was precipitated by the addition of Et₂0 and hexane. The suspension was stirred for 30 min and filtered. The solid was washed with hexane to afford 44 (15 mg, 56%) as dark yellow powder.

[0463] ¾ NMR (500 MHz, DMSO-r e) 5 11.5 (s, 1H), 8.8 (app m, 2H), 8.3 (d, J= 2.0 Hz,

1H), 8.3 (d, J = 1.9 Hz, 1H), 8.1 (dd, J= 8.3, 2.0 Hz, 1H), 7.9 (d, J= 8.3 Hz, 1H), 7.4 (d, J = 7.1 Hz, 1H), 7.2 (app t , J= 7.5 Hz, 1H), 3.5 (app q, J= 6.3 Hz, 2H), 3.3 (s, 2H), 2.9 (t, J= 6.3 Hz, 2H), 2.6 (s, 3H), 2.5 (app s, 3H).

[0464] ¹³C NMR (126 MHz, DMSO-fife) 5 169.6, 165.0, 141.2, 140.0, 138.7, 138.2, 134.8,

131.7, 131.6, 131.2, 131.1, 130.9, 129.7, 129.4, 122.5, 121.3, 120.9, 119.6, 113.7, 58.6, 55.5,

41.7, 36.0, 17.5.

[0465] HRMS (ESI+) calculated for C24H22CI2N4O3 [M+H]⁺: 485.1142, found 485.1111.

methyl N-( 2-( l-(3, 4-dichlorophenyl)-8-methyl-9H-pyrido[3, 4-b lindole-3- carboxamido) ethyl) -N-methylslvcinate 45 (PRC1665).

[0466] To a 6-dram vial were added l-(3,4-dichlorophenyl)-8-methyl-/V-(2- (methylamino)ethyl)-9i/-pyrido[3,4-Z>]indole-3-carboxamide hydrochloride 1 (117 mg, 0.252 mmol) and a magnetic stir bar. To this methanol (6 mL) and K2CO3 (70 mg, 0.507 mmol, 2.0 equiv) were added, the mixture was stirred for 10 minutes at rt, and then the reaction was cooled to ice temperature. To this cold reaction, added methyl 2-bromoacetate (0.024 mL, 1.63 g/mL, 0.255 mmol, 1 equiv) was added via syringe, the mixture was stirred at rt for 48 h. The reaction mixture was concentrated in vacuo, and purified by silica column chromatography using 9.5:0.5 of DCM/MeOH with 5 drops of NH₄OH to give 45 (yield 20 mg, 32%) as dark yellow powder.

[0467] ¾ NMR (500 MHz, DMSO-rie) 5 11.5 (s, 1H), 8.8 (s, 1H), 8.8 (t, J= 5.7 Hz, 1H),

8.3 (d, J = 2.0 Hz, 1H), 8.3 (d, J = 7.8 Hz, 1H), 8.1 (dd, J = 8.3, 2.0 Hz, 1H), 7.9 (d, J = 8.3 Hz, 1H), 7.4 (dt, J= 7.2, 1.1 Hz, 1H), 7.2 (app t , J= 7.5 Hz, 1H), 3.6 (s, 3H), 3.5 (app q, J =

6.3 Hz, 2H), 3.4 (s, 2H), 2.7 (t, J= 6.5 Hz, 2H), 2.6 (s, 3H), 2.4 (s, 3H).

[0468] ¹³C NMR (126 MHz, DMSO-ri₆) d 171.1, 164.4, 141.1, 140.1, 138.5, 138.1, 134.7,

131.5, 131.5, 131.1, 130.9, 130.7, 129.5, 129.3, 122.4, 121.2, 120.7, 119.5, 113.4, 57.5, 55.2, 51.1, 41.7, 36.9, 17.4.

[0469] HRMS (ESI+) calculated for C25H24CI2N4O3 [M+H]⁺: 499.1298, found 499.1297.

hydrochloride 46 (PRC1666).

[0470] Compound 10 1 -(3.4-dichlorophenyl)-/V-(2-(methylamino)ethyl)-9//-pyrido|3.4- Z>]indole-3-carboxamide (9.7 mg) was dissolved in 0.1 M HC1 in methanol (0.3 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 46 (as the depicted HC1 salt, 9.5 mg, 89% yield) as bright yellow solid.

[0471] ¾ NMR (400 MHz, DMSO--ri₆) d 12.02 (s, 1H), 9.03 (t, J = 6.1 Hz, 1H), 8.61 (s,

1H), 8.45 (d, J= 7.8 Hz, 1H), 8.39 (d, = 2.0 Hz, 1H), 8.23 - 8.10 (m, 1H), 7.91 (d, J= 8.4 Hz, 1H), 7.71 (d, J= 8.1 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.34 (t, J= 7.9 Hz, 1H), 3.68 (m, 2H), 3.21 - 3.10 (m, 2H), 2.61 (t, J= 5.4 Hz, 3H).

[0472]

hydrochloride 47 (PRC1652).

[0473] Compound 11 l-(3,4-dichlorophenyl)-/V-(2-(dimethylamino)ethyl)-9i/-pyrido[3,4- Z>]indole-3-carboxamide (31.9 mg) was dissolved in 0.1 MHC1 in methanol (0.75 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (2 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 47 (as the depicted HC1 salt, 30 mg, 87% yield) as dark yellow solid. [0474] ¾ NMR (500 MHz, DMSO-ri₆) d 12.1 (s, 1H), 10.2 (s, 1H), 9.1 (d, J= 5.8 Hz, 1H),

8.9 (s, 1H), 8.5 - 8.4 (m, 2H), 8.2 (d, J= 7.9 Hz, 1H), 7.9 (d, J= 8.0 Hz, 1H), 7.7 (d, J= 7.7 Hz, 1H), 7.6 (t, J= 7.3 Hz, 1H), 7.3 (t , J= 7.1 Hz, 1H), 3.8 - 3.8 (m, 2H), 3.3 (app s, 2H), 2.8 (s, 6H).

[0475] ¹³C NMR (126 MHz, DMSO-ri₆) d 165.3, 141.6, 139.3, 137.9, 137.7, 134.2, 131.6,

131.6, 130.7, 130.5, 130.2, 128.9, 128.9, 122.1, 121.0, 120.3, 113.9, 112.6, 56.1, 42.4, 34.3.

hydrochloride 48 (PRC 1667).

[0476] Compound 12 l-(3,4-dichlorophenyl)-/V-(3-(methylamino)propyl)-9i/-pyrido[3,4- Z>]indole-3-carboxamide (20.0 mg) was dissolved in 0.1 M HC1 in methanol (0.50 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 48 (as the depicted HC1 salt, 21.5 mg, 99% yield) as dark yellow solid.

[0477] ¾ NMR (400 MHz, CDsOD) d 9.00 (s, 1H), 8.36 - 8.28 (m, 2H), 8.04 (dd, J= 8.3,

2.1 Hz, 1H), 7.83 (d, J= 8.3 Hz, 1H), 7.74 - 7.64 (m, 2H), 7.41 (app t , J= 8.0 Hz, 1H), 3.92 (t, J= 5.8 Hz, 2H), 3.51 - 3.45 (m, 2H), 3.03 (m, 5H; overlap of CH and CH₂).

hydrochloride 49 (PRC 1668).

[0478] Compound 13 l-(3,4-dichlorophenyl)-/V-(3-(dimethylamino)propyl)-9i/- pyrido[3,4-Z>]indole-3-carboxamide (15.3 mg) was dissolved in 0.1 M HC1 in methanol (0.40 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 49 (as the depicted HC1 salt, 16.1 mg, 97% yield) as dark yellow solid.

[0479] ¾ NMR (400 MHz, CD₃OD) d 9.06 (s, 1H), 8.37 (d, J= 8.0 Hz, 1H), 8.28 (d, J =

2.0 Hz, 1H), 8.02 (dd, J= 8.3, 2.0 Hz, 1H), 7.85 (d, J= 8.3 Hz, 1H), 7.74 (d, J= 8.4 Hz, 1H), 7.70 (d, J= 8.4 Hz, 1H), 7.44 (app t, .7= 7.8 Hz, 1H), 3.65 (t, .7= 6.5 Hz, 2H), 3.31 - 3.23 (m, 2H), 2.95 (s, 6H), 2.15 (app quintet, J= 6.8 Hz, 2H).

hydrochloride 50 (PRC 1653).

[0480] Free base of compound 50 was prepared similarly to 1 described above, using methyl 1 -(3.4-dichlorophenyl)-9//-pyrido|3.4-/ |indole-3-carbo\ylate 31 (50 mg, 0.135 mmol), ethane- 1,2-diamine (0.05 mL, d = 0.90 g/mL, 0.673 mmol, 5 equiv) affording 46 mg, 86% yield as an off-white powder. A portion of this material (20.9 mg) was dissolved in 0.1 M HC1 in methanol (0.53 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 50 (as the depicted HC1 salt, 20.2 mg, 89% yield) as bright yellow solid.

[0481] ¾ NMR (500 MHz, DMSO-ri₆) d 12.0 (s, 1H), 9.0 (t, J= 6.2 Hz, 1H), 8.9 (s, 1H),

8.4 (d, J= 7.9 Hz, 1H), 8.4 (d, J= 2.0 Hz, 1H), 8.2 (dd, J= 8.3, 2.0 Hz, 1H), 8.0 (s, 3H), 7.9 (d, J= 8.3 Hz, 1H), 7.7 (d, J= 8.2 Hz, 1H), 7.6 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H), 7.3 (app t , J =

7.5 Hz, 1H), 3.7 (q, J= 6.3 Hz, 2H), 3.1 (q, J= 6.0 Hz, 2H).

[0482] ¹³C NMR (126 MHz, DMSO-ri₆) d 165.5, 141.7, 139.5, 137.9, 137.9, 134.3, 131.7,

131.7, 130.8, 130.6, 130.3, 129.0, 128.9, 122.2, 121.1, 120.4, 113.9, 112.7, 38.9, 36.9.

[0483] HRMS (ESI+) calculated for C₂₀H₁₆CI₂N₄O [M+H]⁺: 399.0774, found 399.0762.

carboxamide 51 (PRC1680).

[0484] Compound 51 was prepared similarly to 1 described above, using methyl l-(3,4- dichlorophenyl)-9H-pyrido[3,4-b]indole-3-carboxylate 31 (50 mg, 0.135 mmol), 2-((2- aminoethyl)amino)ethan-l-ol (0.07 mL, d = 1.02 g/mL, 0.673 mmol, 5 equiv) affording 56 mg, 93% yield as an off-white powder.

[0485] 1H NMR (500 MHz, DMSO-d6) d 8.9 (s, 1H), 8.8 (t, J = 5.9 Hz, 1H), 8.4 (d, J = 7.9 Hz, 1H), 8.4 (d, J = 2.1 Hz, 1H), 8.1 (dd, J = 8.3, 2.1 Hz, 1H), 7.9 (d, J = 8.3 Hz, 1H), 7.7 (d, J = 8.2 Hz, 1H), 7.6 (app t, J = 7.4 Hz, 1H), 7.3 (app t, J = 7.5 Hz, 1H), 4.5 (s, 1H), 3.5 - 3.4 (m, 4H), 2.8 (t, J = 6.5 Hz, 2H), 2.6 (t, J = 5.7 Hz, 2H).

[0486] 13C NMR (126 MHz, DMSO-d6) d 164.5, 141.7, 140.0, 138.0, 137.8, 134.2, 131.7,

131.7, 130.9, 130.5, 130.4, 128.9 (two overlapping resonances), 122.2, 121.2, 120.4, 113.7, 112.6, 60.5, 51.5, 48.7. Note that one carbon is obscured by the d6-DMSO septet at 39.8 ppm. [0487] HRMS (ESI+) calculated for C22H20C12N4O2 [M+H]+: 443.1036, found 443.1036.

l-(3,4-dichlorophenyl)-N-(3-morpholinopropyl)-9H-pyrido[3,4-blindole-3-carboxamide 52 (PRC 1681).

[0488] Compound 52 was prepared similarly to 1 described above, using methyl l-(3,4- dichlorophenyl)-9 /-pyrido| 3.4-6 |indole-3-carbo\ylate 31 (40 mg, 0.108 mmol), 3- morpholinopropan-1 -amine (0.08 mL, d = 0.987 g/mL, 0.539 mmol, 5 equiv) affording 40 mg, 77% yield as an off-white powder.

[0489] ¾ NMR (500 MHz, DMSO-fife) d 8.9 (s, 1H), 8.8 (t, J= 6.1 Hz, 1H), 8.4 (d, J= 7.9 Hz, 1H), 8.4 (d, .7= 2.1 Hz, 1H), 8.1 (dd, J= 8.3, 2.1 Hz, 1H), 7.9 (d, J= 8.3 Hz, 1H), 7.7 (d, J= 8.2 Hz, 1H), 7.6 (app t, J= 7.5 Hz, 1H), 7.3 (app t , J= 7.5 Hz„ 1H), 3.6 - 3.5 (m, 4H), 3.4 (q, J = 6.7 Hz, 2H), 2.4 - 2.3 (m, 6H), 1.7 (app quintet, J= 7.0 Hz, 2H).

[0490] ¹³C NMR (126 MHz, DMSO-iife) d 164.5, 141.7, 140.1, 138.0, 138.0, 134.3, 131.7,

131.6, 130.8, 130.6, 130.3, 129.0, 128.9, 122.2, 121.2, 120.3, 113.7, 112.6, 66.1, 56.4, 53.4, 37.7, 26.2.

[0491] HRMS (ESI+) calculated for C25H24CI2N4O2 [M+H]⁺: 483.1349, found 483.1348.

hydrochloride 53 (PRC1641).

[0492] Free base of compound 53 was prepared similarly to 1 described above, using methyl 1 -(3-chlorophenyl)-9//-pyrido|3.4-6|indole-3-carboxylate 78 (50 mg, 0.149 mmol), /V^;-methylethane- 1,2-diamine (0.07 mL, d = 0.85 g/mL, 0.742 mmol, 5 equiv) affording 54 mg, 95% yield as a pale brown powder. A portion of this material (20.2 mg) was dissolved in 0.1 M HC1 in methanol (0.53 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 53 (as the depicted HC1 salt, 20.0 mg, 89% yield) as a yellowish brown solid. [0493] ¾ NMR (500 MHz, DMSO d₆) d 12.0 (s, 1H), 9.0 (t , J = 6.1 Hz, 1H), 8.9 (s, 1H),

8.7 (br s, 2H), 8.4 (d, = 7.9 Hz, 1H), 8.2 (app t, = 1.8 Hz, 1H), 8.1 (dt, J= 7.5, 1.5 Hz, 1H),

7.7 - 7.6 (m, 4H), 7.3 (app t, J= 7.5 Hz, 1H), 3.7 (app q, J= 6.1 Hz, 2H), 3.2 (app quintet, J = 6.0 Hz, 2H), 2.6 (t, J= 5.4 Hz, 3H).

[0494] ¹³C NMR (126 MHz, DMSO-fife) d 165.6, 141.6, 139.5, 139.4, 139.0, 134.3, 133.7,

130.6, 130.1, 128.9, 128.8, 128.4, 127.4, 122.0, 121.1, 120.3, 113.7, 112.7, 48.3, 35.6, 32.7. [0495] HRMS (ESI+) calculated for C21H19CIN4O [M+H]⁺: 379.1320, found 379.1292.

hydrochloride 54 ( PRC1642 ).

[0496] Free base of compound 54 was prepared similarly to 1 described above, using methyl 1 -(3-chlorophenyl)-9//-pyrido|3.4-6|indole-3-carboxylate 78 (50 mg, 0.149 mmol), /V^;,/V^;-dimethylethane-l, 2-diamine (0.09 mL, d = 0.807 g/mL, 0.742 mmol, 5 equiv) affording 46 mg, 79% yield as a pale brown powder. A portion of this material (21.2 mg) was dissolved in 0.1 M HC1 in methanol (0.55 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 54 (as the depicted HC1 salt, 16 mg, 69% yield) as a dark yellow solid.

[0497] ¾ NMR (500 MHz, DMSO-r/e) d 12.0 (s, 1H), 10.1 (s, 1H), 9.0 (t, J= 6.2 Hz, 1H),

8.9 (s, 1H), 8.4 (d, J= 7.9 Hz, 1H), 8.2 (app t, J= 1.9 Hz, 1H), 8.1 (dt, J= 7.5, 1.5 Hz, 1H),

7.7 - 7.6 (m, 4H), 7.3 (app t, J= 7.5 Hz, 1H), 3.8 (app q, J= 6.1 Hz, 2H), 3.3 (app q, J= 5.9 Hz, 2H), 2.8 (d, J= 4.9 Hz, 6H).

[0498] ¹³C NMR (126 MHz, DMSO-fife) d 165.5, 141.6, 139.4, 139.4, 139.1, 134.3, 133.7,

130.6, 130.1, 128.9, 128.8, 128.4, 127.5, 122.0, 121.1, 120.3, 113.7, 112.7, 56.2, 42.5, 34.4. [0499] HRMS (ESI+) calculated for C22H21CIN4O [M+H]⁺: 393.1477, found 393.1453.

hydrochloride 55 (PRC1643).

[0500] Free base of compound 55 was prepared similarly to 1 described above, using methyl l-(3-chlorophenyl)-9i/-pyrido[3,4-Z>]indole-3-carboxylate 78 (50 mg, 0.149 mmol), /V^;-methylpropane- 1,3-diamine (0.08 mL, d = 0.84 g/mL, 0.742 mmol, 5 equiv) affording 46 mg, 79% yield as an off-white powder. A portion of this material (20.5 mg) was dissolved in 0.1 M HCI in methanol (0.52 mL, prepared from 12 N HCI (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 55 (as the depicted HCI salt, 17.1 mg, 76% yield) as a pale yellowish solid.

[0501] ¾ NMR (500 MHz, DMSO-ri₆) d 12.0 (s, 1H), 9.0 (t, J= 6.3 Hz, 1H), 8.9 (s, 1H),

8.7 (br s, 2H), 8.4 (d, J= 7.9 Hz, 1H), 8.2 (t, J= 1.9 Hz, 1H), 8.1 (dt, .7= 7.5, 1.6 Hz, 1H), 7.7 - 7.6 (m, 4H), 7.3 (app t , J= 7.5 Hz, 1H), 3.5 (app q , J= 6.5 Hz, 2H), 2.9 (app quintet, J= 7.3 Hz, 2H), 2.6 (t, J= 5.4 Hz, 3H), 1.9 (app quintet, J= 6.9 Hz, 2H).

[0502] ¹³C NMR (126 MHz, DMSO-ri₆) d 165.4, 141.7, 139.7, 139.5, 139.1, 134.3, 133.8,

130.7, 130.2, 128.9, 128.9, 128.5, 127.5, 122.1, 121.2, 120.4, 113.6, 112.7, 46.3, 36.0, 32.5, 26.3.

[0503] HRMS (ESI+) calculated for C22H21CIN4O [M+H]⁺: 393.1477, found 393.1452.

l-(3-chlorophenyl)-N-(3-(dimethylamino)propyl)-9H-pyrido[3, 4-b]indole-3-carboxamide hydrochloride 56 (PRC1644).

[0504] Free base of compound 56 was prepared similarly to 1 described above, using methyl 1 -(3-chlorophenyl)-9//-pyrido|3.4-/ |indole-3-carbo\ylate 78 (50 mg, 0.149 mmol), /V^;,/V^;-dimethylpropane-l, 3-diamine (0.09 mL, d = 0.812 g/mL, 0.742 mmol, 5 equiv) affording 47 mg, 77% yield as an off-white powder. A portion of this material (19.2 mg) was dissolved in 0.1 M HC1 in methanol (0.50 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 56 (as the depicted HC1 salt, 13.3 mg, 64% yield) as a bright yellowish solid.

[0505] ¾ NMR (500 MHz, DMSO-ri₆) d 12.0 (s, 1H), 10.2 (br s, 1H), 9.0 (t, J= 6.3 Hz,

1H), 8.9 (s, 1H), 8.4 (d, J = 7.9 Hz, 1H), 8.2 (t, J= 2.0 Hz, 1H), 8.1 (d, J= 7.7 Hz, 1H), 7.7 - 7.6 (m, 4H), 7.3 (app t , J= 7.5 Hz, 1H), 3.5 (app q , J= 6.6 Hz, 2H), 3.1 - 3.1 (m, 2H), 2.8 (d, J= 4.9 Hz, 6H), 2.0 (app quintet, ./= 7.3 Hz, 2H).

[0506] ¹³C NMR (126 MHz, DMSO-ri₆) d 165.2, 141.6, 139.7, 139.4, 139.0, 134.2, 133.7,

130.6, 130.2, 128.8, 128.8, 128.4, 127.4, 122.0, 121.1, 120.3, 113.5, 112.7, 54.6, 42.0, 36.1, 24.7.

[0507] HRMS (ESI+) calculated for C23H23CIN4O [M+H]⁺: 407.1633, found 407.1609.

hydrochloride 57 (PRC 1648).

[0508] To an oven-dried 25 mL RBF were added methyl 1 -(4-fluorophenyl)-9H- pyrido[3,4-b]indole-3-carboxylate 79 (332 mg, 1.03 mmol) and a magnetic stir bar. The flask was sealed with a rubber septum and purged with N2 for 5 minutes. Nl-methylethane- 1,2- diamine (0.448 mL, d = 0.85 g/mL, 5.15 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 24 h, at which point TLC indicated complete consumption of 78. The reaction was cooled to rt, placed in an ice bath, and ice-cold water (~5 mL) was added to precipitate the product. The resulting mixture was stirred at rt. for another 10 minutes and the solid was collected by vacuum filtration, washed with cold water, and air-dried to obtain the free base of 57 (352 mg, 93.6 % yield). A portion of this material (38 mg) was dissolved in 0.1 M HC1 in methanol (1.06 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (5 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 57 (33 mg, 85%).

[0509] 1H NMR (400 MHz, Methanol-d4) d 8.78 (s, 1H), 8.25 (d, J = 8.09 Hz, 1H), 8.13 (m, 2H), 7.65 (d, J = 8.30 Hz, 1H), 7.58 (t, J = 7.39 Hz, 1H), 7.35 (m, 3H), 3.66 (t, J = 5.74 Hz, 2H), 2.90 (t, J = 6.30 Hz, 2H), 2.47 (s, 3H).

[0510] 13C NMR (400 MHz, Methanol-d4) d 168.5, 164.7 (d, ^!J_CF = 233.2 Hz), 143.2,

141.9, 140.5, 136.1, 131.8 (d, ³J_CF = 8.5 Hz), 131.7, 129.8, 122.9, 122.5, 121.6, 116.6 (d, ²J_CF = 21.8 Hz), 114.1, 113.5, 51.9, 39.7, 35.9.

[0511] 19F NMR (400 MHz, Methanol-d4) d -114.6.

(PRC 1669).

[0512] To an oven-dried 25 mL RBF were added methyl 1 -(4-bromophenyl)-9H- pyrido[3,4-b]indole-3-carboxylate 80 (0.31 g, 0.81 mmol) and a magnetic stirbar. The flask was sealed with a rubber septum and purged with N2 for 5 minutes. Nl-methylethane- 1,2- diamine (0.39 mL, d = 0.85 g/mL, 4.51 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 26 h, at which point TLC indicated complete consumption of 79. The reaction was cooled to rt, placed in an ice bath, and ice-cold water (~5 mL) was added to precipitate the product. The resulting mixture was stirred at rt. for another 10 minutes and the solid was collected by vacuum filtration, washed with cold water, and air-dried to obtain 58 (0.18 mg, 51.4 % yield).

