NZ759233B2 - Compositions and methods for modulating hair growth - Google Patents

Abstract

The present disclosure relates to compounds that are capable of inhibiting the mitochondrial pyruvate carrier and promoting hair growth. The disclosure further relates to methods of promoting hair growth or treating conditions or disorders affecting hair growth, such as baldness or alopecia.

Description

COMPOSITIONS AND lVIETHODS FORMODULATH‘IG HAIRGROWTH RELATED APPLICATIONS This application claims the bene?t of US. Provisional Patent ation No. 62/527,775, ?led on June 30, 2017, and US. ional Patent Application No. 62/654,095, ?led on April 6, 2018. The contents of each of these applications is hereby incorporated by reference in its entirety.

BACKGROUND Hair follicle stem cells (HFSCs) undergo successive rounds of quiescence (telogen) punctuated by brief s of proliferation correlating with the start of the hair cycle (telogen-anagen transition). Proliferation or activation of HFSCs is well known to be a prerequisite for advancement of the hair cycle. Despite advances in treatment s, baldness and alopecia continue to be ions that cannot be successfully treated in all individuals. Some of the existing treatments are inconvenient for users, others require surgical intervention or other invasive procedures. Additional therapies are needed.

SUMMARY OF THE ION In certain aspects, the present disclosure provides compounds of formula I or II: NR3 (I) Z (II) wherein: each A is independently CH, CR4, or N, g—IID—OR") Y is carboxyl, ester, amide, or y) Z is CH, CR4, or N.

R2 is CN or carboxyl, R3 is H, aryl, aralkyl, or aralkylacyl, and is optionally tuted by one or more R5, wherein each R5 is independently selected from alkyl, alkoxy, or halo, each instance of R4 is ndently alkyl, carboxyl, halo, hydroxy, ester, or CN, R6 is from H, alkyl, or cycloalkyl, R7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy, R10 is hydrogen or alkyl, and n is 0-4, or a pharmaceutically acceptable salt f.

In certain embodiments, the t disclosure provides compounds of formula 111: wherein: -§—F|’—OR10 Y is carboxyl, ester, amide, or (I; R2 is CN or carboxyl, R3 is H, aryl, l, or aralkylacyl, and is optionally substituted by one or more R5, n each R5 is independently selected from alkyl, alkoxy, or halo, each instance of R4 is ndently alkyl, carboxyl, halo, hydroxy, ester, or CN, R6 is from H, alkyl, or cycloalkyl, and R7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy, R10 is hydrogen or alkyl, R11 is hydrogen or alkyl, and n is 0-4, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present disclosure provides compounds of formula V, VI, or VII: wherein: each A is independently CH, CR4, or N; X is NR6 or O; R1 is H or lower alkyl; or either R1 and R6 or R1 and R2, together with the atoms that separate them, complete a heterocycle; R2 is CN or carboxyl; R3 is H, aryl, aralkyl, or lacyl, and is ally tuted by one or more R5, wherein each R5 is independently selected from alkyl, alkoxy, and halo; each instance of R4 is independently alkyl, carboxyl, halo, hydroxy, or CN; R6 is from H, alkyl, or cycloalkyl; and R7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present disclosure provides compounds of formula Va, Via, or Vila wherein: X is NR6 or O; R1 is H or lower alkyl; R2 is CN or carboxyl; or R1 and R2, together with the atoms that te them, complete a heterocycle; R3 is H, phenyl, or benzyl, and is optionally substituted by one or more R5, wherein each R5 is independently selected from alkyl, alkoxy, or halo; each instance of R4 is independently selected from alkyl, carboxyl, halo, hydroxy, or CN; and R6 is selected from H, alkyl, or lkyl; and pharmaceutically acceptable salts thereof.

According to a ular embodiment there is provided a compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

In certain aspects, the present disclosure provides a pharmaceutical ition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient. the next consecutive page is page 4 In certain s, the present disclosure provides methods of ing lactate production in a cell, comprising contacting the cell with a compound or composition of the disclosure.

In certain aspects, the present disclosure provides methods of inhibiting mitochondrial pyruvate oxidation in a cell, comprising contacting the cell with a mitochondrial te ion (MPO) inhibitor, such as a compound of the present disclosure. In certain embodiments, the MPO inhibitor is a mitochondrial pyruvate carrier (MPC) inhibitor. In certain embodiments, inhibiting mitochondrial pyruvate oxidation in a cell has the effect of enhancing lactate production in a cell and/or enhancing the activity of LDH in a cell, and promoting hair , as described herein.

In certain aspects, the present disclosure provides methods of enhancing lactate production in a cell, comprising contacting the cell with an MP0 tor, such as a compound of the present disclosure. In certain embodiments, the MPO tor is a mitochondrial pyruvate r (MPC) inhibitor.

In certain aspects, the present disclosure provides methods of enhancing the activity ofLDH in a cell, comprising contacting the cell with an MP0 inhibitor, such as a compound of the present disclosure. In certain ments, the MPO inhibitor is a mitochondrial pyruvate carrier (MPC) inhibitor.

In certain aspects, the present disclosure provides methods of enhancing the activity of lactic acid dehydrogenase (LDH) in a cell, comprising contacting the cell with an MP0 inhibitor, such as a compound of the present disclosure. In certain embodiments, the MPO inhibitor is a mitochondrial pyruvate carrier (MPC) tor. In certain s, the present disclosure provides methods of ing hair growth or treating a hair growth ion or disorder such as baldness or alopecia, comprising administering to a patient a compound or composition as disclosed herein.

In certain aspects, the present disclosure provides s of ing hair growth or treating a hair growth condition or disorder such as baldness or alopecia, comprising administering to a patient an MP0 inhibitor (e.g., lly, such as with a pharmaceutical composition formulated for topical application), such as a nd of the present disclosure. In certain embodiments, the present disclosure provides methods of promoting hair growth or treating a hair growth condition or disorder such as baldness or alopecia, comprising administering to a patient an MPC inhibitor (e.g., topically, such as with a pharmaceutical composition ated for topical application), such a compound of the present disclosure. In certain embodiments, inhibiting mitochondrial pyruvate oxidation or the mitochondrial pyruvate carrier in a cell has the effect of enhancing lactate production and/or ing the activity of LDH in a cell, and promoting hair growth, as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A-1E show Lactate dehydrogenase activity is enriched in HFSCs. : IHC staining for tha expression across the hair cycle shows tha protein con?ned to the HFSC niche, the bulge, indicated by the bracket. IHC staining for Sox9 on serial sections demarcates the HFSC population. Scale bar tes 20 micrometers. : Immunoblotting on solated HFSC populations (d6low/Cd34+ and 0L6hiCd34+) versus total epidermis (Epi) shows differential expression of tha in the stem cell niche. Sox9 is a marker of HFSCs, and B-actin is a loading control. : Colorimetric assay for th enzyme activity in the epidermis shows highest activity in the bulge (brackets) and subcuticular muscle layer et). This activity is enriched in the bulge across different stages of the hair cycle. Activity is indicated by purple color, pink is a nuclear counterstain.

Note also that developing hair shafts in pigmented mice show strong deposits of melanin as observed here, hair shafts never displayed any purple stain tive ofth activity. Scale bars indicate 50 micrometers. : th activity in sorted cell populations, measured using a plate reader-based assay, also shows the highest th activity in two separate HFSC populations (0L6hl/Cd34 and d6low/Cd34) compared to epidermal cells (Epi) and fibroblasts (FBs). Each bar represents the average signal for each cell type where n=9 mice pooled from 3 independent experiments. Shown as mean :: SEM. Paired t-test was performed, p < 0.05 shown for each cell type versus epidermal cells. : HFSCs and epidermal cells were isolated during telogen (day 50) by FACS, and metabolites were extracted and analyzed by LC-MS. Heatmaps show relative levels of glycolytic and TCA cycle metabolites from cells ed from different mice in independent experiments with cells from three s in each. Asterisks te signi?cant difference in metabolite levels between epidermal cells and HFSCs. For e, paired t-test was med, * denotes p < 0.05, ** denotes p <0.01, *** denotes p < 0.001, ns s p > 0.05, and n=9 mice pooled from 3 independent experiments.

FIGS. 2A-2C show the validation of key reagents and assays. : IHC with antibody izing specifically tha (same as used in ). bottom, IHC with antibody recognizing multiple ms ofth protein. Scale bars indicate 20 micrometers. : the sorting strategy employed to isolate two populations of cells from the bulge.

This particular sort was used to isolate the protein samples shown by western blot in . : Validation of colorimetric th enzyme activity assay. The t th enzyme activity was observed in HFSC bulge and in the muscle. Activity indicated by purple stain; pink color is nuclear fast red counterstain. In absence of substrate e there was no detectable activity e stain). right, Additional tion of colorimetric th enzyme activity assay. Enzyme activity ted by treating skin with HCl before addition of staining solution with substrate e. No th activity (purple stain) ed. Skin in which enzyme activity is not inhibited by Hydrochloric Acid (HCl) shows t th enzyme activity in HFSC bulge and in the muscle. Scale bars indicate 50 micrometers.

FIGs. 3A-3E show that th activity increases during HFSC activation. : GSEA on RNA-seq transcriptome data from HFSCs versus total epidermis shows ment for Glycolysis related genes in HFSCs (NES = 1.72). : GSEA on microarray transcriptome data from HFSCs versus total epidermis shows enrichment for Glycolysis related genes in HFSCs (NES = 1.45). s were generated from three mice of each condition. : RNA-seq data from HFSCs sorted during telogen or telogen-anagen transition show induction of tha21. Data represent the average of three separate animals at each timepoint. : th activity in sorted stem cell populations, measured using a plate reader-based assay, shows elevated th activity as stem cells become activated in telogen to anagen transition (Tel-Ana). Each bar represents the average signal for each condition where n=9 mice pooled from 3 independent experiments. Shown as mean :: SEM.

Paired t-test was performed, p < 0.05. : Heatmap showing relative levels of glycolytic and TCA cycle metabolites extracted from quiescent (Telogen, day 50), activated (Telogen-Anagen, day 70) and HFSCs that have returned to the quiescent state (Anagen, day 90). Data shown were generated from n=3 animals per int in 3 independent experiments.

FIGs. 4A-4B show validation of hair cycle stage measurements. : Analysis of RNA-seq data to validate that HFSCs in telogen-anagen transition were in fact in such a transition. The telogen-anagen transition is known to be driven by Shh (Gli factors are targets) and Wnt (Lefl, AXin, Ccndl are targets) signaling, and correlate with increased proliferation (Ki67 and Pcna). In addition, Sox4 was previously fied as a tor of the telogen-anagen transition. n=3 mice per timepoint. Shown as mean :: SEM. Paired t-test was performed, p < 0.05. : staining for Ki-67 marks dividing cells during various stages of the hair cycle. Brackets indicate the HFSC niche. Scale bars indicate 100 micrometers.

FIGS. SA-SG show that deletion of Mpcl increases lactate production and activation of HFSCs. : ? s show pigmentation and hair growth, tent with entry into the anagen cycle at 8.5 weeks, whereas Mpcl+/+ animals do not show dorsal pigmentation and hair growth this early. Animals shown are representative of at least 12 animals of each genotype. : FACS isolation of HFSC bulge populations in Mpcl+/+ versus Mpcl?/? mice ed by western blotting shows successful deletion of Mpcl protein in the stem cell niche. B-actin is a loading control. : Plate reader assay for th activity on sorted HFSC tions shows elevated activity in Mpcl?/? HFSCs compared to Mpcl+/+ HFSCs. Each bar represents the average signal for each genotype where n=9 mice pooled from 3 independent experiments. Shown as mean :: SEM. Paired t- test was performed, p < 0.05. : Histology on WT versus Mpcl on skin shows induction of anagen in absence of Mpcl. Scale bars indicate 100 micrometers.

Quanti?cation of phenotype at right shows percentage of dorsal follicles in telogen, telogen to anagen transition and anagen in Mpcl +/+ mice versus Mpcl?/? mice (n = 250 follicles from 3 mice per pe). Shown as mean :: SEM. Paired t-test was performed, p < 0.05.

: Immunohistochemistry staining for Ki-67, a marker of proliferation that is only active in HFSCs at the beginning of a new hair cycle, is only present in Mpcl?/? HFSCs at 8.5 weeks, consistent with their accelerated entry into a new hair cycle. Phospo-S6, another marker that is only active in HFSCs at the beginning of a new hair cycle, is only present in Mpcl?/? HFSCs. Staining for Sox9 shows that HFSCs are present in Mpcl deleted niche.

Images taken at 60X magnif1cation. : Deletion of Mpcl in mice bearing the LgrSCreER allele shows strong induction of the hair cycle. Note that red boxes indicate areas of new hair growth. Results are representative of at least 9 animals per genotype. : Quanti?cation of pigmentation in the indicated genotypes across three independent litters (n = 5 mice per genotype).

FIGs. 6A-6D show the effects of long term deletion of Mpcl in HFSCs. : Six months after initiation of deletion of Mpcl in HFSCs (K15CrePR;MpcI?/?), mice lacking Mpcl show no deleterious effects as ed by the hair cycle (left), pathology (middle, H and E), or ng for HFSCs (right, Sox9). Scale bars indicate 100 eters in middle panel, and 50 micrometers in right panel. Images are representative of at least 12 animals per genotype. : To trate that the deletion of Mpcl es proliferation speci?cally in HFSCs, we used K15CrePR;tha?/? mice bearing a lox-stop-lox-Tomato allele to look at K15+ HFSCs and proliferation with and without Mpcl deletion (left). In addition, we took advantage of the ires-GFP within the Lgr5CreER allele to stain for Ki-67 and GFP and look for co-localization with and without Mpcl deletion (right). White brackets denote bulge area. Scale bars represent 20 micrometers. : Deletion ofMpcl in mice bearing the Lgr6CreER allele shows no premature induction of the hair cycle. : th activity assay on sorted HFSCs from either control or Lgr6CreER mediated Mpcl on mice showed increased activity in cells lacking Mpcl. n=6 mice per pe pooled from 2 independent experiments. Shown as mean :: SEM. Paired t-test was performed, p < 0.05.

FIGs. 7A-7D show that cological inhibition of Mpcl promotes HFSC activation. : Animals treated topically with UK-5099 (20uM) show pigmentation and hair growth, indicative of entry into anagen, after 8 days of treatment. Full anagen, indicated by full coat of hair, is achieved after 14 days of treatment. Mice d topically with vehicle control do not show pigmentation nor hair growth even after 12 days of treatment. right, Skin pathology showing that UK-5099 animals enter an accelerated anagen at 8 weeks typified by down growth of the follicle and hypodermal thickening, while vehicle control treated animals showed neither and ed in telogen. Images shown are representative of at least 14 mice from 7 independent experiments. Scale bars indicate 100 micrometers. : Graph showing time to observed ype in vehicle versus UK- 5099 d mice. n = 6 mice per condition. Shown as mean :: SEM. : th enzyme activity assay in the epidermis shows strong activity in HFSCs in vehicle control and UK- 5099 treated s. th enzyme activity also seen in interfollicular epidermis of 9 treated animals. th activity is indicated by purple stain, pink is nuclear fast red counterstain. Scale bars indicate 50 micrometers. : Metabolomic analysis of Lactate on HFSCs isolated from UK-5099 treated skin for 48 hours, Each bar represents the average signal for each condition where n=9 mice pooled from 3 independent experiments. Shown as mean :: SEM. Paired t-test was performed, p < 0.05. shows the effect on lactate production of certain Mpcl tors described herein. shows the effect on lactate production of the certain Mpcl tor described herein. shows the ECSO calculation for UK5099 and JXLOZO. shows that the Mpcl inhibitors of the present invention induce hair growth. shows the effect on lactate production of certain Mpcl inhibitors described herein. shows the effect on total cell count of certain Mpcl tors described herein, normalized to DMSO treatment. shows the effect on cell lactate production of n Mpcl inhibitors described herein, normalized to DMSO treatment. shows the effect on total cell count of certain Mpcl inhibitors described herein, normalized to DMSO treatment. shows the effect on cell lactate production of certain Mpcl inhibitors described herein, normalized to DMSO treatment. shows the effect on total cell count of certain Mpcl inhibitors described herein, normalized to DMSO treatment. shows the effect on cell lactate production of certain Mpcl inhibitors bed herein, normalized to DMSO treatment. shows the effect on total cell count of certain Mpcl inhibitors described herein, normalized to DMSO ent. shows the role ofMPC in the oxidation of pyruvate to acetyl coenzyme A.

ED DESCRIPTION OF THE INVENTION In certain aspects, the present disclosure es compounds of formula I or II: R7 Y _ R7 /A R2 — 2 I \ .2 \A N\ \ (R4)n R3 (I) Z (11) each A is independently CH, CR4, or N, €~Ila—0R1°H Y is carboxyl, ester, amide, or 0 Z is CH, CR4, or N.

R2 is CN or carboxyl, R3 is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R5, wherein each R5 is independently selected from alkyl, alkoxy, or halo, each instance of R4 is independently alkyl, carboxyl, halo, hydroxy, ester, or CN, R6 is from H, alkyl, or cycloalkyl, R7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy, R10 is hydrogen or alkyl, and n is 0-4, or a pharmaceutically acceptable salt f.

In certain ments, the compound is a compound of formula I. In certain embodiments, the compound is a compound of formula II.

In certain embodiments of Formula I or II, Z is CH or N.

In certain embodiments, the present disclosure provides compounds of formula III or R7 Y / R2 i I \ \A N‘ R3 (III) wherein, g—IID—OR") Y is carboxyl, ester, amide, or y) R2 is CN or carboxyl, R3 is H, aryl, l, or aralkylacyl, and is optionally substituted by one or more R5, wherein each R5 is ndently selected from alkyl, alkoxy, or halo, each instance of R4 is independently alkyl, carboxyl, halo, hydroxy, ester, or CN, R6 is from H, alkyl, or cycloalkyl, and R7 is hydrogen, alkyl, halo, yl, alkoxy, or y, R10 is en or alkyl, R11 is hydrogen or alkyl, and n is 0-4, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is a compound of formula III.

?—OR" In certain embodiments of Formula I, II, and III, Y is wherein Y is O certain ments, R10 is H. In certain embodiments, R10 is alkyl (e.g., ethyl). In certain embodiments Y is ester or amido.

In certain embodiments of Formula I, II, or III, R11 is alkyl (e.g., methyl).

In certain embodiments, the present disclosure provides compounds of formula V, VI, or VII: wherein: each A is independently CH, CR4, or N, X is NR6 or O, R1 is H or lower alkyl, or either R1 and R6 or R1 and R2, together with the atoms that te them, complete a heterocycle, R2 is CN or yl, R3 is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R5, wherein each R5 is independently selected from alkyl, alkoxy, and halo, each instance of R4 is independently alkyl, carboxyl, halo, hydroxy, or CN, R6 is from H, alkyl, or lkyl, and R7 is hydrogen, alkyl, halo, yl, alkoxy, or acyloxy, or a pharmaceutically acceptable salt thereof.

