Small molecule modulators of SIRT5 and uses thereof

Abstract

This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of carbothioamide (and structurally related) small-molecule compounds which function as inhibitors of SIRT5, and their use as therapeutics for the treatment of diseases associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

Description

[0001] Attorney Docket No. UM-42977.601

[0002] SMALL MOLECULE MODULATORS OF SIRT5 AND USES THEREOF

[0003] CROSS-REFERENCE TO RELATED APPLICATION

[0004] The present application claims priority to U.S. Provisional Application No. 63 / 566,040, filed March 15, 2024, which is incorporated herein by reference in its entirety.

[0005] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR

[0006] DEVELOPMENT

[0007] This invention was made with government support under CA253986 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0008] FIELD OF THE INVENTION

[0009] This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of carbothioamide (and structurally related) small-molecule compounds which function as inhibitors of SIRT5, and their use as therapeutics for the treatment of diseases associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

[0010] INTRODUCTION

[0011] Posttranslational modifications (PTMs) are covalent processing events that change the properties of a protein by proteolytic cleavage and adding a modifying group. These modifications include phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation, acetylation, succinylation, glutarylation, malonylation, crotonylation, lactylation, lipidation, proteolysis, and so on. These modifications affect a wide range of protein behaviors and characteristics, including enzyme function and assembly, protein lifespan, protein-protein interactions, cell-cell and cell-matrix interactions, molecular trafficking, receptor activation, protein solubility, protein folding and protein localization. Therefore, PTMs play a key role in numerous biological processes such as signal transduction, gene expression regulation, gene activation, DNA repair and cell cycle control (Shahin Ramazi, Javad Zahiri, Database (Oxford) 2021 Apr 7;2021: baab012. doi: 10.1093 / database / baab012).

[0012] Sirtuins, are nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases, were originally discovered as the silent information regulator 2 (Sir2) protein in yeast. Sirtuins are evolutionally conserved enzymes, in mammals, 7 isoforms have been identified, called SIRT1 to SIRT7. Sirtuin 5 (SIRT5) is a predominant mitochondrial sirtuin, which was originally demonstrated to be a deacetylase, but shows a limited and selective deacetylase activity. Instead, SIRT5 displays a unique affinity for negatively charged desuccinylation, demalonylation, and deglutarylation lysine modifications. It is believed that S1RT5 targets a plethora of proteins, with many involved in cellular metabolism. Although conventional SIRT5 knockout mice demonstrate no obvious phenotypes in animal vitality and viability, accumulating evidence suggest that dysregulation or uncontrolled activation of SIRT5 has been implicated in numerous age-related diseases in humans, such as neurodegeneration, cardiovascular diseases, and metabolic diseases. The clinical significance of SIRT5 has also become increasingly recognized as dysregulation of SIRT5 has been implicated in diverse types of cancers, such as melanoma, non-small cell lung cancer (NSCLC), breast tumors, hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), renal cell carcinoma, and acute myeloid leukemia (AML).

[0013] SIRT5 is the only sirtuin member that has been demonstrated to have efficient demalonylase and desuccinylase activity until now, which makes it a valuable target to develop selective SIRT5 inhibitors. To date, several SIRT5 inhibitors have been reported; most of them are peptide derivative inhibitors, for example, thiosuccinyl peptides H3K9TSu and CPS1- derived peptides. However, peptides are generally of limited pharmacological properties due to their high molecular weight, poor membrane permeability, and biological instability, which makes it difficult to apply in vivo or in clinical use. Thus, several small molecules SIRT5 inhibitors have emerged, such as suramin, nicolinamide, sirtinol, cambinol, GW5074, thiobarbiturates, and 9-substituted norharmane derivatives. Given the fact that no selective

[0014] SIRT5 inhibitor has been approved for clinical application, there is a need for new sirtuin modulators that can be used in the prevention or treatment of cancer or other age-related diseases.

[0015] The present invention addresses this need.

[0016] SUMMARY OF THE INVENTION Experiments conducted during the course of developing embodiments described herein generated a new class of carbothioamide (and structurally related) small-molecule compounds shown to function as inhibitors of SIRT5 (see, Examples I-III), and further shown to inhibit cancer cell growth (see, Example IV).