[0513] 1H NMR (400 MHz, Methanol-d4) d 8.78 (s, 1H), 8.24 (d, J = 8.19 Hz, 1H), 8.02 (d, J = 8.42, 2H), 7.71 (d, J = 7.02, 2H), 7.64 (d, J = 7.25, 1H), 7.57 (t, J = 7.02 Hz, 1H), 7.32 (t, J = 7.02, 1H), 3.64 (t, J = 6.29 Hz, 2H), 2.85 (t, J = 6.23 Hz, 2H), 2.44 (s, 3H).

[0514] 13C NMR (400 MHz, Methanol-d4) 166.8, 141.9, 139.1, 136.8, 131.7, 130.4,

130.2, 130.2, 128.5, 122.7, 121.5, 121.2, 120.3, 112.9, 112.0, 50.5, 38.3, 34.4.

(PRC 1670).

[0515] To an oven-dried 25 mL RBF were added methyl 1 -(4-bromophenyl)-9H- pyrido[3,4-b]indole-3-carboxylate 80 (0.36 g, 1.01 mmol) and a magnetic stir bar. The flask was sealed with a rubber septum and purged with N2 for 5 minutes. Nl,Nl-dimethylethane- 1, 2-diamine (0.56 mL, d = 0.85 g/mL, 5.05 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 10 minutes, and then heated to 90 °C for 26 h, at which point TLC indicated complete consumption of 79. The reaction was cooled to rt, placed in an ice bath, and ice-cold water (~10 mL) was added to precipitate the product. The resulting mixture was stirred at rt. for another 10 minutes and the solid was collected by vacuum filtration, washed with cold water, and air-dried to obtain 59 (0.27 mg, 66 % yield).

[0516] 1H NMR (400 MHz, Methanol-d4) d 8.78 (s, 1H), 8.25 (d, J = 8.12 Hz, 1H), 8.03 (d, J = 8.79, 2H), 7.71 (d, J = 8.02, 2H), 7.64 (d, J = 8.12, 1H), 7.57 (t, J = 7.39 Hz, 1H), 7.32 (t, J = 7.32, 1H), 3.64 (t, J = 6.78 Hz, 2H), 2.66 (t, J = 6.14 Hz, 2H), 2.36 (s, 6H).

[0517] 13C NMR (400 MHz, Methanol-d4) d 168.1, 143.3, 140.6, 138.3, 136.2, 133.0,

132.0, 131.6, 129.9, 124.2, 123.0, 122.6, 121.7, 114.3, 113.4, 59.6, 45.5, 38.1.

60 (PRC 1630).

[0518] Free base of compound 60 was prepared similarly to 1 described above, using methyl 1 -(/ tolyl)-9//-pyrido| 3.4-6 |indole-3-carbo\ylate 81 (40 mg, 0.126 mmol), N¹- methylethane- 1,2-diamine (0.06 mL, d = 0.85 g/mL, 0.632 mmol, 5 equiv) affording 29 mg, 64% yield as a pale brown powder. A portion of this material (14.2 mg) was dissolved in 0.1 M HC1 in methanol (0.40 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 60 (as the depicted HC1 salt, 14.5 mg, 93% yield) as a brownish yellow solid.

[0519] ¾NMR (500 MHz, DMSO-ri₆) d 11.8 (s, 1H), 9.0 (t, J= 6.2 Hz, 1H), 8.8 (s, 1H), 8.6 (br s, 2H), 8.4 (d, J= 7.9 Hz, 1H), 8.1 (d, J= 8.1 Hz, 2H), 7.7 (d, J= 8.2 Hz, 1H), 7.6 (ddd, J= 8.2, 6.9, 1.2 Hz, 1H), 7.5 (d, J= 7.9 Hz, 2H), 7.3 (app t, J= 7.5 Hz, 1H), 3.7 (app q, J = 6.0 Hz, 2H), 3.2 (app quintet, J= 5.9 Hz, 2H), 2.6 (t, J= 5.4 Hz, 3H), 2.5 (s, 3H).

[0520] ¹³C NMR (126 MHz, DMSO-ri₆) d 164.75, 141.54, 140.67, 139.79, 138.49, 134.74,

134.10, 129.78, 129.37, 128.53, 128.50, 121.93, 121.23, 120.12, 112.65, 112.61, 50.92, 38.57, 35.93, 20.94.

[0521] HRMS (ESI+) calculated for C22H22N4O [M+H]⁺: 359.1866, found 359.1860.

N-(2-(dimethylamino)ethyl)-l-(p-tolyl)-9H-pyrido[3, 4-b]indole-3-carboxamide hydrochloride 61 (PRC1631).

[0522] Free base of compound 61 was prepared similarly to 1 described above, using methyl l-(p-tolyl)-9H-pyrido[3,4-b]indole-3-carboxylate 81 (40 mg, 0.126 mmol), N1,N1- dimethylethane- 1,2-diamine (0.07 mL, d = 0.807 g/mL, 0.632 mmol, 5 equiv) affording 31 mg, 66% yield as a pale brown powder. A portion of this material (14.4 mg) was dissolved in 0.1 M HC1 in methanol (0.40 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 61 (as the depicted HC1 salt, 15 mg, 94% yield) as a brownish yellow solid.

[0523] 1H NMR (500 MHz, DMSO-d6) d 11.9 (s, 1H), 9.7 (br s, 1H), 9.0 (t, J = 6.2 Hz, 1H), 8.8 (s, 1H), 8.4 (d, J = 7.9 Hz, 1H), 8.1 (d, J = 7.8 Hz, 2H), 7.7 (d, J = 8.2 Hz, 1H), 7.6 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.5 (d, J = 7.8 Hz, 2H), 7.3 (app t, J = 7.5 Hz, 1H), 3.8 (app q, J = 6.1 Hz, 2H), 3.3 (app q, J = 5.9 Hz, 2H), 2.9 (d, J = 4.9 Hz, 6H), 2.5 (s, 3H).

[0524] 13C NMR (126 MHz, DMSO-d6) d 164.5, 141.5, 140.6, 139.7, 138.5, 134.7, 134.0,

129.8, 129.3, 128.5 (two overlapping signals), 121.9, 121.2, 120.1, 112.6, 112.5, 58.2, 45.2,

36.8, 20.9.

[0525] HRMS (ESI+) calculated for C23H24N40 [M+H]+: 373.2023, found 373.2013.

62 (PRC 1632).

[0526] Free base of compound 62 was prepared similarly to 1 described above, using methyl 1 -(/Molyl)-9//-pyrido| 3.4- |indole-3-carbo\ylate 81 (40 mg, 0.126 mmol), N¹- methylpropane-1, 3-diamine (0.07 mL, d = 0.844 g/mL, 0.632 mmol, 5 equiv) affording 27 mg, 57% yield as an off-white powder. A portion of this material (14.6 mg) was dissolved in 0.1 M HC1 in methanol (0.40 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 62 (as the depicted HC1 salt, 15.2 mg, 95% yield) as a dark yellow solid.

[0527] ¾NMR (500 MHz, DMSO-ri₆) d 11.8 (s, 1H), 8.9 (t, J= 6.3 Hz, 1H), 8.8 (s, 1H), 8.6 (br s, 2H), 8.4 (d, J= 7.9 Hz, 1H), 8.1 (d, J= 7.8 Hz, 2H), 7.7 (d, J= 8.2 Hz, 1H), 7.6 (app t, J= 8.0 Hz, 1H), 7.5 (d, J= 7.8 Hz, 2H), 7.3 (app t, J= 7.5 Hz, 1H), 3.5 (app q, J= 6.5 Hz, 2H), 2.9 (dt, J= 12.6, 6.3 Hz, 2H), 2.6 (t, J= 5.4 Hz, 3H), 2.5 (s, 3H), 1.9 (app quintet, J= 6.9 Hz, 2H).

[0528] ¹³C NMR (126 MHz, DMSO-ri₆) d 164.6, 141.5, 140.5, 139.9, 138.4, 134.7, 134.0,

129.8, 129.3, 128.5, 128.4, 121.9, 121.2, 120.1, 112.6, 112.5, 49.9, 37.9, 36.2, 29.0, 20.9. [0529] HRMS (ESI+) calculated for C23H24N4O [M+H]⁺: 373.2023, found 373.2015.

hydrochloride 63 (PRC1633).

[0530] Free base of compound 63 was prepared similarly to 1 described above, using methyl 1 -(p-tolyl)-9i/-pyrido [3 ,4-Z>] indole-3 -carboxy late 81 (40 mg, 0.126 mmol), N^j N^j - dimethylpropane- 1,3-diamine (0.08 mL, d = 0.812 g/mL, 0.632 mmol, 5 equiv) affording 28 mg, 58% yield as an off-white powder. A portion of this material (15.2 mg) was dissolved in 0.1 M HC1 in methanol (0.40 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 63 (as the depicted HC1 salt, 16 mg, 96% yield) as a dark yellow solid.

[0531] ¾ NMR (500 MHz, DMSO-ri₆) d 11.8 (s, 1H), 9.9 (br s, 1H), 8.9 (t, J = 6.3 Hz,

1H), 8.8 (s, 1H), 8.4 (d, J= 7.9 Hz, 1H), 8.1 (d, J= 7.9 Hz, 2H), 7.7 (d, J= 8.2 Hz, 1H), 7.6 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H), 7.5 (d, J= 7.9 Hz, 2H), 7.3 (t, J= 7.5 Hz, 1H), 3.5 (app q, J = 6.6 Hz, 2H), 3.2 - 3.1 (m, 2H), 2.8 (d, J= 4.9 Hz, 6H), 2.5 (s, 3H), 2.1 - 1.9 (m, 2H). [0532] ¹³C NMR (126 MHz, DMSO-ri₆) d 164.6, 141.5, 140.5, 139.9, 138.4, 134.7, 134.0,

129.8, 129.3, 128.5, 128.4, 121.9, 121.2, 120.1, 112.6, 112.5, 57.7, 45.3, 38.1, 26.9, 20.9. [0533] HRMS (ESI+) calculated for C₂₄H₂₆N₄O [M+H]⁺: 387.2179, found 387.2168.

hydrochloride 64 (PRC1683).

[0534] Free base of compound 64 was prepared similarly to 1 described above, using methyl 1 -(3.4-dimetho\yphenyl)-9//-pyrido| 3.4- |indole-3-carbo\ylate 82 (50 mg, 0.138 mmol), ethane- 1,2-diamine (0.05 mL, d = 0.90 g/mL, 0.691 mmol, 5 equiv) affording 42 mg, 78% yield as a brown powder. A portion of this material (20.5 mg) was dissolved in 0.1 M HC1 in methanol (0.52 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 64 (as the depicted HC1 salt, 20 mg, 89% yield) as pale brown solid.

[0535] ¾ NMR (400 MHz, DMSO-ri₆) d 11.9 (s, 1H), 9.0 (t, J= 6.1 Hz, 1H), 8.8 (s, 1H),

8.4 (d, J= 8.0 Hz, 1H), 8.1 (br s, 3H), 7.7 - 7.7 (m, 3H), 7.6 (ddd, J= 8.3, 7.0, 1.2 Hz, 1H), 7.3 (ddd, J= 8.0, 7.0, 1.0 Hz, 1H), 7.2 (d, J= 8.9 Hz, 1H), 4.0 (s, 3H), 3.9 (s, 3H), 3.7 (app q, J= 6.2 Hz, 2H), 3.1 (app q, J= 6.0 Hz, 2H).

[0536] ¹³C NMR ( 126 MHz, DMSO-ri₆) 5 165.71, 149.68, 148.94, 141.54, 141.00, 139.21,

134.19, 130.04, 129.54, 128.55, 122.01, 121.35, 121.27, 120.19, 112.75, 112.50, 111.83, 55.78, 55.68, 38.93, 36.94.

[0537] HRMS (ESI+) calculated for C22H22N4O3 [M+H]⁺: 391.1965, found 391.1975.

hydrochloride 65 (PRC1684).

[0538] Free base of compound 65 was prepared similarly to 1 described above, using methyl 1 -(3.4-dimetho\yphenyl)-9//-pyrido| 3.4-6 |indole-3-carbo\ylate 82 (50 mg, 0.138 mmol), /V^;-methylethane- 1,2-diamine (0.07 mL, d = 0.85 g/mL, 0.691 mmol, 5 equiv) affording 52 mg, 93% yield as a brown powder. A portion of this material (20.5 mg) was dissolved in 0.1 M HC1 in methanol (0.51 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 65 (as the depicted HC1 salt, 20.1 mg, 90% yield) as yellow brownish solid.

[0539] ¾NMR (500 MHz, DMSO-ri₆) d 11.9 (s, 1H), 9.0 (t, J= 6.2 Hz, 1H), 8.8 - 8.8 (m, 3H), 8.4 (d, J= 7.9 Hz, 1H), 7.7 - 7.7 (m, 3H), 7.6 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H), 7.3 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H), 7.2 (d, J= 7.9 Hz, 1H), 4.0 (s, 3H), 3.9 (s, 3H), 3.7 (app q, J= 6.0 Hz, 2H), 3.2 - 3.1 (app q, J= 6.1 Hz, 2H), 2.6 (t, J= 5.4 Hz, 3H).

[0540] ¹³C NMR (126 MHz, DMSO-ri₆) 5 165.78, 149.69, 148.94, 141.55, 141.01, 139.17,

134.20, 130.01, 129.54, 128.56, 122.01, 121.36, 121.27, 120.21, 112.80, 112.76, 112.51, 111.83, 55.78, 55.69, 48.34, 35.59, 32.67.

[0541] HRMS (ESI+) calculated for C23H24N4O3 [M+H]⁺: 405.1921, found 405.1917.

l-(3,4-dimethoxyphenyl)-N-(2-(dimethylamino)ethyl)-9H-pyrido[3,4-b]indole-3-carboxamide hydrochloride 66 (PRC1682).

[0542] Free base of compound 66 was prepared similarly to 1 described above, using methyl 1 -(3.4-dimetho\yphenyl)-9//-pyrido| 3.4-6 |indole-3-carbo\ylate 82 (50 mg, 0.138 mmol), /V^;,/V^;-dimethylethane-l, 2-diamine (0.09 mL, d = 0.807 g/mL, 0.691 mmol, 5 equiv) affording 46 mg, 79% yield as a brown powder. A portion of this material (20.9 mg) was dissolved in 0.1 M HC1 in methanol (0.50 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 66 (as the depicted HC1 salt, 20.3 mg, 89% yield) as pale brownish solid.

[0543] ¾ NMR (500 MHz, DMSO-ri₆) 5 11.9 (s, 1H), 9.9 (br s, 1H), 9.0 (t, J = 6.2 Hz,

1H), 8.8 (s, 1H), 8.4 (d, J= 7.9 Hz, 1H), 7.7 - 7.7 (m, 3H), 7.6 (ddd, J= 8.3, 6.9, 1.2 Hz, 1H), 7.3 (app, J= 7.4 Hz, 1H), 7.2 (d, J= 8.8 Hz, 1H), 4.0 (s, 3H), 3.9 (s, 3H), 3.8 (app q, J= 6.1 Hz, 2H), 3.3 (app q, J= 5.8 Hz, 2H), 2.9 (d, J= 4.8 Hz, 6H).

[0544] ¹³C NMR (126 MHz, DMSO-ri₆) 5 165.8, 149.7, 148.9, 141.5, 141.0, 139.1, 134.2,

130.1, 129.5, 128.6, 122.0, 121.3, 121.3, 120.2, 112.8, 112.7, 112.5, 111.8, 56.4, 55.8, 55.7, 42.5, 34.4.

[0545] HRMS (ESI+) calculated for C24H26N4O3 [M+H]⁺: 419.2078, found 419.2085.

(PRC 1673).

[0546] Compound 67 was prepared similarly to 1 described above, using methyl 1- cyclohe\yl-9//-pyrido| 3.4-6 |indole-3-carbo\ylate 83 (50 mg, 0.162 mmol), /V^;-methylethane- 1, 2-diamine (0.08 mL, d = 0.85 g/mL, 0.811 mmol, 5 equiv) affording 52 mg, 91% yield as an off-white powder.

[0547] ¾ NMR (500 MHz, DMSO-ri₆) 5 11.9 (s, 1H), 8.6 - 8.6 (m, 2H), 8.3 (d, J= 7.9

Hz, 1H), 7.6 (d, J= 8.2 Hz, 1H), 7.6 (app t, J= 7.6 Hz, 1H), 7.3 (app t, J= 7.4 Hz, 1H), 3.4 (app q, J= 6.3 Hz, 2H), 2.7 (app t ,J= 6.4 Hz, 2H), 2.3 (s, 3H), 2.0 - 1.8 (m, 8H), 1.6 - 1.5 (m, 2H), 1.4 - 1.3 (m, 1H).

[0548] ¹³C NMR (126 MHz, DMSO-ri₆) d 164.9, 148.4, 140.8, 139.0, 134.5, 128.2, 127.9,

122.0, 121.5, 119.8, 112.2, 111.7, 51.0, 40.7, 38.6, 36.1, 31.0, 26.2, 25.7.

l-isopropyl-N-(2-(methylamino)ethyl)-9H-pyrido[34-b lindole-3-carboxamide 68 (PRC 1674).

[0549] Free base of compound 68 was prepared similarly to 1 described above, using methyl 1 -isopropyl-9//-pyrido| 3.4-6 |indole-3-carbo\ylate 84 (50 mg, 0.169 mmol), N¹- methylethane- 1,2-diamine (0.08 mL, d = 0.85 g/mL, 0.846 mmol, 5 equiv) affording 44 mg, 84% yield as an off-white powder. A portion of this material (24.0 mg) was dissolved in 0.1 M HC1 in methanol (0.75 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 68 (as the depicted HC1 salt,

23.8 mg, 89% yield) as yellow solid.

[0550] ¾ NMR (500 MHz, DMSO-ri₆) d 12.1 (s, 1H), 8.9 - 8.7 (m, 3H), 8.3 (d, J= 7.9

Hz, 1H), 7.7 (d, J= 8.2 Hz, 1H), 7.6 (app t, J= 7.4 Hz, 1H), 7.3 (app t, J= 7.4 Hz, 1H), 3.9 -

3.8 (m, 3H), 3.1 (app quintet, J= 6.0 Hz, 2H), 2.6 (t, J= 5.4 Hz, 3H), 1.5 (d, J= 6.8 Hz, 6H).

[0551] ¹³C NMR (126 MHz, DMSO-ri₆) d 165.7, 149.1, 141.1, 138.0, 134.4, 128.6, 128.1,

122.1, 121.3, 120.1, 112.5, 112.4, 48.4, 35.6, 32.7, 30.9, 21.3.

hydrochloride 69 (PRC1692).

[0552] To an oven-dried 25 mL RBF were added methyl l-(5-bromothiophen-3-yl)-9H- pyrido[3,4-b]indole-3-carboxylate 85 (40 mg, 0.103 mmol) and a magnetic stirbar. The flask was sealed with a rubber septum and purged with N2 for 5 minutes. /V%methylethane- 1,2- diamine (0.21 mL, d = 0.85 g/mL, 2.06 mmol, 20 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 24 h, at which point TLC indicated complete consumption. The reaction was allowed to cool to r.t, then placed in an ice bath, and ice-cold water (~3 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried obtain the free base of 1 (37 mg, 87% yield). It was dissolved in 0.1 M HCI in methanol (4.8 mL, prepared from 12 N HCI (aq)), concentrated in vacuo. The salt was again dissolved in methanol (5 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 69 (as the depicted HCI salt, 40 mg, 83% yield).

[0553] ¾ NMR (400 MHz, Methanol-ri₄) d 8.81 (s, 1H), 8.32 - 8.20 (m, 2H), 8.12 (d, J =

1.7 Hz, 1H), 7.71 (dt, J= 8.3, 0.9 Hz, 1H), 7.61 (ddd, J= 8.3, 7.1, 1.2 Hz, 1H), 7.35 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 3.86 - 3.79 (m, 2H), 3.3 (2H, overlapped by CD2HOD), 2.77 (s, 3H).

l-( 3, 4-dichlorophenyl)-N-(2-morpholinoethyl)-9H-pyrido[3, 4-b lindole-3-carboxamide hydrochloride 70 (PRC 1693).

[0554] Free base of compound 70 was prepared similarly to 1 described above, using methyl 1 -(3.4-dichlorophenyl)-9//-pyrido|3.4- |indole-3-carbo\ylate 31 (40 mg, 0.108 mmol), 3-morpholinopropan-l -amine (0.08 mL, d = 0.987 g/mL, 0.539 mmol, 5 equiv) affording 40 mg, 80% yield as an off-white powder. A portion of this material (30.0 mg) was dissolved in 0.1 M HC1 in methanol (0.64 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight. This solid was agitated with 1 mL of water for 6 h, filtered to get 70 (as the depicted HC1 salt, 22 mg, 68% yield) an off-white powder.

[0555] 1H NMR (400 MHz, DMSO-d6) d 12.0 (s, 1H), 8.9 (s, 1H), 8.8 (t, J = 5.7 Hz, 1H), 8.4 (d, J = 8.0 Hz, 1H), 8.4 (d, J = 2.1 Hz, 1H), 8.1 (dd, J = 8.3, 2.1 Hz, 1H), 7.9 (d, J = 8.4 Hz, 1H), 7.7 (dt, J = 8.3, 1.0 Hz, 1H), 7.6 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.3 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 3.6 (t, J = 4.6 Hz, 4H), 3.5 (app q, J = 6.3 Hz, 2H), 2.6 (t, J = 6.5 Hz, 2H), 2.5 (s, 3H). [0556] 13C NMR (126 MHz, DMSO-d6) d 164.3, 141.7, 139.9, 138.0, 137.8, 134.2, 131.8,

131.7, 130.9, 130.5, 130.4, 128.9, 128.8, 122.2, 121.1, 120.4, 113.6, 112.6, 66.4, 57.1, 53.2,

35.7.

[0557] HRMS (ESI+) calculated for C24H22C12N402 [M+H]+: 469.1193, found 469.1192.

carboxamide 71 (PRC1694).

[0558] Compound 71 was prepared similarly to 1 described above, using methyl l-(3,4- dichlorophenyl)-9//-pyrido| 3.4-6 |indole-3-carbo\ylate 31 (40 mg, 0.108 mmol), 2-((3- aminopropyl)amino)ethan-l-ol (0.06 mL, d = 1.007 g/mL, 0.539 mmol, 5 equiv) affording 32 mg, 65% yield as an off-white powder.

[0559] ¾NMR (500 MHz, DMSO-ri₆) d 8.9 (t, J= 6.1 Hz, 1H), 8.9 (s, 1H), 8.4 (d, J= 7.9 Hz, 1H), 8.4 (d, J= 2.0 Hz, 1H), 8.2 (dd, J= 8.2, 2.0 Hz, 1H), 7.9 (d, J= 8.3 Hz, 1H), 7.7 (d, J= 8.2 Hz, 1H), 7.6 (app t , J= 7.6 Hz, 1H), 7.3 (app t , J= 7.5 Hz, 1H), 4.5 (s, 1H), 3.5 - 3.4 (m, 8H), 2.7 - 2.6 (m, 4H), 1.7 (app t, J= 6.8 Hz, 2H).

[0560] ¹³C NMR (126 MHz, DMSO-fife) d 164.6, 141.8, 140.1, 138.1, 137.9, 134.3, 131.8,

131.7, 130.9, 130.7, 130.5, 129.1, 129.0, 122.3, 121.2, 120.4, 113.8, 112.7, 60.4, 51.9, 47.3, 37.6, 29.8.

[0561] HRMS (ESI+) calculated for C23H22CI2N4O2 [M+H]⁺: 457.1193, found 457.1197.

carboxamide hydrochloride 72 (PRC1695).