In certain ments, the compound is a compound of formula V. In certain embodiments, the compound is a compound of formula VI. In certain embodiments, the compound is a compound of formula VII.

In certain embodiments of formula I, II, III, V, VI, or VII, at least one A is N, preferably no more than two ences of A are N. In certain red embodiments, exactly one A is N, preferably the A bound to the same carbon as NR3.

In certain embodiments, the present disclosure provides compounds of formula Va, VIa, or VIIa: (R4)n — R1 R3 (V31) wherein: X is NR6 or O, R1 is H or lower alkyl, R2 is CN or carboxyl, or R1 and R2, er with the atoms that separate them, complete a heterocycle, R3 is H, phenyl, or benzyl, and is optionally substituted by one or more R5, n each R5 is independently selected from alkyl, alkoxy, or halo, each instance of R4 is independently selected from alkyl, carboxyl, halo, hydroxy, or CN, and R6 is selected from H, alkyl, or cycloalkyl, and pharmaceutically acceptable salts thereof.

In certain embodiments, the compound is a compound of formula Va. In certain embodiments, the compound is a nd of formula VIa. In certain ments, the compound is a nd of formula VIIa.

In certain ments of a V, VI, VII, Va, VIa, or VIIa, X is NH. In n embodiments, X is O.

In certain embodiments of formula V, VI, VII, Va, VIa, or VIIa, R1 is H. In certain embodiments, R1 is lower alkyl. In certain embodiments, R1 and R6, together with the atoms that separate them, complete a heterocycle (e.g., morpholinyl).

In certain embodiments of formula V, VI, VII, Va, VIa, or VIIa, R6 is hydrogen.

In certain embodiments of formula V, VI, VII, Va, VIa, or VIIa, R2 is CN. In certain embodiments, R2 is carboxyl. In certain embodiments, R1 and R2, together with the atoms that separate them, complete a heterocyclyl selected from thiazolidine-2,4-dionylidene or 2- iminothiazolidinoneylidene.

In certain ments of formula I, II, III, V, VI, VII, Va, VIa, or VIIa, R3 is H. In certain embodiments, R3 is phenyl. In certain embodiments, R3 is phenyl and is substituted by one or more R5. In certain embodiments, R3 is substituted by one R5, and wherein R5 is an . In certain embodiments, R3 is aralkyl (e.g., benzyl or phenethyl). In certain embodiments, R3 is aralkylacyl (e.g., phenylacetyl). In certain embodiments, R3 is benzyl. In n embodiments, R3 is benzyl and is substituted by one or more R5. In certain embodiments, R3 is aralkyl (e.g., benzyl or phenethyl) and is tuted by one or more R5 (preferably on the phenyl ring). In certain embodiments, R3 is aralkylacyl (e.g., phenylacetyl), and is substituted by one or more R5 (preferably on the phenyl ring). In certain embodiments, R3 is substituted by one or two R5, and wherein each R5 is independently selected from lkyl or ?uoro. In certain embodiments, R3 is substituted by two R5, and wherein each R5 is tri?uoromethyl.

In certain embodiments of formula Va, VIa, or VIIa, n is O.

In certain preferred embodiments, the present disclosure provides compounds of formula Vb R3 (Vb).

In certain embodiments, the present disclosure provides compounds of formula Vc _ \R1 R3 (Vc).

In certain embodiments of formula Va, VIa, VIIa, or Vb, n is 1.

In certain preferred embodiments, the present sure es nds of formula Vd _ \R1 R3 (Vd).

In certain embodiments, the present disclosure provides compounds of formula Ve _ \R1 R3 (Ve).

In certain embodiments of formula Vb, Vd or Ve, R4 is selected from halo or haloalkyl. In certain preferred embodiments, R4 is halo (e.g., chloro or bromo). In other preferred ments, R4 is carboxyl or ester.

In certain embodiments of formula VI or VIa, n is O. In n embodiments, n is 2, and R4 is selected from halo or haloalkyl.

In certain embodiments of formula I, II, III, V, VI, VII, Va, Vb, Vc, Vd, Ve, VIa, or VIIa, R7 is hydrogen, hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy). In certain embodiments, R7 is hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy).

In certain ments of formula I, II, III, V, VI, VII, Va, Vb, Vc, Vd, Ve, VIa, or VIIa, the compound is not JXLOOl.

In certain aspects, the compound of the disclosure is a compound of Table 1.

Table l: Exemplary Compounds of the t Invention COzEt COZH COZEt COZEt / CN / / CN CN CN \ N N N\ \ \ \ Ph H H Ph JXLOOZ JXL003 JXL004 JXL005 002Et 002a COzEt / / COZEt CN CN CN / \ \ \ CN N N \ OMe N F JXLOOG JXL007 JXL003 JXL009 COzEt COZEt ,..

CN CN \ \ \ N N ,F N CF3 F ca 0M6 JXL010 JXL011 JXL012 COZH CN ,.— \\ CN N \ \\ OMe CI N Ph F JXL013 JXL014 JXL015 COzH 2 ,,’ COzEt —" CN ——' CN —" \ CN \ \ N F \\ N F N ng N kg KO JXL016 JXL017 JXLO18 JXL019 COZH CN COzEt 0 CN ’f, \\ CN "' J}: \\ NH N CF3 / \ N\ N__ Ph N JXL020 CF3 JXL021 JXL022 JXL023 7 7 7 7 o COZEt NH COW CQH S CN \ CN N N N N \ Ph \ \ Ph Ph Ph JXL024 JXL025 JXL026 JXL027 7 7 7 7 COZH COZH / / CN CN \ \ C02H \ F COQH Eh ON \ ON F Ph JXL028 JXL029 JXL030 JXL031 7 7 7 7 CI —" F C co H co H CozH 3m 2 m 2 \ N\ CN CN Ph JXL032 JXL033 JXLO34 JXL035 7 7 7 COZH COZH CN CN F F \ \ \ N CFs N F N F JXL°37 JXL036 F JXL038 7 7 7 co H2 COzH COZH / / CN F ON F CF3 JXL039 JXL040 JXL041 F30 COZH COH \ F COZH \ 2 \ \ DO c~ CN F F Me F CF3 JXL042 JXL043 JXL044 JXL045 COZH COZH \ \ CO H \ 2 COZH ON ON CI F CN CN CFs CF3 JXL046 JXL047 JXL048 JXL049 7 7 7 7 COZH COZH Br / ON ON N ,CF3 N CI:CF3 N\\C:;:F3 JXL050 JXL051 JXL052 JXL053 u u COZH COZH N ,0 3N\\Q:F JXL054 JXL055 JXL056 COZH COzH \ \ N CF3 BnO N, {CF3OBn N ,0 JXL057 JXL058 JXL059 N N CFs CF3 JXL060 JXL061 JXL062 COZH COZH \ \ \ N N CI CF23 CF3 CF3 JXL063 JXL064 JXL065 NH OCZtBu CO Et ’ s/KNH :Qf \ \ N JXL066 JXL067 JXL068 7 7 7 l \ o O \ I \ N/ N NH NH / F ’ L / 3A0 s O F3C \ \ F3C N F N \ \ CF Ph Ph CFs JXL069 JXL070 JXL071 JXL072 O ’[:::I:f<:=;?;::§:CN (j \ NH \ JXL074 JXL075 02H COZH COZEt JXL077 JXL078 3JXL079 JXL080 COZEt 0025‘ $3N F3C1:; c; CF3 JXL081 JXL082 JXL083 JXL084 7 7 COZEt %P-oa \OEt 002Et CN CI / ON ON |\ \ | \ ) N’ N N N CF3 CF3 JXL085 JXL086 JXL087 JXL088 COZEt COZEt COzEt COZMe/ / 002Me F30 N CFs CFs CF3 JXL089 JXL090 JXL091 JXL092 O\‘P-0Et O\‘P-OH COzEt \ \ CN N/ N Ph Fc?w CF3 CFs JXL093 JXL094 JXL095 and JXL096 7 7 In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is formulated for topical administration.

In certain aspects, the present disclosure provides methods of enhancing lactate production in a cell, comprising contacting the cell with a compound or composition of the disclosure. In certain embodiments, the cell is a hair follicle stem cell.

In certain aspects, the present disclosure provides methods of promoting hair growth or treating hair growth ions or disorders such as baldness or alopecia, comprising administering to a patient a compound or composition as disclosed herein.

In certain aspects, the present disclosure provides methods of enhancing lactate production in a cell, comprising ting the cell with a mitochondrial pyruvate carrier (MPC) inhibitor. In n embodiments, the MPC is MPCl.

In certain aspects, the present sure provides methods of ing hair growth or treating a hair growth condition or disorder such as baldness or alopecia, comprising stering to a t a mitochondrial pyruvate carrier (MPC) inhibitor (e.g., topically, such as with a pharmaceutical composition formulated for topical application). In n embodiments, the MPC is MPCl.

In certain aspects, the present disclosure provides methods of inhibiting mitochondrial pyruvate oxidation in a cell, comprising ting the cell with a mitochondrial oxidation (MPO) inhibitor.

In certain aspects, the present sure provides s of promoting hair growth or treating a hair growth condition or disorder such as baldness or alopecia, comprising administering to a patient a mitochondrial oxidation (MPO) inhibitor (e.g., lly, such as with a pharmaceutical composition formulated for topical application).

In certain ments, the MPC or MPO inhibitor is a nd of the disclosure.

Discussion us studies have uncovered unique gene expression signatures in hair follicle stem cells (HF SCs) versus other follicle cells or cells of the interfollicular epidermis. Many of these ures are regulated by transcription factors that were later shown to play important roles in HFSC homeostasis.

Lactate dehydrogenase is most commonly encoded by the tha and thb genes in mammals, the protein products of which form homo- or hetero-tetramers to catalyze the NADH-dependent reduction of pyruvate to lactate and NAD+-dependent oxidation of lactate to pyruvate. By immunostaining, it has been discovered that tha is enriched in quiescent HFSCs in silu (telogen) (), and ming immunohistochemistry staining (IHC) with an antibody that recognizes both tha and thb showed that only tha appears to be localized to the HFSC niche ().

IHC is also showed tha expression was enriched in HFSCs (Sox9+) at three stages of the hair cycle (). Consistently, immunoblotting of lysates from sorted cells showed strong expression oftha in the basal HFSCs (0L6HlCD34‘l'), and suprabasal (0L6LOCD34‘l') HFSC populations relative to total mis (Fig 1B) (Sorting strategy is outlined in Fig 2B).

To determine whether tha expression patterns correlate with activity of the th enzyme, a colorimetric-based enzymatic assay was used to assess th activity capacity in situ. Typically performed on protein lysates or aliquots with a plate reader, the th activity assay was adapted to work in silu on frozen tissue sections. Note that since both the in silu and in vitro th activity assays employ use of excess substrate (lactate), the results from these assays re?ect the capacity for th ty, and not the steady-state activity.

Applying this assay to skin s demonstrated that th activity capacity was signi?cantly higher in HFSCs, consistent with the sion pattern oftha ().

Furthermore, th activity was enriched in HFSCs across the hair cycle (). As a control, assays conducted without the tic substrate te) or on acid-treated tissue yielded zero activity (). To further validate these results, we sorted mal tions, ted cell lysates on the sorted cells, and performed a similar colorimetric- based enzymatic assay on the sorted cell lysates, which also showed increased th activity in HFSCs (). To better characterize the metabolism of HFSCs, we med metabolomics analysis on sorted populations from mouse skin by liquid chromatography- mass spectrometry (LC-MS) (Fig le). Several glycolytic metabolites, ing glucose/fructosephosphate, fructose-bisphosphate, dihydroxyacetone phosphate, 3- phosphoglycerate, and lactate, were routinely higher in HFSCs relative to total epidermis across three independent experiments (isolated from different mice on different days). sely, most TCA cycle metabolites were not consistently different between the epidermis and HFSCs (). Collectively these results suggest that while all cells in the epidermis use the TCA cycle extensively to generate energy, HFSCs also have increased tha expression, th activity, and glycolytic metabolism.

Measuring metabolism across the hair cycle therefore would capture any dynamic changes that occur in HFSCs that ate with activation or quiescence. Analysis of RNA- seq data from HFSCs isolated during either telogen or the telogen-anagen transition demonstrated not only that tha is the predominant th isoform expressed in HFSCs (, but is also induced during the telogen-anagen transition (FIGs. 3A and 3B (NIHGEOGSE67404 and GSES 1635). To con?rm that the cells analyzed by RNA-seq were indeed either in telogen or the telogen to anagen transition, important markers of this transition were assessed including the Shh and Wnt pathways (611], 2, 3; Lef], Axin], Axin2, CcndI) as well as proliferation markers (Ki-6 7, Pcna and 50x4) (Fig 4A).

The in vitro th activity assay on lysates from sorted HFSCs uncovered a modest induction of th activity correlating with the telogen to anagen transition (Fig 3D). Hair cycle staging was validated by Ki-67 immunostaining to ine HFSC activation (Fig 4B). Additionally, measurements of steady-state metabolites extracted from sorted HFSCs showed an increase in lactate in HFSCs as they transition from n to telogen-anagen transition, and then se again in anagen as HFSCs return to quiescence (Fig 3E).

To determine whether induction of lactate production could affect HFSC activation or the hair cycle, we crossed K15CrePR animals to those ?oxed for mitochondrial pyruvate carrier 1 (Mpcl) (K15CrePR;MpcI?/?). Mpcl, as a heterodimer with Mpc2, forms the mitochondrial pyruvate carrier MPC, a transporter on the inner ondrial membrane required for te entry into the mitochondria. Loss of function of Mpcl has been shown to drive lactate production through ed conversion of pyruvate to lactate by th.

Furthermore, inhibition ofMPC results in a decrease in mitochondrial pyruvate ion (MPO) to acetyl coenzyme A ().

In animals with Mpcl deletion in HFSCs, we observed a strong acceleration of the ventral and dorsal hair cycles with all the typical features of a n-anagen transition () (11 = 12 littermate pairs). Mifepristone treated K15CrePR;MpcI?/? animals were the only to show any signs of dorsal anagen by day 70. Western ng on sorted HFSCs validated the loss of Mpcl protein (). Importantly, purif1ed HFSCs g Mpcl showed a strong induction ofth activity (). ?cation of the dorsal hair cycle across three pairs of littermates showed a strong induction of anagen in backskin lacking Mpcl (, right), and histology showed that the anagen induction was normal in appearance with a typical hypodermal expansion (). Immunostaining demonstrated the induction in Mpcl-null HFSCs of various markers of hair cycle activation such as Ki-67 and p86, while Sox9 expression was unaffected (). Long term deletion ofMpcl did not lead to aberrant follicles or exhaustion of HFSCs as judged by pathology and staining for Sox9 (). Furthermore, deletion ofMpcl with Lgr5CreER showed a very similar phenotype as deletion with K15CrePR ( and 5G), validating the fact that deletion of this protein in HFSCs leads to their activation (11 = 12 pairs of littermates). Finally, immuno?uorescence for the Ires—GFP of the Lgr5CreER transgene along with Ki-67 and lineage tracing with Kl5CrePR,Mpcl?/?,lsl-Tomato mice also trated that the HFSCs were indeed erative ing induction ofMpcl deletion by tamoxifen or mifepristone ().

UK-5099 (also ated herein as JXLOOl) is a well-established pharmacological inhibitor of the mitochondrial pyruvate r and is known to promote lactate production as a result in various settings. UK-5099 has the following structure: Topical treatment of animals in telogen (day 50) with UK-5099 led to a robust acceleration of the hair cycle, as well as minor hyperproliferation of the interfollicular epidermis (). Quanti?cation of the hair cycle across at least 6 pairs of animals (vehicle vs UK-5099) indicated a strong acceleration of the hair cycle, in as few as 6-9 days (). Similar to genetic deletion ofMpc] blockade of the , pharmacological mitochondrial pyruvate carrier by UK-5099 for 48 hours during telogen promoted increased th activity in HFSCs and the interfollicular epidermis, consistent with increased capacity for lactate production (). Finally, metabolomic analysis demonstrated that topical application of UK-5099 ses total levels of lactate in sorted HFSCs ().

Compounds were synthesized that could topically promote increased lactate levels and therefore drive the hair cycle.

The compounds were lly prepared by reaction of the corresponding aldehydes, e.g., for JXLOOl, l-phenylindolecarboxaldehyde, with ethyl cyanoacetate in the presence of 40% aq. L-proline to give exclusively the E—isomer of the ethyl 2-cyano(l-phenylindol- 3yl)propenoate, e.g., JXLOO4. Hydrolysis of the ester with mild lithium ide afforded the E—isomer of the acid, e.g., JXLOOl. All of the other nds were prepared by analogous methods using the specific aldehyde. The two cyclic compounds, JXLOZ3 and JXL024, were prepared from the condensation of l-phenyl-indolecarboxaldehyde with thiazolidine-2,4-dione and 2-iminothiazolidinone. The structures of all of the compounds were determined using normal organic chemistry methods, especially high field proton, carbon, and ?uorine NMR spectra. In particular, 3Jc.H coupling measurements demonstrated that the nds all had the E—stereochemistry about the key carbon-carbon double bond.

To determine whether these compounds could promote cellular lactate tion, we treated ed epithelial cells with the compounds and measured lactate levels in the culture media using a Nova Biomedical BioProflle Basic Analyzer. , cultured epithelial cells were d with DMSO, 9 (also called JXLOOl), or certain of the exemplary nds disclosed herein for 24-30 hours, and media e levels were measured and normalized to cell number and duration of the experiment to e a ar lactate production rate (nmol lactate, million cells, hour). The results are shown in FIGs. 8 and 9.

Lactate production rates of treated cells are shown in As expected since they are 9 analogues, most of the novel compounds assayed increased lactate tion.

A separate assay was performed to calculate the ECso of some of the compounds as shown in .

To determine the ef?cacy of the compounds on the hair cycle, mice were shaved at postnatal day 50, and topically treated with a compound disclosed herein suspended in lotion in every other day for 3 weeks. As seen in , all the ues that showed the ability to promote lactate production in the in vitro assay were also able to stimulate hair growth over the course of 2 weeks. ceutical Compositions The compositions and methods of the present invention may be utilized to treat an dual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human . When administered to an animal, such as a human, the ition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the ion and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or es such as glycols, glycerol, oils such as olive oil, or able organic esters. In preferred embodiments, when such pharmaceutical compositions are for human stration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical ition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

A pharmaceutically acceptable r can contain logically able agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight ns or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug ry system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for e, which comprise olipids or other lipids, are ic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

The phrase "pharmaceutically acceptable" is employed herein to refer to those nds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals t excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a able benefit/risk ratio.