[0017] Accordingly, the invention relates to a new class of carbothioamide (and structurally related) small-molecule compounds which function as inhibitors of SIRT5, and their use as therapeutics for the treatment of diseases associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

[0018] Certain carbothioamide (and structurally related) small-molecule compounds as described herein may exist as stereoisomers including optical isomers. The invention includes all stereoisomers, both as pure individual stereoisomer preparations and enriched preparations of each, and both the racemic mixtures of such stereoisomers as well as the individual diastereomers and enantiomers that may be separated according to methods that are well known to those of skill in the art. Indeed, the term “compound” or “small-molecule compound”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers) thereof, as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof where applicable, in context. Within its use in context, the term compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds. The term also refers, in context to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. It is noted that in describing the present compounds, numerous substituents and variables associated with same, among others, are described. In a particular embodiment, compounds encompassed within the following formulas are

[0019] Formula 1-1-1 Formula 1-1 -1-1

[0020] Formula I-2 Formula 1-2-1

[0021] Formula 1-3-1 Formula 1-3-1 -1

[0022] 2 Z34

[0023] A%

[0024] Formula I-3-2 , and Formula I-3-2-1 ; including pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, triphenylphosphonium (TPP) tagged derivatives, proteolysis targeting chimera (PROTAC) derivatives, mitochondria tagged derivatives, biotin tagged derivatives, boromdipyrromethene

[0025] (BODIPY) tagged derivatives, stereoisomers, and / or deuterated analogues thereof.

[0026] 10 Formula I is not limited to a particular chemical moiety for Ri, R2, R3, R4, Rs, Re, Rg,

[0027] R12, A], A2, A3, A4, A$, Bi, B2, B3, T, U, V, X, Y, Z, o, and n. In some aspects, the particular chemical moiety for Ri, R2, R3, R4, Rs, Re, Rg, R12, Ai, A2, A3, A4, As, Bi, B2, B3, T, U, V, X, Y, Z, o, and n independently include any chemical moiety that permits the resulting compound to inhibit SIRT5 activity. In some aspects, the particular chemical moiety for Ri, R2, R3, R4, Rs, Re, Rg, R12, AI, A2, A3, A4, As, 61, 62, B3, T, U, V, X, Y, Z, o, and n independently include any chemical moiety that permits the resulting compound effective as a therapeutic for the treatment of diseases associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

[0028] In some aspects,

[0029] X, Y and T are independently selected from the group consisting of: H, O, S, halogen, NH, N-OH, N-CN, and C1-C3 alkyl; or

[0030] X and T, independently, together with the atoms to which they are attached, is a monocyclic heterocycle optionally substituted with H, alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, and having zero to two ring heteroatoms selected from the group consisting of N, O, and S ; or

[0031] X and T, independently, together with the atoms to which they are attached, is monocyclic aromatic ring optionally substituted with alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, thereby forming a bicyclic ring system; wherein the dotted line represents an optional bond in case X, Y or T selected from the group consisting of: O, S, N-OH and N-CN.

[0032] In some aspects, U and V are independently selected from the group consisting of: N, CH and C-OH.

[0033] In some aspects, Z is selected from the group consisting of: NH, CH2, O and C=O.

[0034] In some aspects, n is selected from the group consisting of: 0, 1, 2, and 3.

[0035] In some aspects, o is selected from the group consisting of: 0, 1, 2, and 3.

[0036] In some aspects,

[0037] Ri R2, R3, R4, and R5 are independently selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, halogen, tetrazole, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted Cl C6 amino alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1 -C6 alkoxy C3-C6 cycloalkyl, substituted C5-C7 aryl or Het, OR?, COR?, O(CH2)inC(=O)R?, COOR7, SO3R7, ASO3R7, BOR7OR8, (CH2)mR?, NR?Rg, SO2R?Rg, CONR?Rg, NHCOR7, NHCOCHR?R8, SO2NR?R8, and NHSO2R?; or

[0038] Ri with R2, R2with R3, R3 with R4, Ra with Rs, independently, together with the atoms to which they are attached, is a monocyclic heterocycle optionally substituted with H, alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, and having zero to two ring heteroatoms selected from the group consisting of N, O, and S; or

[0039] Ri with R2, R2with R3, R3 with R4, R4 with Rs together with the atoms to which they are attached, is monocyclic aromatic ring optionally substituted with alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, thereby forming a bicyclic ring system.