[0562] To an oven-dried 2 mL vial were added methyl l-(4-chloro-3-fluorophenyl)-9L7- pyridol 3.4-6 |indole-3-carbo\ylate 86 (64 mg, 0.180 mmol) and a magnetic stirbar. The flask was sealed with a rubber septum and purged with N2 for 5 minutes. N¹, /V'-dimethylethane-l .2- diamine (0.092 mL, d = 0.807 g/mL, 0.985 mmol, 5 equiv) was added via syringe, the mixture was yellow color and stirred at r.t. for 5 minutes, and then heated to 90 °C for 22 h, at which point TLC indicated complete consumption of 86 The reaction was allowed to cool to rt, then placed in an ice bath, and ice-cold water (~1 mL) was added to precipitate the product. The resulting mixture was stirred at r.t. for another 5 minutes and the solid was collected by vacuum filtration, and washed with cold water, and air-dried to obtain the free base (53.8 mg, 77% yield). A portion of this material (41.4 mg) was dissolved in 0.1 N HC1 in methanol (1.04 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (5 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 72 (37.3 mg, 86% yield). [0563] ¾ NMR (400 MHz, Methanol-c¾) d 8.93 (s, 1H), 8.31 (dt, J= 8.0, 1.0 Hz, 1H),

8.08 (dd, J= 10.2, 2.0 Hz, 1H), 7.96 (ddd, J= 8.3, 2.0, 0.8 Hz, 1H), 7.76 (dd, J= 8.3, 7.6 Hz, 1H), 7.70 (dt, = 8.3, 1.0 Hz, 1H), 7.65 (ddd, J= 8.3, 7.0, 1.2 Hz, 1H), 7.39 (ddd, J= 8.0, 6.9, 1.1 Hz, 1H), 3.91 (dd, J= 6.2, 5.3 Hz, 2H), 3.51 - 3.44 (t, J= 5.62H), 3.02 (s, 6H).

[0564] HRMS: calc. 411.1382; found 411.1378.

hydrochloride 73 (PRC1696).

[0565] Free base of compound 73 was prepared similarly to 1 described above, using methyl 1 -(3.4.5-trichlorophenyl)-9//-pyrido| 3.4- |indole-3-carbo\ylate 87 (40 mg, 0.0986 mmol), ethane- 1,2-diamine (0.033 mL, d = 0.90 g/mL, 0.493 mmol, 5 equiv) affording 35 mg, 82% yield as an off-white powder. A portion of this material (20.7 mg) was dissolved in 0.1 M HC1 in methanol (0.47 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 73 (as the depicted HC1 salt, 20.1 mg, 90% yield) as bright yellow solid.

[0566] ¾ NMR (500 MHz, CDsOD) d 8.9 (s, 1H), 8.3 - 8.3 (m, 3H), 7.7 (dt, J= 8.3, 1.0

Hz, 1H), 7.6 (ddd, J= 8.2, 6.9, 1.2 Hz, 1H), 7.4 (ddd, J= 8.0, 6.9, 1.1 Hz, 1H), 3.8 (t, J= 5.8 Hz, 2H), 3.2 (t, J= 5.8 Hz, 2H).

[0567] ¹³C NMR (126 MHz, DMSO-ri₆) d 165.5, 141.7, 139.6, 138.1, 136.8, 134.4, 133.5,

130.6, 130.3, 129.3, 129.1, 122.3, 121.1, 120.5, 114.4, 112.7, 38.9, 36.9.

[0568] HRMS (ESI+) calculated for C20H15CI3N4O [M+H]⁺: 433.0384, found 433.0376.

hydrochloride 74 (PRC1697).

[0569] Free base of compound 74 was prepared similarly to 1 described above, using methyl 1 -(3.4.5-trichlorophenyl)-9//-pyrido| 3.4-6 |indole-3-carbo\ylate 87 (40 mg, 0.0986 mmol), /V^;-methylethane- 1,2-diamine (0.05 mL, d = 0.85 g/mL, 0.493 mmol, 5 equiv) affording 37 mg, 84% yield as an off-white powder. A portion of this material (20.0 mg) was dissolved in 0.1 M HC1 in methanol (0.44 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 74 (as the depicted HC1 salt, 19.8 mg, 92% yield) as bright yellow solid.

[0570] ¾ NMR (500 MHz, DMSO-ri₆) d 12.1 (s, 1H), 9.1 (t, J= 6.1 Hz, 1H), 8.9 (s, 1H),

8.7 (br s, 2H), 8.5 (d, J= 7.9 Hz, 1H), 8.4 (s, 2H), 7.7 (d, J= 8.2 Hz, 1H), 7.6 (app t, J= 7.7 Hz, 1H), 7.3 (app t , J = 7.4 Hz, 1H), 3.7 (app q, J= 6.1 Hz, 2H), 3.2 (app quintet, J= 6.0 Hz, 2H), 2.6 (t, J= 5.4 Hz, 3H).

[0571] ¹³C NMR (126 MHz, DMSO-ri₆) d 165.5, 141.7, 139.6, 138.0, 136.8, 134.4, 133.5,

130.6, 130.3, 129.3, 129.1, 122.3, 121.1, 120.6, 114.4, 112.7, 48.3, 35.6, 32.7.

[0572] HRMS (ESI+) calculated for C21H17CI3N4O [M+H]⁺: 447.0541, found 447.0536.

N-(2-(dimethylamino)ethyl)-l-(3, 4, 5-trichlorophenyl)-9H-pyrido[3, 4-b lindole-3- carboxamide hydrochloride 75 (PRC1698).

[0573] Free base of compound 75 was prepared similarly to 1 described above, using methyl 1 -(3.4.5-trichlorophenyl)-9//-pyrido| 3.4-6 |mdole-3-carbo\ylate 87 (40 mg, 0.0986 mmol), /V^;,/V^;-dimethylethane-l, 2-diamine (0.06 mL, d = 0.807 g/mL, 0.493 mmol, 5 equiv) affording 40 mg, 89% yield as an off-white powder. A portion of this material (20.1 mg) was dissolved in 0.1 M HC1 in methanol (0.43 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 75 (as the depicted HC1 salt, 20.2 mg, 93% yield) as bright yellow solid.

[0574] ¾ NMR (500 MHz, DMSO-ri₆) d 12.1 (s, 1H), 10.0 (br s, 1H), 9.1 (t, J= 6.2 Hz,

1H), 8.9 (s, 1H), 8.5 (d, J= 7.9 Hz, 1H), 8.4 (s, 2H), 7.7 (d, J= 8.2 Hz, 1H), 7.6 (app t , J= 7.6 Hz, 1H), 7.3 (app t, J= 7.5 Hz, 1H), 3.8 (app q, J= 6.1 Hz, 2H), 3.3 (app q, J= 6.0 Hz, 2H), 2.9 (d, J= 4.9 Hz, 6H).

[0575] ¹³C NMR (126 MHz, DMSO-ri₆) d 165.4, 141.7, 139.5, 138.0, 136.8, 134.4, 133.5,

130.6, 130.3, 129.3, 129.1, 122.3, 121.1, 120.6, 114.4, 112.7, 56.3, 42.5, 34.5.

[0576] HRMS (ESI+) calculated for C22H19CI3N4O [M+H]⁺: 461.0697, found 461.0697.

hydrochloride 76 (PRC1699).

[0577] Free base of compound 76 was prepared similarly to 1 described above, using methyl 1 -(3.4.5-trichlorophenyl)-9//-pyrido| 3.4- |indole-3-carbo\ylate 87 (40 mg, 0.0986 mmol), /V^;-methylpropane- 1,3-diamine (0.06 mL, d = 0.844 g/mL, 0.493 mmol, 5 equiv) affording 40 mg, 89% yield as an off-white powder. A portion of this material (20.6 mg) was dissolved in 0.1 M HC1 in methanol (0.46 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (1 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 76 (as the depicted HC1 salt, 20.7 mg, 93% yield) as bright yellow solid.

[0578] ¾ NMR (500 MHz, DMSO-ri₆) d 12.1 (s, 1H), 9.1 (t, J= 6.3 Hz, 1H), 8.9 (s, 1H),

8.7 (br s, 2H), 8.4 (d, J= 7.9 Hz, 1H), 8.4 (s, 2H), 7.7 (d, J= 8.2 Hz, 1H), 7.6 (ddd, J= 8.2, 6.9, 1.2 Hz, 1H), 7.3 (app t , J 7.5 Hz, 1H), 3.5 (app q, J= 6.6 Hz, 2H), 2.9 (app quintet, J = 6.0, 2H), 2.6 (t, J= 5.4 Hz, 3H), 1.9 (app quintet, J= 6.9 Hz, 2H).

[0579] ¹³C NMR (126 MHz, DMSO-ri₆) d 165.2, 141.7, 139.8, 138.1, 136.8, 134.3, 133.4,

130.6, 130.3, 129.3, 129.1, 122.2, 121.1, 120.5, 114.2, 112.7, 46.2, 36.0, 32.4, 26.3.

[0580] HRMS (ESI+) calculated for C22H19CI3N4O [M+H]⁺: 461.0697, found 461.0694.

hydrochloride 77 (PRC 1700).

[0581] To an oven-dried 25 mL RBF were added methyl l-(3,4-fluorophenyl)-9H- pyrido[3,4-b]indole-3-carboxylate 88 (77 mg, 0.21 mmol) and a magnetic stir bar. The flask was sealed with a rubber septum and purged with N2 for 5 minutes. Nl,Nl-dimethylethane- 1, 2-diamine (0.15 mL, 1.05 mmol, 5 equiv) was added via syringe, the mixture was stirred at rt for 5 minutes, and then heated to 90 °C for 24 h, at which point TLC indicated complete consumption of 88. The reaction was cooled to rt, placed in an ice bath, and ice-cold water (~5 mL) was added to precipitate the product. The resulting mixture was stirred at rt. for another 10 minutes and the solid was collected by vacuum filtration, washed with cold water, and air- dried to obtain the free base of 77 (76 mg, 85 %). A portion of this material (35 mg) was dissolved in 0.1 M HC1 in methanol (1.06 mL, prepared from 12 N HC1 (aq)), concentrated in vacuo. The salt was again dissolved in methanol (5 mL) and concentrated in vacuo to remove residual water. The solid was triturated with toluene and dried overnight to obtain 77 (34 mg, 89%). [0582] 1H NMR (400 MHz, Methanol-d4) d 8.80 (s, 1H), 8.26 (d, J = 7.25 Hz, 1H), 8.09 (m, 1H), 7.95 (m, 1H), 7.66 (m, 1H), 7.59 (m, 1H), 7.51 (m, 1H), 7.34(m, 1H), 3.65 (t, J = 6.8 ,2H), 2.67 (t, J = 6.8, 2H), 2.37 (s, 6H).

[0583] A 150 mL RBF was charged with L-trptophan methyl ester hydrochloride salt (2.0 g, 7.9 mmol), 4 A molecular sieves (4.0 g, powder form), 3-chloro benzaldehyde (0.800 mL, d = 1.24 g/mL , 7.9 mmol, 1.0 equiv), and CH2CI2 (17 mL), capped with a septum and purged with nitrogen. After stirring at rt for 20 h, TFA (1.23 mL, d = 1.18 g/mL, 15.8 mmol, 2 equiv) was added dropwise. After stirring for an additional 18 h. TLC indicated complete consumption of imine intermediate, and the reaction mixture was basified with saturated aq. sodium bicarbonate (20 mL). The molecular sieves were removed by filtration, and the remaining mixture was extracted with EtOAc (4 x 40 mL). The combined organic phases were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by silica plug wash (5:5:1 Hexanes/DCM/EtOAc) to give mixture of cis- and trans- diastereomers (yield 2.5 g, 92%). To another oven-dried 100 mL RBF were added this mixture (520 mg, 1.53 mmol), iodobenzene diacetate (983 mg, 3.05 mmol, 2.0 equiv) and DMF (3 mL). The mixture was stirred at r.t. under N2 for 5 h until completion was indicated by TLC. After completion, the reaction mixture was neutralized with aq. sodium bicarbonate (~14 mL). The mixture was extracted with EtOAc (3 x 15 mL), the combined organic phases washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude product was triturated with toluene (3 x 2 mL), vacuum filtered, and air dried to give 78 (463 mg, 90%) as a pale brown solid.

[0584] ¾ NMR (400 MHz, DMSO-ri₆) d 12.04 (s, 1H), 8.96 (s, 1H), 8.45 (d, J= 7.9 Hz,

1H), 8.17 - 7.96 (m, 2H), 7.75 - 7.57 (m, 4H), 7.35 (app t , J= 7.5 Hz, 1H), 3.94 (s, 3H). [0585] HRMS (ESI+) calculated for C19H13CIN2O2 [M+H]⁺: 337.0738, found: 337.0731.

[0586] Tryptophan methyl ester (1.46 g, 5.73 mmol, 1 equiv) and 4-Fluorobenzaldehyde (0.695 mL, 5.7 mmol, 1 equiv) were combined to do a Pictet-Spengler reaction. The cis and trans products (1.23 g, 67% yield) were separated using column chromatography. Pictet- Spengler product (0.23g, 0.701 mmol, 1 equiv), iodobenzene diacetate(0.48 g, 1.48 mmol, 2 equiv) , and DMF (1.55 mL) were stirred at room temperature in a RBF for 6 hours. The reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was dried with Na₂SC>₄, filtered, and concentrated in vacuo to give 78 (0.154 g, 70%).

[0587] 1H NMR (400 MHz, DMSO-d6) d 8.94 (s, 1H), 8.44 (d, J = 7.92 Hz, 1H), 8.08 (m, 2H), 7.70 (d, J = 8.08 Hz, 1H), 7.61 (m, 1H), 7.47 (t, J = 9.01 Hz, 2H), 7.34 (t, J = 7.14 Hz, 1H), 3.94 (s, 3H).

[0588] 13C NMR (400 MHz, DMSO-d6) d 166.1, 162.6 (d, ^_CF = 245.3 Hz), 141.6, 141.1,

136.3, 134.0, 130.8 (d, ³JCF = 8.13 Hz), 129.3, 128.7, 122.1, 121.1, 120.4, 116.8, 115.7 (d, ²JCF = 21.45), 112.8, 52.3.

[0589] 19F NMR (400 MHz, DMSO-d6) d -112.7.

[0590] Tryptophan methyl ester (1.37 g, 5.37 mmol, 1 equiv) and 4-Bromobenzaldehyde

(0.83 mL, 5.3 mmol, 1 equiv) were combined to do a Pictet-Spengler reaction. The cis and trans products (1.34 g, 3.52 mmol 69% yield) were separated using column chromatography.

Pictet- Spengler product (1.25g, 3.47 mmol, 1 equiv), iodobenzene diacetate(2.24 g, 6.96 mmol, 2 equiv) , and DMF (4.1 mL) were stirred at room temperature in a RBF for 6 hours. The reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was dried with Na₂SC>₄, filtered, and concentrated in vacuo to give 79 (0.79 g, 63%).

[0591] 1H NMR (400 MHz, Methanol-d4) d 8.90 (s, 1H), 8.43 (d, J = 9.3 Hz, 1H), 7.97 (d, J = 9.3 Hz, 2H), 7.82 (d, 9.3 Hz, 2H), 7.67 (d, J = 8.16 Hz, 1H), 7.6 (t, J = 7.9 Hz, 1H), 7.32 (t, J = 7.03 Hz, 1H), 2.48 (s, 3H).

[0592] 13C NMR (400 MHz, Methanol-d4) d 165.9, 141.5, 140.8, 136.7, 136.6, 134.5,

131,7, 130.7, 129.4, 128.8, 122.5, 122.1, 120.5, 117.0, 112.8, 52.2.

[0593] A 150 mL RBF was charged with L-trptophan methyl ester hydrochloride salt (2.0 g, 7.8 mmol), 4 A molecular sieves (4.0 g, powder form), 4-methyl benzaldehyde (0.94 mL, d = 1.02 g/mL, 7.9 mmol, 1.0 equiv), and CH2CI2 (20 mL), capped with a septum and purged with nitrogen. After stirring at rt for 22 h, TFA (1.5 mL, d = 1.18 g/mL, 15.7 mmol, 2 equiv) was added dropwise. After stirring for an additional 49 h TLC indicated complete consumption of imine intermediate, and the reaction mixture was basified with saturated aq. sodium bicarbonate (20 mL). The molecular sieves were removed by filtration, and the remaining mixture was extracted with EtOAc (3 x 40 mL). The combined organic phases were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by silica plug wash (5:5:1 Hexanes/DCM/EtOAc) to give mixture of cis- and trans- diastereomers in 2:1 ratio (yield 1.5 g, 61%). To another oven-dried 100 mL RBF were added cis isomer of this product (500 mg, 1.56 mmol), iodobenzene diacetate (1.005 g, 3.12 mmol, 2.0 equiv) andDMF (3 mL). The mixture was stirred at r.t. under N2 for 5 h until completion was indicated by TLC. After completion, the reaction mixture was neutralized with aq. sodium bicarbonate (~12 mL). The mixture was extracted with EtOAc (3 x 15 mL), the combined organic phases washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude product was triturated with toluene (3 x 2 mL), vacuum filtered, and air dried to give 81 (435 mg, 88%) as a pale brown solid. [0594] ¾ NMR (400 MHz, DMSO-ri₆) d 11.9 (s, 1H), 8.9 (s, 1H), 8.4 (d, J= 7.9 Hz, 1H),

7.9 (d, J= 8.0 Hz, 2H), 7.7 (d, J= 8.2 Hz, 1H), 7.6 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H), 7.5 (d, J = 7.8 Hz, 2H), 7.4 - 7.3 (m, 1H), 3.9 (s, 3H), 2.5 (s, 3H).

[0595] ¹³C NMR (126 MHz, DMSO-ri₆) d 166.1, 142.2, 141.5, 138.5, 136.6, 134.8, 134.5,

129.4, 129.1, 128.6, 128.5, 122.0, 121.2, 120.4, 116.5, 112.8, 52.1, 21.0.

[0596] A 150 mL RBF was charged with L-tryptophan methyl ester hydrochloride salt (1.5 g, 5.9 mmol), 4 A molecular sieves (4.0 g, powder form), 4-methyl benzaldehyde (983 mg, 5.9 mmol, 1.0 equiv), and CH2CI2 (17 mL), capped with a septum and purged with nitrogen. After stirring at rt for 23 h, TFA (1.6 mL, d = 1.18 g/mL, 20.9 mmol, 2 equiv) was added dropwise. After stirring for an additional 1 week. TLC indicated complete consumption of imine intermediate, and the reaction mixture was basified with saturated aq. sodium bicarbonate (20 mL). The molecular sieves were removed by filtration, and the remaining mixture was extracted with EtOAc (3 x 40 mL). The combined organic phases were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by silica plug wash (5:5:1 Hexanes/DCM/EtOAc) to give mixture of cis- and trans- diastereomers (yield 1.9 g, 88%). To another oven-dried 100 mL RBF were added this mixture (500 mg, 1.36 mmol), iodobenzene diacetate (879 mg, 2.79 mmol, 2.0 equiv) and DMF (3 mL). The mixture was stirred at r.t. under N2 for 17 h until completion was indicated by TLC. After completion, the reaction mixture was neutralized with aq. sodium bicarbonate (~12 mL). The mixture was extracted with EtOAc (3 x 15 mL), the combined organic phases washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude product was triturated with toluene (3 x 2 mL), vacuum filtered, and air dried to give 82 (325 mg, 66%) as a pale brown solid.

[0597] ¾ NMR (500 MHz, DMSO-rie) d 11.9 (s, 1H), 8.9 (s, 1H), 8.4 (d, J= 7.9 Hz, 1H),

7.7 (d, J= 8.2 Hz, 1H), 7.6 - 7.5 (m, 3H), 7.3 (app t , J= 7.5 Hz, 1H), 7.2 (d, J= 8.1 Hz, 1H), 4.0 - 3.9 (m, 9H).

[0598] HRMS (ESI+) calculated for C21H18N2O4 [M+H]⁺: 363.1339, found: 363.1342.

[0599] Pictet-Spengler adduct was prepared according to literature⁸ to give mixture of cis- and trans- diastereomers in 2:1 ratio (yield 1.2 g, 73%). To an oven-dried 100 mL RBF were added mixture of isomers of this product (300 mg, 0.96 mmol), iodobenzene diacetate (619 mg, 1.92 mmol, 2.0 equiv) and DMF (1.5 mL). The mixture was stirred at r.t. under N2 for 9 h until completion was indicated by TLC. After completion, the reaction mixture was neutralized with aq. sodium bicarbonate (~9 mL). The mixture was extracted with EtOAc (3 x 15 mL), the combined organic phases washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude product was triturated with toluene (3 x 2 mL), vacuum filtered, and air dried to give 83 (165 mg, 56%) as a pale brown solid.

[0600] ¾ NMR (400 MHz, , DMSO-ri₆) d 12.0 (s, 1H), 8.8 (d, J= 0.5 Hz, 1H), 8.3 (dt, J 7.8, 1.0 Hz, 1H), 7.7 (dt, J= 8.2, 1.0 Hz, 1H), 7.6 - 7.6 (m, 1H), 7.3 - 7.3 (m, 1H), 3.9 (s, 3H), 2.0 - 1.7 (m, 8H), 1.6 - 1.5 (m, 2H), 1.4 - 1.3 (m, 1H).

[0601] HRMS (ESI+) calculated for C19H20N2O2 [M+H]⁺: 305.1598, found: 305.1591.

84 methyl l-isopropyl-9H-pyrido[34-blindole-3-carboxylate 84.

[0602] Pictet-Spengler adduct was published prepared according to literature⁹ to give trans- diastereomer (yield 90 mg, 93%). To an oven-dried 100 mL RBF were added mixture of isomers of this product (300 mg, 1.01 mmol), iodobenzene diacetate (710 mg, 2.2 mmol, 2.0 equiv) and DMF (1.5 mL). The mixture was stirred at r.t. under N2 for 9 h until completion was indicated by TLC. After completion, the reaction mixture was neutralized with aq. sodium bicarbonate (~9 mL). The mixture was extracted with EtOAc (3 x 15 mL), the combined organic phases washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude product was triturated with toluene (3 x 2 mL), vacuum filtered, and air dried to give 84 (201 mg, 68%) as a pale brown solid.

[0603] ¾ NMR (400 MHz, DMSO-ri₆) d 12.0 (s, 1H), 8.8 (d, J= 0.6 Hz, 1H), 8.4 (dt, J =

7.9, 0.7 Hz, 1H), 7.7 (dt, .7= 8.2, 1.0 Hz, 1H), 7.6 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H), 7.3 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 3.9 (s, 3H), 3.7 - 3.7 (m, 1H), 1.4 (d, J= 6.8 Hz, 6H).

[0604] ¹³C NMR (126 MHz, DMSO-ri₆) d 166.3, 150.3, 140.7, 136.1, 134.8, 128.4, 127.3,

122.0, 121.4, 120.1, 116.0, 112.3, 51.9, 31.1, 21.3.

[0605] HRMS (ESI+) calculated for C16H16N2O2 [M+H]⁺: 269.1285, found: 269.1275.

[0606] To an oven-dried 100 mL RBF were added (0.27 g, 1.05 mmol) tryptophan methyl ester hydrochloride, 5-bromothiophene-3-carbaldehyde (0.2 g, 1.05 mmol, 1 equiv), 0.6 g of 4A Molecular sieves and 4mL dry DCM. The reaction mixture was stirred at r.t. under N2 for 24 h. Then (0.4 mL, 5.25mmol, 5 equiv) TFA was added and stirred for 2 days. After completion, the reaction mixture was neutralized with aq. sodium bicarbonate (10 mL) and the molecular sieves was separated by vacuum filtration. The collected liquid was extracted with EtOAc (3x15 mL). The combined organic phases washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude product was purified by silica chromatography (Hexane: DCM: EtOAc= 5:5:1) to obtain cis/trans isomers (350 mg, 85%).