The phrase aceutically acceptable carrier" as used herein means a pharmaceutically acceptable al, composition or vehicle, such as a liquid or solid flller, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically able carriers include: (1) , such as lactose, glucose and sucrose, (2) starches, such as corn starch and potato starch, (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, (4) powdered tragacanth, (5) malt, (6) gelatin, (7) talc, (8) excipients, such as cocoa butter and suppository waxes, (9) oils, such as peanut oil, cottonseed oil, saf?ower oil, sesame oil, olive oil, corn oil and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol, (12) esters, such as ethyl oleate and ethyl laurate, (13) agar, (14) buffering , such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and n capsules), boluses, powders, granules, pastes for application to the ), absorption h the oral mucosa (e.g., sublingually), subcutaneously, transdermally (for example as a patch applied to the skin), and topically (for example, as a cream, nt or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions le for same can be found in, for e, US. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, ,541,231, 5,427,798, 5,358,970 and 896, as well as in s cited therein.

The formulations may iently be ted in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier al to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more ory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or ?nely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), s, pills, tablets, lozenges (using a d basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an s or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

To prepare solid dosage forms for oral stration (capsules (including le capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more ceutically acceptable carriers, such as sodium citrate or ium phosphate, and/or any of the following: (1) flllers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid, (2) binders, such as, for e, carboxymethylcellulose, alginates, n, polyvinyl pyrrolidone, sucrose and/or acacia, (3) ants, such as glycerol, (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarding agents, such as paraf?n, (6) absorption accelerators, such as quaternary ammonium compounds, (7) wetting , such as, for example, cetyl alcohol and ol monostearate, (8) ab sorbents, such as kaolin and bentonite clay, (9) ants, such a talc, calcium stearate, magnesium stearate, solid hylene glycols, sodium lauryl sulfate, and mixtures thereof, (10) complexing agents, such as, modi?ed and unmodi?ed cyclodextrins, and (l l) coloring agents. In the case of capsules (including sprinkle capsules and n capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as flllers in soft and hard-fllled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed s may be prepared using binder (for example, gelatin or ypropylmethyl ose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a le machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, es (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release pro?le, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, ?ltration through a bacteria-retaining ?lter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a n portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.

Liquid dosage forms useful for oral administration include pharmaceutically able emulsions, les for reconstitution, mulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may n inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsi?ers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, l,3-butylene glycol, oils (in ular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene s and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, ?avoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, yethylene sorbitol and an esters, microcrystalline ose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Dosage forms for the topical or ermal administration include powders, sprays, ointments, , creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile ions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraf?ns, starch, tragacanth, cellulose tives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chloro?uorohydrocarbons and le unsubstituted hydrocarbons, such as butane and propane.

Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by ving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the ?ux of the compound across the skin. The rate of such ?ux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical stration, y by injection, and includes, without limitation, enous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, icular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical itions suitable for parenteral administration comprise one or more active compounds in combination with one or more ceutically acceptable sterile isotonic s or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable ons or sions just prior to use, which may contain antioxidants, s, bacteriostats, solutes which render the ation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, ble oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper ?uidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, n, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium de, and the like into the itions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay tion such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed tion of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. ing on the ratio of drug to r, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for e, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. s of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled ry of drugs, including proteinaceous biopharmaceuticals.

A variety of biocompatible rs ding hydrogels), including both biodegradable and non-degradable rs, can be used to form an implant for the sustained release of a compound at a ular target site.

Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, t being toxic to the patient.

The ed dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, seX, weight, ion, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A ian or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.

For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the amount of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the , seX, age, and medical history of the subject.

Other factors which ce the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the nd of the invention. A larger total dose can be delivered by le administrations of the agent.

Methods to determine cy and dosage are known to those skilled in the art (Isselbacher et al. (1996) on’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

In general, a le daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose ive to e a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

If desired, the effective daily dose of the active compound may be administered as one, two, three, four, ?ve, siX or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In n embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily. -3 2- The patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, , swine, sheep, cats, and dogs, poultry, and pets in general.

In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.

The present disclosure includes the use of pharmaceutically able salts of nds of the ion in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not d to, alkyl, dialkyl, yl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, e, deanol, diethanolamine, diethylamine, 2- (diethylamino)ethanol, ethanolamine, ethylenediamine, N—methylglucamine, hydrabamine, lH-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not d to, l-hydroxynaphthoic acid, 2,2-dichloroacetic acid, oxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)—camphoric acid, (+)—camphor-lO-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, ic acid, glycerophosphoric acid, glycolic acid, hippuric acid, romic acid, hydrochloric acid, yric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, c acid, malonic acid, mandelic acid, methanesulfonic acid nicotinic acid, nitric acid, , naphthalene-l,5-disulfonic acid, naphthalenesulfonic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, 1- pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, tri?uoroacetic acid, and lenic acid acid salts.

The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or itious to such solvent.

Wetting agents, emulsi?ers and lubricants, such as sodium lauryl sulfate and ium stearate, as well as coloring agents, release agents, coating agents, sweetening, ?avoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium ate, sodium metabisul?te, sodium sul?te and the like, (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated ytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like, and (3) metal-chelating agents, such as citric acid, ethylenediamine cetic acid (EDTA), sorbitol, ic acid, oric acid, and the like.

De?nitions Unless otherwise de?ned herein, scienti?c and technical terms used in this ation shall have the meanings that are commonly understood by those of ordinary skill in the art.

Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, lar y, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, iology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.

The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various l and more speci?c references that are cited and discussed throughout this speci?cation. See, e.g. "Principles of Neural Science", McGraw-Hill Medical, New York, NY. (2000), Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc.

, Lodish et al., "Molecular Cell Biology, 4th ed.", W. H. Freeman & Co., New York (2000), Grif?ths et al., "Introduction to Genetic Analysis, 7th ed.", W. H. Freeman & Co., NY. (1999), and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

Chemistry terms used herein, unless otherwise de?ned herein, are used according to conventional usage in the art, as exempli?ed by "The McGraw-Hill Dictionary of Chemical Terms", Parker 8., Ed, McGraw-Hill, San sco, CA. (1985).

All of the above, and any other publications, patents and hed patent ations referred to in this application are speci?cally incorporated by reference herein. In case of con?ict, the present speci?cation, including its speci?c de?nitions, will l.

The term "agent" is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or n thereof, e.g., a peptide, a lipid, a carbohydrate), or an t made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for e, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit AR or promote AR degradation may render them suitable as peutic agents" in the methods and compositions of this sure.

A "patient,77 (L subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and s (e.g., mice and rats). ing" a condition or patient refers to taking steps to obtain bene?cial or desired results, including clinical results. As used herein, and as well understood in the art, ment" is an approach for obtaining bene?cial or desired results, including clinical s. Bene?cial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not ing) state of disease, preventing spread of disease, delay or slowing of disease ssion, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

The term "preventing" is art-recognized, and when used in on to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome x such as heart failure or any other medical condition, is well tood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable ous growths in a population of patients receiving a prophylactic treatment relative to an untreated control tion, and/or delaying the ance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically cant amount.

"Administering" or "administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.

For e, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.

Appropriate methods of administering a substance, a compound or an agent to a t will also depend, for example, on the age and/or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered , e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release ation, or administered using a device for such slow or ed release.

As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different eutic agents such that the second agent is stered while the usly administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either itantly or tially. Thus, an individual who receives such treatment can bene?t from a combined effect of different therapeutic agents.

A "therapeutically effective " or a "therapeutically effective dose" of a drug or agent is an amount of a drug or an agent that, when administered to a subject, will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after stration of a series of doses.

Thus, a therapeutically effective amount may be administered in one or more administrations.

The precise effective amount needed for a subject will depend upon, for e, the subject’s size, health and age, and the nature and extent of the ion being treated, such as cancer or MDS. The skilled worker can y ine the effective amount for a given situation by routine experimentation.

The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarble(O)—, preferably alkle(O)-.

The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarble(O)NH-.

The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarble(O)O-, preferably alkle(O)O-.

The term "alkoxy" refers to an alkyl group having an oxygen attached thereto.

Representative alkoxy groups e methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general a alkyl-O-alkyl.

The term "alkyl" refers to saturated aliphatic groups, ing straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or ed chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1- for straight chains, C3-3o for ed chains), and more preferably 20 or fewer.

Moreover, the term "alkyl" as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more s of the hydrocarbon backbone, including haloalkyl groups such as tri?uoromethyl and 2,2,2- tri?uoroethyl, etc.

The term "CK-y" or "CK-Cy", when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. Coalkyl tes a hydrogen where the group is in a terminal position, a bond if internal. A C1.6alkyl group, for example, contains from one to six carbon atoms in the chain.

The term "alkylamino", as used herein, refers to an amino group substituted with at least one alkyl group.

The term "alkylthio", as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

The term "amide", as used herein, refers to a group EANIRQ n R9 and R10 each independently represent a hydrogen or hydrocarbyl group, or R9 and R10 taken together with the N atom to which they are attached te a heterocycle having from 4 to 8 atoms in the ring structure.

The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by R9 R9 3.51: or 3—,;ltR1o R10 R10! wherein R9, R10, and R10’ each independently represent a en or a hydrocarbyl group, or R9 and R10 taken er with the N atom to which they are attached complete a heterocycle haVing from 4 to 8 atoms in the ring structure.

The term "aminoalkyl", as used herein, refers to an alkyl group tuted with an amino group.

The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group.

The term "aryl" as used herein e substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7- membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems haVing two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term mate" is art-recognized and refers to a group O O HI\OJLN,R1O or 55‘\NJJ\O,R10 R9 R9 wherein R9 and R10 independently represent hydrogen or a hydrocarbyl group.

The term "carbocyclylalkyl", as used herein, refers to an alkyl group substituted with a carbocycle group.

The terms "carbocycle", "carbocyclyl", and "carbocyclic", as used , refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon.

Preferably a carbocycle ring contains from 3 to 10 atoms, more preferably from 5 to 7 atoms.

The term "carbocyclylalkyl", as used herein, refers to an alkyl group substituted with a ycle group.

The term "carbonate" is art-recognized and refers to a group -OC02-.

The term "carboxy", as used herein, refers to a group represented by the formula -C02H.

The term "ester", as used herein, refers to a group -C(O)OR9 n R9 represents a hydrocarbyl group.

The term "ether", as used , refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either rical or unsymmetrical.

Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

The terms "halo" and en" as used herein means halogen and includes chloro, ?uoro, bromo, and iodo.

The terms "hetaralkyl" and "heteroaralkyl", as used herein, refers to an alkyl group substituted with a hetaryl group.

The terms "heteroaryl" and "hetaryl" include tuted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems haVing two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be lkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups e, for e, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

The term "heterocyclylalkyl", as used herein, refers to an alkyl group substituted with a heterocycle group.

The terms "heterocyclyl", "heterocycle", and ocyclic" refer to substituted or unsubstituted non-aromatic ring structures, ably 3- to lO-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two atoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems haVing two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be lkyls, cycloalkenyls, cycloalkynyls, aryls, aryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term "hydrocarbyl", as used herein, refers to a group that is bonded h a carbon atom that does not have a =0 or :8 substituent, and typically has at least one carbon- hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms.

Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even tri?uoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, cycle, alkyl, alkenyl, alkynyl, and combinations thereof.

The term xyalkyl", as used herein, refers to an alkyl group tuted with a hydroxy group.

The term "lower" when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A "lower alkyl", for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy tuents de?ned herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, r they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

The terms "polycyclyl", "polycycle", and "polycyclic" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings". Each of the rings of the polycycle can be substituted or unsubstituted. In n embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

The term "sulfate" is art-recognized and refers to the group —OSO3H, or a ceutically acceptable salt thereof.

The term "sulfonamide" is art-recognized and refers to the group represented by the general formulae E—?—N‘ or 3_N/S"o 0 R9 wherein R9 and R10 independently represents hydrogen or hydrocarbyl.

The term "sulfoxide" is art-recognized and refers to the group—S(O)—.

The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

The term "sulfone" is art-recognized and refers to the group -.

The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substitution" or "substituted with" es the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, ation, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic tuents of organic compounds.

The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have en tuents and/or any permissible substituents of organic nds described herein which satisfy the es of the atoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a yl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a oryl, a phosphate, a onate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a amido, a sulfonyl, a cyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

The term "thioalkyl", as used herein, refers to an alkyl group substituted with a thiol group.

The term "thioester", as used herein, refers to a group -C(O)SR9 or —SC(O)R9 wherein R9 represents a arbyl.

The term "thioether", as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

The term "urea" is art-recognized and may be represented by the general formula fiNJLNtRm R9 R9 wherein R9 and R10 independently represent hydrogen or a hydrocarbyl.

The term "modulate" as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.

The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in t with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable bene?t/risk ratio.

"Pharmaceutically able salt" or "salt" is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.

The term "pharmaceutically acceptable acid addition salt" as used herein means any non-toxic organic or inorganic salt of any base compounds represented by formula I or II.

Illustrative inorganic acids which form le salts include hydrochloric, hydrobromic, sulfuric and oric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen e. Illustrative c acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, ic, citric, ascorbic, , benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of formula I or II are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of formula I or II for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

The term "pharmaceutically acceptable basic addition salt" as used herein means any non-toxic organic or inorganic base on salt of any acid nds represented by formula I or II or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium ide.

Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The ion of the appropriate salt will be known to a person skilled in the art.

Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This genic center may be present in a R or a S uration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure plates all stereoisomeric forms such as omeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible es of stereoisomers). See, e.g., WO 01/062726.

Furthermore, certain nds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the sure includes both mixture and separate individual isomers.

Some of the compounds may also exist in tautomeric forms. Such forms, although not itly indicated in the formulae described herein, are intended to be included within the scope of the t disclosure.

"Prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I or II ). Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, d, ed, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, ted, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of gs using ester or phosphoramidate as ically labile or cleavable (protecting) groups are disclosed in U.S.

Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of this sure are lized to produce a compound of formula I or II . The present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs" Ed. H. Bundgaard, Elsevier, 1985.

The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.

The term "Log of solubility", "LogS" or "logS" as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous lity of a nd significantly affects its absorption and distribution characteristics. A low lity often goes along with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol/liter.

The term "comprise" and variants of the term such as "comprises" or "comprising" are used herein to denote the inclusion of a stated integer or stated rs but not to exclude any other r or any other integers, unless in the context or usage an exclusive interpretation of the term is required EXAMPLES The invention now being generally described, it will be more y understood by reference to the following examples which are included merely for purposes of ration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

Example 1: Pre aration of Exem la Com ounds COZEt C02" \ Phl, Cu20 ACOzEt o.5N LiOH H DMF, reflux L-p-roline, EtOH 39% 95% 65% ‘ph JXL001/UK5099 To the solution of indolecarboxaldehyde (2.8 mmol, 411 mg) in dry DMF (6 mL) were added CuzO (0.3 equiv, 0.84 mmol, 120 mg), K2CO3 (2.0 equiv, 5.6 mmol, 774 mg), and iodobenzene (2.0 equiv, 5.6 mmol, 624 uL) sequentially. The reaction was stirred and re?uxed for 24 h, at which point TLC indicated that the reaction was completed. After it was cooled to 21 °C, the on mixture was ?ltrated through a Celite pad eluting with ethyl acetate. The ?ltrate was washed by saturated NaCl solution and organic phase was dried by sodium e and concentrated. The residue was puri?ed by ?ash column chromatography (hexanes/EtOAc = 8: 1) to provide the desired product. yield: 89%, 550.7 mg.

To the solution of 1-phenyl-indolecarbaldehyde (1 mmol, 221 mg) in ethanol (1 mL) were added ethyl 2-cyanoacetate (1.3 equiv, 1.3 mmol, 140 uL) and L-proline (40 mol%, 0.4 mmol, 58 mg). The reaction was stirred at 21 0C for 12 h and yellow solid itated gradually. After completion of the on, ice-cold water (2 mL) was added into the reaction vial. The solid was separated by Buchner funnel ?ltration and washed with water (2 mL X 3) and dried to afford the desired product. yield: 95%, 300 mg.

To the solution of (E)—ethyl 2-cyano(1-phenyl-1H—indolyl)acrylate (0.32 mmol, 100 mg) in THF (2 mL) was added 0.5N LiOH on (3 equiv, 0.6 mmol, 1.2 mL). The reaction mixture was d at 21 0C for 1 h. After reaction completion shown by TLC, THF was evaporated. Concentrated HCl was added se to acidify the reaction mixture until the pH was lower than 1, meanwhile yellow solid itated. Ice-cold water (5 mL) was added to the reaction e and the solid was separated by Buchner funnel ?ltration and washed with water (5 mL X 3). After dried by vacuum, the solid was washed by 2 mL of solvent mixture (hexanes/EtOAc = 5: 1) 5 to 10 times and monitored by TLC until non-polar impurities disappear (The non-polar compound was the retro-Aldol condensation product, which can be recovered from the ?ltrate). Finally, the purity of the product was checked by NMR. yield: 65%, 60 mg.

(E)Cyan0(1-phenyl-1H—ind01—3-yl)acrylic acid (JXL001/UK5099) 1H NMR (500 MHz, DMSO-d6) 5 8.59 (s, 1H), 8.56 (s, 1H), 8.06 (m, 1H), 7.65 (m, 4H), 7.53 (m, 2H), 7.34 (m, 2H). 13C NMR (126 MHz, 6) 8 164.5, 145.6, 137.7, 136.3, 133.6, 130.5, 128.9, 128.0,125.0,124.9,123.3,119.9,118.4,111.9,96.7.

COzEt COzH ’ ’ \ I l cu CN Br \ F30 NCACOZEt \ 0.5N LiOH \ N\ —> —> _> N N KOH, DMF L-proline, EtOH THF H 90% F c3 55/0o 93% F3C cm CFs CF3 JXL020 The following compounds were synthesized by a route similar to that described for JXLOOl: JXL002, JXL003, JXL004, JXL005, JXL006, JXL007, JXL012, JXL013, JXL014, JXL021, JXL025, JXL026, JXL027, JXL028, JXL029, JXL035, JXL093.

(E)Cyan0(lH-indolyl)acrylic acid 2) 1H NMR (500 MHz, DMSO-d6) 5 12.48 (s, 1H), 8.51 (s, 1H), 8.49 (s, 1H), 7.91 (d, J = 6.5 Hz, 1H), 7.53 (d, J: 7.0 Hz, 1H), 7.23 (m, 2H). 13C NMR(126 MHz, DMSO-d6) 5 165.0, 146.5, 136.5, 132.4, 127.3, 123.9, 122.4, 118.9, 118.8, 113.2, 110.2, 94.0.