[0040] In some aspects, Ri and R2are independently selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCP3, OMe, SMe, OEt, SEt, F, Cl, Br, I, Me, Et, t-Bu, i-Pr, SO?Me, NHSO2Me, S(O)Me, S(O)Et, SO2Me, SO2Et, O(i-Pr), O(t-Bu), F, Cl, Br, I, Me, Et, n-Pr, n-Bu, t-Bu, i-Pr, Ph, SO2Me, NHSO2Me, COMe, COEt, COCF3, OC(=O)Me, OC(=O)Et, COOMe, COOEt, CH2OH, NH2, NHMe, NHEt, NMe2, NEt2, NHCH2PH, SO2Me, SO2Et,

[0041] CONH?, CONHMe, CONHEt, CONMe?, CONEt2, NHCOMe, NHCOEt, NHCOCH3,

[0042] NHCOCH2Me, NHCOCH2Et, NHCOCHMe2, NHCOCHEt2, SO2NH2, SO2NHMe, SO2NHEt,

[0043] SO2NMe2, SO2NEt2, NHSO2Me, and NHSO2Et.

[0044] In some aspects, R? and Rg are independently selected form the group consisting of: H, deuterium (D), OH, OD, OMe, NO2, CN, CF3, OCF3, halogen, C1-C6 alkyl, C1-C6 alkoxy, COR9, (CH2)mOH, (CH2)mCOOR9, substituted phenyl, substituted C5-C7 aryl and Het; wherein m is selected from the group consisting of: 0, 1, 2, and 3.

[0045] In some aspects, Rg is selected from the group consisting of: H, D, and Cl-6 alkyl.

[0046] In some aspects,

[0047] Re is selected from the group consisting of: unsubstituted or substituted Cl -C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 aminoalkyl, unsubstituted or substituted Cl-C6haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C8 cycloalkyl, OR10, COR10, OC(=0)Rio, COOR10, (CH)pRioRn, NR10R11, SO2Rw, CONR10R11, NHCOR10, NHCOCR10R11, S02NRioRn, NHSO2RW. unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl, Het, heteroaryloxy, arylalkyl, and heteroaryl alkyl; or Re and X, together with the atoms to which they are attached, may optionally form a substituted or unsubstituted monocyclic heterocycle having zero to two ring heteroatoms selected from the group consisting of N, O, and S; or a substituted or unsubstituted monocyclic aromatic ring, thereby forming a bicyclic ring system; wherein p is selected from 0, 1, 2, or 3.

[0048] In some aspects, R6 is selected from the group consisting of:

[0049] In some aspects, Rio and Rn are independently selected from the group consisting of: unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 aminoalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted Cl -6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl, and Het.

[0050] In some aspects, Al, A2, A3, A4, A5, A6, and A7 are independently selected from the group consisting of: O, S, CH, CH2, N, NH, CRB, and NR13.

[0051] In some aspects, B l, B2, and B3 are independently selected from the group consisting of:

[0052] O, S, CH, CH2, N, NH, CRB, and NR13.

[0053] In some aspects, RB is independently selected from the group consisting of: H, deuterium

[0054] (D), OH, OD, NO2, CN, CF3, OCF3, CONH2, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 amino alkyl, unsubstituted or substituted Cl -C6 haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl or Het, heteroaryloxy, arylalkyl, or

[0055] 25 heteroarylalkyl; OR14, COR14, OC(=O)Ru, COOR14, (CH2)PRi4Ris, NR14R15, SO2R14, CONR14R15, NHCOR14, NHCOCHR14R15, SO2NR14R15, and NHSO2R14; wherein p is selected from 0, 1, 2, or 3.

[0056] In some aspects, RJ2and R13 are independently selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, OMe, SMe, OEt, SEt, S(O)Me, S(O)Et, SO2Me,

[0057] SO2Et, O(i-Pr), O(t-Bu), F, Cl, Br, I, Me, Et, n-Pr, n-Bu, t-Bu, i-Pr, Ph, SO2Me, NHSO2Me,

[0058] COMe, COEt, COCF3, OC(=O)Me, OC(=O)Et, COOMe, COOEt, CH2OH, NH2, NHMe, NHEt,

[0059] NMe2, NEt2, NHCH2PH, SO2Me, SO2Et, CONH2, CONHMe, CONHEt, CONMe2, CONEt2,

[0060] NHCOMe, NHCOEt, NHCOCH3, NHCOCH2Me, NHCOCH2Et, NHCOCHMe2, NHCOCHEt2,

[0061] SO2NH2, SO2NHMe, SO2NHEt, SO2NMe2, SO2NEt2, NHSO2Me, NHSO2Et; VN

[0062] NO2

[0063] X N

[0064] S NH

[0065] Cl , and

[0066] In some aspects, R14 and R15 are independently selected from the group consisting of: H, D, and C1-C6 alkyl.