[0607] To an oven-dried 100 mL RBF were added cis/trans isomers of methyl l-(5- bromothiophen-3-yl)-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-3-carboxylate (350 mg, 0.89 mmol), iodobenzene diacetate (577 mg, 1,78 mmol, 2.0 equiv) and DMF (5 mL). The mixture was stirred at r.t. under N2 for 12 h. After completion, the reaction mixture was neutralized with aq. sodium bicarbonate (~12 mL). The mixture was extracted with EtOAc (3 x 15 mL), the combined organic phases washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude product was purified with silica chromatography (Hexane: EtOAc=5: 1) to give 85 (78 mg, 22%) as a white crystal. [0608] ¾ NMR (400 MHz, DMSO-ri₆) d 11.91 (s, 1H), 8.43 (dt, J= 7.9, 1.0 Hz, 1H), 8.32

(d, = 1.6 Hz, 1H), 7.91 (d, = 1.6 Hz, 1H), 7.73 (dt, = 8.2, 1.0 Hz, 1H), 7.63 (ddd, = 8.3, 7.1, 1.2 Hz, 1H), 7.35 (ddd, ./= 8.1, 7.0, 1.0 Hz, 1H), 3.94 (s, 3H).

methyl l-(4-chloro-3-fluorophenyl)-9H-pyrido[34-b lindole-3-carboxylate 86.

[0609] Pictet-Spengler reaction was carried out as described above, using tryptophan methyl ester (1.0 g, 3.93 mmol) and 4-chloro-3-fluorobenzaldehyde (610.04 mg 3.85 mmol, 0.98 equiv). Following workup and chromatography, a mixture of the cis- and trans- methyl 1 -(4-chloro-3-riuorophenyl)-2.3.4.9-tetrahydro- 17/-pyrido| 3.4-6 |indole-3-carbo\ylate was obtained (1.02 g, 62%). A portion of this material (500 mg, 1.39 mmol) was added to an oven- dried 100 mL round-bottomed flask and equipped with a magnetic stirbar. Phenyliodine (III) diacetate (943 mg 2.93 mmol, 2.1 equiv) was added, the flask was sealed with a rubber septum and purged with N2 for 5 minutes. Dimethylformamide (3 mL) and the reaction was stirred for 1 day, at which point TLC indicated the complete consumption of the starting material. The reaction was quenched by adding NaHCCh solution until pH = 7. The reaction mixture was transferred to a 250-mL separation funnel for the liquid-liquid separation process. The water layer was collected after ethyl acetate wash (3 X 15 mL). The organic layer was collected after washed by 30 mL saturated NaCl solution and dried by Na2SC>4 for 10 minutes, and concentrated in vacuo to leave an orange solid. The crude product was dried in high-vac for 30 minutes. The crude product was purified by trituration with toluene (3 X 2 mL). The toluene layer was orange color, and obtained the solid product 86 (293 mg, 59% yield).

[0610] ¾ NMR (400 MHz, DMSO-ri₆) d 8.97 (s, 1H), 8.45 (dt, J= 8.0, 1.0 Hz, 1H), 8.02

(dd, J= 10.4, 1.9 Hz, 1H), 7.90 (dd, J= 8.4, 1.9 Hz, 1H), 7.86 (dd, J= 8.3, 7.3 Hz, 1H), 7.70 (dt, J= 8.3, 1.0 Hz, 1H), 7.63 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H), 7.35 (ddd, J= 7.9, 7.0, 1.1 Hz, 1H), 3.94 (s, 3H).

[0611] A 150 mL RBF was charged with L-trptophan methyl ester hydrochloride salt (606 mg, 2.4 mmol), 4 A molecular sieves (3.0 g, powder form), 4-methyl benzaldehyde (500 mg, 2.4 mmol, 1.0 equiv), and CH2CI2 (17 mL), capped with a septum and purged with nitrogen. After stirring at rt for 24 h, TFA (0.76 mL, d = 1.18 g/mL, 4.7 mmol, 2 equiv) was added dropwise. After stirring for an additional 48 h TLC indicated complete consumption of imine intermediate, and the reaction mixture was basified with saturated aq. sodium bicarbonate (15 mL). The molecular sieves were removed by filtration, and the remaining mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by silica plug wash (7:7:1 Hexanes/DCM/EtOAc) to give mixture of cis- and trans- diastereomers (yield 720 mg, 75%). To another oven-dried 100 mL RBF were added this mixture product (500 mg, 1.22 mmol), iodobenzene diacetate (786 mg, 2.44 mmol, 2.0 equiv) and DMF (3 mL). The mixture was stirred at r.t. under N2 for 5 h until completion was indicated by TLC. After completion, the reaction mixture was neutralized with aq. sodium bicarbonate (~12 mL). The mixture was extracted with EtOAc (3 x 15 mL), the combined organic phases washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude product was triturated with toluene (3 x 2 mL), vacuum filtered, and air dried to give 87 (352 mg, 71%) as a pale brown solid.

[0612] ¾NMR (400 MHz, DMSO-ri₆) d 12.1 (s, 1H), 9.0 (s, 1H), 8.5 (dt, J= 8.0, 1.0 Hz, 1H), 8.2 (s, 2H), 7.7 (dt, J= 8.2, 1.0 Hz, 1H), 7.6 (ddd, J= 8.2, 6.9, 1.2 Hz, 1H), 7.4 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 3.9 (s, 3H).

[0613] HRMS (ESI+) calculated for C19H11CI3N2O2 [M+H]⁺: 404.9959, found : 404.9952.

[0614]

References for Example 3

(1) Murithi, J. M.; Owen, E. S.; Istvan, E. S.; Lee, M. C. S.; Ottilie, S.; Chibale, K.; Goldberg, D. E.; Winzeler, E. A.; Llinas, M.; Fidock, D. A.; Vanaerschot, M. Combining Stage Specificity and Metabolomic Profiling to Advance Antimalarial Drug Discovery. Cell Chem Biol 2020, 27, 158-171 e3.

(2) Ghavami, M.; Merino, E. F.; Yao, Z.-K.; Elahi, R.; Simpson, M. E.; Femandez-Murga, M. L.; Butler, J. H.; Casasanta, M. A.; Krai, P. M.; Totrov, M. M.; Slade, D. I; Carlier, P. R.; Cassera, M. B. Biological Studies and Target Engagement of the 2-C-Methyl- -Erythritol 4- Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (l//.35')- MV00 138 and Analogs. ACS Infect. Dis. 2018, 4 , 549-559.

(3) Reyser, T.; Paloque, L.; Ouji, M.; Nguyen, M.; Menard, S.; Witkowski, B.; Augereau, J. M.; Benoit-Vical, F. Identification of compounds active against quiescent artemisinin- resistant Plasmodium falciparum parasites via the quiescent-stage survival assay (QSA). Journal of Antimicrobial Chemotherapy 2020, 75, 2826-2834.

(4) Bowman, J. D.; Merino, E. F.; Brooks, C. F.; Striepen, B.; Carlier, P. R.; Cassera, M. B. Antiapicoplast and gametocytocidal screening to identify the mechanisms of action of compounds within the malaria box. Antimicrob Agents Chemother 2014, 58, 811-9.

(5) Smilkstein, M.; Sriwilaijaroen, N.; Kelly, J. X.; Wilairat, P.; Riscoe, M. Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening. Antimicrob Agents Chemother 2004, 48, 1803-6.

(6) Kamal, A.; Tangella, Y.; Manasa, K. L.; Sathish, M.; Srinivasulu, V.; Chetna, J.; Alarifi, A. PhI(OAc)2-mediated one-pot oxidative decarboxylation and aromatization of tetrahydro-b- carbolines: synthesis of norharmane, harmane, eudistomin U and eudistomin I. Org. Biomol. Chem. 2015, 13, 8652-8662.

(7) Yao, Z.-K.; Krai, P. M.; Merino, E. F.; Simpson, M. E.; Slebodnick, C.; Cassera, M. B.; Carlier, P. R. Determination of the active stereoisomer of the MEP pathway-targeting antimalarial agent MMV008138, and initial structure-activity studies. Bioorg. Med. Chem. Lett. 2015, 25, 1515-1519.

(8) Cagasova, K. ; Ghavami, M. ; Y ao, Z. -K. ; Carlier, P. R. Questioning the g-gauche effect: stereoassignment of l,3-disubstituted-tetrahydro- -carbolines using 1H-1H coupling constants. Org. Biomol. Chem. 2019, 17, 6687-6698.

(9) Xiao, S.; Lu, X.; Shi, X.-X.; Sun, Y.; Liang, L.-L.; Yu, X.-FL; Dong, J. Syntheses of chiral 1,3-disubstituted tetrahydro- -carbolines via CIAT process: highly stereoselective Pictet-Spengler reaction of d-tryptophan ester hydrochlorides with various aldehydes. Tetrahedron: Asymmetry 2009, 20, 430-439. Example 4. PRC 1492

[0615] As discussed elsewhere herein, the free base of PRC1584 is Compound 30 (also referred to as PCR1492). FIG. 13 shows the estimated metabolic stability of Compound 30 (PRC 1492). FIG. 14 shows images that can demonstrate the effect Compound 30 (PRC 1492) has on phenotype and its stage specify. FIG. 15 shows the results for ex vivo testing of PRC1492 against Uganda field isolates (n=31). No significant resistance was observed.

Example 5

[0616] Compounds A9 (FIG. 17) and A15 (Table 2) emerged from optimization of the Malaria Box compound MMV008138. Compound A15 is described in Table 2 below but is the 4'-ethoxy analog of A9. Unlike tetrahydro- -carboline MMV008138 (FIG. 18), A9 and A15 are acylated atN2 and unsubstituted at C3. As shown in FIG. 17, A9 has excellent potency in vitro against three strains of asexual blood-stage Plasmodium falciparum. Analog A15 is similarly potent to Dd2 strain P. falciparum (ECso = 138 ± 11 nM, Table 2). Compound A9 arrests P. falciparum in vitro cultures in the trophozoite stage under continuous drug pressure; washout experiments indicate that it is cytotoxic in late trophozoite/early schizont stages. Unlike MMV008138, P. falciparum growth inhibition by A9 is not reversed by supplementation with isopentenyl pyrophosphate (IPP). Thus, the antimalarial target of A9 is not within the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway. In addition, Dd2- KAE609^R strain P. falciparum is susceptible to A9 (FIG. 17), signifying that the antimalarial target of A9 is not the ATPase P/ATP4, the enzyme responsible for the antimalarial activity of KAE609 (cipargamin). Note that KAE609 is a l,l,3-trisubstituted-tetrahydro- -carboline (FIG. 18). Thus, although A9/A15, MMV008138, and KAE609 all contain the tetrahydro-b- carboline core structure, they are differently substituted and consequently engage different antimalarial targets. Thus, the antimalarial activity of A9/15A could not be predicted from the structures of MMV008138 and KAE609.

[0617] Thus far A9 has shown an excellent safety profile. As depicted in FIG. 17, A9 shows excellent selectivity against four mammalian cell lines (EC5o/CC5o³ 100) and against a major component of the gut microbiome ( E . coli MIC > 250 mM). Thus, A9 is not generally cytotoxic. Although A9 and A15 are unknown, their racemic forms are known (Chemical Abstracts Registry No. 312515-92-7 & 312521-73-6) and in this application are termed A7 and A26, respectively. No biological (or any other properties) of A7 or A26 are known, but A7 was disclosed and evaluated for antimalarial activity by Novartis (GNF-Pf-5009 in the Novartis P .falciparum whole-cell HTS hit dataset), as part of their contribution to the Malaria Box¹ effort. A7 was not considered promising enough to be included as one of the 400 compounds of the Malaria Box and thus is not found there.

[0618] As mentioned above, none of the pure ( R )- or (//(-enantiomers of A7 (i.e., A9 and 8A) nor of A26 (i.e., A15 and A14) have been described previously. The Examples here and elsewhere herein can demonstrate the superior antimalarial action of the (//(-enantiomers. As shown in FIG. 19, Dd2 P. falciparum growth inhibition of (//(-configured A9 is superior to that of (//(-configured A8 because it displays a simple monophasic concentration-response, suggesting that A9 engages a single target. In contrast (//(-configured A8 shows a biphasic concentration-response, suggesting more than one biological target. Note that A7, as a 50:50 mixture of A8 and A9, gives a hybrid but clearly biphasic concentration-response (data not shown). Secondly, since the concentration-response curve of A9 is steeper than that of A8, the EC95 of A9 is much lower than that of A8 (2.5 and 10 mM respectively). The EC95 value is an important parameter for evaluating malaria drug candidates, since it provides an indication of the concentration needed to stop all parasite growth. As shown in FIG. 20 the same phenomenon is observed for (.//(-configured A15 and (//(-configured A14. The EC95 values of A15 and A14 are 0.65 and 5 mM respectively.

[0619] FIG.21 shows a structure-activity relationship diagram of compounds of Examples 5 and 6. FIGS.22A-22C can demonstrate that compound A7 (racemic form of A9) is cytotoxic to liver stage P. berghei at 5-10 mM (FIGS. 22A-22B), but is not cytotoxic to HepG2 cells at or below 10 mM (FIG. 22C).

[0620] Lastly, a broad panel of ADME and pharmacokinetic data on A9 has been accumulated that suggest acceptable drug-like properties, that we could further optimize (FIG. 17). First of all, A9 is stable in mouse plasma (100% remaining at 1 h) and the stabilities in mouse liver microsomes and mouse hepatocytes are excellent (tin values of 75 and 179 min respectively). Secondly, despite its low solubility (<0.044 mM) and bioavailability (11%), A9 achieves high plasma exposure² following 40 mg/kg oral administration (AUCo-24_h = 32.5 h*pg/mL). with a high elimination phase /1/2 value of 8 h. Asexual Blood Stage Structure-Activity Relationship Data

[0621] 43 compounds were examined (including A9 and A15) for activity against asexual blood-stages of Dd2 strain P. falciparum (Table 2).

Table 2. Summary of compounds tested for activity against asexual blood stages of Dd2 strain P. falciparum.

Cpd PRC#** stereo X A B Y R Z ECso⁷²¹¹

# _g a Dd2 Strain Growth Inhibition³

A1 1571 (±)- 4'-Cl na na na na na 5-10 mM

A2 1567 (±)- 4'-Cl na na na na na 2.5-5 mM

A3 1568 (±)- 4'-Cl na na na na na 2.5-5 mM

A4 1569 (±)- 4'-Cl na na na na na 726 ± 102 nM

A5 1570 (±)- 4'-Cl na na na na na 1.25-2.5 mM

A6 1591 (±)- 4'-Cl na na na na 682 ± 73 nM

A7 1581 (±)- 4'-Cl O CH 5"-Br H 40 and 976 nM^b

A8 1589 (s 4'-Cl O CH 5"-Br H H 28 and 2800 nM^b

A9 1590 (R)- 4'-Cl O CH 5"-Br H H 107 ± 10 nM

A10 1588 (IS, 35) 4'-Cl O CH 5"-Br H C0₂Me 220 ± 32 nM

All 1592 (±)- 4'-F O CH 5"-Br H H 826 ± 42 nM^c

A12 1593 (±)- 4'-Br O CH 5"-Br H H 50 and 1170 nM^b

A13 1602 (±)- 2', 4'- O CH 5"-Br H H 316 ± 37 nM Cl₂

A14 1617 (S)- 4'-OEt O CH 5"-Br H H 625-1,250 nM

A15 1618 (R)- 4'-OEt O CH 5"-Br H H 138 ± 11 nM

A16 1566 (±)- 2', 4'- na na na na na 5-10 mM

Cl₂

A27 1626 (R)- 4'-Cl O CH 5"-Cl H 173 ± 16

A28 1627 (R)- 4'-Cl O CH 5"-H H

1250-2500 A29 1628 (R)- 4'-OEt O CH 5"-H H H 1247 ± 105

A30 1629 (R)- 4'-OEt O CH 5"-Cl H H 129 ± 9

A31 1649 (. R )- 4'-Cl NH CH 5"-Cl H H 1250-2500

A32 1650 ( R )- 4'-OEt NH CH 5"-Cl H H ~1250^d

A33 1651 ( ?)- 4'-OEt NH N 5"-Br H H 625-1250

A34 1654 ( ?)- 4'-OEt O CH 5"-Br Me H 1,536 ± 269

A35 1655 (R)- 4'-OEt O CH 5"-Br CH2CO2 H 1,300 ± 132

Me

A36 1657 4'-OEt O N 5"-Br H H 770 ± 140

A37 1658

4'-OEt O CH 5"-Br CH2CO2 H 1250-2500

H

A38 1660 ( ?)- 4'-OEt O CH 5"-F H H 123 ± 37

A39 1661 (R)- 4'-CN O CH 5"-Cl H H 390 ± 140

A40 1662 (R)- 4'- O CH 5"-Br H H 95 ± 10

OMe

A41 1663 (R)- 4'- O CH 5"-Cl H H 75 ±24

OMe

A42 1671 (R)- 4'-CN O CH 5"-Br H H 216 ± 24 ^aIn vitro growth inhibition of asexual blood-stages of P. falciparum. Dd2 strain is MRA-150, chloroquine-resistant (intermediate), pyrimethamine-resistant, mefloquine-resistant. Inhibition measured at 72 h using SYBR Green I.³ ^bGradual concentration-response curve spans nearly four log units of concentration ^cGradual concentration-response curve spans more than three log units of concentration.

[0622] From the data the at least the following can be concluded. These observations are also summarized in FIG. 5. Tetrahydro- -carbolines bearing N2 substitution of C(0)-(5"- bromobenzofuran-2”-yl) have excellent potency for growth inhibition of P. falciparum, e.g., compound A9 (X = 4'-Cl) which has EC50 = 107 ± 10 nM, A15 (X = 4'-OEt), which has EC50 = 138 ± 11 nM, and A40 (X = 4'-OMe) which has EC50 = 95 ± 10 nM. For comparison, for compounds bearing N2 substituents of H, C(0)Ph, C(0)CEh, C(0)4"-methoxyphenyl (compounds 1-3, 5), all have EC50 > 1 mM. Compounds bearing N2 substituents of C(0)(CH2)2- C-C5H9, C(0)4"-bromophenyl (compounds 4, 6) have EC50 > 500 nM. Within this series of R = C(0)-(5"-bromobenzofuran-2”-yl), X = 4'-Cl (e.g., A9) is superior to X = 4'-F or 2',4'-Cl₂ (e.g., All, 13). Within the series of R = C(0)-(5"-bromobenzofuran-2”-yl), X = 4'-Cl, the racemate and fV)-enantiomers (compounds A7, A8) give gradual and biphasic growth inhibition curves over 4 log concentration units. The biphasic response of the fV)-enantiomer A8 and the racemate A7 (which contains 50% A8) suggests the fV)-enantiomer engages more than one biological target. The (//(-enantiomer (compound A9) gives a typically steep monophasic growth inhibition curve. This simple pharmacological response of the ( R )- enantiomer A9 suggests it is engaging one biological target. Similarly, for X = 4'-OEt, the (S)- enantiomer A14 gives a broad concentration response and has a high preliminary EC50 value of 625-1,250 nM. But the (///-enantiomer A15 gives a sharp concentration-response and an EC50 value of 138 ± 11 nM, similar to the EC50 of (iZ)-enantiomer A9 (X = 4'-Cl). Excellent potency is also seen for compounds bearing N2 substitution of C(0)-(5"-chlorobenzofuran- 2”-yl), i.e. A30 (X = 4'-OEt) and A41 (X = X = 4'-OMe) which have EC50 values of 129 ± 9 nM and 75 ± 24 nM respectively, andN2 substitution of C(0)-(5"-fluorobenzofuran-2”-yl) i.e. A38 (X = 4'-OEt) which has EC50 = 123 ± 37 nM. Thus, favored substitution on the benzofuran ring includes 5"-bromo, chloro, and fluoro. Favored substitution on the D-ring includes 4'- chloro, ethoxy, and methoxy.

[0623] Although A9 has no activity towards Stage V gametocytes of P. falciparum, it shows weak activity towards liver stage P. berghei (EC50 = 5-10 mM, Figure 6). Thus, the possibility exists to optimize the structure of A9 for both asexual blood stages and liver stages of the parasite.

[0624] The absolute configurations of A9 and A15 have been determined by X-ray crystallography, as shown in FIGS. 7 and 8. Finally both A9 and A15 were found to be >95% ee by chiral stationary phase HPLC (FIGS. 9 and 10).

[0625] Table 5 shows additional analogs and compounds of Formula IX.

Table 5. Exemplary compounds according to Formula IX

Formula IX

Cpd PRC#** stereo X A B Y R Z #

A43 337918- (±) 4’- H O CH 5”, 6” H H

81-7 - H

A49 571156- (±) 4’-CH₃ O CH 5”, 6” H H

22-4 - H A50 571155- (±) 3’- O CH 5”, 6” H H

67-4 CH₃ - H

A51 571160- (±) 2’ - O CH 5”, 6” H H

94-6 CH₃ - H

A52 571151- (±) 4’- O CH 5”, 6” H H

87-6 OCH₃ - H

A53 571153- (±) 4’- Cl O CH 5”, 6” H H

70-3 - H

A54 571153- (±). 4’-H O CH 5”-Br, H H

06-5 6”-H

A55 571153- (±) 4’- O CH 5”, 6” H H

27-0 OCH₂ - H

CH₃

A56 571153- (±) 4’- O CH 5”-Br, H H

25-7 CH₃ 6”-H

A57 571152- (±) 4’- O CH 5”-H, H H

68 6 NO₂ 6”-H

A58 571155- (±) 3’- O CH 5”-Br, H H

70-9 CH₃ 6”-H

A59 571160- (±) 2’- O CH 5”-Br, H H

97-9 CH₃ 6”-H

A60 353478- (±) 5’- O CH 5”, 6” H H

74-7 OCH₂ - H

0 - 4’

A61 571157- (±) 3’N0₂ O CH 5”, 6” H H

35-2 - H

A62 571151- (±) 4’- O CH 5”-Br, H H

92-3 OCH₃ 6”-H

A63 571156- (±) 4’-CF₃ O CH 5”, 6” H H

62-2 - H

A64 312521- (±) 4’OEt O CH 5”-Br, H H

73-6 6”-H

A65 571160- (±) 2’- O CH 5”, 6” H H

07-1 NO₂ - H

A66 312518- (±) 4’- O CH 5”-Br, H H

68-6 NO₂ 6”-H

A67 374633- (±) 5’- O CH 5”- H H

94-0 OCH₂ OMe,

0 - 4’ 6” - H

A68 352683- (±) 5’- O CH 5”- H H

35-3 OCH₂ Br, 6”

0 - 4’ - H

A69 571157- (±) 3’- O CH 5”-Br, H H

40-9 NO₂ 6”-H

A70 571159- (±) 4’- O CH 5”-H, H H

09-6 NO₂, 6”-H

5’ -Cl

A71 571154- (±) 4’- Cl, O CH 5”-H, H H

77-3 5’- 6”-H

N0₂

A72 571156- (±) 4’-CF₃ O CH 5”-Br, H H

66-6 6” - H A73 571160- (±) 2’- 4’-GT₃ OH 5”-Br, EH 5H-Br. 6” - H H

11-7 NO2 6” - H H

A74 374633- (±) 5’- O CH 5”- H H

93-9 OCH2 NO2,

0 - 4’ 6” - H

A75 571159- (±) 4’- 4’-GT₃ OH 5”-Br, HH 5HBr, 6” - H H

12 1 NO2, 6” - H H

5’- Cl

A76 571154- (±) 4’- Cl, 0 CH 5”-Br, H H

80-8 5’- 6”-H

NO2

A77 374635- (±) 5’- 0 CH 5”-H, (CH₂)₂N( H

09-3 OCH2 6”-H CH₃)₂

0 -4’

A78 374633- (±) 5’- 0 CH 5”-Br, (CH₂)₂N( H

92-8 OCH2 6”-H CH₃)₂

0 - 4’

Synthetic Procedures and Tabulation of Analytical Data

[0626] Was prepared according to the literature method.⁴

[0627] ¾ NMR (400 MHz, CDCI3) d 7.69 (s, 1H), 7.60 - 7.54 (m, 1H), 7.31 (d, J= 8.5

Hz, 2H), 7.22 (d, J= 8.5 Hz, 2H), 7.20 - 7.19 (m, 1H), 7.18 - 7.09 (m, 2H), 5.11 (s, 1H), 3.32 (ddd, J = 12.6, 5.3, 4.1 Hz, 1H), 3.12 (ddd, J = 12.6, 8.5, 4.8 Hz, 1H), 2.92 (dddd, J= 15.6, 8.5, 5.3, 2.0 Hz, 1H), 2.82 (dddd, J= 15.6, 4.9, 4.1, 1.8 Hz, 1H), 1.91 (s, 1H).