COZEt JXL003 Ethyl (E)cyano(1H—indolyl)acrylate 1H NMR (500 MHz, CDCl3) 5 12.55 (s, 1H), 8.53 (s, 1H), 8.52 (s, 1H), 7.92 (d, J: 7.6 Hz, 1H), 7.53 (d, J: 7.8 Hz, 1H), 7.26 (app. t, J: 7.4 Hz, 1H), 7.22 (app. t, J: 7.4 Hz, 1H), 4.24 (q, J: 7.0 Hz, 2H), 1.26 (t, J: 7.0 Hz, 3H). 13C NMR(126 MHz, CDC13) 5 163.6, 147.0, 136.6, 133.0, 127.3, 124.0, 122.5, 118.9, 118.4, 113.3, 110.3, 92.6, 61.8, 14.5.

COzEt JXL004 Ethyl (E)cyan0(1-phenyl-1H-indolyl)acrylate (JXL004) 1H NMR (500 MHz, CDC13) 5 8.71 (s, 1H), 8.66 (s, 1H), 7.90 (d, J: 7.2 Hz, 1H), 7.54 (m, 6H), 7.36 (m, 2H), 4.39 (q, J: 7.1 Hz, 2H), 1.42 (t, J: 7.1 Hz, 3H). 13C NMR(126 MHz, CDC13) 5 163.6, 145.6, 137.8, 136.4, 133.2, 129.9, 128.5, 124.8,124.4,123.0,118.5,117.9,111.6,111.5,95.4,62.0,14.3. 002121 CI N JXLOOS Ethyl (6-chlor0phenyl-1H-indolyl)cyan0acrylate (JXL005) 1H NMR (500 MHz, CDC13) 5 8.67 (s, 1H), 8.58 (s, 1H), 7.81 (d, J: 8.5 Hz, 1H), 7.60 (m, 2H), 7.52 (m, 4H), 7.34 (d, J: 8.4 Hz, 1H), 4.39 (q, J: 7.1 Hz, 2H), 1.41 (t, J: 7.1 Hz, 3H). 13C NMR(126 MHz,CDC13)5163.4,1451,1373,136.8,133.5,130.5,130.0, 128.8, 126.8, 124.8, 123.6, 119.5, 117.5, 111.6, 111.4, 96.4, 62.1, 14.2.

COZEt N \ JXL006 Ethyl (E)cyan0(1-(2-meth0xyphenyl)—1H-indolyl)acrylate (JXL006) 1H NMR (500 MHz, CDC13) 5 8.67 (s, 1H), 8.66 (s, 1H), 7.89 (d, J: 7.8 Hz, 1H), 7.49 (app. t, J: 8.6 Hz, 1H), 7.41 (d, J: 7.6 Hz, 1H), 7.35 (app. t, J: 7.3 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.23 (d, J: 8.1 Hz, 1H),7.13 (m, 2H), 4.39 (q, J: 7.1 Hz, 2H), 3.81 (s, 3H), 1.41 (t,J= 7.1 Hz, 3H). 13C NMR(126 MHz, CDC13) 5 163.8, 154.2, 146.0, 137.2, 135.2, 130.3, 127.8, 126.0, 124.0, 122.6, 120.8, 118.2, 118.0, 112.3, 111.8, 111.0, 94.7, 61.8, 55.7, 14.3. 002Et Ethleng-Z-cyano?-(l-(4-methoxyphenyl)—1H-indolyl)acrylate (JXL007) 1H NMR (500 MHz, CDC13) 5 8.65 (s, 1H), 8.64 (s, 1H), 7.89 (d, J: 7.2 Hz, 1H), 7.44 (m, 3H), 7.35 (m, 2H), 7.07 (d, J: 8.8 Hz, 2H), 4.38 (q, J: 7.1 Hz, 2H), 3.90 (s, 3H), 1.41 (t, J: 7.1Hz,3H). 13C NMR (126 C13)6163.8, 159.5, 145.6, 136.8, 133.5, 130.6, 128.3, 126.2, 124.2, 122.9, 118.4, 118.0, 115.0, 111.5, 111.1, 94.9, 61.9, 55.6, 14.2. 00214 JXLO12 (E)Cyan0(1-(4-meth0xyphenyl)—lH-indolyl)acrylic acid (JXL012) 1H NMR (500 MHz, DMSO-d6) 5 8.54 (s, 1H), 8.52 (s, 1H), 8.05 (d, J: 7.7 Hz, 1H), 7.58 (app. d, J: 8.7 Hz, 2H), 7.44 (m, 1H), 7.33 (m, 2H), 7.16 (app. d, J: 8.7 Hz, 2H), 3.82 (s, 3H). 13C NMR(126 MHz, DMSO-d6) 5 164.7, 160.5, 136.7, 133.9, 130.5, 127.8, 126.6, 124.8,123.2,120.0,119.5,118.6,115.6,115.4,111.9,110.9,55.9.

Cl N‘ JXLO13 (E)(6-Chlor0phenyl-lH-indolyl)cyanoacrylic acid (JXL013) 1H NMR (500 MHz, DMSO-d6) 5 13.58 (br. s, 1H), 8.59 (s, 1H), 8.54 (s, 1H), 8.11 (d, J: 7.5 Hz, 1H), 7.67 (m, 4H), 7.53 (m, 2H), 7.35 (d, J: 7.5 Hz, 1H). 13C NMR(126 MHz, DMSO-d6) 5 164.3, 145.4, 137.3, 136.7, 134.4, 130.6, 129.6, 129.1,126.7,125.1,123.5,121.5,118.2,111.6,111.3,97.9.

N \ JXL014 (E)Cyan0(1-(2-meth0xyphenyl)—lH-indolyl)acrylic acid (JXL014) 1H NMR (500 MHz, DMSO-d6) 5 8.55 (s, 1H), 8.47 (s, 1H), 8.02 (d, J: 7.4 Hz, 1H), 7.54 (m, 2H), 7.31 (m, 3H), 7.15 (m, 2H), 3.74 (s, 3H). 13C NMR(126 MHz, DMSO-d6) 5 164.6, 154.2, 145.8, 137.3, 135.1, 131.1, 128.2, 127.3, 125.7, 124.6, 123.0, 121.5, 119.3, 118.5, 113.6, 112.2, 110.8, 96.1, 56.2.

JXL021 2-((1-Phenyl-lH-indolyl)methylene)malon0nitrile (JXL021) 1H NMR (500 MHz, CDC13) 5 8.62 (s, 1H), 8.13 (s, 1H), 7.80 (d, J: 7.4 Hz, 1H), 7.61 (m, 2H), 7.53 (m, 4H), 7.40 (m, 2H). 13C NMR(126 MHz, CDC13) 5 149.8, 137.3, 136.5, 133.6, 130.1, 128.9, 127.7, 124.9,124.8,123.7,118.2,115.1,115.0,111.9,111.8,73.7.

COZEt JXL025 2-(Eth0xycarb0nyl)—3-(l-phenyl-1H—ind01yl)acrylic acid (a mixture ofE/Z isomers, 1:1 ratio) (JXL025) 1H NMR (500 MHz, DMSO-d6) 5 13.08 (br. s, 1H), 7.87 (m, 3H), 7.61 (m, 4H), 7.52 (m, 2H), 7.30 (m, 2H), 4.26 (m, 2H), 1.23 (m, 3H). 13C NMR(126 MHz, DMSO-d6) 5 168.9, 167.8, 166.1, 164.9, 138.3, 136.1, 132.9, 132.1,131.1,130.9,130.8,128.5,124.9,124.4,122.6,122.2,119.5,111.6,111.0,61.7,61.3, 14.7, 14.4.

JXL026 (E)Cyan0(4-flu0r0phenyl-1H—indolyl)acrylic acid (JXL026) 1H NMR (500 MHz, DMSO-d6) 5 8.65 (s, 1H), 8.61 (s, 1H), 7.67 (m, 4H), 7.57 (m, 1H), 7.36 (m, 2H), 7.19 (m, 1H). 13C NMR (126 MHz, DMSO-d6) 5 164.4, 156.8 (d, J81: 245.6 Hz), 146.4, 138.7, 137.6, 133.4, 130.7, 129.5, 125.9, 125.4, 118.2, 116.3, 116.2, 109.5 (d, J81: 34.5 Hz), 109.2 (d, J81: 23.2 Hz), 98.0.

F N‘ JXL027 Cyan0(6-flu0r0phenyl-1H—indolyl)acrylic acid (JXL027) 1H NMR (500 MHz, DMSO-d6) 5 13.59 (br. s, 1H), 8.62 (s, 1H), 8.59 (s, 1H), 8.16 (m, 1H), 7.66 (m, 4H), 7.56 (m, 1H), 7.36 (d, J: 9.2 Hz, 1H), 7.25 m, 1H). 13C NMR (126 MHz, DMSO-d6) 5 164.6, 160.8 (d, Jc-f: 240.0 Hz), 145.7, 137.6, 136.6,134.4,130.8,129.1,125.0,124.7,1216,1184,111.8(d,Jc.f= 24.2 Hz), 111.5, 98.7 (d, J81: 26.2 Hz), 97.7.

JXL028 (E)Cyan0(7-flu0r0phenyl-1H—indolyl)acrylic acid (JXL028) 1H NMR (500 MHz, DMSO-d6) 5 13.62 (br. s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 7.89 (br. s, 1H), 7.61 (m, 5H), 7.30 (br. s, 1H), 7.17 (br. s, 1H). 13C NMR (126 MHz, DMSO-d6) 5 164.4, 149.7 (d, Jc-f: 247.5 Hz), 145.5, 139.0, 131.9,129.9,129.3,126.2,124.3,124.0,118.3,115.9,111.8,110.9(d,Jc-f:17.4 Hz), 98.1.

(E)Cyan0(5-flu0r0phenyl-1H—indolyl)acrylic acid (JXL029) 1H NMR (500 MHz, DMSO-d6) 5 13.57 (br. s, 1H), 8.67 (s, 1H), 8.60 (s, 1H), 8.01 (d, J: 9.0 Hz, 1H), 7.70 (m, 4H), 7.58 (m, 2H), 7.24 (m, 1H). 13C NMR (126 MHz, DMSO-d6) 5 164.6, 159.4 (d, J81: 237.8 Hz), 145.8, 137.7, 135.1,133.1,130.7,129.2,129.1,125.2,118.5,113.7,113.2(d,Jc-f=26.5 Hz), 111.4, 105.7 (d, J81: 24.2 Hz), 97.2.

JXL035 (E)(4-Chlor0phenyl-1H—ind01yl)—2-cyanoacrylic acid (JXL035) 1H NMR (500 MHz, DMSO-d6) 5 9.22 (s, 1H), 8.68 (s, 1H), 7.64 (m, 3H), 7.59 (m, 2H), 7.48 (d, J: 7.6 Hz, 1H), 7.38 (m, 1H), 7.32 (m, 1H). 13C NMR (126 MHz,DMSO-d6)6164.5, 146.4, 138.0, 137.4, 134.5, 130.7, 130.5, 129.5,125.7,125.3,124.9,123.7,118.4,111.7,110.9,97.5.

COzEt JXL093 Ethyl (E)(4-chlor0phenyl-lH-indolyl)—2-cyan0acrylate (JXL093) 1H NMR (500 MHz, CDCl3) 5 9.51 (s, 1H), 8.78 (s, 1H), 7.59 (m, 2H), 7.51 (m, 3H), 7.40 (dd, J: 8.3, 0.8 Hz, 1H), 7.32 (dd, J: 7.7, 0.8 Hz, 1H), 7.22 (app. t, J: 8.0 Hz, 1H), 4.38 (q, J: 7.1 Hz, 2H), 1.40 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz,CDCl3)6163.6, 147.6, 138.1, 137.4, 134.2, 130.1, 129.0, 126.9,125.3,124.6,124.5,124.3,118.0,111.8,110.6,96.0,62.1,14.3. mental details for the sis of JXL020 COzEt C02H ’ ’ o CN CN \2 Br \ F36 NcAcozEt \ 0.5N LiOH \ : N \ N N KOH, DMF L-prollne, EtOH_ THF H 90% F3C 93% 55% F3C Fgc CFs CF3 JXLOZO To the solution of indolecarboxaldehyde (3 mmol, 435 mg) in dry DMF (6 mL) were added 3,5-bis(tri?uoromethyl)benzyl bromide (1.2 equiv, 3.6 mmol, 660 uL) and KOH (1.2 equiv, 3.6 mmol, 200 mg) at 0 °C. The reaction mixture was stirred at 21 0C for 2 h. After the reaction completion shown by TLC, water (6 mL) was added to the on vial. The reaction mixture was extracted by dichloromethane (15 mL X 3). The combined organic layer was dried by sodium sulfate and concentrated. The residue was puri?ed by ?ash column chromatography (hexanes/EtOAc = 8: 1) to provide the desired product. yield: 90%, 1001.7 mg.

To the solution of 1-(3,5-bis(tri?uoromethyl)benzyl)—1H-indolecarbaldehyde (1 mmol, 371 mg) in ethanol (1 mL) were added ethyl oacetate (1.3 equiv, 1.3 mmol, 140 uL) and L-proline (40 mol%, 0.4 mmol, 58 mg). The reaction was stirred at 21 °C for 12 h and yellow solid precipitated gradually. After completion of the reaction, ice-cold water (2 mL) was added into the reaction vial. The solid was separated by Buchner funnel ?ltration and washed with water (2 mL X 3) and dried to afford the desired product. yield: 93%, 433 mg.

To the solution of (E)—ethyl 3-(1-(3,5-bis(tri?uoromethyl)benzyl)- lH—indolyl) cyanoacrylate (0.21 mmol, 100 mg) in THF (2 mL) was added 0.5N LiOH on (3 equiv, 0.4 mmol, 0.8 mL). The reaction mixture was stirred at 21 0C for l h. After reaction completion shown by TLC, THF was evaporated. Concentrated HCl was added dropwise to acidify the reaction e until pH was lower than 1, meanwhile yellow solid precipitated. Ice-cold water (5 mL) was added to the reaction mixture and the solid was separated by Buchner funnel ?ltration and washed with water (5 mL X 3). After dried by vacuum, the solid was washed by 2 mL of solvent mixture (hexanes/EtOAc = 5:1) 5 to 10 times and monitored by TLC until non- polar impurities disappear (The non-polar nd was the retro-Aldol condensation product, which can be recovered from the ?ltrate). Finally, the purity of the product was checked by NMR. yield: 55%, 52 mg.

(E)(1-(3,5-Bis(trifluoromethyl)benzyl)—lH-indolyl)—2-cyan0acrylic acid (JXL020) 1H NMR (500 MHz, DMSO-d6) 5 13.37 (br. s, 1H), 8.75 (s, 1H), 8.48 (s, 1H), 7.99 (m, 4H), 7.65 (s, 1H), 7.28 (m, 2H), 5.83 (s, 2H). 13C NMR(126 MHz,DMSO-d6)5164.7, 145.7, 140.3, 136.3, 134.8, 131.1, 130.8 (q, J: 31.1 Hz), 128.9, 128.7, 127.9, 124.8, 124.3, 122.9 (q, J: 273.4 Hz), 122.2, 119.3, 118.3, 95.6, 49.2.

The following compounds were synthesized by a route similar to that described for JXL020: JXL008, JXL009, JXL010, JXLOl 1, JXL015, JXL016, JXL017, , JXL019, JXL036, JXL037, JXL038, JXL039, JXL040, JXL041, , JXL051, JXL052, JXL053, JXL054, JXL055, JXL56, JXL057, JXL058, JXL059, JXL060, JXL061, JXL062, JXL063, JXL064, JXL065, JXL066, JXL068, JXL069, JXL072, JXL073, , JXL077, JXL078, , JXL082, JXL087, JXL088, JXL089, JXL090, JXL091.

COzEt JXLOOS Ethyl (E)cyan0(1-(4-flu0r0benzyl)—lH-indolyl)acrylate (JXL008) 1H NMR (500 MHz, CDC13) 5 8.60 (app. 8, 2H), 7.85 (d, J: 6.8 Hz, 1H), 7.32 (m, 3H), 7.15 (m, 2H), 7.03 (app. t, 2H), 5.39 (s, 2H), 4.37 (q, J: 7.1 Hz, 2H), 1.40 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 163.7, 162.5 (d, Jc-f= 247.7 Hz), 145.7, 136.1, 133.8, 130.9, 128.6, 128.5, 124.0, 122.7, 118.6, 118.0, 116.0 (d, 1.9 Hz), 110.9, 110.4, 94.6, 61.9, 50.7, 14.2.

COZEt JXL009 Ethyl (E)cyan0(1-(3,4-diflu0r0benzyl)—lH-indolyl)acrylate (JXL009) 1H NMR (500 MHz, CDC13) 5 8.60 (s, 1H), 8.59 (s, 1H), 7.86 (d, J: 7.8 Hz, 1H), 7.33 (m, 2H), 7.28 (s, 1H), 7.13 (m, 1H), 6.95 (m, 1H), 6.89 (m, 1H), 5.39 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 163.7, 150.7 (dd, J: 251.2, 13.2 Hz), 150.2 (dd, J: 250.4, 12.6 Hz), 145.7, 136.1, 133.7, 132.3, 128.6, 124.3, 122.9, 122.7, 120.0, 118.8, 118.0 (d,J= 17.5 Hz), 115.9 (d,J= 18.0 Hz), 110.8, 110.6, 95.2, 62.1, 50.4, 14.4.

COZEt JXLO10 Ethyl (E)cyan0(1-(3,5-diflu0r0benzyl)—lH-indolyl)acrylate (JXL010) 1H NMR (500 MHz, CDC13) 5 8.61 (s, 1H), 8.59 (s, 1H), 7.87 (d, J: 7.1 Hz, 1H), 7.33 (m, 2H), 7.26 (d, J: 7.2 Hz, 1H), 6.75 (app. t, J: 8.7 Hz, 1H), 6.64 (app. d, J: 5.7 Hz, 2H), 5.41 (s, 2H), 4.38 (q, J: 7.1 Hz, 2H), 1.40 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 163.6, 163.3 (dd, Jc-f= 251.0, 12.5 Hz), 145.5, 139.2, 136.0, 133.6, 128.4, 124.3, 122.9, 118.7, 118.0, 110.7, 110.6, 109.5 (dd, Jc-f= 19.9, 6.4 Hz), 103.8 (t, Jc-f= 25.2 Hz), 95.3, 62.0, 50.4, 14.2.