[0067] In some aspects, R,2is selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, CONH2, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 amino alkyl, unsubstituted or substituted Cl-C6haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl or Het, heteroaryloxy, arylalkyl, or heteroarylalkyl; OR14, CORM, OC(=O)Ri4, COOR14, (CH2)PRi4Ri5, NR14R15, SO2R14, CONR14R15, NHCOR14, NHCOCHR14R15, SO2NR14R15, and NHSO2R]4; wherein p is selected from 0, 1, 2, or 3. In some aspects, Pi, P2, P3, and P4 are independently selected from the group consisting of: O, S, C, N, CRie, and NRie-

[0068] In some aspects, R|(lis selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, CONH2, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 amino alkyl, unsubstituted or substituted Cl-C6haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl or Het, heteroaryloxy, arylalkyl, or heteroarylalkyl; OR17, CORie, OC(=O)Rn, COOR17, (CH2)PRi7Ri8, NR17R18, SO2R17, CONR17R18, NHCOR17, NHCOCHR17R18, SO2NR17R18, and NHSO2R17; wherein p is selected from 0, 1, 2, or 3; wherein p is selected from 0, 1, 2, or 3.

[0069] In some aspects, R17 and Ris are independently selected from the group consisting of: H, D, and C1-C6 alkyl.

[0070] In some aspects, the compound encompassed within Formulas 1, 1-1, 1-1-1, I-l-l-l, 1-1-2, I-1-2-1, 1-1-3, 1-1-3-1, 1-2, 1-2-1, 1-2-1-1, 1-2-2, 1-2-2-1, 1-2-3, 1-2-3-1, 1-3, 1-3-1, 1-3-1-1, 1-3-2, and 1-3-2- 1 is shown in Table 1. In some aspects, the new class of carbothioamide (and structurally related) small-molecule compounds described herein is shown in Table 1. Table 1 further shows the molecular weight and cLogP values for each small-molecule compound.

[0071] Table 1. Structures of representative compounds contemplated for Formulas 1, 1-1, 1-1-1, I-l-l-l, 1-1-2, 1-1-2-1, 1-1-3, I-1-3-1, 1-2, 1-2-1, 1-2-1-1, 1-2-2, 1-2-2-1, 1-2-3, 1-2-3-1, 1-3, 1-3- 1, 1-3-1-1, 1-3-2, and 1-3-2- 1

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079] co

[0080] <o

[0081]

[0082]

[0083]

[0084]

[0085]

[0086] 1

[0087] >

[0088] N)

[0089] N> CO

[0090]

[0091]

[0092]

[0093]

[0094] w w

[0095]

[0096] w O1

[0097] w a>

[0098]

[0099] w co

[0100]

[0101] o

[0102]

[0103] 6

[0104]

[0105]

[0106] n

[0107]

[0108]

[0109] o

[0110]

[0111]

[0112]

[0113] 1

[0114] I H

[0115] O s / F2-fluoro-4-(7-nitro- 1,2,3, 4-tetrahydroisoquinolin

[0116] TL11632N' ■NY sNe-2- r .OH 375.07 3.22 carbothioamido)benzoic acid

[0117] 0

[0118] Cl-

[0119] O 'N' 4-(4-(4-chlorophenyl)piperazine- 1 -carbothioamido)-2-

[0120] TL1164 393.07

[0121] Y 4.10

[0122] S Y T fluorobenzoic acid

[0123] O

[0124] ■ N ^^x ^ 4-(4-(2,4-dimethylphenyl)piperazine-l-carbothioamido)-

[0125] TL1166 F

[0126] ■NY 387.14 4.22 s 2-fluorobenzoic acid

[0127] O

[0128] BrX /

[0129] I

[0130] ‘N '