[0628] ¹³C NMR (101 MHz, CDCI3) d 140.4, 136.0, 134.1, 133.9, 129.9, 129.0, 127.4,

122.0, 119.6, 118.4, 110.9, 110.5, 57.4, 42.7, 22.5. HRMS: calculated for Ci₇Hi₆ClN₂ ⁺ 283.0997, found 283.1017 (l-( 4-chlorophenyl)-l, 3, 4, 9-tetrahydro-2H-pyrido[3, 4-b ]indol-2-yl)iphenyl)methanone (A2 )

( PRC1567 )

[0629] Was prepared according to the literature.⁴

[0630] ¾ NMR (400 MHz, DMSO-fife) d 11.05 (s, 1H), 7.51 - 7.31 (m, 11H), 7.10 (td, J

= 7.10, 1.17 Hz, 1H), 7.02 (td, J= 6.9, 1.10 Hz, 1H), 6.92 (s, 1H), 3.66 (d, J= 9.8 Hz, 1H), 3.24 (t, = 11.5 Hz, 1H), 2.8 (t, J= 15.1 Hz, 1H), 2.76 (d, = 14.9 Hz, 1H).

[0631] ¹³C NMR (101 MHz, DMSO-r/e) d 169.7, 139.2, 136.3, 136.1, 132.5, 131.0, 129.9,

129.6, 128.6, 128.5, 126.4, 126.2, 121.5, 118.8, 118.0, 111.3, 108.2, 51.0, 41.2, 21.6. HRMS: calculated for C₂₄H₂₀ClN₂O⁺ 387.1259, found 387.1241

( PRC1568 )

[0632] Was prepared according to the literature.⁵

[0633] ¾ NMR (400 MHz, DMSO-fife) d 10.97 (s, 1H), 7.547 (d, J= 7.8 Hz, 1H), 7.41 (d,

J= 8.5 Hz, 2H), 7.30 (d, J= 8.0 Hz, 1H), 7.22 (d, J= 8.3 Hz, 2H), 7.09 (td, J= 7.2, 1.2 Hz, 1H), 7.01 (td, .7= 7.17, 1.1 Hz, 1H), 6.81 (s, 1H), 3.98 (dd, J= 14.2, 5.0 Hz, 1H), 3.24 - 3.14 (m, 1H), 2.94 - 2.84 (m, 1H), 2.79 (dd, J= 15.5, 3.2 Hz, 1H), 2.15 (s, 3H).

[0634] ¹³C NMR (101 MHz, DMSO-r/e) d 168.8, 139.6, 136.2, 132.3, 131.4, 129.8, 128.3,

126.1, 121.3, 118.7, 117.9, 111.2, 108.5, 50.2, 40.1, 21.49, 21.46.

[0635] HRMS: calculated for C₁₉H₁₈C1N₂0⁺ 325.1102, found 325.1103.

1-fl-f 4-chlorophenyl)-l, 3, 4, 9-tetrahydro-2H-pyrido[3, 4-b Jindol-2-yl)-3-cvclopentylpropan- 1-one (A4) ( PRC1569 )

[0636] A 25 mL RBF was charged with A1 (30 mg, 0.106 mmol) and purged with nitrogen. Then of anhydrous THF (2 mL) was added as solvent. Triethylamine (32 mg 0.04 mL,0.32 mmol) was added then the mixture was cooled in ice/water bath. Then 3-cyclopentylpropanoyl chloride (17.9 mg, 17 pL, 0.11 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C followed by 1 h at room temperature. The mixture was diluted with CFLCh (5 mL) and FLO (15 mL), and the mixture extracted with CFLCL (3 x 5 mL). The organic phase was separated, combined and washed with brine, dried with sodium sulfate, and concentrated in vacuo. This material was redissolved in CFLCL and purified by filtration through a silica plug (total volume 100 mL CFLCL), to give A4 (33 mg, 77%) as a white solid.

[0637] ¾ NMR (400 MHz, CDCL) d 7.87 (s, 1H), 7.54 (d, J= 7.7 Hz, 1H), 7.32 (dt, J =

8.0, 1.0 Hz, 1H), 7.25 (br s,4H), 7.21 (td, J= 7.2, 1.3 Hz, 1H), 7.15 (td, .7= 7.3, 1.1 Hz, 1H), 7.00 (s, 1H), 3.97 (dd, .7= 13.8, 4.6 Hz, 1H), 3.36 (ddd,J= 14.1, 11.1, 5.1 Hz, 1H), 3.07 - 2.76 (m, 3H), 2.43 (t, J= 7.9 Hz, 2H), 1.89 - 1.44 (m, 10H).

[0638] ¹³C NMR (101 MHz, CDCL) d 165.9, 138.7, 136.4, 131.4, 130.3, 128.8, 122.5,

119.9, 118.3, 111.2, 110.3, 77.3, 51.2, 39.9, 39.9, 33.2, 32.7, 32.6, 31.7, 25.3, 22.4.

[0639] HRMS (ESI+) calculated for C₂₅H₂₇C1N₂0⁺ 407.1885, found 407.1868

(l-( 4-chlorophenyl)-l, 3, 4, 9-tetrahydro-2H-pyrido[3, 4-b Jindol-2-yl)(4- methoxyphenvDmethanone (A5) (PRC 1570)

[0640] A 25 mL RBF was charged with A1 (30 mg, 0.106 mmol) and purged with nitrogen. Then anhydrous THF (2 mL) was added as solvent. Triethylamine (32 mg 0.04 mL,0.32 mmol) was added and the mixture was cooled in an ice/water bath. Then 4-methoxybenzoyl chloride (19 mg, 15 pL, 0.11 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C followed by 24 h at 60 °C. The mixture was diluted with CH2CI2 (5 mL) and H2O (15 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The organic phase was separated, combined and washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by column chromatography (5:5:1 Hexanes/ CH2CI2 /EtOAc) to give A5 (32 mg, 52%) as a white solid.

[0641] ¾ NMR (400 MHz, CDCL) d 8.14 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.37 (d, J =

8.8 Hz, 2H), 7.35 - 7.24 (m, 5H), 7.21 (td, J= 8.0, 1.4 Hz, 1H), 7.15 (td,J= 7.1, 1.12 Hz, 1H), 7.04 (br.s, 1H), 6.93 (dt, J= 8.9, 2.3 Hz, 2H), 3.89 (app br s, 1H), 3.84 (s, 3H), 3.33 (app t , J = 12.5 Hz, 1H), 2.98 (apptd, J= 11.9, 5.1 Hz, 1H), 2.82 (app dd, J= 15.5, 3.7 Hz, 1H). ¹³C NMR (101 MHz, CDCL) d 170.8, 160.9, 138.6, 136.5, 134.1, 131.1, 130.3, 128.8, 128.7, 128.3, 126.7, 122.4, 119.8, 118.3, 113.9, 111.4, 109.7, 77.3, 52.1, 41.7, 22.4.

[0642] HRMS: calculated for C₂₅H₂₂C1N₂0₂ ⁺ 417.1364, found 417.1355

( 4-bromophenyl) ( 1 -f4-chlorophenyl)-l, 3, 4, 9-tetrahvdro-2H-pyrido[3, 4-b lindol-2- vDmethanone (A6) (PRC1591)

[0643] A 25 mL RBF was charged with A1 (50 mg, 0.176 mmol), 4- dimethylaminopyridine (2.1 mg, 0.017 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (3 mL) was added as solvent. Triethylamine (53 mg 0.07 mL, 0.530 mmol) was added then the mixture was cooled in ice/water bath. Then 4-bromobenzoyl chloride (42 mg, 0.024 mL, 0.176 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 48 h at room temperature at which point TLC indicated consumption of the acid chloride. The mixture was diluted with CH2CI2 (5 mL) and H2O (15 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (150 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recry stallized from 8:2 EtOH/THF to give A6 (34 mg, 42%) as colorless needles.

[0644] ¾ NMR (400 MHz, DMSO-ri₆) d 11.05 (s, 1H), 7.68 (d, J= 8.4 Hz, 2H), 7.53 -

7.42 (m, 3H), 7.36 (dd, .7= 20.4, 8.1 Hz, 5H), 7.11 (td, J= 8.0, 1.1 Hz, 1H), 7.03 (td, .7= 7.1,1.1 Hz, 1H), 6.90 (s, 1H), 3.64 (app d, J= 12.5 Hz, 1H), 3.26 (app t, J= 11.9 Hz, 1H), 2.88 (app td, J= 11.1, 2.1 Hz, 1H), 2.76 (app d, J= 12.9 Hz, 1H).

[0645] ¹³C NMR (101 MHz, DMSO-ri₆) d 168.7, 139.1, 136.3, 135.1, 132.6, 131.6, 130.8,

129.9, 128.7, 128.6, 126.1, 123.0, 121.5, 118.8, 118.0, 111.3, 108.2, 51.1, 41.3, 21.6.

[0646] HRMS calculated for C₂₄Hi₉BrClN₂0⁺ 465.0364, found 465.0357

[0647] A 25 mL RBF was charged with A1 (32 mg, 0.113 mmol), 4- dimethylaminopyridine (1.3 mg, 0.011 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (34 mg 0.05 mL, 0.340 mmol) was added then the mixture was cooled in ice/water bath. Then 5-Bromo~benzofuran-2- carbonyl chloride (30 mg, 0.118 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recrystallized from 8:2 EtOH/THF to give A7 (39 mg, 67%) as colorless needles.

[0648] ¾ NMR (400 MHz, CDCL) d 7.97 (s, 1H), 7.81 (d, J= 2.0 Hz, 1H), 7.58 (d, J =

7.7 Hz, 1H), 7.51 (dd, J= 8.8, 2.0 Hz, 1H), 7.43 (d, J= 8.8 Hz, 1H), 7.39 - 7.26 (m, 6H), 7.23 (td, J= 7.1, 1.3 Hz, 1H), 7.18 (td, J= 7.3,1.1 Hz, 1H), 6.99 (s, 1H), 4.49 (br d, J= 14.1 Hz, 1H), 3.49 (br t, J= 13.8 Hz, 1H), 3.22 (app. ddd, J= 15.5, 11.5, 5.3 Hz, 1H), 2.98 (br d, J = 15.4 Hz, 1H). [0649] ¹³C NMR (101 MHz, CDCI3) d 159.9, 153.5, 150.2, 149.5 137.8, 136.5, 134.6,

130.55, 130.51, 129.8, 128.9, 126.6, 125.0, 122.7, 120.1, 118.5, 116.9, 113.6, 111.4, 111.2, 110.6, 53.1, 41.2, 22.8.

[0650] HRMS: calculated for C₂₆H₁₉BrClN₂0₂ ⁺ 505.0313, found 505.0302.

[0651] A 25 mL RBF was charged with A17 (30 mg, 0.107 mmol), 4- dimethylaminopyridine (1.3 mg, 0.011 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (32 mg 0.045 mL,0.318 mmol) was added then the mixture was cooled in ice/water bath. Then 5-Bromo-benzofuran-2-· carbonyl chloride (29 mg, 0.11 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recrystallized from 8:2 EtOH/THF to give A8 (35 mg, 65%) as colorless needles. [0652] ¾ NMR (400 MHz, DMSO-c/₆)5 11.05 (s, 1H), 7.98 (d, J= 2.0 Hz, 1H), 7.70 (d, J

= 9.2 Hz, 1H), 7.61 (dd, J= 8.8, 2.1 Hz, 1H), 7.54 - 7.44 (m, 4H), 7.34 (dd, J= 8.4, 3.4 Hz, 3H), 7.12 (td, = 7.1, 1.24 Hz, 1H), 7.04 (td, = 7, 0.9 Hz, 1H), 6.87 (s, 1H), 4.34 (app d, J = 15.4 Hz, 1H), 3.39 (app t ,J = 12.3 Hz, 1H), 3.10 (app t, J= 11.9 Hz ,1H), 2.93 (app d, J= 14.9 Hz, 1H).

[0653] ¹³C NMR (126 MHz, DMSO-fife) d 159.2, 152.9, 149.3, 138.6, 136.3, 132.8, 130.7,

130.2, 129.3, 128.9, 128.6, 126.1, 124.9, 121.6, 118.8, 118.1, 116.0, 114.0, 111.4, 110.2, 108.4, 52.1, 40.9, 22.1.

[0654] HRMS: calculated for C₂₆H₁₉BrClN₂0₂ ⁺ 505.0313, found 505.0308.

[0655] A 25 mL RBF was charged with A18 (30 mg, 0.107 mmol), 4- dimethylaminopyridine (1.3 mg, 0.011 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (32 mg 0.045 mL,0.318 mmol) was added then the mixture was cooled in ice/water bath. Then 5 -B romo-ben zofuran ~2~ carbonyl chloride (29 mg, 0.11 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recrystallized from 1 : 1 EtOH/THF to give A9 (36 mg, 67%) as colorless needles. The absolute stereochemistry was confirmed by X-Ray crystallography (FIG.23), and chiral stationary phase HPLC indicated >95% ee (FIG. 25).

Ή NMR data at 70 °C

[0656] ¾ NMR (600 MHz, DMSO-ri₆) d 10.86 (s, 1H), 7.97 (d, J= 2.1 Hz, 1H), 7.67 (d,

J= 8.7 Hz, 1H), 7.59 (dd, J= 8.8, 2.1 Hz, 1H), 7.51 (d, J= 7.8 Hz, 1H), 7.44 (d, J= 6.8 Hz, 2H), 7.35 (dd, J= 11.9, 8.3 Hz, 2H), 7.12 (td, J= 7.15,0.9 Hz„ 1H), 7.04 (td, J= 7.15,0.6 Hz, 1H), 6.85 (s, 1H), 4.45 - 4.35 (app br.s,lH), 3.40 (app s, 1H), 3.06 (app ddd, J= 15.5, 11.7, 5.2 Hz, 1H), 2.92 (app dd, J= 15.5, 3.3 Hz, 1H).

NMR data at 25 °C

[0657] ¾ NMR (600 MHz, DMSO-ri₆) d 11.05 (s, 1H), 7.98 (d, J= 2.0 Hz, 1H), 7.70 (d,

J= 8.8 Hz, 1H), 7.61 (dd, J= 8.8, 2.1 Hz, 1H), 7.54 - 7.44 (m, 4H), 7.35 (dd, J= 8.1, 5.6 Hz, 3H), 7.12 (t, J= 7.6 Hz, 1H), 7.04 (t, J= 7.4 Hz, 1H), 6.88 (s, 1H), 4.34 (br d , J = 13.9 Hz, 1H), 3.40 (br s, 1H), 3.10 (br s, 1H), 2.93 (br d, J= 15.2 Hz, 1H).

[0658] ¹³C NMR (101 MHz, DMSO-ri₆) d 159.2, 152.8, 149.3, 138.6, 136., 132.8, 130.6,

[0659] HRMS: calculated for C₂₆H₁₉BrClN₂0₂ ⁺ 505.0313, found 505.0298

methyl (IS, 3S)-2-( 5-bromobenzofuran-2-carbonyl)-l-( 4-chlorophenyl)-2, 3, 4, 9-tetrahydro- lH-pyrido[3 4-blindole-3-carboxylate (A10) (PRC 1588)

[0660] A 25 mL RBF was charged with A19 (40 mg, 0.115 mmol), sodium bicarbonate (11.6 mg, 0.138 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Then the mixture was cooled in ice/water bath and 5 -Bromo- benzofuran-2- carbonyl chloride (32 mg, 0.123 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 71 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by column chromatography (8:2 Hexanes/EtOAc) to give A10 (31 mg, 48%) as a white solid.

[0661] ¾ NMR (400 MHz, CDCL) d 7.81 (dd, J= 2.0, 0.6 Hz, 1H), 7.74 (s, 1H), 7.62 (d,

J= 7.7 Hz, 1H), 7.52 (dd, J= 8.8, 2.0 Hz, 1H), 7.41 (ddd, J= 8.8, 0.9, 0.5 Hz, 1H), 7.39 - 7.27 (m, 6H), 7.23 (app. td, .7= 7.9, 1.4 Hz, Hz 1H), 7.19 (td, J= 7.5, 1.25 Hz, 1H), 7.07 (d, J= 1.6 Hz, 1H), 5.63 (br s, 1H), 3.72 (app d, J= 15.8 Hz, 1H), 3.24 (app ddd, J= 15.9, 6.9, 1.8 Hz, 1H), 3.14 (s, 3H). ¹³C NMR (101 MHz, CDCL) d 170.6, 161.4, 153.6, 149.5, 137.4, 136.6, 134.4, 131.1, 130.1, 129.2, 128.8, 128.63, 128.61, 126.5, 125.1, 122.9, 120.2, 118.8, 117.1, 113.6, 111.9, 111.2, 54.4, 52.3, 39.5, 22.5.

[0662] HRMS: calculated for C₂₈H₂₁BrClN₂0₄ ⁺ 563.0368, found 563.0353

[0663] A 25 mL RBF was charged with A20 (40 mg, 0.15 mmol), 4- dimethylaminopyridine (1.8 mg, 0.015 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (45 mg 0.06 mL, 0.450 mmol) was added then the mixture was cooled in ice/water bath. Then 5-Bromo4ienzofuran-2-carbonyi chloride (41 mg, 0.157 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (120 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recrystallized from 8:2 EtOH/THF to give All (44 mg, 60%) as colorless needles.

[0664] ¾ NMR (400 MHz, CDCI3) d 7.93 (s, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.58 (d, J =

6.5 Hz, 1H), 7.51 (dd, J= 8.8, 2.0 Hz, 1H), 7.43 (d, J= 8.6 Hz, 3H), 7.34 (d, J= 7.9 Hz, 1H), 7.28 (s, 1H), 7.23 (td, J= 7.8, 1.4 Hz, 1H), 7.17 (td, J= 7.4, 1.2 Hz, 1H), 7.00 (t, J= 8.6 Hz, 3H), 4.49 (br d , J = 13.7 Hz, 1H), 3.51 (br.s, 1H), 3.22 (app td, J= 12.6, 5.3 Hz, 1H), 2.99 (br d, J = 15.3 Hz, 1H).¹³C NMR (101 MHz, CDCI3) d 162.8 (d, ^lJ_Cf = 247 Hz), 159.8, 153.5, 150.2, 136.5, 135.2 (d, V_CF = 3.1 Hz), 131.0, 130.9, 130.8, 129.7, 128.9, 126.7, 125.0, 122.7, 120.1, 118.5, 116.9, 115.7 (d, V_CF = 21.4 Hz), 113.6, 111.3, 111.2, 53.0, 41.1, 22.8.

[0665] HRMS: calculated for C₂₆H₁₉BrFN₂0₂ ⁺ 489.0608, found 489.0605

[0666] A 25 mL RBF was charged with A21 (50 mg, 0.152 mmol), 4- dimethylaminopyridine (1.8 mg, 0.015 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (46 mg 0.05 mL,0.45 mmol) was added then the mixture was cooled in ice/water bath. Then 5-Bromo-benzofuran-2- carbonyl chloride (41 mg, 0.16 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (120 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recrystallized from 8:2 EtOH/THF to give A12 (53 mg, 63%) as colorless needles. [0667] ¾ NMR (400 MHz, CDCL) d 8.20 (s, 1H), 7.80 (dd, J= 2.0, 0.6 Hz, 1H), 7.58 (d,

J= 8.4 Hz, 1H), 7.51 (dd, J= 8.8, 2.0 Hz, 1H), 7.43 (d, J= 8.8 Hz, 1H), 7.39 (d, J= 8.5 Hz, 2H), 7.34 (d, J= 8.0 Hz, 1H), 7.28 (s, 1H), 7.23 (td, J= 7.4, 1.4 Hz, 1H), 7.17 (td, J= 7.2, 1.1 Hz, 1H), 6.97 (s, 1H), 4.48 (br d, J= 13.9 Hz, 1H), 3.48 (br t, J= 13.6 Hz, 1H), 3.21 (app td, J = 11.2, 5.01 Hz, 1H), 2.97 (br d, J= 13.2 Hz, 1H). ¹³C NMR (101 MHz, CDCL) d 159.9, 153.5, 150.1, 138.3, 136.6, 131.9, 130.8, 130.5, 129.8, 128.9, 126.7, 125.0, 122.74, 122.70, 120.1, 118.5, 116.9, 113.6, 111.4, 110.3, 53.1, 41.2, 22.8 (23 resonances found).

[0668] HRMS: calculated for C₂₆H₁₉Br2N₂0₂ ⁺ 548.9808, found 548.9804.

[0669] A 25 mL RBF was charged with A22 (30 mg, 0.094 mmol), 4- dimethylaminopyridine (1.2 mg, 0.001 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (28 mg 0.04 mL, 0.283 mmol) was added then the mixture was cooled in ice/water bath. Then 5-Bromo-benzofuran-2-· carbonyl chloride (26 mg, 0.104 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recrystallized from 8:2 EtOH/THF to give A13 (40 mg, 64%) as light yellow crystals.

[0670] ¾NMR (400 MHz, DMSO-fife) d 10.98 (s, 1H), 7.97 (dd, J= 2.0, 0.6 Hz,IH), 7.74 (d, J = 1.6 Hz, 1H), 7.68 (d, J= 9.0 Hz, 1H), 7.60 (dd, J= 8.8, 2.1 Hz, 1H), 7.47 (d, J= 7.8 Hz, 2H), 7.39 (dd, J= 8.4, 2.2 Hz, 1H), 7.34 (d, J= 8.1 Hz, 1H), 7.16 - 7.08 (m, 2H), 7.03 (td, J= 6.9, 0.9 Hz, 1H), 6.88 (d, J= 8.4 Hz, 1H), 4.41 (br s, 1H), 3.40 (br s, 1H), 2.92 - 2.74 (m, 2H).

[0671] ¹³C NMR (101 MHz, DMSO-fife) d 160.0, 152.8, 149.4, 136.3, 135.9, 134.2, 133.7,

132.3, 130.2, 129.4, 129.3, 128.9, 127.3, 126.1, 124.9, 121.7, 118.9, 118.1, 116.0, 114.1, 111.5, 110.8, 108.7, 56.0, 50.1, 22.4.

[0672] HRMS: calculated for C₂₆H₁₈BrCl₂N₂0₂ ⁺ 538.9923, found 538.9914

dimethylaminopyridine (1.6 mg, 0.013 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (39 mg 0.05 mL, 0.389 mmol) was added then the mixture was cooled in ice/water bath. Then 5-Bromo-benzofuran-2- carbonyl chloride (35 mg, 0.136 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recry stallized from 7:1 MeOH/THF to give A14 (25 mg, 38%) as light yellow crystals.