COZEt JXL011 Ethyl (1-(3,5-bis(trifluoromethyl)benzyl)—lH-indolyl)—2-cyanoacrylate (JXL011) 1H NMR (500 MHz, CDC13) 5 8.62 (s, 1H), 8.61 (s, 1H), 7.90 (d, J: 7.7 Hz, 1H), 7.85 (s, 1H), 7.57 (s, 2H), 7.35 (m, 2H), 7.23 (d, J: 7.8 Hz, 1H), 5.56 (s, 2H), 4.38 (q, J: 7.1 Hz, 2H), 1.40 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 163.6, 145.6, 138.1, 136.0, 133.4, 132.7 (q, J: 33.8 Hz), 128.6, 126.8, 124.7, 123.2, 122.9 (q,J= 273.4 Hz), 122.6, 119.0, 118.0, 111.2, 110.4, 95.9, 62.1, 50.5, 14.3.

JXLO15 (E)Cyan0(1-(4-?u0r0benzyl)—lH-indolyl)acrylic acid (JXL015) 1H NMR (500 MHz, DMSO-d6) 5 8.64 (s, 1H), 8.46 (s, 1H), 7.93 (d, J: 7.1Hz, 1H), 7.61 (d, J: 7.3Hz, 1H), 7.33 (m, 2H), 7.26 (m, 2H), 7.16 (m, 2H), 5.60 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.8, 162.0 (d, Jc-f= 244.3 Hz), 145.6, 136.4, 134.6,133.1,130.0,1280,1241,1228,119.2,118.5,116.0(d,Jc.f= 21.7 Hz), 112.0, 109.8, 95.0, 49.6.

JXL016 (E)Cyan0(1-(3,4-diflu0r0benzyl)—lH-indolyl)acrylic acid 6) 1H NMR (500 MHz, DMSO-d6) 5 13.34 (br. s, 1H), 8.62 (s, 1H), 8.47 (s, 1H), 7.94 (d, J: 7.3 Hz, 1H), 7.61 (d, J: 7.6 Hz, 1H), 7.40 (m, 2H), 7.27 (m, 2H), 7.10 (br. s, 1H), .61 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.8, 149.7 (dd, Jc-f= 253.3, 13.6 Hz), 149.4 (dd, Jc-f= 246.3, 11.6 Hz), 145.7, 136.4, 134.7, 134.5, 128.0, 124.7 (dd, Jc-f= 5.9, 3.0 Hz), 124.2, 122.8, 119.2, 118.4, 118.3 (d, .181: 17.0 Hz), 117.1 (d, Jc-f= 17.6 Hz), 112.0, 109.9, 95.0, 49.3.

JXL017 (E)Cyan0(1-(3,5-diflu0r0benzyl)—lH-indolyl)acrylic acid (JXL017) 1H NMR (500 MHz, DMSO-d6) 5 8.67 (s, 1H), 8.48 (s, 1H), 7.95 (d, J: 4.8 Hz, 1H), 7.59 (d, J: 4.4 Hz, 1H), 7.27 (m, 2H), 7.15 (s, 1H), 6.98 (br. s, 2H), 5.65 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.8, 162.9 (dd, Jc-f= 247.0, 12.8 Hz), 145.6, 141.4, 136.4, 134.8, 128.0, 124.2, 122.9, 119.3, 118.4, 111.9, 111.0 (d, Jc-f= 26.1 Hz), 110.8, 103.8 (t, Jc-f= 26.5 Hz), 95.5, 49.5.

COzEt JXL018 Ethyl (1-benzyl-1H—ind01yl)cyan0acrylate (JXL018) 1H NMR (500 MHz, CDC13) 5 8.61 (s, 1H), 8.60 (s, 1H), 7.85 (d, J: 7.9 Hz, 1H), 7.33 (m, 6H), 7.17 (m, 2H), 5.42 (s, 2H), 4.37 (q, J: 7.1 Hz, 2H), 1.40 (t, J: 7.1 Hz, 3H). 13C NMR(126 MHz, CDC13) 5 163.8, 145.7, 136.2, 135.1, 134.0, 129.0, 128.5, 128.2, 126.8, 124.0, 122.6, 118.5, 118.1, 111.0, 110.3, 94.3, 61.8, 51.4, 14.2.

JXL019 (E)(1-Benzyl-1H-indolyl)—2-cyan0acrylic acid (JXL019) 1H NMR (500 MHz, DMSO-d6) 5 13.34 (br. s, 1H), 8.65 (s, 1H), 8.48 (s, 1H), 7.93 (d, J: 6.9 Hz, 1H), 7.60 (d, J: 6.8 Hz, 1H), 7.25 (m, 7H), 5.62 (s, 2H). 13C NMR(126 MHz,DMSO-d6)6164.8, 145.7, 136.8, 136.5, 134.7, 129.1, 128.2, 127.6, 124.0, 122.7, 120.0, 119.2, 118.5, 112.1, 109.7, 94.7, 50.4.

JXLO36 (E)Cyan0(1-(3,4-diflu0r0benzyl)—5-flu0r0-1H-indolyl)acrylic acid (JXL036) 1H NMR (500 MHz, DMSO-d6) 5 8.69 (s, 1H), 8.47 (s, 1H), 7.84 (d, J: 9.6 Hz, 1H), 7.63 (dd, J: 8.9, 4.3 Hz, 1H), 7.41 (m, 2H), 7.14 (m, 2H), 5.61 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.9, 159.4 (d, Jc-f: 237.3 Hz), 149.8 (dd, Jc-f: 247.1, 12.7 Hz), 149.5 (dd, Jc-f: 246.6, 12.3 Hz), 146.0, 136.1, 134.5, 133.1, 129.1, 125.0, 118.4,117.4,113.6,112.5(d,Jc.f= 26.2 Hz),110.1,105.2(d,Jc-f= 25.1 Hz), 95.5, 49.7.

JXL037 (E)Cyan0(1-(3,5-diflu0r0benzyl)—5-flu0r0-lH-indolyl)acrylic acid (JXL037) 1H NMR (500 MHz, 6) 5 8.71 (s, 1H), 8.48 (s, 1H), 7.85 (dd, J: 9.6, 2.0 Hz, 1H), 7.62 (dd, J: 8.9, 4.3 Hz, 1H), 7.16 (m, 2H), 7.00 (app. d, J: 6.2 Hz, 2H), 5.65 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.9, 163.0 (d, Jc-f: 247.7 Hz), 159.3 (d, Jc-f: 237.6 Hz),145.9,141.4,136.3,133.2,129.1,118.5,113.6,112.6(d,Jc-f= 26.3 Hz), 111.3, 110.2, 105.3 (d, Jc-f: 24.9 Hz), 104.0 (t, Jc-f: 25.2 Hz), 95.9, 49.8.

JXL038 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—5-fluoro-1H—indolyl)cyan0acrylic acid (JXL038) 1H NMR (500 MHz, DMSO-d6) 5 8.80 (s, 1H), 8.49 (s, 1H), 8.06 (s, 1H), 8.04 (s, 2H), 7.86 (dd, J: 9.6, 2.1 Hz, 1H), 7.69 (dd, J: 8.9, 4.3 Hz, 1H), 7.17 (dt, J: 9.0, 2.2 Hz, 1H), 5.83 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.8, 159.3 (d, J61: 237.5 Hz), 145.9, 140.3, 136.2, 133.1, 131.1 (q, Jed: 33.1 Hz), 129.1, 123.6 (q, Jed: 272.2 Hz), 118.4, 113.5, 112.7, 112.5, 110.4, 105.5, 105.3, 96.1, 49.6.

(E)Jg;3:1n0(1-(3,4-diflu0r0benzyl)—6-flu0r0-1H—ind01—3-yl)acrylic acid (JXL039) 1H NMR (500 MHz, DMSO-d6) 5 8.64 (s, 1H), 8.46 (s, 1H), 7.99 (dd, J: 8.7, 5.1 Hz, 1H), 7.58 (dd, J: 9.8, 1.8 Hz, 1H), 7.43 (m, 2H), 7.12 (m, 2H), 5.57 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.8, 160.3 (d, Jc-f: 239.3 Hz), 149.8 (dd, Jc-f: 239.3, 25.2 Hz), 149.6 (dd, Jc-f: 246.3, 25.2 Hz), 145.8, 136.8, 135.3, 134.5, 125.1, 125.0, 124.6, 121.1, 118.5, 117.5, 111.3 (d, Jc-f= 23.9 Hz), 110.2, 98.7 (d, Jc-f: 26.5 Hz), 96.2, 49.4.

F N JXL04O (E)Cyan0(1-(3,5-diflu0r0benzyl)—6-flu0r0-1H—ind01—3-yl)acrylic acid (JXL040) 1H NMR (500 MHz, 6) 5 8.65 (s, 1H), 8.46 (s, 1H), 8.00 (dd, J: 8.6, 5.2 Hz, 1H), 7.57 (d, J: 9.7 Hz, 1H), 7.15 (m, 2H), 7.03 (s, 1H), 7.02 (s, 1H), 5.62 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.8, 163.0 (d, Jc-f: 239.4 Hz), 162.9 (d, Jc-f: 248.6 Hz), 160.4 (d,Jc-f: 239.4 Hz),145.5,141.3,136.8,135.2,124.6,121.1,118.4,111.3, 111.1, 110.3, 104.0 (t, Jc-f: 25.2 Hz), 98.7 (d, Jc-f: 26.5 Hz), 96.9, 49.6.

JXL041 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—6-fluoro-1H—indolyl)cyan0acrylic acid 1H NMR (500 MHz, DMSO-d6) 5 8.74 (s, 1H), 8.48 (s, 1H), 8.06 (app. 8, 3H), 8.01 (dd, J: 8.7, 5.1 Hz, 1H), 7.66 (dd, J: 9.8, 2.0 Hz, 1H), 7.13 (dt, J: 9.3, 2.1 Hz, 1H), 5.78 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.7, 159.9 (d, Jc-f= 264.6 Hz), 145.8, 140.2, 136.8, 135.3, 131.1 (q, J01: 33.3 Hz), 129.1, 124.5, 123.6 (q, J01: 273.7 Hz), 122.5, 121.2, 118.4, 111.4 (d, J01: 25.2 Hz), 110.4, 98.6 (d, J01: 27.2 Hz), 96.7, 49.4.

JXL050 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—4-chloro-1H—indolyl)cyan0acrylic acid (JXL050) 1H NMR (500 MHz, DMSO-d6) 5 9.20 (s, 1H), 8.90 (s, 1H), 8.06 (m, 3H), 7.72 (d, J = 7.5 Hz, 1H), 7.32 (m, 2H), 5.86 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.7, 146.7, 140.0, 138.0, 135.6, 131.1 (q, Jc-f= 33.1 Hz), 129.1, 125.6, 125.1, 124.7, 124.5, 123.7, 123.6 (q, Jc-f= 273.7 Hz), 122.5, 111.6, 109.9, 96.7, 49.6.

JXL051 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—4-bromo-lH-indolyl)—2-cyan0acrylic acid (JXL051) 1H NMR (500 MHz, DMSO-d6) 5 9.37 (s, 1H), 8.91 (s, 1H), 8.07 (app. 8, 3H), 7.77 (d, J: 8.2 Hz, 1H), 7.51 (d, J: 7.6 Hz, 1H), 7.23 (t, J: 8.0 Hz, 1H), 5.85 (s, 2H). 13C NMR(126 MHz, DMSO-d6) 5 164.7, 146.3, 140.0, 138.0, 135.8, 131.0 (q, J84: 33.1 Hz), 129.1, 127.9, 125.4, 124.9, 123.7 (q, .181: 273.2 Hz), 122.5, 118.2, 113.6, 122.1, 110.2, 96.6, 49.5.

JXL052 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—4-fluoro-1H—indolyl)cyan0acrylic acid (JXL052) 1H NMR (500 MHz, DMSO-d6) 5 8.80 (s, 1H), 8.58 (s, 1H), 8.05 (app. 8, 3H), 7.54 (d, J: 8.2 Hz, 1H), 7.29 (d, J: 12.9 Hz, 1H), 7.09 (dd, J: 11.1, 8.2 Hz, 1H), 5.85 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.5, 155.7 (d, J84: 239.4 Hz), 146.5, 140.1, 138.8, 134.5, 131.1 (q, J84: 33.0 Hz), 129.0, 125.1 (d, J84: 7.6 Hz), 124.7, 123.6 (q, J84: 273.5 Hz), 122.5, 118.1, 116.1 (d, .181: 18.5 Hz), 108.8, 108.5, 97.2, 49.7.

JXL053 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—7-fluoro-1H—indolyl)cyan0acrylic acid (JXL053) 1H NMR (500 MHz, DMSO-d6) 5 8.73 (br. s, 1H), 8.48 (br. s, 1H), 8.06 (br. s, 1H), 7.89 (br. s, 2H), 7.78 (br. S, J: 7.4 Hz, 1H), 7.22 (br. s, 1H), 7.10 (br. s, 1H), 5.89 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.6, 159.7 (d, Jc-f= 245.7 Hz), 145.6, 141.0, 136.2, 132.1, 130.0 (q, Jc-f= 33.0 Hz), 128.4, 123.9, 123.8, 123.6 (q, Jc-f= 273.3 Hz), 122.4 (d, Jc-f= 18.9 Hz), 118.1, 115.8, 110.6, 110.2 (61,1181: 18.9 Hz), 97.3, 52.0.

JXL054 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—5-chloro-1H—indolyl)cyan0acrylic acid (JXL054) 1H NMR (500 MHz, DMSO-d6) 5 8.78 (s, 1H), 8.51 (s, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 8.03 (s, 2H), 7.70 (d, J: 7.4 Hz, 1H), 7.33 (d, J: 7.0 Hz, 1H), 5.83 (s, 2H). 13C NMR(126 MHz, DMSO-d6) 5 164.7, 145.7, 140.2, 135.9, 135.1, 131.1 (q, Jc-f= 33.0 Hz), 129.3, 129.0, 127.9, 124.4, 123.6 (q, .101: 274.0 Hz), 122.5, 119.5, 118.4, 113.6, 109.9, 96.9, 49.5.

JXL055 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—4-cyano-1H-indolyl)—2-cyanoacrylic acid (JXL055) 1H NMR (500 MHz, DMSO-d6) 5 9.03 (s, 1H), 9.00 (s, 1H), 8.09 (m, 4H), 7.80 (d, J = 7.3 Hz, 1H), 7.47 (t, J: 7.8 Hz, 1H), 5.90 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.4, 144.4, 139.9, 136.7, 131.1 (q, 118-1: 33.0 Hz), 129.7, 129.2, 126.6, 124.3, 123.6 (q, .181: 273.7 Hz), 122.7, 118.6, 117.9, 117.8, 109.3, 101.7, 98.1, 49.5.

COzH / JXLO56 (E)(3,5-Bis(tri?u0r0methyl)benzyl)—3-(2-carboxy-Z-cyanovinyl)—1H-indole carboxylic acid (JXL056) 1H NMR (500 MHz, DMSO-d6) 5 9.26 (br. s, 1H), 8.88 (br. s, 1H), 8.05 (app. 8, 3H), 7.94 (br. s, 1H), 7.76 (br. s, 1H), 7.37 (br. s, 1H), 5.85 (s, 2H). 13C NMR(126 MHz, 6) 5 169.3, 165.0, 150.6, 140.2, 137.7, 136.0, 131.1 (q, J84: 33.0 Hz), 129.0, 125.9, 125.2, 124.7, 123.6 (q, J84: 273.7 Hz), 123.5, 122.5, 118.3, 116.1,110.1, 96.4, 49.3.

JXL057 (E)(4-(Benzyloxy)—1-(3,5-bis(trifluoromethyl)benzyl)—1H-indolyl)—2-cyan0acrylic acid 7) 1H NMR (500 MHz, DMSO-d6) 5 9.15 (s, 1H), 8.72 (s, 1H), 8.04 (s, 1H), 7.99 (s, 2H), 7.54 (br. s, 3H), 7.37 (br. s, 2H), 7.28 (m, 2H), 6.95 (s, 1H), 5.81 (s, 2H), 5.28 (s, 2H). 13C NMR(126 MHz, DMSO-d6) 5 165.0, 153.7, 148.6, 140.5, 137.9, 133.4, 131.2 (q, Jc-f= 32.8 Hz), 128.9, 128.8, 128.1, 127.5, 125.4, 124.7, 123.6 (q, Jc-f= 273.7 Hz), 122.3, 118.5, 117.0, 110.5, 105.6, 105.2, 95.5, 70.0, 49.5.

BnO N JXL058 (E)(6-(Benzyloxy)—1-(3,5-bis(trifluoromethyl)benzyl)—1H-indolyl)—2-cyan0acrylic acid (JXL058) 1H NMR (500 MHz, DMSO-d6) 5 8.63 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 8.03 (s, 2H), 7.86 (d, J: 8.5 Hz, 1H), 7.32 (m, 6H), 6.97 (d, J: 8.3 Hz, 1H), 5.77 (s, 2H), 5.09 (s, 13C NMR(126 MHz, DMSO-d6) 5 165.0, 156.7, 146.1, 140.5, 137.5, 137.3, 134.3, 131.0 (q, Jc-f= 32.8 Hz), 128.9, 128.8, 128.3, 128.2, 126.9, 123.6 (q, Jc-f= 273.4 Hz), 122.4, 121.9, 118.5, 113.3, 110.5, 96.8, 95.6, 70.2, 49.2.

N CFs OBn KQ JXL059 (E)(7-(Benzyloxy)—1-(3,5-bis(trifluoromethyl)benzyl)—1H-indolyl)—2-cyan0acrylic acid (JXL059) 1H NMR (500 MHz, DMSO-d6) 5 8.61 (br. s, 1H), 8.45 (br. s, 1H), 7.97 (br. s, 1H), 7.60 (br. s, 2H), 7.51 (br. s, 1H), 7.25 (br. s, 2H), 7.16 (br. s, 2H), 6.91 (br. s, 1H), 5.94 (s, 2H), 5.13 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.8, 146.6, 145.7, 142.3, 136.6, 135.4, 130.7 (q, Jc-f= 32.8 Hz), 130.5, 128.8, 128.4, 128.0, 127.5, 125.7, 124.1, 123.6 (q, Jc-f= 273.7 Hz), 121.8, 118.3, 111.8, 110.3, 107.1, 96.2, 70.3, 52.4.

JXLOGO (E)(1-(3,5-Bis(tri?uoromethyl)benzyl)—4-methoxy-1H—indolyl)—2-cyan0acrylic acid (JXL060) 1H NMR (500 MHz, DMSO-d6) 5 8.99 (s, 1H), 8.71 (s, 1H), 8.05 (s, 1H), 8.00 (s, 2H), 7.24 (app. 3, 2H), 6.82 (d, J: 6.0 Hz, 1H), 5.81 (s, 2H), 3.92 (s, 3H). 13C 6 MHz, DMSO-d6) 5 165.0, 154.8, 148.6, 140.5, 137.8, 133.3, 131.0 (q, Jc-f= 32.8 Hz), 128.9, 125.4, 123.6 (q, Jc-f= 273.7 Hz), 122.5, 118.5, 116.8, 110.5, 105.0, 104.3, 95.3, 56.2, 49.5.