[0131] ,N 4-(4-(4-bromophenyl)piperazine- 1 -carbothioamido)-2-

[0132] TL1167 . 437.02 4.25

[0133] T I uI^OH fluorobenzoic acid

[0134] O

[0135] Brx . N=N

[0136] I L, NH l-((4-(2 169 N H-tetrazol-5-yl)phenyl)sulfonyl)-4-(4-bromo-2-

[0137] TL1 'N i - 462.05 4.31 methylphenyl)piperazine

[0138] 0

[0139] Brv o o methyl 4-(4-(5 70X-bromo-3-methylpyridin-2-yl)piperazine-

[0140] TL11 N / N jA /

[0141] • N - 451.03 3.67 731 l-carbonyl)-2-chlorobenzoate

[0142] 0

[0143] X NI o

[0144] 4-(4-(5-bromo-3-methylpyridin-2-yl)piperazine-l-

[0145] TL1171 N‘ ‘OH

[0146] N F 437.01 3.43

[0147] Cl carbonyl)-2-chlorobenzoic acid

[0148] O

[0149] A

[0150] BiV / L , riN

[0151] 4-(4-(5 -bromo-4-methoxypyrimidin-2-yl)piperazine- 1

[0152] TL1178 421 484.99 3.43

[0153] 'V carbothioamido)-2-chlorobenzoic acid s JL / °Ho

[0154]

[0155]

[0156] cn o

[0157] O1

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171] The invention further provides processes for preparing any of the compounds of the present invention.

[0172] The invention also provides the use of compounds to not only inhibit SIRT5 activity but also signaling pathways dependent upon SIRT5 activity. The invention also relates to the use of compounds for sensitizing cells to additional agent(s), such as agents known to be effective in the treatment of conditions associated with aberrant SIRT5 activity. The invention also relates to the use of compounds for sensitizing cells to additional agent(s), such as agents known to be effective in the treatment of conditions associated with aberrant posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing’s sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

[0173] In certain aspects, methods for treating, ameliorating, or preventing of conditions associated with aberrant posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0174] In certain aspects, methods for treating, ameliorating, or preventing of conditions (e.g., disorders, diseases) associated with SIRT5 activity (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of condition associated with SIRT5 activity) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0175] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of cancer (e.g., melanoma, NSCLC, HCC, ovarian cancer, CRC, AML, Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of cancer) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0176] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of diabetes are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of diabetes) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0177] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of an autoimmune disorder (e.g., autoimmune condition, autoimmune disease) (e.g., multiple sclerosis (MS), celiac disease, rheumatoid arthritis, diabetes (e.g., type 1 diabetes mellitus), autoimmune diseases of the thyroid (e.g., Hashimoto's thyroiditis, Graves' disease), thyroid- associated ophthalmopathy and dermopathy, hypoparathyroidism, Addison's disease, premature ovarian failure, autoimmune hypophysitis, pituitary autoimmune disease, immunogastritis, pernicious anemia, celiac disease, vitiligo, myasthenia gravis, pemphigus vulgaris and variants, bullous pemphigoid, dermatitis herpetiformis Duhring, epidermolysis bullosa acquisita, systemic sclerosis, mixed connective tissue disease, Sjogren's syndrome, systemic lupus erythematosus, Goodpasture’s syndrome, rheumatic heart disease, autoimmune polyglandular syndrome type 1 , Aicardi-Goutieres syndrome, Acute pancreatitis Age-dependent macular degeneration, Alcoholic liver disease, Liver fibrosis, Metastasis, Myocardial infarction, Nonalcoholic steatohepatitis (NASH), Parkinson’s disease, Polyarthritis / fetal and neonatal anemia, Sepsis, and inflammatory bowel disease) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from an autoimmune disorder) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein. In certain aspects, methods for treating, ameliorating, or preventing of any type or form of an inflammatory disorder (e.g., inflammatory condition, inflammatory disease) (e.g., arthritis, rheumatoid arthritis, asthma, inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic obstructive pulmonary disease (COPD), allergic rhinitis, vasculitis (polyarteritis nodosa, temporal arteritis, Wegener's granulomatosis, Takayasu’s arteritis, or Behcet’s syndrome), inflammatory neuropathy, psoriasis, systemic lupus erythematosus (SEE), chronic thyroiditis, Hashimoto's thyroiditis, Addison's disease, polymyalgia rheumatica, Sjogren’s syndrome, or Churg-Strauss syndrome) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from an inflammatory disorder) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0178] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of a fibrosis or fibrotic disorder (e.g., fibrosis or fibrotic condition, fibrosis or fibrotic disease) (e.g., collagen disease, interstitial lung disease, human fibrotic lung disease (e.g., obliterative bronchiolitis, idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, tumor stroma in lung disease, systemic sclerosis affecting the lungs, Hermansky-Pudlak syndrome, coal worker’s pneumoconiosis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS- associated pulmonary hypertension, sarcoidosis, and the like), fibrotic vascular disease, arterial sclerosis, atherosclerosis, varicose veins, coronary infarcts, cerebral infarcts, myocardial fibrosis, musculoskeletal fibrosis, post-surgical adhesions, human kidney disease (e.g., nephritic syndrome, Alport's syndrome, HIV-associated nephropathy, polycystic kidney disease, Fabry's disease, diabetic nephropathy, chronic glomerulonephritis, nephritis associated with systemic lupus, and the like), cutis keloid formation, progressive systemic sclerosis (PSS), primary sclerosing cholangitis (PSC), liver fibrosis, liver cirrhosis, renal fibrosis, pulmonary fibrosis, cystic fibrosis, chronic graft versus host disease, scleroderma (local and systemic), Grave's opthalmopathy, diabetic retinopathy, glaucoma, Peyronie’s disease, penis fibrosis, urethrostenosis after the test using a cystoscope, inner accretion after surgery, scarring, myelofibrosis, idiopathic retroperitoneal fibrosis, peritoneal fibrosis from a known etiology, drug-induced ergotism, fibrosis incident to benign or malignant cancer, fibrosis incident to microbial infection (e.g., viral, bacterial, parasitic, fungal, etc.), Alzheimer’s disease, fibrosis incident to inflammatory bowel disease (including stricture formation in Crohn's disease and microscopic colitis), fibrosis induced by chemical or environmental insult (e.g., cancer chemotherapy, pesticides, radiation (e.g., cancer radiotherapy), and the like)) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from a fibrosis or fibrotic disorder) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0179] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of cardiovascular disorder (e.g., cardiovascular condition, cardiovascular disease) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of cardiovascular disorder) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0180] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of neurodegenerative disorder (e.g., neurodegenerative condition, neurodegenerative disease) (e.g., Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD)) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of neurodegenerative disorder) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0181] The invention also provides pharmaceutical compositions comprising the carbothioamide (and structurally related) small-molecule compounds of the invention in a pharmaceutically acceptable carrier.