[0674] ¾ NMR (400 MHz, CDCL) d 8.02 (s, 1H), 7.79 (dd, J= 2.0, 0.6 Hz, 1H), 7.58 (d,

J= 7.8 Hz, 1H), 7.50 (dd, J= 8.8, 2.0 Hz, 1H), 7.42 (dt, J= 8.8, 0.8 Hz, 1H), 7.32 (d, J= 7.5 Hz, 3H), 7.25 (s, 1H), 7.21 (td,J= 7.6, 1.4 Hz, 1H), 7.16 (td, J= 7.4, 1.3 Hz, 1H), 6.96 (s, 1H), 6.82 (d, J= 8.8 Hz, 2H), 4.46 (br d , J = 14.0 Hz, 1H), 4.00 (m, 2H), 3.55 (br s, 1H), 3.22 (br td, J= 11.6, 5.0 Hz, 1H), 2.97 (br d, J= 15.3 Hz, 1H), 1.40 (t, J= 7.0 Hz, 3H).

[0675] ¹³C NMR (101 MHz, CDCL) d 159.7, 159.1, 153.4, 150.5, 136.5, 131.5, 131.3,

130.5, 129.6, 129.1, 126.7, 124.9, 122.4, 119.9, 118.4, 116.8, 114.6, 113.5, 111.3, 110.9, 110.0, 63.6, 53.2, 41.1, 22.8, 14.9.

[0676] HRMS: calculated for C₂₈H₂₄BrN₂0₃ ⁺ 515.0965, found 515.0953.

(R)-(5-bromobenzofuran-2-yl) (l-( 4-ethoxyphenyl)-l, 3, 4, 9-tetrahydro-2H-pyrido[3, 4-b lindol- 2-yl)methanone (A15 ) (PRC 1618)

[0677] A 25 mL RBF was charged with A25 (38 mg, 0.130 mmol), 4- dimethylaminopyridine (1.6 mg, 0.013 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (39 mg 0.05 mL, 0.389 mmol) was added then the mixture was cooled in ice/water bath. Then 5-Bromo-benzofuran-2- carbonyl chloride (35 mg, 0.136 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recry stallized from 7:1 MeOH/THF to give A15 (25 mg, 38%) as light yellow crystals. The structure stereochemistry was confirmed by X-Ray crystallography (FIG. 24). Chiral stationary phase HPLC indicated >95% enantiopurity (FIG. 26).

[0678] ¾ NMR (400 MHz, CDCL) d 8.02 (s, 1H), 7.79 (dd, J= 2.0, 0.6 Hz, 1H), 7.58 (d,

J= 7.8 Hz, 1H), 7.50 (dd, J= 8.8, 2.0 Hz, 1H), 7.42 (dt, J= 8.8, 0.8 Hz, 1H), 7.32 (d, J= 7.5 Hz, 3H), 7.25 (s, 1H), 7.21 (td,J= 7.6, 1.4 Hz, 1H), 7.16 (td, J= 7.4, 1.3 Hz, 1H), 6.96 (s, 1H), 6.82 (d, J= 8.8 Hz, 2H), 4.46 (br d , J = 14.0 Hz, 1H), 4.00 (m, 2H), 3.55 (br s, 1H), 3.22 (br td, J= 11.6, 5.0 Hz, 1H), 2.97 (br d, J= 15.3 Hz, 1H), 1.40 (t, J= 7.0 Hz, 3H). ¹³C NMR (101 MHz, CDCL) d 159.7, 159.1, 153.4, 150.5, 136.4, 131.4, 131.3, 130.5, 129.6, 129.0, 126.7,

124.9, 122.4, 119.9, 118.4, 116.8, 114.6, 113.5, 111.2, 110.9, 110.0, 63.6, 53.2, 41.8, 22.8,

14.9.

[0679] HRMS: calculated for C₂₈H₂₄BrN₂0₃ ⁺ 515.0965, found 515.0954.

[0680] A 25 mL RBF was charged with A22 (25 mg, 0.08 mmol), and purged with nitrogen. Then anhydrous Tetrahydrofuran THF (1.5 mL) was added as solvent. Triethylamine (9.6 mg 0.013 mL, 0.095 mmol) was added then the mixture was cooled in ice/water bath. Then benzyl chloride (12 mg, 0.087 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CFLCL (2 mL) and FLO (4 mL), and the mixture extracted with CFLCL (3 x 3 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by column chromatography (1:1 Hexanes/ CH2CI2) to give A16 (16 mg, 45.5%) as a white solid.

[0681] ¾ NMR (400 MHz, CDCL) d 7.51 (d, J 8.4 Hz, 2H), 7.48 (d, J 2.1 Hz, 1H),

7.45 (s, 1H), 7.33 - 7.30 (m, 4H), 7.25 - 7.22 (m, 2H), 7.20 (dd, J= 8.5, 2.1 Hz, 1H), 7.14 (td, J= 7.4, 1.4 Hz,IH), 7.10 (td,J= 7.2, 1.3 Hz, 1H), 5.27 (s, 1H), 3.84 (d, J= 13.5 Hz, 1H), 3.47 (d, J= 13.5 Hz, 1H), 3.18 (ddd, J= 11.8, 5.0, 3.8 Hz, 1H), 2.94 - 2.74 (m, 2H), 2.66 (ddd, J =

11.8, 9.3, 4.2 Hz, 1H).

[0682] ¹³C NMR (101 MHz, CDCL) d 139.1, 138.3, 136.4, 134.8, 134.2, 133.4, 131.9,

129.4, 128.7, 128.4, 128.0, 127.2, 126.9, 122.0, 119.6, 118.5, 111.0, 109.8, 60.1, 58.6, 47.6,

20.9.

[0683] HRMS: calculated for C₂₄H_2IC1₂N₂ ⁺ 407.1076, found 407.1058

[0684] A 250 mL RBF was charged with A1 (1.5 g, 5.3 mmol) and acetyl- -leucine (918 mg, 5.3 mmol). A solution of 5: 1 MeOH/ EtOAc (60 mL) was added as a solvent. The resulting thick slurry was heated to 60 °C for 1 hour. The mixture was allowed to cool to 20 °C without stirring. After 5 h, the solid was collected by filtration, and washed with ice-cold CHCL. The solid was dried by air suction for 1 h to give the salt (400 mg, 37%) as white solid. A portion of the salt (55 mg, 0.12mmol) was dissolved in CHCL (5.0 mL) and transferred to a 30 mL separatory funnel. The organic solution was agitated vigorously with 1 N NaOH (5 mL) for 15 min. After the phase separation, the combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo to give A17 (33 mg, 99%) as a white solid. The structure stereochemistry was confirmed by X-Ray crystallography (FIG. 25).

[0685] ¾ NMR (400 MHz, DMSO-ri₆) d 10.43 (s, 1H), 7.42 (d, J= 7.0 Hz, 1H), 7.39 (d,

J= 8.5 Hz, 2H), 7.30 (d, J= 8.5 Hz, 2H), 7.23 (d, J= 7.6 Hz, 1H), 7.01 (td, J= 7.4, 1.4 Hz, 1H), 6.95 (td, .7= 7.1, 1.2 Hz, 1H), 5.09 (s, 1H), 3.16 (s, 1H), 3.04 (dt, J= 12.3, 5.3 Hz, 1H), 2.94 (ddd, J = 12.2, 6.8, 5.0 Hz, 1H), 2.79 - 2.60 (m, 2H).

[0686] ¹³C NMR (101 MHz, DMSO-ri₆) d 142.2, 135.9, 134.9, 131.7, 130.3, 128.0, 126.8,

120.6, 118.2, 117.6, 111.0, 108.3, 55.8, 41.2, 22.1.

[0687] HRMS: calculated for Ci7Hi₆ClN₂ ⁺ 283.0997, found 283.1017

( R)-l-(4-chlorophenyl)-23, 4,9-tetrahydro-lH-pyridof 3, 4-b lindole (A 18)

[0688] A 250 mL RBF was charged with A1 (2 g, 7.07 mmol) and acetyl-D-leucine (1.23 g, 7.07 mmol). Asolution of 5:1 MeOH/ EtOAc (50 mL) was added as a solvent. The resulting thick slurry was heated to 60 °C for 1 hour. The mixture was allowed to cool to 20 °C without stirring. After 5 h, the solid was collected by filtration, and washed with ice-cold CHCL. The solid was dried by air suction for 1 h to give the salt (1.08 g, 34%) as white solid. The salt (1.08 g, 2.4 mmol) was dissolved in CHCL (30 mL) and transferred to a 125 mL separatory funnel. The organic solution was agitated vigorously with 1 N NaOH (30 mL) for 15 min. After the phase separation, the combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo to give A18 (663 mg, 99%) as a white solid.

[0689] ¾ NMR (400 MHz, CDCL) d 7.69 (s, 1H), 7.60 - 7.54 (m, 1H), 7.31 (d, J= 8.5

Hz, 2H), 7.22 (d, J= 8.5 Hz, 2H), 7.20 - 7.19 (m, 1H), 7.18 - 7.09 (m, 2H), 5.11 (s, 1H), 3.33 (ddd, J = 12.6, 5.3, 4.1 Hz, 1H), 3.13 (ddd, J = 12.6, 8.5, 4.8 Hz, 1H), 2.92 (dddd, J= 15.6, 8.5, 5.3, 2.0 Hz, 1H), 2.82 (dddd, J= 15.6, 4.9, 4.1, 1.8 Hz, 1H), 1.82 (s, 1H).

[0690] ¹³C NMR (101 MHz, CDCL) d 140.5, 136.0, 134.1, 134.0, 130.0, 129.1, 127.4,

122.0, 119.6, 118.4, 110.9, 110.6, 57.5, 42.8, 22.6.

[0691] HRMS: calculated for C_I7H_I6C1N₂ ⁺ 283.0997, found 283.1018

(A19)

[0692] Was synthesized according to the literature procedure.⁶ Analytical data matched the literature.

[0693] Prepared according to the literature.⁴

[0694] ¾ NMR (400 MHz, CDCh) d 7.61 - 7.60 (m, 1H), 7.58 - 7.52 (m, 1H), 7.28 (dd,

V_HF = 8.7, 5.1 Hz, 2H), 7.23 - 7.20 (m, 1H), 7.18 - 7.09 (m, 2H), 7.03 (t, V_HH ~ V_HF = 8.6 Hz, 2H), 5.14 (s, 1H), 3.35 (ddd, J= 12.5, 5.3, 3.9 Hz, 1H), 3.13 (ddd, J= 12.5, 8.7, 4.8 Hz, 1H), 2.93 (dddd, J = 15.7, 8.7, 5.3, 2.0 Hz, 1H), 2.82 (dddd, J= 15.7, 4.8, 3.9, 1.8 Hz, 1H), 1.89 (s, 1H).

[0695] ¹³C NMR (101 MHz, CDCh) d 162.7 (d, ^lJcs = 246.9 Hz), 137.8 (d, V_CF = 3.1 Hz),

136.0, 134.3, 130.2 (d, V_CF = 8.1 Hz), 127.4, 122.0, 119.6, 118.4, 115.8 (d, V_CF = 21.6 Hz), 110.9, 110.5, 57.4, 42.8, 22.6.

[0696] HRMS: calculated for C_I7H_I6FN₂ ⁺ 267.1292, found 267.1315

[0697] Prepared according to the literature.⁴

[0698] ¾ NMR (400 MHz, CDCh) d 7.58 - 7.52 (m, 2H), 7.47 (d, J= 8.4 Hz, 2H), 7.23

- 7.20 (m, 1H), 7.19 (d, J= 8.2 Hz, 2H), 7.16 - 7.09 (m, 2H), 5.12 (s, 1H), 3.33 (ddd, J= 12.5, 5.3, 4.0 Hz, 1H), 3.13 (ddd, J= 12.5, 8.6, 4.8 Hz, 1H), 2.92 (dddd, J= 15.6, 8.6, 5.3, 2.0 Hz, 1H), 2.82 (dddd, J= 15.6, 4.8, 4.0, 1.8 Hz, 1H), 1.86 (s, 1H).

[0699] ¹³C NMR (101 MHz, CDCh) d 141.0, 136.0, 133.9, 132.1, 130.3, 127.4, 122.2,

122.1, 119.6, 118.4, 111.0, 110.6, 57.6, 42.8, 22.6.

[0700] HRMS: calculated for Ci₇Hi₆BrN₂ ⁺ 327.0491, found 327.0510

7-/2, 4-dichlorophenyl)-2, 3, 4, 9-tetrahydro-lH-pyridof 3, 4-b lindole (A22 )

[0701] Prepared according to the literature procedure.⁶ Analytical data matched the literature.

[0702] A 250 mL 2 neck RBF was attached to a condenser and charged with tryptamine (500 mg, 3.12 mmol) and activated 4 A Molecular Sieves (2 g) and purged with nitrogen. Then anhydrous acetonitrile (12 mL) was added as solvent. 4-ethoxybenzaldehyde (492 mg, 3.28 mmol) was added and the resulting mixture was stirred for 10 min. Trifluoroacetic acid (711 mg, 6.24 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 48 h at 65 °C. sodium bicarbonate saturated solution (20 mL) was added and the mixture was stirred for 20 min. The mixture was diluted with EtOAc (20 mL), and the mixture extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though column chromatography (9: 1 CH2CI2/ MeOH). Following concentration in vacuo to give A23 (912 mg, 89%) as an orange solid.

[0703] A 250 mL RBF was charged with A23. (600 mg, 2.05 mmol) and acetyl-Z-leucine (355 mg, 2.05 mmol). A solution of 1:1 MeOH/ EtOAc (8.5 mL) was added as a solvent. The resulting thick slurry was heated to 60 °C for 1 hour. The mixture was allowed to cool to 20 °C without stirring. After 12 h, the solid was collected by filtration, and washed with ice-cold CHCL. The solid was dried by air suction for 1 h to give the salt (130 mg, 28%) as white solid. The salt (130 mg, 0.29 mmol) was dissolved in CHCL (8 mL) and transferred to a 30 mL separatory funnel. The organic solution was agitated vigorously with 1 N NaOH (8 mL) for 15 min. After the phase separation, the combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo to give A24 (79 mg, 99%) as a white solid. The absolute configuration was deduced as ( S )- because 1) the enantiomeric compound A25 was subsequently converted to A15, which 2) was revealed to be (//(-configured by X-ray crystallography.

[0704] ¾ NMR (400 MHz, DMSO-ri₆) d 10.36 (s, 1H), 7.39 (d, J= 7.8 Hz, 1H), 7.21 (d,

J= 7.8 Hz, 1H), 7.17 (d, J= 8.6 Hz, 2H), 6.99 (td, J= 7.4, 1.3 Hz,IH), 6.93 (td, J= 7.2, 1.2 Hz,IH), 6.87 (d, J= 8.7 Hz, 2H), 5.02 (s, 1H), 4.00 (q, J= 7.0 Hz, 2H), 3.31 (br s, 1H), 3.05 (dt, J= 12.2, 5.2 Hz, 1H), 2.91 (ddd, J= 12.2, 7.0, 4.9 Hz,lH), 2.78 - 2.59 (m, 2H), 1.31 (t, J = 7.0 Hz, 3H).

[0705] ¹³C NMR (101 MHz, DMSO-ri₆) d 157.7, 135.88, 135.82, 135.1,129.5, 126.9,

120.4, 118.1, 117.4, 113.9, 111.0, 108.1, 62.9, 56.0, 41.3, 22.3, 14.7.

[0706] HRMS: calculated for Ci₉H_2iN₂0⁺ 293.1648, found 293.1668

[0707] Compound A23 was prepared as described in the synthesis of A24 above. A 250 mL RBF was charged with A23 (600 mg, 2.05 mmol) and acetyl-D-leucine (355 mg, 2.05 mmol). A solution of 1:1 MeOH/ EtOAc (8.5 mL) was added as a solvent. The resulting thick slurry was heated to 60 °C for 1 hour. The mixture was allowed to cool to 20 °C without stirring.

After 12 h, the solid was collected by filtration, and washed with ice-cold CHCL. The solid was dried by air suction for 1 h to give the salt (110 mg, 26%) as white solid. The salt (110 mg,

0.243 mmol) was dissolved in CHCL (8 mL) and transferred to a 30 mL separatory funnel. The organic solution was agitated vigorously with 1 N NaOH (8 mL) for 15 min. After the phase separation, the combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo to give A25 (67 mg, 99%) as a white solid.

[0708] ¾ NMR (400 MHz, DMSO-ri₆) d 10.36 (s, 1H), 7.39 (d, J= 7.8 Hz, 1H), 7.21 (d,

J= 7.8 Hz, 1H), 7.17 (d, J= 8.6 Hz, 2H), 6.99 (td, J= 7.4, 1.3 Hz,IH), 6.93 (td, J= 7.2, 1.2 Hz,IH), 6.87 (d, J= 8.7 Hz, 2H), 5.02 (s, 1H), 4.00 (q, J= 7.0 Hz, 2H), 3.31 (br s, 1H), 3.05 (dt, = 12.2, 5.2 Hz, 1H), 2.91 (ddd, J= 12.2, 7.0, 4.9 Hz,lH), 2.78 - 2.59 (m, 2H), 1.31 (t, J

= 7.0 Hz, 3H).

[0709] ¹³C NMR (101 MHz, DMSO-ri₆) d 157.7, 135.88, 135.82, 135.1, 129.5, 126.9,

120.4, 118.1, 117.5, 113.9, 111.0, 108.1, 62.9, 56.0, 41.3, 22.3, 14.7.

[0710] HRMS: calculated for Ci₉H_2iN₂0⁺ 293.1648, found 293.1667

( 5-bromobenzofuran-2-yl) ( 1 -(4-ethoxyphenyl)-l 3 49-tetrahvdro-2H-pyrido[3 4-b lindol-2- vDmethanone (A26)

[0711] Compound A26 was prepared from A23, according to the procedure for A14. The analytical data for A26 were identical to that of A14.

( R)-f 5-chlorobenzofuran-2-yl ) (l-( 4-chlorophenyl)-l 349-tetrahvdro-2H-pyrido[34-b lindol- 2-yl)methanone (A27)

[0712] A 25 mL RBF was charged with A18 (40 mg, 0.14 mmol), 4- dimethylaminopyridine (1.8 mg, 0.014 mmol) and purged with nitrogen. Then anhydrous CH₂C1₂ (2 mL) was added as solvent. Triethylamine (43 mg 0.06 mL, 0.424 mmol) was added then the mixture was cooled in ice/water bath. Then 5 ~C hi or o-benzof u an-2- carbonyl chloride (33 mg, 0.16 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH₂C1₂ (3 mL) and H₂0 (5 mL), and the mixture extracted with CH₂C1₂ (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recrystallized from 9:1 MeOH/THF to give A27 (13 mg, 20%) as colorless needles crystals.

[0713] ¾ NMR (400 MHz, CDCL) d 8.02 (s, 1H), 7.64 (dd, J= 2.2, 0.6 Hz, 1H), 7.58 (d,

J= 8.3 Hz, 1H), 7.47 (d, J= 8.9 Hz, 1H), 7.38 (dd, J= 8.8, 2.2 Hz, 3H), 7.33 (d, J= 8.2 Hz, 1H), 7.31 - 7.27(m, 3H), 7.25 - 7.20 ((td, J= 7.3, 1.3 Hz, 1H), 7.20 - 7.14 (td, J= 7.1, 1.2 Hz, 1H), 6.99 (s, 1H), 4.51 (d, J= 11.0 Hz, 1H), 3.50 (br s, 1H), 3.29 - 3.16 (m, 1H), 2.98 (d, J = 15.4 Hz, 1H).

[0714] ¹³C NMR (101 MHz, CDCL) d 159.9, 153.1, 150.3, 137.8, 136.5, 134.6, 130.5,

129.5, 128.9, 128.3, 127.1, 126.6, 122.7, 121.9, 120.1, 118.5, 113.1, 111.5, 111.3, 110.6, 53, 41.3, 22.7.

[0715] HRMS: calculated for C₂₆Hi₉Cl₂N₂0₂ ⁺ 461.0818, found 461.0804.

(R)-benzofuran-2-yl( 1 -( 4-chlorophenyl)-l 349-tetrahvdro-2H-pyrido[34-b lindol-2- vljmethanone (28).

[0716] A 25 mL RBF was charged with A18 (40 mg, 0.14 mmol), 4- dimethylaminopyridine (1.8 mg, 0.014 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (43 mg 0.06 mL, 0.424 mmol) was added then the mixture was cooled in ice/water bath. Then Benzofuran-2- carbonyl chloride (29 mg, 0.16 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recry stallized from 8:2 EtOH/THF to give A28 (28 mg, 47%) as light-yellow crystals. [0717] ¾ NMR (400 MHz, CDCI3) d 8.24 (s, 1H), 7.68 (d, J = 6.6 Hz, 1H), 7.62 - 7.52

(m, 2H), 7.43 (td, J= 7.2, 1.3 Hz, 1H), 7.39 - 7.29 (m, 5H), 7.27 (d, J= 8.4 Hz, 2H), 7.22 ((td, J = 7.3, 1.4 Hz, 1H), 7.19 - 7.14 ((td, = 7.2, 1.4 Hz, 1H), 7.02 (s, 1H), 4.59 (d, = ll.l Hz, 1H), 3.47 (br s, 1H), 3.30 - 3.16 (m, 1H), 2.96 (s, 1H).

[0718] ¹³C NMR (101 MHz, CDCI3) d 160.3, 154.8, 148.9, 138.0, 136.5, 134.4, 130.6,

130.5, 128.9, 127.0, 126.8, 126.7, 123.8, 122.6, 122.4, 119.9, 118.4, 112.2, 112.0, 111.3, 110.4, 53.0, 41.1, 22.7.

[0719] HRMS: calculated for C26H_2OC1N₂02⁺ 427.1208, found 427.1199. (R)-benzofuran-2-yl( l -( 4-ethoxyphenyl)-l 349-tetrahvdro-2H-pyrido[34-b ]indol-2- vDmethanone (A29)

[0720] A 25 mL RBF was charged with A25 (40 mg, 0.136 mmol), 4- dimethylaminopyridine (1.7 mg, 0.013 mmol) and purged with nitrogen. Then anhydrous CH₂C1₂ (2 mL) was added as solvent. Triethylamine (41 mg 0.06 mL,0.41 mmol) was added then the mixture was cooled in ice/water bath. Then Benzofuran~2~ carbonyl chloride (27 mg, 0.15 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH₂C1₂ (3 mL) and H₂0 (5 mL), and the mixture extracted with CH₂C1₂ (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recrystallized from MeOH to give A29 (26 mg, 44%) as white crystals.

[0721] ¾ NMR (400 MHz, CDCL) d 8.17 (s, 1H), 7.67 (d, J= 7.8 Hz, 1H), 7.58 (d, J =

7.5 Hz, 1H), 7.55 (d, J= 8.3 Hz, 1H), 7.41 (td, J= 7.2, 1.3 Hz, 1H), 7.36 - 7.28 (m, 4H), 7.24 - 7.12 (m, 2H), 6.98 (s, 1H), 6.82 (d, J= 8.8 Hz, 3H), 4.54 (d, J= 9.2 Hz, 1H), 3.99 (q, J= 7.0 Hz, 2H), 3.56 (br s, 1H), 3.32 - 3.15 (m, 1H), 2.98 (d, J= 16.4 Hz, 1H), 1.40 (t, J= 7.0 Hz, 3H). [0722] ¹³C NMR (101 MHz, CDCI3) d 160.2, 159.0, 154.7, 149.3, 136.4, 131.6, 131.5,

130.5, 127.1, 126.8, 126.6, 123.7, 122.4, 122.3, 119.8, 118.3, 114.5, 112.0, 111.8, 111.2, 110.0, 63.6, 53.1, 41.0, 22.8, 14.9.