JXL061 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—5-bromo-1H-indolyl)—2-cyan0acrylic acid 1H NMR (500 MHz, DMSO-d6) 5 8.75 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 8.02 (m, 3H), 7.64 (app. 3, 1H), 7.44 (app. 3, 1H), 5.82 (s, 2H). 13C NMR (126 MHz,DMSO-d6)6164.7, 145.3, 140.3, 135.5, 135.3, 131.1 (q, Jc-f: 32.8 Hz), 129.8, 128.9, 127.0, 124.7, 123.6 (q, Jc-f= 274.0 Hz), 122.5, 122.3, 118.5, 113.9, 109.9, 97.7, 49.5.

Br N JXL062 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—6-bromo-1H-indolyl)—2-cyan0acrylic acid (JXL062) 1H NMR (500 MHz, DMSO-d6) 5 8.72 (s, 1H), 8.47 (s, 1H), 8.06 (s, 2H), 8.03 (s, 1H), 7.94 (d, J: 8.2 Hz, 1H), 7.39 (d, J: 7.9 Hz, 1H), 5.81 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.7, 145.6, 140.2, 137.4, 135.3, 131.1 (q, Jc-f= 32.8 Hz), 1291, 127.0, 125.9, 123.6 (q, Jc-f= 274.0 Hz), 1225, 121.5, 118.2, 117.2, 114.8, 110.3, 96.9, 49.3.

CI N JXL063 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—6-chloro-1H—indolyl)cyan0acrylic acid 1H NMR (500 MHz, DMSO-d6) 5 8.75 (s, 1H), 8.47 (s, 1H), 8.05 (m, 3H), 8.00 (d, J = 7.4 Hz, 1H), 7.89 (s, 1H), 7.28 (d, J: 6.5 Hz, 1H), 5.81 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.7, 145.6, 140.2, 137.0, 135.4, 131.1 (q, J64: 32.8 Hz), 129.2, 129.0, 126.7, 123.6 (q, .181: 274.0 Hz), 123.3, 122.5, 121.2, 118.2, 111.9, 110.3, 97.0, 49.3.

JXL064 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—7-chloro-1H—indolyl)cyan0acrylic acid (JXL064) 1H NMR (500 MHz, DMSO-d6) 5 8.69 (s, 1H), 8.50 (s, 1H), 8.03 (s, 1H), 7.97 (d, J: 7.5 Hz, 1H), 7.73 (s, 2H), 7.32 (d, J: 7.1 Hz, 1H), 7.25 (m, 1H), 6.14 (s, 2H). 13C NMR(126 MHz, DMSO-d6) 5 164.5, 145.1, 142.1, 136.9, 131.5, 131.2 (q, J64: 32.8 Hz), 127.6, 126.1, 124.1, 123.6 (q, .181: 274.0 Hz), 122.5, 122.0, 118.8, 118.0, 116.9, 110.3, 97.9, 51.8.

COZEt JXL065 Ethyl (E)(1-(3,5-bis(trifluoromethyl)benzyl)—4-bromo-1H—indolyl)cyanoacrylate (JXL065) 1H NMR (500 MHz, 6) 5 9.67 (s, 1H), 8.71 (s, 1H), 7.86 (s, 1H), 7.56 (s, 2H), 7.52 (d, J: 7.4 Hz, 1H), 7.17 (m, 2H), 5.55 (s, 2H), 4.37 (q, J: 7.1 Hz, 2H), 1.40 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) 5 163.4, 146.9, 137.6, 137.4, 134.3, 132.7 (q, J84: 33.9 Hz), 128.2, 126.7, 125.6, 125.1, 122.8 (q, Jc-f= 273.4 Hz), 122.7, 118.0, 114.9, 111.8, 109.9, 96.3, 62.2, 50.6, 14.3.

COzEt JXL066 Ethyl (E)(1-(3,5-bis(trifluoromethyl)benzyl)—4-fluoro-1H-indolyl)—2-cyan0acrylate (JXL066) 1H NMR (500 MHz, DMSO-d6) 5 8.86 (s, 1H), 8.61 (s, 1H), 7.86 (s, 1H), 7.56 (s, 2H), 7.23 (m, 1H), 7.01 (m, 2H), 5.54 (s, 2H), 4.37 (q, J: 7.1 Hz, 2H), 1.39 (t, J: 7.1 Hz, 13C NMR (126 MHz, DMSO-d6) 5 163.1, 157.4 (d, J: 243.9 Hz), 147.4, 138.2 (d, J = 10.1 Hz), 137.8, 133.2, 132.7 (q, Jc-f= 33.9 Hz), 126.7, 125.3, 122.8 (q, J84: 273.4 Hz), 122.7, 117.9, 116.9 (d, J84: 17.6 Hz), 110.0, 109.0 (d, J84: 19.5 Hz), 106.6, 97.1, 62.2, 50.7, 14.3.

C02IBU JXL068 tert-Butyl (E)(1-(3,5-bis(trifluoromethyl)benzyl)—1H—indolyl)cyanoacrylate (JXL068) 1H NMR (500 MHz, CDC13) 5 8.57 (s, 1H), 8.54 (s, 1H), 7.86 (d, J: 7.6 Hz, 1H), 7.84 (s, 1H), 7.56 (s, 2H), 7.33 (m, 2H), 7.22 (d, J: 7.4 Hz, 1H), 5.55 (s, 2H), 1.59 (s, 9H). 13C NMR (126 MHz, CDC13) 5 162.4, 144.7, 138.2, 135.9, 133.0, 132.7 (q, Jc-f= 32.8 Hz), 128.6, 126.7, 124.5, 123.0, 122.9 (q, .101: 277.2 Hz), 122.6, 119.0, 118.2, 111.1, 110.4, 97.7, 82.9, 50.4, 28.1.

JXL069 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—lH-pyrrolo [2,3-b] nyl)—2-cyan0acrylic acid (JXL069) 1H NMR (500 MHz, DMSO-d6) 5 8.85 (s, 1H), 8.47 (m, 3H), 8.09 (s, 2H), 8.04 (s, 1H), 7.35 (dd, J: 7.1, 4.6 Hz, 1H), 5.84 (s, 2H). 13C NMR(126 MHz, DMSO-d6) 5 185.9, 164.6, 147.8, 146.1, 145.5, 141.0, 135.2, 131.0 (q, Jc-f= 32.8 Hz), 129.4, 126.9, 123.6 (q, Jc-f= 274.0 Hz), 122.3, 120.1, 119.1, 118.2, 97.1, 47.8.

JXL072 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—lH-pyrrolo[3,2-b]pyridinyl)—2-cyan0acrylic acid (JXL072) 1H NMR (500 MHz, DMSO-d6) 5 8.94 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 8.11 (m, 4H), 7.35 (s, 1H), 5.87 (s, 2H). 13C NMR(126 MHz, DMSO-d6) 5 164.5, 145.9, 144.2, 140.1, 135.9, 131.1 (q, 118-1: 32.8 Hz), 129.6, 129.2, 124.7, 123.6 (q, Jc-f= 274.0 Hz), 122.5, 120.0, 119.5, 117.9, 110.1, 97.2, 49.8.

JXL073 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—lH-pyrrolo [2,3-c]pyridinyl)—2-cyan0acrylic acid (JXL073) 1H NMR (500 MHz, DMSO-d6) 5 9.14 (s, 1H), 8.96 (s, 1H), 8.55 (s, 1H), 8.40 (d, J: .1 Hz, 1H), 8.19 (s, 2H), 8.11 (app. 8, 2H), 5.95 (s, 2H). 13C NMR(126 MHz, DMSO-d6) 5 164.5, 145.5, 140.7, 139.9, 138.1, 134.5, 133.6, 131.1 (q, J81: 32.8 Hz), 129.4, 127.2, 123.6 (q, 118-1: 274.0 Hz), 122.7, 118.0, 114.6, 109.7, 97.9, 49.8.

JXL076 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—4-chlor0-lH-pyrrolo[2,3-b]pyridinyl)—2- cyanoacrylic acid (JXL076) 1H NMR (500 MHz, DMSO-d6) 5 9.00 (s, 1H), 8.98 (s, 1H), 8.36 (s, 1H), 8.12 (s, 2H), 8.04 (br. s, 1H), 7.47 (br. s, 1H), 5.85 (s, 2H). 13C NMR(126 MHz, DMSO-d6) 5 164.4, 148.7, 145.8, 145.7, 140.2, 136.1, 135.3, 131.0 (q, Jc-f= 32.8 Hz), 129.5, 123.6 (q, Jc-f= 274.0 Hz), 122.4, 120.4, 117.7, 116.8, 108.2, 98.1, 48.2.

JXL077 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—4-br0m0-lH-pyrrolo[2,3—b]pyridinyl)—2- crylic acid (JXL077) 1H NMR (500 MHz, DMSO-d6) 5 9.17 (s, 1H), 9.02 (s, 1H), 8.27 (d, J: 5.0 Hz, 1H), 8.12 (s, 2H), 8.05 (s, 1H), 7.63 (d, J: 5.0 Hz, 1H), 5.85 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 164.4, 148.2, 145.5, 145.3, 140.2, 135.4, 131.0 (q, Jc-f= 32.8 Hz), 129.6, 124.9, 123.7, 123.6 (q, Jc-f= 274.0 Hz), 122.4, 118.4, 117.7, 108.6, 97.9, 48.2.

COZMe JXLO78 Methyl (E)(1-(3,5-bis(trifluoromethyl)benzyl)—lH-indolyl)cyan0acrylate (JXL078) 1H NMR (500 MHz, CDC13) 5 8.62 (s, 1H), 8.61 (s, 1H), 7.89 (d, J: 7.7 Hz, 1H), 7.84 (s, 1H), 7.57 (s, 2H), 7.35 (m, 2H), 7.24 (m, 1H), 5.55 (s, 2H), 3.92 (s, 3H). 13C NMR (126 MHz, CDC13) 5 164.5, 145.8, 138.1, 136.0, 133.5, 132.7 (q, Jc-f= 32.8 Hz), 128.6, 126.8, 124.7, 123.9, 123.6 (q, .101: 274.0 Hz), 123.2, 119.1, 118.0, 111.2, 110.5, 95.4, 53.0, 50.5. 0 (\o CF3 JXL081 (E)(1-(3,5-Bis(trifluoromethyl)benzyl)—lH-indolyl)(morpholine carbonyl)acrylonitrile (JXL081) 1H NMR (500 MHz, CDC13) 5 8.48 (s, 1H), 8.34 (s, 1H), 7.84 (s, 2H), 7.56 (app. 8, 2H), 7.32 (m, 2H), 7.22 (m, 1H), 5.54 (s, 2H), 3.77 (br. s, 8H). 13C NMR (126 MHz, CDC13) 5 164.0, 145.2, 138.4, 135.8, 132.7 (q, Jc-f= 34.0 Hz), 131.8, 128.4, 126.8, 125.0, 124.5, 123.1 (q, .181: 273.3 Hz), 122.8, 121.8, 119.0, 118.6, 111.4, 110.3, 98.1, 66.7, 50.3, 50.0.

JXL082 Ethyl (E)(1-(3,5-bis(trifluoromethyl)benzyl)—lH-pyrrolo[2,3-b]pyridinyl)—2- crylate (JXL082) 1H NMR (500 MHz, CDC13) 5 8.64 (s, 1H), 8.51 (s, 1H), 8.48 (dd, J: 4.6, 1.2 Hz, 1H), 8.21 (dd, J: 7.9, 1.2 Hz, 1H), 7.83 (s, 1H), 7.77 (s, 2H), 7.34 (dd, J: 7.9, 4.6 Hz, 1H), .69 (s, 2H), 4.38 (q, J: 7.1 Hz, 2H), 1.40 (t, J: 7.1 Hz, 3H). 13C NMR(126 MHz, CDC13) 5 163.3, 147.6, 145.7, 145.0, 138.5, 132.7, 132.3 (q, J84 = 33.6 Hz), 127.9, 127.7, 123.1 (q, .181: 273.3 Hz), 122.5, 120.3, 119.0, 117.6, 109.4, 97.0, 62.3, 48.3, 14.3. 002Et JXL087 Ethyl (E)(1-(3,5-bis(trifluoromethyl)benzyl)—4-chlor0-lH-pyrrolo[2,3-b]pyridinyl)— 2-cyan0acrylate (JXL087) 1H NMR (500 MHz, CDC13) 5 9.22 (s, 1H), 8.77 (s, 1H), 8.32 (d, J: 5.2 Hz, 1H), 7.83 (s, 1H), 7.77 (s, 2H), 7.31 (d, J: 5.2 Hz, 1H), 5.67 (s, 2H), 4.37 (q, J: 7.1 Hz, 2H), 1.39 (t, J: 7.1 Hz, 3H). 13C NMR(126 MHz, CDC13) 5 163.0, 148.5, 146.2, 145.4, 138.1, 137.4, 133.1, 132.4 (q, J84: 33.7 Hz), 128.0, 122.9 (q, J84: 273.4 Hz), 122.6, 121.8, 117.6, 117.2, 109.7, 97.8, 62.4, 48.6, 14.3.

JXLOBB Ethyl (E)(1-(3,5-bis(trifluor0methyl)benzyl)—4-br0mo-lH-pyrrolo[2,3-b]pyridinyl)— 2-cyan0acrylate (JXL088) 1H NMR (500 MHz, CDC13) 5 9.40 (s, 1H), 8.78 (s, 1H), 8.22 (d, J: 5.1 Hz, 1H), 7.83 (s, 1H), 7.77 (s, 2H), 7.49 (d, J: 5.1 Hz, 1H), 5.67 (s, 2H), 4.37 (q, J: 7.1 Hz, 2H), 1.39 (t, J: 7.1 Hz, 3H). 13CNMR(126MHz,CDC13)6163.1,148.1,1457,145.1,138.1,137.4,1334,1324 (q, J61: 33.7 Hz), 123.7, 122.9 (q, 116-1: 273.4 Hz), 122.6, 119.7, 117.6, 110.0, 101.4, 97.4, 62.4, 48.6, 14.3. 002Et JXL089 Ethyl (E)(1-(3,5-bis(trifluor0methyl)benzyl)—5-chloro-1H—indolyl)—2-cyanoacrylate (JXL089) 1H NMR (500 MHz, CDC13) 5 8.60 (s, 1H), 8.50 (s, 1H), 7.85 (s, 1H), 7.83 (s, 1H), 7.55 (s, 2H), 7.28 (dd, J: 8.7, 1.7 Hz, 1H), 7.14 (d, J: 8.7 Hz, 1H), 5.54 (s, 2H), 4.38 (q, J: 7.1 Hz, 2H), 1.40 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 163.2, 144.8, 137.7, 134.3, 134.1, 132.8 (q, 116-1: 33.7 Hz), 129.7, 129.3, 126.7, 125.1, 122.8 (q, Jc-f= 273.4 Hz), 122.7, 118.9, 117.7, 111.6, 110.6, 96.9, 62.3, 50.6, 14.3.

COZEt JXL090 Ethyl (E)(1-(3,5-bis(trifluoromethyl)benzyl)—4-cyano-lH-indolyl)cyanoacrylate (JXL090) 1H NMR (500 MHz, CDC13) 5 9.29 (s, 1H), 8.78 (s, 1H), 7.87 (s, 1H), 7.68 (dd, J = 7.4, 0.8 Hz, 1H), 7.56 (s, 2H), 7.49 (dd, J: 8.4, 0.8 Hz, 1H), 7.38 (dd, J: 8.4, 7.4 Hz, 1H), .62 (s, 2H), 4.38 (q, J: 7.1 Hz, 2H), 1.40 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 162.6, 144.3, 137.3, 136.2, 135.1, 132.9 (q, Jc-f= 33.7 Hz), 129.4, 127.3, 126.7, 124.1, 123.0, 122.8 (q, .181: 273.4 Hz), 117.9, 117.5, 115.4, 110.7, 103.5, 98.6, 62.4, 50.6, 14.3.

CO2Et 002Me / JXL091 Methyl (E)(3,5-bis(tri?u0r0methyl)benzyl)(2-cyan0ethoxy0x0pr0pen -indolecarb0xylate (JXL091) 1H NMR (500 MHz, CDC13) 5 9.36 (s, 1H), 8.71 (s, 1H), 7.93 (dd, 1H, J: 7.4, 1.1 Hz, 1H), 7.85 (s, 1H), 7.55 (s, 2H), 7.40 (dd, J: 8.3, 1.1 Hz, 1H), 7.34 (dd, J: 8.3, 7.4 Hz, 1H), 5.58 (s, 2H), 4.37 (q, J: 7.1 Hz, 2H), 4.04 (s, 3H), 1.40 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 167.8, 163.5, 150.1, 137.8, 137.2, 134.9, 132.8 (q, Jc-f = 33.7 Hz), 126.7, 125.8, 125.1, 123.6, 122.8 (q, .181: 273.4 Hz), 122.7, 121.7, 118.0, 114.6, 111.3, 96.4, 62.1, 52.6, 50.5, 14.3.

Experimental detail for the synthesis of JXL024 O O C05,0 Z‘NH NH s50 , s50 N‘ NaOAc, AcOH Ph 130°C N 34% Ph JXL024 To the solution of 1-pheny1-1H—indolecarba1dehyde (0.4 mmol, 90 mg) in AcOH (3 mL) were added thiazolidine-2,4-dione (1 equiv, 0.4 mmol, 46.8 mg) and NaOAc (3 equiv, 98 mg).

The reaction mixture was stirred at re?ux for 24 hours. After it was cooled to 21 0C, the reaction mixture was ?ltered by vacuum ?ltration and washed by AcOH (3 mL X 3) and water (5 mL X 3). After drying by vacuum, the desired product was produced. yield: 34%, 44 mg.

(Z)((1-Phenyl-lH-indolyl)methylene)thiazolidine-2,4-di0ne 4) 1H NMR (500 MHz 6) 5 7.98 (m, 2H), 7.79 (s, 1H), 7.66 (app. d, J: 7.7 Hz, 2H), 7.62 (app. t, J: 7.7 Hz, 2H), 7.54 (d, J: 8.0 Hz, 1H), 7.49 (t, J: 7.1 Hz, 1H), 7.30 (m, 13C NMR(126 MHz, DMSO-d6) 5 172.5, 169.5, 138.4, 136.2, 130.5, 129.9, 128.3, 128.2,125.0,124.6,122.4,121.5,121.4,119.6,113.0,111.5.

The following compounds were synthesized by a route r to that described for JXL024:: JXLO67, JXLO70, JXLO72, , JXLO75.