[0182] The invention also provides kits comprising one or more carbothioamide (and structurally related) small-molecule compounds of the invention and instructions for administering the compound to an animal. The kits may optionally contain other therapeutic agents, e.g., agents useful in treating disorders associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer, diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

[0183] The present disclosure further provides bifunctional compounds that function to recruit endogenous proteins to an E3 Ubiquitin Ligase for degradation, and methods of using the same. In particular, the present disclosure provides bifunctional or proteolysis targeting chimeric (PROTAC) compounds, which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and / or otherwise inhibited. An exemplary advantage of the compounds provided herein is that a hroad range of pharmacological activities is possible, consistent with the degradation / inhibition of targeted polypeptides from virtually any protein class or family. In addition, the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as any type of condition associated with aberrant SIRT5 activity.

[0184] In an additional aspect, the disclosure provides bifunctional or PROTAC compounds, which comprise an E3 Ubiquitin Ligase binding moiety (e.g., a ligand for an E3 Ubquitin Ligase or "ULM" group), and a moiety that binds a target protein (e.g., a protein / polypeptide targeting ligand or "PTM" group) such that the target protein / polypeptide is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein (e.g., inhibit SIRT5 activity). In certain embodiments, the PTM is any of the compounds as described herein showing inhibitory activity against SIRT5 activity. In some embodiments, the ULM is a VHL, cereblon, mouse double minute 2 (MDM2), and / or inhibitor of apoptosis protein (IAP) E3 ligase binding moiety. For example, the structure of the bifunctional compound can be depicted as PTM-ULM.

[0185] The respective positions of the PTM and ULM moieties, as well as their number as illustrated herein, is provided by way of example only and is not intended to limit the compounds in any way. As would be understood by the skilled artisan, the bifunctional compounds as described herein can be synthesized such that the number and position of the respective functional moieties can be varied as desired.

[0186] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be depicted as PTM-L- ULM, where PTM is a protein / polypeptide targeting moiety (e.g., any of the compounds as described herein showing inhibitory activity against SIRT5 activity), L is a linker, and ULM is a VHL, cereblon, MDM2, or IAP E3 ligase binding moiety binding moiety.