[0723] HRMS: calculated for C₂₈H₂₅N₂0₃ ⁺ 437.1860, found 437.1854.

( R)-f 5-chlorobenzofuran-2-yl ) (l-( 4-ethoxyphenyl)-l 3 49-tetrahvdro-2H-pyrido[3 4-b lindol- 2-yl)methanone (A30)

[0724] A 25 mL RBF was charged with A25 (40 mg, 0.136 mmol), 4- dimethylaminopyridine (1.7 mg, 0.013 mmol) and purged with nitrogen. Then anhydrous CH₂C1₂ (2 mL) was added as solvent. Triethylamine (41 mg 0.06 mL,0.41 mmol) was added then the mixture was cooled in ice/water bath. Then 5-Chloro-benzofuran-2- carbonyl chlonde (32 mg, 0.15 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH₂C1₂ (3 mL) and H₂0 (5 mL), and the mixture extracted with CH₂C1₂ (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recry stallized from MeOH to give A30 (32mg, 50%) as light-yellow crystals.

[0725] ¾ NMR (400 MHz, CDCL) d 8.02 (s, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.58 (d, J =

7.6 Hz, 1H), 7.47 (d, J= 8.8 Hz, 1H), 7.40 - 7.28 (m, 4H), 7.26 (s, 1H), 7.21 (td, J= 7.8, 1.4 Hz, 1H), 7.16 (d, .7 =7.4, 0.8 Hz, 1H), 6.96 (s, 1H), 6.82 (d, J= 8.8 Hz, 2H), 4.46 (d, J= 9.0 Hz, 1H), 3.99 (q, J = 7.0 Hz, 2H), 3.55 (br s, 1H), 3.27 - 3.15 (m, 1H), 2.97 (d, J= 15.3 Hz, 1H), 1.40 (t, J = 7.0 Hz, 3H). [0726] ¹³CNMR (101 MHz, CDCls) 5159.7, 159.1, 153, 150.6, 136.4, 131.5, 131.3, 130.5, 129.4, 128.4, 126.9, 126.7, 122.4, 121.8, 119.9, 118.4, 114.6, 113.1, 111.3, 111.1, 63.6, 53.1, 41.0, 22.8, 14.9.

[0727] HRMS: calculated for C₂₈H₂₄C1N₂0₃ ⁺ 471.1470, found 471.1460.

( ^'R)-(5-chloro-lH-indol-2-yl)( 1 -( 4-chlorophenyl)-l 349-tetrahvdro-2H-pyrido[34-b lindol- 2-yl)methanone (A31 )

[0728] A 25 mL RBF was charged with A18 (40 mg, 0.141 mmol), 4- dimethylaminopyridine (1.7 mg, 0.014 mmol) and purged with nitrogen. Then anhydrous CH₂C1₂ (2 mL) was added as solvent. Triethylamine (42 mg 0.06 mL,0.42 mmol) was added then the mixture was cooled in ice/water bath. Then 5-chloro- 1 //-indole-2- carbonyl chloride (33 mg, 0.15 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH₂C1₂ (3 mL) and H₂0 (5 mL), and the mixture extracted with CH₂C1₂ (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc) to give A31 (37mg, 62%) as light-yellow solid.

[0729] ¾ NMR (400 MHz, DMSO) 5 11.94 (s, 1H), 11.04 (s, 1H), 7.69 (d, J= 2.0 Hz,

1H), 7.52 (d, J= 7.8 Hz, 1H), 7.47 (d, J= 8.6 Hz, 1H), 7.44 (d, J= 8.8 Hz, 1H), 7.41 - 7.31 (m, 3H), 7.21 (dd, .7= 8.7, 2.1 Hz, 1H), 7.12 (td, J =7.3, 1.3 Hz, 1H), 7.04 (td, J= 7.1, 1.1 Hz, 1H), 6.91 (br d, J= 9.1 Hz, 2H), 4.53 (d, J = 14.0 Hz, 1H), 3.42 (br s, 1H), 3.14 - 3.06 (m, 1H), 2.93 (d, J= 15.3 Hz, 1H).

[0730] ¹³C NMR (101 MHz, d6-DMSO) 5 138.9, 136.3, 134.5, 132.6, 131.2, 131.1, 130.1

128.5, 127.9, 126.1, 124.3, 123.5, 121.5, 120.5, 118.8, 118.1, 113.6, 111.3, 108.4, 102.9, 51.5, 41.5, 21.8.

[0731] C=0 carbon was not observed. [0732] HRMS: calculated for C26H_2OC1₂N30⁺ 460.0978, found 460.0961.

( ^'R)-(5-chloro-lH-indol-2- l)( 1 -( 4-ethoxyphenyl)-l 349-tetrahvdro-2H-pyrido[34-b lindol- 2-yl)methanone (A32)

[0733] A 25 mL RBF was charged with A25 (40 mg, 0.136 mmol), 4- dimethylaminopyridine (1.7 mg, 0.013 mmol) and purged with nitrogen. Then anhydrous CH₂C1₂ (2 mL) was added as solvent. Triethylamine (41 mg 0.06 mL,0.41 mmol) was added then the mixture was cooled in ice/water bath. Then 5-chloro- 1 //-indole-2- carbonyl chloride (35 mg, 0.16 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH₂C1₂ (3 mL) and H₂0 (5 mL), and the mixture extracted with CH₂C1₂ (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recry stallized from 6:4 THF/iPrOH to give A32 (20 mg, 31%) as light- yellow crystals.

[0734] ¾ NMR (400 MHz, DMSO) d 11.92 (s, 1H), 11.02 (s, 1H), 7.69 (d, J= 2.2 Hz,

1H), 7.51 (d, J= 7.7 Hz, 1H), 7.43 (d, J= 8.7 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.25 (br d, J = 8.2 Hz, 2H), 7.20 (dd, J= 8.7, 2.1 Hz, 1H), 7.10 (td, J= 7.2, 1.3 Hz, 1H), 7.03 (td, .7=7.0, 1.1 Hz, 1H), 6.92 (d, J= 8.8 Hz, 2H), 6.89 (d, J= 6.4 Hz, 2H), 4.48 (d, J= 13.8 Hz, 1H), 4.00 (q, J= 7.0 Hz, 2H), 3.50 - 3.39 (m, 1H), 3.15 - 3.03 (m, 1H), 2.92 (d, J= 15.1 Hz, 1H), 1.30 (t, .7= 6.9 Hz, 3H).

[0735] ¹³C NMR (101 MHz, DMSO) d 161.5, 158.2, 136.3, 134.4, 131.9, 131.5, 129.6,

127.9, 126.2, 124.2, 123.4, 121.3, 120.5, 118.7, 117.9, 114.3, 113.7, 111.3, 108.1, 102.8, 63.1, 51.8, 41.0, 22.1, 14.6.

[0736] HRMS: calculated for C₂₈H₂₅C1N 0₂ ⁺ 470.1630, found 470.1627. (R)-(5-bromo-lH-benzo[d limidazol-2-yl) ( l -(4-ethoxyphenyl)-l , 3, 4, 9-tetrahydro-2H- pyrido[3 4-b ]indol-2-yl)methanone (A33)

[0737] A 25 mL RBF was charged with A25 (40 mg, 0.136 mmol), HBTU (62 mg, 0.164 mmol), 5-bromo-li/-benzo[if]imidazole-2-carboxylic acid (40 mg, 0.164 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (17 mg 0.02 mL,0.41 mmol) and the resulting mixture was stirred for 24 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recry stallized from MeOH to give A33 (10 mg, 14%) as light-yellow crystals.

[0738] ¾ NMR (400 MHz, d6-DMSO) d 13.43 (s, 1H), 11.10 (s, 1H), 11.02 (s, 1H), 7.32

(d, J= 8.0 Hz, 1H), 7.28 (d, J= 8.0 Hz, 1H), 7.24 (d, J= 8.8 Hz, 2H), 7.19 (d, J= 8.7 Hz, 1H), 7.09 (dddd, J = 8.2, 7.1, 5.8, 1.3 Hz, 2H), 7.01 (dddd, J= 8.0, 7.0, 3.2, 1.1 Hz, 2H), 6.97 (s, 1H), 6.93 (d, J= 8.8 Hz, 2H), 6.88 (d, J= 8.8 Hz, 1H), 5.53 (dd , J = 13.4, 5.2 Hz, 1H), 4.69 (dd ,J= 12.3, 4.3 Hz, 1H), 3.99 (dq, J= 11.7, 7.0 Hz, 4H), 3.17 (d, J= 3.3 Hz, 2H), 3.12 - 2.98 (m, 1H), 2.91 (dd , J= 14.4, 4.5 Hz, 1H), 1.33 - 1.26 (m, 5H).

[0739] ¹³C NMR (101 MHz, d6-DMSO) d 158.64, 158.37, 158.25, 158.02, 136.32, 136.27,

132.21, 131.92, 131.73, 131.40, 129.56, 129.13, 126.18, 126.16, 121.38, 118.72, 118.03, 114.42, 114.32, 111.29, 108.7, 108.3, 63.11, 54.78, 52.19, 22.04, 14.62: note two tautomers are present.

[0740] HRMS: calculated for C₂₇H₂₄BrN0₂ ⁺ 515.1077, found 515.1059.

[0741] (R)-(5-bromobenzofuran-2-yl)(l-(4-ethoxyvhenyl)-9-methyl-l ,3, 4,9-tetrahydro- 2H-pyrido[3, 4-b ]indol-2-yl)methanone (A34)

[0742] A 25 mL RBF was charged with A15 (25 mg, 0.048 mmol), sodium hydride 60 % dispersion in mineral oil (5 mg, 0.145 mmol) and purged with nitrogen. Then anhydrous THF (2 mL) was added as solvent. Iodomethane (14 mg 0.06 mL, 0.097 mmol) was added, and the resulting mixture was stirred for 1 h at r.t. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo. Following concentration in vacuo, the residue was recrystallized from 9:1 EtOH/THF to give A34 (15 mg, 60%) as light-yellow crystals.

[0743] ¾ NMR (400 MHz, CDCL) d 7.80 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H),

7.50 (dd, J= 8.8, 2.2 Hz, 1H), 7.43 (d, J= 9.0 Hz, 1H), 7.32 (d, J= 8.2 Hz, 3H), 7.26 (m, 2H), 7.17 (td, J= 6.9, 1.2 Hz, 1H), 7.05 (s, 1H), 6.84 (d, J= 8.7 Hz, 2H), 4.40 (dd, J= 13.9, 5.4 Hz, 1H), 4.01 (q, J= 7.0 Hz, 2H), 3.55 - 3.46 (m, 1H), 3.44 (s, 3H), 3.29 - 3.17 (m, 1H), 2.99 (dd, J= 14.9, 3.6 Hz, 1H), 1.40 (t, J= 7.0 Hz, 3H).

[0744] ¹³C NMR (101 MHz, CDCL) d 159.6, 159.1, 153.4, 150.4, 137.5, 132.9, 130.9,

130.3, 129.5, 129.1, 126.4, 124.9, 121.9, 119.5, 118.3, 116.8, 114.6, 113.5, 110.8, 109.2, 108.6, 63.6, 52.2, 40.7, 29.9, 22.8, 14.9.

[0745] HRMS: calculated for C29H₂₆BrN₂03⁺ 529.1121, found 529.1101.

Ethyl (R)-2-(2-(5-bromobenzofuran-2-carbonyl)-l-(4-ethoxyphenyl)-l,2, 3, 4-tetrahydro-9H-

A35 (67%)

[0746] A 25 mL RBF was charged with A15 (25 mg, 0.048 mmol), sodium hydride 60 % dispersion in mineral oil (5 mg, 0.145 mmol) and purged with nitrogen. Then anhydrous THF (2 mL) was added as solvent. Ethyl 2-bromoacetate (16 mg 0.1 mL, 0.097 mmol) was added, and the resulting mixture was stirred for 24 h at r.t. The mixture was diluted with CFLCL (3 mL) and FLO (5 mL), and the mixture extracted with CFLCL (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo. Following concentration in vacuo, the residue was recry stallized from 6:4 EtOH/THF to give A35 (19 mg, 67%) as light-yellow crystals.

[0747] ¾ NMR (400 MHz, CDCL) d 7.80 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 7.3 Hz, 1H),

7.50 (dd, J= 8.9, 2.0 Hz, 1H), 7.39 (dd, J= 25.8, 8.5 Hz, 3H), 7.30 - 7.14 (m, 4H), 6.99 (s, 1H), 6.83 (d, J= 8.4 Hz, 2H), 4.59 (d, J= 17.8 Hz, 1H), 4.42 (d, J= 17.5 Hz, 2H), 4.02 (dq, J = 14.0, 7.0 Hz, 4H), 3.55 (t, J= 11.2 Hz, 1H), 3.31 - 3.20 (m, 1H), 2.99 (dd, J= 15.5, 2.8 Hz, 1H), 1.40 (t, J = 7.0 Hz, 3H), 1.27 (t, .7= 7.2 Hz, 3H).

[0748] ¹³C NMR (101 MHz, CDCL) d 168.1, 159.5, 159.3, 153.4, 150.4, 137.4, 132.4,

130.6, 130.3, 129.5, 129.1, 126.7, 124.9, 122.5, 120.1, 118.6, 116.8, 114.8, 113.5, 110.8, 110.0, 109.2, 63.6, 61.7, 52.2, 45.1, 40.7, 29.8, 22.7, 14.9.

[0749] HRMS: calculated for C32H₃oBrN₂03⁺ 601.1333, found 601.1320 (R)-(5-bromobenzo[d]oxazol-2-yl) (l-( 4-ethoxyphenyl)-l, 3, 4, 9-tetrahvdro-2H-pyrido[3, 4- b]indol-2-yl)methanone (A36)

[0750] A 25 mL RBF was charged with A25 (24 mg, 0.08 mmol), HBTU (37 mg, 0.1 mmol), 5-bromobenzo[<7]oxazole-2-carboxylic acid (20 mg, 0.85 mmol) and purged with nitrogen. Then anhydrous DMF (2 mL) was added as solvent. Triethylamine (12 mg 0.01 mL,0.12 mmol) and the resulting mixture was stirred for 24 h at r.t. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc) to give A36 (34 mg, 81%) as yellow solid.

[0751] ¾ NMR (400 MHz, DMS 0) 5 11.05 (s, 1H), 8.20 (d, J= 2.0 Hz, 1H) 7.86 (d, J =

0.5 Hz, 1H), 7.73 (dd, J= 8.7, 2.0 Hz, 1H), 7.51 (d, J= 7.2 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.22 (d, J= 0.6 Hz, 2H), 7.11 (td, .7= 7.5, 1.2 Hz 1H), 7.03 (td, .7= 7.1, 1.1 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.90 (s, 1H), 4.61 (dd, J= 13.6, 5.0 Hz, 1H), 4.01 (q, J= 7.0 Hz, 2H), 3.47 - 3.38 (m, 1H), 3.13 - 3.02 (m, 1H), 2.91 (dd, J= 15.4, 3.6 Hz, 1H), 1.31 (t, .7= 7.0 Hz, 3H). [0752] ¹³C NMR (101 MHz, CDCL) d 159.3, 156.3, 149.1, 141.9, 136.5, 130.9, 130.7,

130.5, 130.4, 129.7, 126.7, 124.4, 122.5, 119.9, 118.4, 118.1, 114.7, 112.9, 111.2, 110.3, 63.6, 56.1, 41.2, 22.5, 14.9.

[0753] HRMS: calculated for C₂₇H₂₄BrN₄0₂ ⁺ 516.0917, found 516.0895.

[0754] (i?)-2-(2-(5-bromobenzofuran-2-carbonyl)-l -(4-ethoxyphenyl)- 1,2,3, 4-tetrahydro-

9//-pyrido| 3.4-6 |indol-9-yl)acetic acid (A37)

A37 (48%)

[0755] A 25 mL RBF was charged with A35 (45 mg, 0.075 mmol) . Then 1 : 1 MeOH/NaOH (2N) (2 mL) was added as solvent, and the resulting mixture was stirred for 2 h at 60°C. Then diluted hydrochloric acid was added to lower the pH of the mixture to 2. The mixture was diluted with CH2CI2 (3 mL) and LLO (5 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo and purified by column chromatography (93:7 DCM/MeOH) to give A37 (20 mg, 48%) as dark-yellow solid.

[0756] ¾ NMR (400 MHz, CDCL) d 7.78 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.49 (d, J =

9.4 Hz, 1H), 7.41 (d, J= 9.4 Hz, 1H), 7.34 (d, J= 7.8 Hz, 2H), 7.24 - 7.15 (m, 3H), 7.00 (s, 1H), 6.81 (d, J= 7.8 Hz, 2H), 4.64 (d, J= 18.1 Hz, 1H), 4.40 (d, J= 18.2 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.55 (t, J= 12.8 Hz, 1H), 3.31 - 3.17 (m, 1H), 2.99 (d, J= 12.6 Hz, 1H), 1.38 (t, J= 7.0 Hz, 3H).

[0757] ¹³C NMR (101 MHz, CDCL) d 159.7, 159.4, 153.5, 137.3, 132.4, 130.64, 130.63,

130.0, 129.7, 129.0, 126.7, 125.0, 122.6, 120.2, 118.6, 116.9, 114.8, 113.5, 111.6, 110.3, 109.1, 104.963.6, 52.4, 44.7, 40.9, 29.8, 14.9.

[0758] HRMS: calculated for C₃oH₂₆BrN₂0₅ ⁺ 573.1020, found 573.1033.

(R)-( 1 -(4-ethoxyphenyl)-l, 3, 4, 9-tetrahydro-2H-pyrido[3, 4-b lindol-2-yl)(5-fluorobenzofuran- 2-yl)methanone

[0759] A 25 mL RBF was charged with A25 (50 mg, 0.17 mmol), 4- dimethylaminopyridine (2 mg, 0.017 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (52 mg 0.07 mL,0.51 mmol) was added then the mixture was cooled in ice/water bath. Then 5-Fluoro~henzofuran-2- carbonyl chloride (37 mg, 0.18 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at r.t. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recry stallized from 8:2 EtOH/THF to give A38 (77mg, 95%) as light-yellow crystals.

[0760] ¾ NMR (400 MHz, CDCL) d 7.99 (s, 1H), 7.58 (d, J= 7.6 Hz, 1H), 7.48 (dd, J =

9.0, 4.1 Hz, 1H), 7.37 - 7.27 (m, 5H), 7.25 - 7.09 (m, 3H), 6.97 (s, 1H), 6.83 (d, J= 8.7 Hz, 2H), 4.48 (d, J= 13.8 Hz, 1H), 4.00 (q, J= 6.9 Hz, 2H), 3.55 (br s, 1H), 3.29 - 3.11 (m, 1H), 2.97 (d, J= 14.4 Hz, 1H), 1.40 (t, J= 7.0 Hz, 3H).

[0761] ¹³C NMR (101 MHz, CDCL) d 159.8, 159.6 (d, J= 239.9 Hz), 159.2, 159.1, 150.0,

136.4, 131.5, 131.3, 130.5, 127.9 (d, J= 10.8 Hz), 126.7, 122.4, 119.9, 118.4, 114.8, 114.6, 112.8 (d, J= 9.5 Hz), 111.2, 111.7, 110.1, 107.6 (d, J= 24.8 Hz), 63.6, 53.3, 41.3, 22.8, 14.9.

[0762] HRMS: calculated for C₂₈H₂₄FN₂0₃ ⁺ 455.1765, found 455.1755. (R)-4-(2-(5-chlorobenzofuran-2-carbonyl)-2, 3, 4, 9-tetrahvdro-lH-pyrido[3, 4-b lindol-1- vDbenzonitrile (A39)

[0763] A 25 mL RBF was charged with A48 (40 mg, 0.146 mmol), 4- dimethylaminopyridine (1.8 mg, 0.014 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (44 mg 0.06 mL, 0.439 mmol) was added then the mixture was cooled in ice/water bath. Then 5-Chloro-benzofuran-2- carbonyl chloride (34 mg, 0.16 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at r.t. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recry stallized from 9:1 EtOH/THF to give A39 (40 mg, 61%) as light-yellow crystals.

[0764] ¾ NMR (400 MHz, CDCL) d 8.06 (s, 1H), 7.63 (dd, J= 2.1, 0.6 Hz, 1H), 7.61 -

7.51 (m, 5H), 7.46 (dt, J= 8.9, 0.8 Hz, 1H), 7.37 (dd, J= 8.8, 2.1 Hz, 1H), 7.33 (dt, J= 8, 0.9 Hz 1H), 7.30 (s, 1H), 7.23 (td, J= 7.3, 1.4 Hz, 1H), 7.17 (td, J= 7.3, 1.1 Hz, 1H), 7.03 (s, 1H), 4.54 (br d, J= 13.8 Hz, 1H), 3.43 (br t, J= 12 Hz, 1H), 3.24 (app. ddd, J= 15.7, 11.5, 5 Hz, 1H), 2.99 (br d, J= 14.8 Hz, 1H).

[0765] ¹³C NMR (101 MHz, CDCL) d 160.1, 153.1, 150.0, 144.4, 136.6, 132.6, 129.8,

129.6, 129.5, 128.2, 127.3, 126.5, 123.0, 122.0, 120.2, 118.6, 118.5, 113.1, 112.5, 111.9, 111.4, 110.8, 53.2, 41.4, 22.7.

[0766] HRMS: calculated for C₂₇H_I9C1N₃0₂ ⁺ 452.1160, found 452.1145 (R)-(5-bromobenzofuran-2-yl) (l-( 4-methoxyphenyl)-l, 3, 4, 9-tetrahvdro-2H-pyrido[3, 4- b]indol-2-yl)methanone (A40 )

[0767] A 25 mL RBF was charged with A47 (40 mg, 0.143 mmol), 4- dimethylaminopyridine (1.8 mg, 0.014 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (43 mg 0.06 mL,0.43 mmol) was added then the mixture was cooled in ice/water bath. Then 5 -Bromo-benzofuran-2- carbonyl chloride (41 mg, 0.16 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at room temperature. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recrystallized from 9:1 EtOH/THF to give A40 (47 mg, 65%) as light- yellow crystals.

[0768] TlNMR ^OO MHz, DMSO) d 11.02 (s, 1H), 7.98 (s, 1H), 7.70 (d, J= 7.3 Hz, 1H),

7.60 (dd, J= 8.8, 2.1 Hz, 1H), 7.50 (d, J= 7.0 Hz, 1H), 7.46 (s, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.25 (br d, J= 8.4 Hz, 1H), 7.1 (td, J= 7.1, 1.1 Hz,IH), 7.03 (td, J= 6.9, 1.1 Hz, 1H), 6.94 (d, J = 8.9 Hz, 2H), 6.85 (s, 1H), 4.29 (br d, J= 12.2 Hz, 1H), 3.74 (s, 3H), 3.44 (brt, J= 11.3 Hz, 1H), 3.09 (br t, J= 11.1 Hz, 1H), 2.92 (d, J= 15.7 Hz, 1H).

[0769] ¹³C NMR (101 MHz, DMSO) d 159.1, 158.9, 152.8, 136.3, 131.7, 131.4, 129.6,

129.1, 129.0, 126.1, 124.8, 121.4, 118.7, 117.9, 115.9, 114.0, 113.9, 111.3, 109.8, 109.5, 108.1,

55.1, 52.1, 40.9, 22.1.