JXL023 (Z)Imin0((1-phenyl-1H-indolyl)methylene)thiazolidin0ne (JXL023) 1H NMR (500 MHz, DMSO-d6) 5 11.94 (br. s, 1H), 9.33 (br. s, 1H), 8.97 (s, 1H), 7.64 (m, 10H). 13C NMR(126 MHz, DMSO-d6) 5 180.9, 174.8, 172.5, 138.6, 136.2, 130.5, 129.3, 128.1,126.3,124.8,124.5,122.2,120.3,119.7,113.5,111.5.

JXL067 (Z)((1-(3,5-Bis(triflu0r0methyl)benzyl)—1H—indolyl)methylene)—2-imin0thiazolidin- 4-0ne (JXL067) 1H NMR (500 MHz, DMSO-d6) 5 9.21 (s, 1H), 9.01 (s, 1H), 8.03 (s, 1H), 7.94 (br. s, 3H), 7.86 (d, J: 7.7 Hz, 1H), 7.81 (s, 1H), 7.58 (d, J: 7.9 Hz, 1H), 7.24 (m, 1H), 7.19 (m, 1H), 5.76 (s, 2H). 13C NMR (126 MHz, DMSO-d6) 5 180.0, 174.9, 141.4, 136.5, 131.0 (q, Jc-f= 32.8 Hz), 130.4, 128.5, 127.9, 125.1, 123.8, 123.6 (q, .181: 274.0 Hz), 122.1, 121.7, 120.8, 119.3, 111.8, 111.3, 48.9.

JXL070 (Z)((4-Flu0r0-l-phenyl-lH-indolyl)methylene)thiazolidine-2,4-di0ne (JXL070) 1H NMR (500 MHz, DMSO-d6) 5 12.45 (br. s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.65 (m, 4H), 7.52 (s, 1H), 7.32 (m, 2H), 7.12 (m, 1H). 13C NMR (126 MHz, DMSO-d6) 5 168.0, 167.7, 156.9 (d, Jc-f: 245.7 Hz), 138.7 (d, Jc-f: 10.1 Hz), 137.9, 130.8, 130.5, 128.8, 125.5, 125.4, 124.3, 120.0, 116.2 (d,Jc.f= 18.9 Hz), 110.7, 108.5, 108.1 (d, Jc-f: 18.9 Hz).

JXL071 ((6-Flu0r0-l-phenyl-lH-indolyl)methylene)thiazolidine-2,4-di0ne (JXL071) 1H NMR (500 MHz, DMSO-d6) 5 12.42 (s, 1H), 8.06 (app. s, 2H), 7.85 (s, 1H), 7.67 (m, 2H), 7.62 (m, 2H), 7.50 (m, 1H), 7.31 (d, J: 9.6 Hz, 1H), 7.16 (t, J: 8.5 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) 5 168.0, 167.7, 160.6 (d, Jc-f= 245.7 Hz), 138.0, 136.3 (d, Jc-f= 12.6 Hz), 131.0, 130.6, 128.5, 125.0, 124.8, 123.5, 121.3 (d, Jc-f= 10.0 Hz), 120.0, 112.6, 111.1 (d, Jc-f= 18.9 Hz), 98.2 (d, Jc-f= 18.9 Hz).

JXL074 (Z)Benzylidenethiazolidine-2,4-di0ne (JXL074) 1H NMR (500 MHz, DMSO-d6) 5 12.60 (br. s, 1H), 7.77 (s, 1H), 7.58 (app. d, J = 7.3 Hz, 2H), 7.51 (app. t, J: 7.4 Hz, 2H), 7.46 (m, 1H). 13C NMR(126 MHz, DMSO-d6) 5 168.4, 167.8, 133.5, 132.3, 130.9, 130.5, 129.8, 124.0.

JXLO75 (Z)((1H-Indolyl)methylene)thiazolidine-2,4-di0ne 5) 1H NMR (500 MHz, DMSO-d6) 5 12.28 (s, 1H), 12.11 (s, 1H), 8.03 (s, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.72 (s, 1H), 7.48 (d, J: 7.6 Hz, 1H), 7.23 (m, 1H), 7.18 (m, 1H). 13C NMR(126 MHz, DMSO-d6) 5 168.2, 167.8, 136.7, 129.1, 127.3, 125.0, 123.5, 121.5,118.8,116.7,112.9,110.9. mental detail for the synthesis of JXL022 @o NCACOZEt 0°23 C02" \ \ 0.5N LiOH \ \ —>| —>| L-proline,EtOH N / CN N / CN JXL022 To the on of 4-pyridinecarboxa1dehyde (1 mmol, 107 mg) in ethanol (1 mL) were added ethyl 2-cyanoacetate (1.3 equiv, 1.3 mmol, 140 uL) and L-proline (40 mol%, 0.4 mmol, 58 mg). The reaction was stirred at 21 0C for 12 h and yellow solid precipitated gradually. After completion of the reaction, ice-cold water (2 mL) was added into the reaction Vial. The solid was separated by r funnel ?ltration and washed with water (2 mL X 3) and dried to afford the desired product, ethyl (E)cyano(pyridinyl)acrylate, which was used for the next step without r puri?cation.

To the solution of (E)—2-cyano(pyridinyl)acrylate (0.21 mmol, 42.4 mg) in THF (2 mL) was added 0.5N LiOH on (3 equiv, 0.4 mmol, 0.8 mL). The reaction mixture was stirred at 21 0C for l h. After reaction completion shown by TLC, THF was evaporated.

Concentrated HCl was added dropwise to acidify the reaction mixture until pH was lower than 1, meanwhile yellow solid precipitated. Ice-cold water (5 mL) was added to the reaction mixture and the solid was separated by Buchner funnel ?ltration and washed with water (5 mL X 3). After dried by vacuum, the solid was washed by 2 mL of solvent e (hexanes/EtOAc = 5:1) 5 to 10 times and monitored by TLC until non-polar impurities disappear. Finally, the purity of the product was checked by NMR. yield: 64%, 23.4 mg.

Ethyl (E)cyan0(pyridinyl)acrylate (JXL022) 1H NMR (500 MHz, CDC13) 5 8.81 (d, J: 5.2 Hz, 2H), 8.18 (s, 1H), 7.74 (d, J: 5.2 Hz, 2H), 4.41 (q, J: 7.1 Hz, 2H), 1.41 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 161.2, 152.0, 151.0, 137.9, 123.2, 114.2, 108.2, 63.2, 14.0.

The following compounds were synthesized by a route similar to that described for JXLO22: JXLO30, JXLO3l, JXLO32, , JXLO34, JXLO42, JXL43, JXLO44, JXLO45, , JXLO47, JXLO48, JXLO49.

JXL030 (E)Cyan0(2-flu0r0phenyl)acrylic acid (JXL030) 1H NMR (500 MHz, DMSO-d6) 5 8.49 (s, 1H), 8.31 (t, J: 7.4 Hz, 1H), 7.63 (m, 1H), 7.36 (t, J: 7.4 Hz, 1H), 7.29 (m, 1H). 13C NMR (126 MHz, DMSO-d6) 5 162.9, 161.5 (d, J61: 256.2 Hz), 1454 (d, J61: 7.8 Hz), 1350 (d, J61: 9.2 Hz), 128.7, 124.7, 119.8 (d, J61: 10.9 Hz), 115.8 (d, J61: 21.9 Hz), 1149, 105.9.

JXL032 Cyan0(4-flu0r0phenyl)acrylic acid (JXL032) 1H NMR (500 MHz, DMSO-d6) 5 8.30 (s, 1H), 8.10 (m, 2H), 7.29 (m, 2H). 13C NMR (126 MHz,DMSO-d6)5165.2(d,Jc-f= 255.2 Hz), 163.5, 153.1, 133.3 (d, Jc-f= 9.3 Hz), 128.3, 116.0 (d, Jc-f: 22.4 Hz), 115.3, 103.2.

F30 COZH JXL033 (E)cyan0(3-(trifluor0methyl)phenyl)acrylic acid (JXL033) 1H NMR (500 MHz, CD3OD) 5 8.24 (s, 1H), 8.17 (m, 2H), 7.80 (d, J: 7.8 Hz, 1H), 7.70 (app. t, J: 7.8 Hz, 1H).

JXLO34 (E)Cyan0(4-(tri?uoromethyl)phenyl)acrylic acid (JXL034) 1H NMR (500 MHz, DMSO-d6) 5 8.39 (s, 1H), 8.17 (d, J: 7.7 Hz, 2H), 7.84 (d, J: 7.7 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) 5 162.8, 152.6, 135.4, 133.1 (q, Jc-f= 32.9 Hz), 1310, 125.7, 123.7 (q, Jc-f= 272.2 Hz), 114.8, 106.7.

JXL042 (E)Cyan0(3-flu0r0methylphenyl)acrylic acid (JXL042) 1H NMR (500 MHz, DMSO-d6) 5 8.28 (s, 1H), 7.78 (m, 2H), 7.49 (t, J: 8.0 Hz, 1H), 2.30 (s, 3H). 13C NMR (126 MHz, DMSO-d6) 5 163.6, 160.9 (d, Jc-f= 244.6 Hz), 1535, 133.0, 131.6 (d, Jc-f= 7.5 Hz), 130.8 (d, Jc-f= 17.6 Hz), 1272, 117.9 (d, Jc-f= 23.9 Hz), 116.4, 104.5, .0.

JXL043 (E)Cyan0(3,4-diflu0r0phenyl)acrylic acid (JXL043) 1H NMR (500 MHz, DMSO-d6) 5 8.32 (s, 1H), 8.09 (d, J: 8.0 Hz, 1H), 7.94 (br. s, 1H), 7.67 (d, J: 8.8 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) 5 163.3, 152.3, 152.2 (dd, Jc-f: 255.4, 12.6 Hz), 149.9 (dd, Jc-f: 248.2, 12.6 Hz), 129.8, 128.8, 120.1 (d, Jc-f: 17.6 Hz), 119.1 (d, Jc-f: 17.6 Hz),116.3,105.8.

(E)3;?n0(2A-di?u0r0phenyl)acrylic acid 4) 1H NMR (500 MHz, DMSO-d6) 5 14.2 (br. s, 1H), 8.27 (s, 1H), 8.24 (m, 1H), 7.52 (m, 1H), 7.35 (dt, J: 8.6, 2.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) 5 165.5 (dd, Jc-f: 255.8, 12.6 Hz), 163.1, 161.9 (dd, Jc-f: 270.5,12.6 HZ),145.1,131.1,117.0,115.9,113.5(d,Jc-f: 22.7 Hz), 106.8, 105.6 (t, Jc-f = 26.5 Hz).

F30 COZH JXL045 (E)(3,5-bis(trifluoromethyl)phenyl)—2-cyanoacrylic acid (JXL045) 1H NMR (500 MHz, CD3OD) 5 8.59 (s, 2H), 8.48 (s, 1H), 8.19 (s, 1H).

F3C COZH JXLO4G (E)(2-Chl0r0(trifluoromethyl)phenyl)—2-cyanoacrylic acid (JXL046) 1H NMR (500 MHz, DMSO-d6) 5 8.50 (s, 1H), 8.23 (d, J: 7.7 Hz, 1H), 8.05 (d, J: 7.4 Hz, 1H), 7.75 (app. t, J: 7.9 Hz, 1H). 13C NMR(126 MHz, DMSO-d6) 5 162.6, 150.5, 134.4, 133.5, 132.1, 131.2, 128.9, 128.3 (q, J84: 30.2 Hz), 123.1 (q, J84: 274.1 Hz) 115.1, 111.1.

JXL047 (E)Cyan0(4-flu0r0(tri?u0r0methyl)phenyl)acrylic acid (JXL047) 1H NMR (500 MHz, DMSO-d6) 5 8.46 (dd, J: 7.1, 1.8 Hz, 1H), 8.44 (s, 1H), 8.40 (m, 1H), 7.75 (m, 1H). 13C NMR (126 MHz, DMSO-d6) 5 163.3, 161.1 (d, Jc-f: 262.1 Hz), 152.2, 137.6 (d, Jc-f: 10.1 Hz), 130.5, 129.3, 122.6 (q, Jc-f: 272.8 Hz), 118.9 (d, Jc-f: 21.2 Hz), 118.2 (qd, Jo- f: 32.9, 12.6 Hz), 116.2, 106.3.

JXL048 (E)Cyan0phenylacrylic acid (JXL048) 1H NMR (500 MHz, DMSO-d6) 5 8.33 (s, 1H), 8.02 (m, 2H), 7.59 (m, 3H). 13C NMR (126 MHz,DMSO-d6)5163.7, 154.9, 133.6, 132.0, 131.1, 129.8, 116.5, 104.3.

JXL049 (E)cyan0(4-hydr0xyphenyl)acrylic acid (JXL049) 1H NMR (500 MHz, DMSO-d6) 5 8.16 (s, 1H), 7.95 (d, J: 8.8 Hz, 2H), 6.92 (d, J: 8.8 Hz, 2H). 13C 6 MHz, DMSO-d6) 5 164.2, 163.0, 153.7, 133.6, 122.8, 117.2, 116.3, 99.2.

Experimental detail for the synthesis of JXL079 FaC F c M910) 002" 3 OH DIBAL, DCM MsCl, Et3N —> —> then dry'Ice 90% 32% CF: CF3 COZTBU COZTBU TFA, DCM CF3 NaH, THF F36 JXL079 A ?ask containing Mg powder (10 mmol, 240 mg) and a stir bar was sealed and ed and d with argon three times. Anhydrous l ether (32 mL) and bis(tri?uoromethy1)benzy1 bromide (8 mmol, 1.46 mL) was added to the on ?ask. The reaction mixture was stirred and re?uxed for 30 min and then ground dry ice powder (5 g) was added into the reaction ?ask. After 1 h, the reaction was complete as shown by TLC. The extra Mg powder was ?ltered off and the solvent was evaporated under vacuum. 1N HC1 (20 mL) was added to the residue and the precipitate was ?ltered and dried to provide the desired carboxylic acid.

A ?ask cotaining a stir bar was sealed, vacuumed and re?lled with argon three times.

Anhydrous dichloromethane (20 mL) and DIBAL (1 M in hexanes, 6 mmol, 6 mL) were added to the ?ask. The crude carboxylic acid (2 mmol, 544 mg) dissolved in dry dichloromethane (10 mL) was added to the reaction ?ask at —78 0C. After 2 h, the reaction was complete as shown by TLC and it was then quenched by adding sat. ammonium chloride (10 mL). The resulting mixture was extracted with romethane (2O mL><3) and the organic phases were combined and evaporated on the rotavap. The residue was puri?ed by ?ash column chromatography (hexanes:ethy1 acetate = 10: 1) to afford the d product 2-(3,5- bis(tri?u0r0methyl)phenyl)ethanol (yield: 90%, 464 mg).

To a solution of 2-(3,5-bis(tri?uoromethy1)pheny1)ethanol (0.2 mmol, 51.6 mg) in dichloro-methane (2 mL) was added triethylamine (0.22 mmol, 31 uL) and mesyl chloride (MsCl, 0.2 mmol, 17 uL) at 0 0C. After stirring for 1 h, the reaction was complete as shown by TLC. The solvent was removed by ?owing air over the open ?ask. The e was puri?ed by ?ash column chromatography (hexanes:ethyl acetate = 10: 1) to afford the desired product 3,5-bis(tri?uoromethyl)phenethyl methanesulfonate (yield: 82%, 55.1 mg).

A ?ask containing NaH (60%, 0.22 mmol, 8.8 mg) and a stir bar was sealed, vacuumed and re?lled with argon three times. Anhydrous THF (3 mL) and a solution of lerl—butyl (E) cyano(1H-indolyl)acrylate (0.2 mmol, 53.6 mg) in THF (2 mL) were added into the reaction ?ask. The reaction e was stirred for 30 min and then 3,5- bis(tri?uoromethyl)phenethyl esulfonate (0.164 mmol, 55.1 mg) in 2 mL THF was added. The on was stirred for 24 h and quenched by sat. NH4Cl solution. The resulting mixture was extracted with dichloromethane (4 mL><3) and the organic phases were combined and evaporated on the rotavap. The residue was puri?ed by ?ash column chromatography (hexanes:ethyl e = 10: 1) to afford the desired product tert-butyl (E)(1-(3,5- i?u0r0methyl)phenethyl)—1H-indolyl)—2-cyano-acrylate (yield: 68%, 69 mg).

To a solution of methyl lerl—butyl (E)(1-(3,5-bis(tri?uoromethyl)phenethyl)-1H—indol- 3-yl)cyanoacrylate (0.1 mmol, 50.8 mg) in dichloromethane (2 mL) was added tri?uoroacetic acid (3 equiv, 0.3 mmol, 34 11L). The reaction mixture was d at 21 0C for min and a yellow solid precipitated. After the reaction was complete as shown by TLC, the reaction solvent was evaporated by ?owing air over the open ?ask. The solid was washed by 2 mL of solvent mixture (hexanes/EtOAc = 5: 1) 5 to 10 times and monitored by TLC until all the non-polar impurities disappeared. Finally, the purity of the product was checked by NMR. yield: 87%, 39 mg.

(E)(1-(3,5-Bis(trifluoromethyl)phenethyl)—1H-indolyl)cyan0acrylic acid (JXL079) 1H NMR (500 MHz, CD3OD) 5 8.51 (s, 1H), 8.14 (s, 1H), 7.83 (d, J: 7.3 Hz, 1H), 7.74 (s, 1H), 7.52 (m, 3H), 7.31 (m, 2H), 4.64 (t, J: 6.4 Hz, 2H), 3.35 (t, J: 6.3 Hz, 2H). 13C NMR(126 MHz, CD3OD) 5 165.3, 145.3, 141.1, 136.1, 133.6, 131.3 (q, J84: 32.8 Hz), 1293, 128.3, 123.7, 123.3 (q, Jc-f= 272.5 Hz), 1223, 120.3, 118.1, 117.6, 110.6, 109.6, 94.1, 47.8, 35.0.

Experimental detail for the synthesis of JXL080 COZEt COZEt / ’ F3C \ CN °°2H DCC,DMAP \ N + —> JXL080 N DCM’ 0 cc H c|=3 O To a solution of ethyl (E)cyano(1H—indoly1)acry1ate (0.5 mmol, 112 mg) in dichloromethane (5 mL) were added -bis(tri?uoromethy1)pheny1)acetic acid (0.55 mmol, 150 mg), DMAP (catalytic amount, 6 mg), and DCC (0.5 mmol, 103 mg) at 0 CC. The mixture was allowed to reach 21 oC and stirred overnight. The white precipitate was d, and the resulting solution was concentrated in vacuum. The solid was puri?ed by ?ash column chromatography (hexanes:ethy1 acetate = 10: 1) to afford the desired t (yield: 78%, 192.6 Ethyl (E)(1-(2-(3,5-bis(trifluoromethyl)phenyl)acetyl)—1H-indolyl)—2-cyanoacrylate (JXL080) 1H NMR (500 MHz, CDC13) 5 8.90 (s, 1H), 8.52 (s, 1H), 8.49 (d, J: 8.1 Hz, 1H), 7.88 (s, 1H), 7.86 (s, 2H), 7.78 (d, J: 7.5 Hz, 1H), 7.47 (m, 2H), 4.50 (s, 2H), 4.41 (q, J: 7.1 Hz, 2H), 1.43 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 168.0, 162.2, 144.2, 135.6, 134.4, 132.3 (q, Jc-f= 33.6 Hz),130.1,129.8,128.8,127.8,127.3,125.5,123.1(q,Jc.f= 273.3 Hz), 118.3, 117.1, 117.0, 115.9, 101.8, 62.8, 41.9, 14.3.