[0770] HRMS: calculated for C₂₇H₂₂BrN₂0₃ ⁺ 501.0808, found 501.0795. (R)-(5-chlorobenzofuran-2-yl) (l-( 4-methoxyphenyl)-l, 3, 4, 9-tetrahvdro-2H-pyrido[3, 4- b]indol-2-yl)methanone (A41)

[0771] A 25 mL RBF was charged with A47 (40 mg, 0.146 mmol), 4- dimethylaminopyridine (1.8 mg, 0.014 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (44 mg 0.06 mL, 0.439 mmol) was added then the mixture was cooled in ice/water bath. Then 5 -Chloro-benzofuran-2- carbonyl chloride (41 mg, 0.16 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at r.t. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recrystallized from 9:1 EtOH/THF to give A41 (50 mg, 78%) as light-yellow crystals.

[0772] ¾NMR (400 MHz, DMSO) d 11.02 (s, 1H), 7.83 (d, J= 1.7 Hz, 1H), 7.75 (d, J =

8.8 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.47 (d, J= 0.9 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.25 (d, J= 8.2 Hz, 2H), 7.10 (td, J= 7.0, 1.3 Hz, 1H), 7.03 (td, J= 7.1, 1.1 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.85 (s, 1H), 4.29 (br d , J = 12.5 Hz, 1H), 3.74 (s, 3H), 3.4 ((br t, J= 11.5 Hz, 1H), 3.09 ((br t, J= 12.2 Hz, 1H), 2.92 (d, J= 15.7 Hz, 1H).

[0773] ¹³C NMR (101 MHz, DMSO) d 159.5, 158.9, 152.4, 149.8, 136.3, 131.6, 131.2,

129.6, 128.3, 128.1, 126.5, 126.1, 121.8, 121.4, 118.7, 117.9, 113.9, 113.5, 111.3, 110.0, 108.1, 55.1, 52.2, 41.4, 22.5.

[0774] HRMS: calculated for C₂₇H₂₂C1N₂0₃ ⁺ 457.1313, found 457.1303. (R)-4-(2-(5-bromobenzofuran-2-carbonyl)-2, 3, 4, 9-tetrahydro-lH-pyridof 3, 4-b lindol-1- vDbenzonitrile (A42 )

[0775] A 25 mL RBF was charged with A48 (40 mg, 0.146 mmol), 4- dimethylaminopyridine (1.8 mg, 0.014 mmol) and purged with nitrogen. Then anhydrous CH2CI2 (2 mL) was added as solvent. Triethylamine (44 mg 0.06 mL, 0.439 mmol) was added then the mixture was cooled in ice/water bath. Then 5 -Bromo-benzofuran-2- carbonyl chloride (41 mg, 0.16 mmol) was added dropwise via syringe, and the resulting mixture was stirred for 1 h at 0 °C, followed by 47 h at r.t. The mixture was diluted with CH2CI2 (3 mL) and H2O (5 mL), and the mixture extracted with CH2CI2 (3 x 5 mL). The combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo, and purified by filtration though a silica plug (100 mL 8:2 Hexanes/EtOAc). Following concentration in vacuo, the residue was recry stallized from 9:1 EtOH/THF to give A42 (14 mg, 20%) as light-yellow crystals

[0776] ¾ NMR (400 MHz, CDCL) d 7.94 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H) 7.65 - 7.55

(m, 5H), 7.53 (dd, J= 8.8, 1.9 Hz, 1H), 7.43 (d, J= 8.9 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.32 (s, 1H), 7.24 (td, J= 7.2, 1.2 Hz,,IH), 7.19 (td, J= 7.1, 1.2 Hz, 1H), 7.05 (s, 1H), 4.56 (br d, J = 13.9 Hz, 1H), 3.44 (brt, J= 13.4 Hz, 1H), 3.32 - 3.17 (m, 1H), 3.01 (br d, J= 15.2 Hz, 1H). [0777] ¹³C NMR (101 MHz CDCL) d 160.1, 153.5, 144.4, 136.6, 132.6, 131.7, 130.0,

129.9, 129.5, 128.9, 126.6, 125.1, 123.0, 120.3, 118.6, 118.5, 117.0, 113.5, 112.5, 111.8, 111.4, 110.7, 53.2, 41.2, 22.5.

[0778] HRMS: calculated for C₂₇Hi₉BrN₃0₂ ⁺ 496.0655, found 496.0635. l-( 4-methoxyphenyl)-2, 3, 4, 9-tetrahydro-lH-pyridof 3, 4-b lindole (A45 )

[0779] The racemate was prepared according to the procedure for the racemic ethoxy A23. [0780] ¾ NMR (400 MHz, CDCh) d 7.60 - 7.48 (m, 2H), 7.26 - 7.19 (m, 3H), 7.17 - 7.07

(m, 2H), 6.88 (d, J= 8.7 Hz, 2H), 5.13 (s, 1H), 3.81 (s, 3H), 3.38 (ddd, J= 12.5, 5.3, 3.6 Hz, 1H), 3.14 (ddd, J= 12.5, 9.1, 4.8 Hz, 1H), 2.93 (dddd, J = 15.4, 9.0, 5.3, 2.1 Hz, 1H), 2.81 (dddd, J= 15.4, 4.8, 3.6, 1.8 Hz, 1H), 1.82 (s, 1H).

[0781] ¹³C NMR (101 MHz, CDCI3) d 159.6, 135.9, 134.9, 133.9, 129.7, 127.5, 121.8,

119.5, 118.3, 114.3, 110.9, 110.2, 57.6, 55.4, 43.1, 22.6.

[0782] HRMS: calculated for Ci₈H₉N₂0⁺ 279.1492, found 279.1464.

6 (d, J = 7.1 Hz, 1H),

7.52 (s, 1H), 7.45 (d, J= 8.0 Hz, 2H), 7.25 (d, J= 7.9 Hz, 1H), 7.22 - 7.09 (m, 2H), 5.22 (s, 1H), 3.30 (dt, J= 12.6, 5.0 Hz, 1H), 3.15 (ddd, J= 12.6, 7.9, 4.9 Hz, 1H), 2.93 (dddd, J= 15.2, 7.9, 5.3, 1.9 Hz, 1H), 2.83 (dtd, J= 15.5, 4.8, 1.7 Hz, 1H), 1.83 (s, 1H).

[0785] ¹³C NMR (101 MHz, CDCI3) d 147.4, 136.1, 132.8, 132.7, 129.4, 127.3, 122.3,

119.8, 118.7, 118.5, 112.1, 111.0, 110.9, 57.5, 42.4, 22.5.

[0786] HRMS: calculated for CI₈HI₆N3⁺ 274.1339, found 274.1327. (R)-l-( 4-methoxyphenyl)-2, 3, 4, 9-tetrahydro-lH-pyridof 3, 4-b lindole (A47 )

[0787] A 250 mL RBF was charged with A45 (1.55 g, 5.57 mmol) and acetyl-D-leucine (965 mg, 5.57 mmol). A solution of 1:1 MeOH/ EtOAc (25 mL) was added as a solvent. The resulting thick slurry was heated to 60 °C for 1 hour. The mixture was allowed to cool to 20 °C without stirring. After 12 h, the solid was collected by filtration, and washed with ice-cold CHCL. The solid was dried by air suction for 1 h to give the salt (1.17 g, 93%) as white solid. The salt (1.17 g, 2.59 mmol) was dissolved in CHCL (20 mL) and transferred to separatory funnel. The organic solution was agitated vigorously with 1 N NaOH (15 mL) for 15 min. After the phase separation, the combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo to give A47 (606 mg, 84%) as a yellow solid.

[0788] ¾ NMR (400 MHz, CDCI3) d 7.61 (s, 1H), 7.59 - 7.49 (m, 1H), 7.30 - 7.14 (m,

3H), 7.19 - 7.06 (m, 2H), 6.87 (d, J= 8.7 Hz, 2H), 5.11 (s, 1H), 3.80 (s, 3H), 3.37 (ddd, J =

12.5, 5.3, 3.6 Hz, 1H), 3.13 (ddd, J= 12.5, 9.0, 4.8 Hz, 1H), 2.92 (dddd, J= 15.3, 9.0, 5.3, 2.1

Hz, 1H), 2.81 (dddd, J= 15.4, 4.8, 3.6, 1.8 Hz, 1H), 2.13 (s, 1H).

[0789] ¹³C NMR (101 MHz, CDCI3) d 159.6, 135.9, 134.8, 133.9, 129.8, 127.5, 121.8,

119.5, 118.3, 114.2, 110.9, 110.2, 57.6, 55.4, 43.0, 22.6.

[0790] HRMS: calculated for Ci8H₉N₂0⁺ 279.1492, found 279.1469.

[0791] A 250 mL RBF was charged with A46 (1.4 g, 5.12 mmol) and acetyl-D-leucine (887 mg, 5.12 mmol). A solution of 5:1 MeOH/ EtOAc (25 mL) was added as a solvent. The resulting thick slurry was heated to 60 °C for 1 hour. The mixture was allowed to cool to 20 °C without stirring. After 12 h, the solid was collected by filtration, and washed with ice-cold CHCI3. The solid was dried by air suction for 1 h to give the salt (1.14 g, 96%) as white solid. The salt (1.1 g, 2.46 mmol) was dissolved in CHCI3 (20 mL) and transferred to separatory funnel. The organic solution was agitated vigorously with 1 N NaOH (15 mL) for 15 min. After the phase separation, the combined organic extracts were washed with brine, dried with sodium sulfate, concentrated in vacuo to give A48 (442 mg, 66%) as a white solid.

[0792] ¾ NMR (400 MHz, CDCI3) d 7.62 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 6.6 Hz, 2H),

7.44 (d, J= 8.0 Hz, 2H), 7.25 (d, J= 8.7 Hz, 1H), 7.22 - 7.09 (m, 2H), 5.23 (s, 1H), 3.29 (dt, J= 12.5, 5.0 Hz, 1H), 3.15 (ddd, J= 12.6, 7.8, 4.9 Hz, 1H), 2.93 (dddd, J= 15.1, 7.9, 5.3, 1.8 Hz, 1H), 2.84 (dtd, J= 15.5, 4.8, 1.7 Hz, 1H), 2.22 (s, 1H).

[0793] ¹³C NMR (101 MHz, CDCI3) d 147.3, 136.1, 132.7, 132.6, 129.4, 127.2, 122.3,

119.8, 118.6, 118.5, 112.1, 111.0, 110.9, 57.5, 42.3, 22.4.

[0794] HRMS: calculated for Ci₈Hi₆N₃ ⁺ 274.1339, found 274.1330.

References for Example 5

(1) Spangenberg, T.; Burrows, J. N.; Kowalczyk, P.; McDonald, S.; Wells, T. N. C.; Willis, P. PLOS One 2013, 8, e62906.

(2) Kems, E. H.; Di, L. In Drug-like Properties: Concepts, Structure Design, and Methods 2008, p 228-241.

(3) Ghavami, M.; Merino, E. F.; Yao, Z.-K.; Elahi, R.; Simpson, M. E.; Femandez-Murga, M. L.; Butler, J. H.; Casasanta, M. A.; Krai, P. M.; Totrov, M. M.; Slade, D. J.; Carlier, P. R.; Cassera, M. B . ACS Infect. Dis. 2018, 4 , 549-559.

(4) Spindler, A.; Stefan, K.; Wiese, M. J. Med. Chem. 2016, 59, 6121-6135.

(5) Chauhan, J.; Luthra, T.; Sen, S. Eur. J. Org. Chem. 2018, 2018, 4776-4786.

(6) Yao, Z.-K.; Krai, P. M.; Merino, E. F.; Simpson, M. E.; Slebodnick, C.; Cassera, M. B.; Carlier, P. R. Bioorg. Med. Chem. Lett. 2015, 25, 1515-1519.

Example 6

[0795] PRC1590 is the (i?)-enantiomer of compound 7 (see e.g., Table 2, Example 5), also referred to as PRC 1591 See e.g., FIG. 27. Both enantiomers (PRC 1590 and PRC 1589 (see e.g., Compounds A8 and A9). Both enantiomers have potency against the Dd2 strain, but the

(S)-enantiomer has a biphasic concentration-response, which can indicate that it may act at multiple targets. See e.g., FIG. 28. In contrast, PRC 1590 has a monophasic concentration response. The racemate (PRC 1581) is selective against HEK-293 and E. coli, and killed P. berghei liver stages (EC50 about 3 mM). See e.g., FIG. 29. 1590 eliminated stage IV -V P. falciparum gametocytes at 10 pM. Ex vivo testing of PRC 1581 (the racemate) demonstrated some resistance observed in Uganda field isolates (n = 39). See e.g., FIG. 30. Further, asexual stages phenotyping of PCR 1590 was used to establish timing for washout experiments (see e.g., FIG. 31), the results of which are shown in FIG. 32.

[0796] Various modifications and variations of the described methods, pharmaceutical compositions, and kits of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it will be understood that it is capable of further modifications and that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention. 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 present disclosure come within known customary practice within the art to which the invention pertains and may be applied to the essential features herein before set forth.

Claims

CLAIMS What is claimed is:

1. A composition according to Formula I or a salt thereof,

wherein Ri, R₂, R₃, and R4 are each individually selected from: H, a halogen, or a substituted or unsubstituted alkyl, wherein R₅ is selected from OCH₃, NH(CH₂)3Me, NHMe, NH(CH₂)₂OH, NH(CH₂)₂NHMe, NH(CH₂)₂N(Me)₂, NH(CH₂)₃NHMe, NH(CH₂)₃N(Me)₂, NH(CH₂)_nNHCH₂CH₂OH, NH(CH₂)_nN(CH₂CH₂OH)₂, NH(CH₂)_mNH₂, or NH(CH₂)_nNHCH₂C0₂H, wherein n is 2 or 3 and m is 2-6, wherein Rr, and R7 are each individually selected from H, a halogen, or a substituted or unsubstituted alkyl, and wherein Z is C or N.

2. The composition of claim 1 , wherein Ri, R₂, R₃, and R₄ are all different from each other.

3. The composition of claim 1, wherein Ri, R₂, R3, and R4 are all the same.

4. The composition of claim 1, wherein at least two or three of Ri, R₂, R3, and R4 are the same.

5. The composition of claim 1, wherein at least two or three of Ri, R₂, R₃, and R4 are different.

6. The composition of any one of claims 1-5, wherein ¾ and R7 are different from each other.

7. The composition of any one of claims 1-5, wherein ¾ and R₇ are the same.

8. A composition according to Formula II or a salt thereof,

FORMULA II wherein X is selected from 7-CH3, 7-subsituted or unsubstituted alkyl or heteroalkyl, or 7-H, wherein Y is a substituent at positions 3 and 4 or positions 3, 4, and 5 of ring D, wherein each substituent at each position is individually selected from Cl, Br, F, I, Me, or H, and wherein Z is selected from, OCH₃, NH(CH2)3Me, NHMe, NH(CH₂)₂0H, NH(CH₂)₂NHMe, NH(CH₂)₂N(Me)2, NH(CH₂)3NHMe, NH(CH₂)3N(Me)₂, NH(CH2)nNHCH₂CH₂OH, NH(CH₂)nN(CH2CH₂OH)2, NH(CH₂)_mNH₂, or NH(CH₂)_nNHCH₂C0₂H, wherein n is 2 or 3 and m is 2-6.

9. The composition of claim 8, wherein Y is selected from 3’, 4 ’-CI2; 4’Cl; 2’,4’-Cl₂; 3’, 4’- F₂; 3’,4’-Br₂; or 3’,4’-I₂.

10. The composition of any one of claims 8-9, wherein X is selected from 7-CFb, 7- substituted or unsubstituted alkyl or heteroalkyl, or 7-H.

11. The composition of any one of claims 8-10, wherein Y is a 3’ and 4’ where the substituent at the 3’ position is selected from Cl, Br, F, Me, or H and the substituent at the 4’ position is selected from Cl, Br, F, Me, or H.

12. The composition of claim 1 l,wherien the combination for the substituents at the 3’ and 4’ position is selected from: Cl and Cl; Br and Br; F and F; Me and Me; Cl and Br; Br and Cl; Cl and F; F and Cl; Br and F; F and Br; Cl and Me; Me and Cl; Br and Me; Me and Br; F and Me; Me and F; H and Cl; H and Br; H and F; or H and Me.

13. The composition of claim 8, wherein Y is a halogen substituent at each of positions 3, 4, and 5 of ring D.

14. The composition of claim 13, wherein the substituent at positions 3, 4, and 5 are each individually selected from Cl, Br, and F.

15. The composition of claim 14, wherein Br, when optionally present as a substituent, is only present at one of positions 3, 4, or 5 of ring D.

15. A composition according to Formula III or a salt thereof,

16. The composition of claim 15, wherein R.₆ and R7 are different from each other.

17. The composition of claim 15, wherein R6 and R7 are the same.

18. The composition of any one of claims 15-17, wherein ¾ is Cl, Br, F, or Me.

19. The composition of any one of claims 15-19, wherein R7 is Cl, Br, F, or Me.

20. The composition of any of claims 15-19, wherein R4 is Me, Cl or H.

21. A composition according to Formula IV or a salt thereof,

22. The composition of claim 21, wherein R₆ and R7 are different from each other.

23. The composition of claim 21, wherein R6 and R7 are the same.

24. The composition of any of claims 21-23, wherein RJ5 and R7 are both a halogen.

25. The composition of any one of claims 21 or 23-24, wherein R₆ and R7 are both Cl.

26. The composition of any one of claims 21-25, wherein R4 is Me, Cl or H.

27. A composition according to Formula V or a salt thereof,

28. The composition of claim 27, wherein R.₆ and R7 are different from each other.

29. The composition of claim 27, wherein R6 and R7 are the same.

30. The composition of any one of claims 27-29, wherein R₆ and R7 are both a halogen.

31. The composition of any one of claims 27 or 29-30, wherein R₆ and R7 are both Cl.

32. A composition according to Formula VI or a salt thereof,

33. The composition of claim 32, wherein R.6 and R7 are different from each other.

34. The composition of claim 32, wherein R₆ and R7 are the same.

35. The composition of any one of claims 32-33, wherein R₆ and R7 are both a halogen.

36. The composition of any one of claims 32 or 34-35, wherein R₆ and R7 are both Cl.

37. The composition of any one of claims 32-36, wherein the 4’, 5’, 6’, or T position of the A ring is substituted with F.

38. The composition of any one of claims 32-36, wherein at least two or at least three of the 4’, 5’, 6’, or T positions of the A ring are substituted with F.

39. The composition of any one of claims 32-38, wherein the 4’ and 5’, 4’ and 6’, or 4’ and T positions of the A ring are substituted with F.

40. The composition of any of claims 32-36, wherein the 5’ and 6’or 5’ and T positions of the A ring are substituted with F.

41. The composition of any of claims 32-36, wherein the T and 6’or 5’ and T positions of the A ring are substituted with F.

42. The composition of claim 1, wherein the composition is any one of compounds 1-77.

43. The composition of any one of claims lor 42, wherein the composition is compound 1.

44. The composition of any one of claims 1-43, wherein the composition is effective to modulate hERG inhibition.

45. The composition of claim 44, wherein R₅ of Formula I or Z of Formula II is NH(CH₂)_nNHCH₂CH₂OH or NH(CH₂)nCH₂C0₂H, wherein n is 2 or 3.

46. The composition of claim 44 or 45, wherein the composition is 1, 40, 42, 43, 44, or any combination thereof.

47. The composition of any one of claims 1-46, wherein the composition is 1-16, 7, 12,

30, 38, 40-44, 46-48, 50-51, 58-59, 72-77, or any combination thereof.

48. The composition of any one of claims 1-47, wherein the composition is effective to kill quiescent rings formed by exposure to dihydroartemisinin.

49. A composition according to Formula VII or a salt thereof,

51. The composition of claim 49, wherein the composition is the (///-enantiomer.

52. The composition of claim 49, wherein the composition is the (_<S)-enantiomer.

53. The composition of claim 49, wherein the halogen is Cl, Br, or F.

54. The composition of any one of claims 49-53, wherein X is 4’-Cl.

55. The composition of any one of claims 49-53, wherein X is 4’-F.

56. The composition of any one of claims 49-53, wherein X is 4’-Br.

57. The composition of any one of claims 49-53, wherein X is 4’-OEt.

58. The composition of any one of claims 49-50, wherein X is 2’, 4’-Cl2.

59. The composition of any one of claims 49-58, wherein Y is H.

60. The composition of any one of claims 49-59, wherein R is C(0)-(5"-bromobenzofuran-

2”-yl).

61. The composition of claim 49, wherein the composition is any one of compounds Al- A42.

62. The composition of claim 49, wherein the composition is compound A7.

63. The composition of claim 49, wherein the composition is compound A8.

64. The composition of claim 49, wherein the composition is compound A9.

65. The composition or any one of claims 1-49, wherein the composition is effective to kill or inhibit an organism from the genus Plasmodium.

66. The composition of claim 65, wherein the organism from the genus Plasmodium is capable of causing malaria.

67. The composition or any one of claims 65-66, wherein the Plasmodium is P. falciparum, P. vivax, P. ovale, P. malariae, P. knowlesi, or any combination thereof.

68. The composition or any one of claims 65-66, wherein the composition is effective against an asexual blood stage, sexual blood stage, liver stage, or a combination thereof of the Plasmodium organism.

69. A pharmaceutical formulation comprising: a. a composition as in any one of claims 1-68; b. a composition according to Formula IX,

wherein Xi, X₂, and X₃ are each independently selected H, CH₃, OCH₃, a halogen (e.g., Cl, Br, F), OCH2CH3, NO2, CF3, where optionally Xi and X2 together form a 3, 4, 5, or 6 member heterocycle (e.g., X₂ and X₃ are substituted such that 5’-0CH₂CH-0-4’ and form a 5 member heterocycle), wherein B is CH, wherein Y is substituted at the 5”, the 6”, or both where each are selected from a halogen or H, where the halogen is Br, Cl, or F, and wherein R is H or (CFb)2N(CF[3)2, one or more of any of compounds 1-77 and A1-A106; or c. a combination thereof; and a pharmaceutically acceptable carrier.

70. The pharmaceutical formulation of claim 69, wherein the pharmaceutical formulation is adapted for oral administration.

71. The pharmaceutical formulation of claim 69, wherein the pharmaceutical formulation is adapted for intravenous administration.

72. The pharmaceutical formulation of claim 71, wherein the pharmaceutically acceptable carrier comprises and an amount of DMSO, an amount of Cremophor EL, an amount of glycerol, an amount of PEG 400 and an amount of a solution comprising Na₂HP0₄ and Tween 20

73. The pharmaceutical formulation of claim 23, wherein the pharmaceutically acceptable carrier comprises about 10% DMSO, about 10% Cremophor EL, about 10% glycerol, about 30% PEG400 and about 40% of a solution containing about 50 mM Na2HP04 and 2% Tween 20

74. The pharmaceutical formulation of any one of claims 69-73, wherein the pharmaceutical formulation further comprises an auxiliary active agent.

75. The pharmaceutical formulation of claim 74, wherein the auxiliary active agent is another antimalarial agent or an antiparasitic agent.

76. A method of treating or preventing Plasmodium infection in a subject in need thereof, the method comprising: administering a composition as in any one of claims 1-68 or a pharmaceutical formulation as in any one of claims 69-75 to the subject in need thereof.

77. The method of claim 76, wherein administration is oral or intravenous.

78. The method of any one of claims 76-77, further comprising administering a co-therapy to the subject in need thereof.

79. The method of claim 78, wherein the compound as in any one of claims 1-68 or pharmaceutical formulation as in any one of claims 69-75 and the co-therapy are administered simultaneously.

80. The method of claim 78, wherein the compound as in any one of claims 1-68 or pharmaceutical formulation as in any one of claims 69-75 and the co-therapy are administered at substantially different times.

81. A kit comprising: a composition as in any one of claims 1-68 or a pharmaceutical formulation as in any of claims 69-75, and optionally a co-therapy.