Experimental detail for the synthesis of JXL083 COZEt HO Cl ’0 O 0 ’ \ \ \ \ N NaClOz, NaHzPO4 N N (C0Cllz, DCM N NCACOZEt —> —> —> LDA, THF, —78 °c F30 */ F3C F36 acetone CF3 c1=3 CF3 JXL083 To a solution of 1-(3,5-bis(tri?uoromethyl)benzyl)—1H—indolecarbaldehyde (10 mmol, 3.71 g) in acetone (60 mL) was added 2-methylbutene (9 mL), NaH2PO4 (3 equiv, 4.4 g) and NaC102 (6.6 mmol, 6 g) in 6 mL water. The reaction e was stirred at 21 0C for 24 h. After the reaction was complete as shown by TLC, the reaction solvent was ated on the rotavap. The crude material was dissolved in ethyl acetate (30 mL) and water (30 mL) and extracted with ethyl acetate (30 mL X 3). The organic phase was combined, dried with sodium sulfate and ated on the p. The solid was puri?ed by ?ash column chromatography (hexanes:ethyl acetate = 2: 1) to afford the desired product 1-(3,5- bis(triflu0r0methyl)benzyl)—1H-indolecarb0xylic acid (yield: 89%, 3.44 g).

A 100 mL round bottom ?ask with a stir bar containing the carboxylic acid (5 mmol, 1935 mg) from the previous step was sealed, vacuumed and d with argon three times. To the ?ask was added 50 mL dichloromethane and oxalyl chloride (25 mmol, 2.1 mL) dropwise.

The reaction mixture was stirred at 21 0C for 1.5 h. The reaction solvent was evaporated by vacuum and the resulting compound was used for the next step.

A 100 mL round bottom ?ask with a stir bar was sealed, vacuumed and re?lled with argon three times. Diisopropylamine (5.5 mmol, 765 uL) and THF (10 mL) were added into the ?ask and it was cooled to -78 oC. nBuLi (2.5 M in hexanes, 5 mmol, 2 mL) was added slowly to the ?ask. After the mixture had stirred for 30 min, a solution of ethyl 2-cyanoacetate (5 mmol, 590 uL) in THF (10 mL) was added slowly to the ?ask. After the mixture had stirred for 1 h, a solution of the acyl chloride (5 mmol from previous step) in THF (5 mL) was added slowly to the reaction mixture. After 1 h, the reaction was quenched by adding aqueous 1M HCl on (10 mL) and extracted with ethyl acetate (10 mL X 3). The organic phase was combined, dried with sodium sulfate and evaporated by rotavap. The solid was puri?ed by ?ash column chromatography es:ethyl acetate = 10:1) to afford the desired product Ethyl (Z)(1- (3,5-bis(triflu0r0methyl)benzyl)—1H-indolyl)cyan0hydr0xyacrylate (JXL083) (yiekl 8096,1.93 g) 1H NMR (500 MHz, CDC13) 5 14.61 (s, 1H), 8.67 (s, 1H), 8.31 (dd, J: 7.0 1.3 Hz, 1H), 7.84 (s, 1H), 7.57 (s, 2H), 7.33 (m, 2H), 7.21 (d, J: 7.4 Hz, 1H), 5.53 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 179.1, 172.2, 138.1, 136.0, 135.7, 132.7 (q, J01: 33.6 Hz), 126.9, 124.5, 123.7, 123.6, 122.6, 122.9 (q, Jc.f= 273.4 Hz), 121.8, 118.3, 110.1, 109.6, 73.1, 62.3, 50.4, 14.3.

Experimental detail for the synthesis of JXL084 COzEt C02Et HO AcO / / ON ON \ \ N N AcCl, pyridine F3C F3C CF3 CF3 JXL083 JXL084 To a solution of JXL083 (0.5 mmol, 240 mg) in dichloromethane (10 mL) was added pyridine (0.5 mmol, 40 11L) and acetyl chloride (1.0 mmol, 84 11L). The reaction mixture was stirred for 1h and TLC ted that the reaction was complete. The reaction solvent was ated by ?owing air over the open ?ask. The residue was puri?ed by ?ash column chromatography (hexanes:ethy1 acetate = 10:1) to afford the desired product Ethyl (Z) acetoxy(1-(3,5-bis(tri?uoro-methyl)benzyl)-1H-ind01yl)cyan0acrylate (JXL084) (yield: 86%, 225 mg). 1H NMR (500 MHz, CDC13) 5 8.56 (s, 1H), 7.90 (m, 1H), 7.85 (s, 1H), 7.61 (s, 2H), 7.32 (m, 2H), 7.24 (m, 1H), 5.51 (s, 2H), 4.29 (q, J: 7.1 Hz, 2H), 2.48 (s, 3H), 1.36 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDC13) 5 166.9, 161.4, 137.7, 136.2, 135.5, 132.8 (q, J01: 33.9 Hz), 127.0, 126.7, 124.6, 123.6, 122.8 (q, Jc.f= 273.4 Hz), 122.7, 121.8, 117.7, 110.7, 109.8, 89.3, 61.8, 50.5, 29.7, 21.3, 14.2.

Experimental detail for the synthesis of JXL085 C02Et COzEt H0 c1 / / CN CN \ \ N N POCI3, Et3N DCM, reflux F3C F3C CF3 CF3 JXL083 JXL085 To a solution of JXL083 (0.5 mmol, 240 mg) in dichloromethane (10 mL) was added triethylamine (1.0 mmol, 139.5 11L) and oryl chloride (0.55 mmol, 520 11L). The reaction mixture was stirred for 1h at re?ux and TLC indicated that the reaction was te.

The reaction solvent was evaporated by ?owing air over the open ?ask. The residue was puri?ed by ?ash column chromatography (hexanes:ethyl acetate = 10:1) to afford the desired product Ethyl (Z)(1-(3,5-bis(trifluoromethyl)benzyl)—1H—ind01yl)—3-chl0r0 cyanoacrylate (JXL085) (yield: 84%, 210 mg). 1H NMR (500 MHz, CDCl3) 6 7.91 (s, 1H), 7.85 (s, 1H), 7.77 (m, 1H), 7.65 (s, 2H), 7.63 (s, 1H), 7.30 (m, 2H), 5.48 (s, 2H), 4.18 (q, J: 7.1 Hz, 2H), 1.18 (t, J: 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) 5 161.0, 155.6, 138.1, 136.2, 135.4, 133.4, 132.7 (q, Jc-f = 33.7 Hz), 127.1, 126.6, 124.5, 124.3, 122.8 (q, Jc-f= 273.4 Hz), 121.5, 115.8, 122.1, 110.4, 102.5, 62.4, 50.0, 13.9.

Experimental detail for the synthesis of JXL086 05‘P,0Et ’0 \OEt \ OEt CN Nc/\P’zOEt \ N II o N Fsc L-proline, EtOH 50°C,24hours F3C JXL086 Diethyl (E)-(2-(1-(3,5-bis(trifluoromethyl)benzyl)—1H—ind01yl)—1- cyanovinyl)ph0sphonate (JXL086) To the solution of 1-(3,5-bis(tri?uoromethyl)benzyl)-1H—indolecarboxaldehyde (1 mmol, 371 mg) in ethanol (3 mL) were added diethyl cyanomethylphosphate (1.3 equiv, 1.3 mmol, 204 11L) and L-proline (40 mol%, 0.4 mmol, 58 mg). The reaction was stirred at 50 °C for 24 h. After tion of the reaction as indicated by TLC, the on solvent was ated by ?owing air over the open ?ask. The solid was d by ?ash column chromatography (hexanes:ethyl acetate = 2: 1) to afford the desired product JXL086 (yield: 90%, 477 mg). 1H NMR (500 MHz, CDC13) 5 8.55 (s, 1H), 8.33 (d, J: 19.7 Hz, 1H), 7.86 (d, J: 7.9 Hz, 1H), 7.83 (s, 1H), 7.58 (s, 2H), 7.31 (m, 2H), 7.22 (m, 1H), 5.54 (s, 2H), 4.21 (m, 4H), 1.39 (t, J: 7.0 Hz, 6H). 13C NMR (126 MHz, CDC13) 5 149.8, 138.3, 135.8, 132.7 (q, J03: 33.7 Hz), 132.6, 128.2, 126.8, 124.5, 123.0, 122.9 (q, Jc.f= 273.4 Hz), 122.5, 119.0, 117.8 (d, 116.1,: 11.3 Hz), 112.2 (d, 116.1,: 18.9 Hz), 110.3, 91.6 (d, 116.1,: 207.9 Hz), 63.2, 50.4, 16.3.

JXL095 was synthesized by the similar route as JXL086.

JXL095 Diethyl (E)-(2-(1-(3,5-bis(tri?uoromethyl)benzyl)—lH-pyrrolo[2,3-b]pyridinyl)—1- cyanovinyl)ph0sphonate (JXL095) 1H NMR (500 MHz, CDC13) 5 8.58 (s, 1H), 8.46 (dd, J: 4.7, 1.4 Hz, 1H), 8.24 (d, J = 19.5 Hz 1H), 8.20 (dd, J: 8.0, 1.4 Hz, 1H), 7.82 (s, 1H), 7.77 (s, 2H), 7.32 (dd, J: 8.0, 4.7 Hz, 1H), 5.67 (s, 2H), 4.22 (m, 4H), 1.40 (t, J: 7.1 Hz, 6H). 13C NMR (126 MHz, CDC13) 5 149.2 (d, JC-p: 8.2 Hz), 147.4, 145.6, 138.6, 132.4 (q, Jc-f= 33.7 Hz), 132.0, 127.9, 127.8, 123.0 (q, Jc-f= 273.4 Hz), 122.4, 119.9, 118.9, 117.4 (d, JC-p: 11.3 Hz), 110.5 (d, JC-p: 19.5 Hz), 92.8 (d, JC-p: 205.1 Hz), 63.4, 48.3, 16.3.

Experimental detail for the synthesis of JXL096 0° ,OEt 09 ,OH P‘oa P\0H ’ ’ CN cu \ \ N 1)TMSBr,DCM N 2) MeOH F3C F3C ca cu=3 JXL086 JXL096 (E)-(2-(1-(3,5-Bis(trifluoromethyl)benzyl)—1H-indolyl)—1-cyanovinyl)ph0sph0nic acid (JXL096) A solution ofJXL086 (30 mg, 0.057 mmol) in dichloromethane (2 mL) was cooled to 0 0C and rimethylsilane (40 uL, 0.3 mmol) was added dropwise under argon. The mixture was warmed to 21 0C and stirred for 12 h. The solvent was evaporated under vacuum and the ing residue was then dissolved in methanol (2 mL). The mixture was stirred at 21 0C for 2 h. Evaporation of all volatiles under vacuum gave the oric acid JXL096 (yield: 92%, mg). 1H NMR (500 MHz, CD3OD) 5 8.58 (s, 1H), 8.25 (d, J = 19.6 Hz, 1H), 7.90 (s, 1H), 7.87 (m, 1H), 7.76 (s, 2H), 7.45 (m, 1H), 7.31 (m, 2H), 5.75 (s, 2H). 13C NMR (126 MHZ,CD3OD)6146.7(JC-p= 7.2 Hz), 140.2, 136.1, 132.1, 131.9 (q, Jc-f: 33.7 Hz), 128.0, 127.2, 123.8, 122.3, 123.2 (q, Jc-f: 273.4 Hz), 121.4, 118.2, 117.4 (d, JC-p: 11.3 Hz), 111.5 (JG—p: 18.4 Hz), 110.5, 94.6 (d, JC-p: 201.2 Hz), 49.1.

Experimental detail for the synthesis of JXL092 COztBu COZH co Me2 ’0 COzMe I COzMe / CM CM NCAcoztBu \ \ TFA, DCM —> _> N N L-proline, EtOH 90% F3C F3C CF3 CF3 JXL092 To a solution of methyl 1-(3,5-bis(tri?uoromethy1)benzy1)formy1-1H—indolecarboxy1ate (1 mmol, 429 mg) in ethanol (3 mL) were added lerl—butyl 2-cyanoacetate (1.3 equiv, 1.3 mmol, 183 11L) and ine (40 mol%, 0.4 mmol, 58 mg). The reaction was stirred at 21 °C for 12 h and a yellow solid precipitated gradually. After tion of the reaction, ice-cold water (2 mL) was added into the reaction. The solid was separated by Buchner funnel ?ltration and washed with water (2 mL X 3) and dried to afford the desired t. yield: 95%, 524 mg.

(E)(1-(3,5-Bis(tri?uoromethyl)benzyl)—4-(methoxycarbonyl)—1H-indolyl) cyanoacrylic acid (JXL092) To the on of methyl (E)1-(3,5-bis(tri?uoromethy1)benzy1)-3 -(3 -(tert-butoxy)—2-cyano-3 - oxoprop-l-eny1)—1H—indolecarboxy1ate (0.5 mmol, 276 mg) in dichloromethane (2 mL) was added roacetic acid (3 equiv, 1.5 mmol, 0.2 mL). The reaction mixture was stirred at 21 0C for 30 min and a yellow solid precipitated. After the reaction was complete as shown by TLC, the reaction solvent was evaporated by ?owing air over the open ?ask. The solid was washed by 2 mL of solvent mixture (hexanes/EtOAc = 5:1) 5 to 10 times and monitored by TLC until all the non-polar impurities disappeared. Finally, the purity of the product was checked by NMR. yield: 90%, 223 mg. 1H NMR (500 MHz, CDC13) 5 9.09 (s, 1H), 8.58 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.68 (s, 1H), 7.47 (s, 2H), 7.34 (d, J = 8.2 Hz, 1H), 7.20 (app. t, J = 7.9 Hz, 1H), 5.51 (s, 2H), 3.87 (s, 3H). 13C NMR(126 MHz, CDC13) 5 167.8, 165.1, 149.5, 138.2, 137.2, 134.8, 132.3 (q, Jc-f = 33.7 Hz), 126.8, 126.2, 125.5, 124.8, 123.3, 122.8 (q, J81: 273.4 Hz), 122.3 118.2, 114.7, 110.9, 97.2, 52.4, 50.2.

Experimental detail for the synthesis of JXL094 COZH NH2 CN / N 1) soc12, reflux 2) 30% NH3 in H20 benzene 85% Fac JXL001 JXL094 (E)(1-(3,5-Bis(tri?uoromethyl)benzyl)—1H-indolyl)cyan0acrylamide (JXL094) The mixture of (E)(1-(3 1H-indol-3 -yl)cyanoacrylic , 5-bis(tri?uoromethyl)benzyl)- acid JXL001 (0.1 mmol, 43.8 mg) and thionyl chloride (0.5 ml) was d for 1 h. After concentration under vacuum, the resulting acyl chloride was dissolved in 1 ml benzene and % a in water (1 ml) was added. The reaction mixture was stirred at 21 0C for 24 h.

After completion of the reaction as indicated by TLC, the reaction solvent was evaporated under vacuum. The solid was puri?ed by ?ash column chromatography (hexanes:ethyl acetate = 2: 1) to afford the desired product JXL094 (yield: 85%, 37 mg). 1H NMR (500 MHz, CDC13) 5 8.70 (s, 1H), 8.47 (s, 1H), 7.92 (d, J = 7.1 Hz, 1H), 7.85 (s, 1H), 7.58 (s, 2H), 7.34 (m, 2H), 7.23 (m, 1H), 5.55 (s, 2H). 13C NMR (126 MHz, CDC13) 5 163.0, 144.8, 138.1, 136.0, 132.7 (q, Jc-f= 33.7 Hz), 132.5, 128.6, 126.8, 126.1, 124.6, 123.1, 122.9 (q, J04: 273.4 Hz), 122.6, 119.3, 111.3, 110.3, 96.1, 50.4.

Additional exemplary compounds of the present invention can be prepared by methods analogous to those described above.

Example .2: Treatment of Epithelial Cells with Exemplary Compounds To ine whether these compounds could promote cellular lactate tion, we treated cultured epithelial cells with the compounds and measured e levels in the culture media using a Nova Biomedical BioProflle Basic Analyzer. Brie?y, cultured epithelial cells were treated with DMSO, 9 (also called JXLOOl), or certain of the exemplary compounds disclosed herein for 24-30 hours, and media lactate levels were ed and normalized to cell number and duration of the experiment to acquire a ar lactate production rate (nmol lactate, million cells, hour).

Lactate production rates of treated cells are shown in FIGS. 8, 9, and 12. As expected based on the present disclosure, since they are UK-5099 analogues, most of the novel compounds assayed increased lactate production. rmore, the total cell count following treatment with the UK-5099 analogues is shown in Figure 13. Most of the compounds were tolerated by the cells. A separate assay was med to calculate the EC50 of some of the compounds as shown in .

Example 3: In vivo test of Exemplary Compounds To determine the efficacy of the compounds on the hair cycle, mice were shaved at postnatal day 50, and topically treated every other day with a compound disclosed herein suspended in lotion in every other day for 2 weeks, and es were taken. As seen in , all the analogues that showed the ability to promote lactate production in the in vitro assay were also able to stimulate hair growth over the course of 2 weeks.

INCORPORATION BY REFERENCE All publications and patents mentioned herein are hereby incorporated by nce in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

EQUIVALENTS While specific embodiments of the subject invention have been sed, the above specification is illustrative and not restrictive. Many variations of the ion will become apparent to those skilled in the art upon review of this ication and the claims below.

The full scope of the invention should be determined by nce to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

Claims (9)

1. A nd, n the compound is or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is .

3. The compound of claim 1, wherein the compound is a pharmaceutically acceptable salt of

4. A pharmaceutical composition comprising a compound of any one of the preceding claims and a pharmaceutically acceptable excipient.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is formulated for topical stration.

6. Use of a compound of any one of claims 1-3, or the composition of claim 4 or 5, in the manufacture of a medicament for promoting hair growth.

7. Use of a compound of any one of claims 1-3, or the ition of claim 4 or 5, in the manufacture of a medicament for treating a condition or disorder affecting hair growth.

8. The use of claim 7, wherein the ion or disorder is baldness or alopecia.

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