[0187] Such embodiments are not limited to a specific type of linker. In some embodiments, the linker group is optionally substituted (poly)ethyleneglycol having between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and 10 ethylene glycol units, between 1 and about 8 ethylene glycol units and 1 and 6 ethylene glycol units, between 2 and 4 ethylene glycol units, or optionally substituted alkyl groups interdispersed with optionally substituted, O, N, S, P or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. In certain embodiments, the linker may be asymmetric or symmetrical. In some embodiments, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units.

[0188] The ULM group and PTM group may be covalently linked to the linker group through any group which is appropriate and stable to the chemistry of the linker. In exemplary aspects of the present invention, the linker is independently covalently bonded to the ULM group and the PTM group in certain embodiments through an amide, ester, thioester, keto group, carbamate (urethane), carbon or ether, each of which groups may be inserted anywhere on the ULM group and PTM group to provide maximum binding of the ULM group on the ubiquitin ligase and the PTM group on the target protein to be degraded. In certain aspects where the PTM group is a ULM group, the target protein for degradation may be the ubiquitin ligase itself. In certain exemplary aspects, the linker may be linked to an optionally substituted alkyl, alkylene, alkene or alkyne group, an aryl group or a heterocyclic group on the ULM and / or PTM groups.

[0189] In certain embodiments, the compounds as described herein comprise multiple ULMs, multiple PTMs, multiple chemical linkers, or any combinations thereof.

[0190] In some embodiments, the present invention provides a method of ubiquitinating / degrading SIRT5 activity in a cell comprising administering a bifunctional compound as described herein comprising an ULM and a PTM, in certain embodiments linked through a linker moiety, as otherwise described herein, wherein the ULM is coupled to the PTM and wherein the ULM recognizes a ubiquitin pathway protein and the PTM recognizes the target protein such that degradation of the target protein occurs when the target protein is placed in proximity to the ubiquitin ligase, thus resulting in degradation / inhibition of the effects of the target protein and the control of protein levels. The control of protein levels afforded by the present invention provides treatment of a disease state or condition, which is modulated through the target protein by lowering the level of that protein in the cells of a patient.

[0191] BRIEF DESCRIPTION OF THE DRAWINGS

[0192] FIG. 1 : Melting Curves of SIRT5 by target compounds in the thermal shift assay in the absence of cofactor NAD+and substrate Ksucc. The DMSO control curves are shown in red, the target compounds curves are shown in blue.

[0193] FIG. 2: Melting Curves of SIRT5 by target compounds in the thermal shift assay in the presence of cofactor NAD+and substrate Ksucc. The DMSO control curves are shown in red, the target compounds curves are shown in blue. FIG. 3A-B: Trypsin-coupled sirtuin activity assay using fluorescent substrates for (a) SIRT5, (b) SIRT1 / 2 / 3.

[0194] FIG. 4: IC50 curves of target compounds in SIRT5 enzymatic assay in the presence of 200 pM cofactor NAD+and 10 pM substrate Ksucc.

[0195] DETAILED DESCRIPTION OF THE INVENTION

[0196] Described herein are a new class of carbothioamide (and structurally related) smallmolecule compounds which function as inhibitors of SIRT5, and their use as therapeutics for the treatment of diseases associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer, diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

[0197] Section headings as used in this section and the entire disclosure herein are merely for organizational purposes and are not intended to be limiting.

[0198] 1. Definitions

[0199] Certain terms employed in the specification, examples, and appended claims are further described here in the present invention. These definitions should be read in light of the entire invention and as would be understood by a person skilled in art.

[0200] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “and” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of,” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0201] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0202] Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0203] As used herein, “treat," “treating,” and the like means a slowing, stopping, or reversing of progression of a disease or disorder when provided a compound or composition described herein to an appropriate control subject. The term also means a reversing of the progression of such a disease or disorder to a point of eliminating or greatly reducing the symptoms. As such, “treating” means an application or administration of the compositions described herein to a subject, where the subject has a disease or a symptom of a disease, where the purpose is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease or symptoms of the disease.

[0204] A “subject” or “patient” may be human or non-human and may include, for example, animal strains or species used as “model systems" for research purposes, such a mouse model as described herein. Likewise, patient may include either adults or juveniles (e.g., children). Moreover, patient may mean any living organism, preferably a mammal (e.g., humans and nonhumans) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment, the mammal is a human.

[0205] As used herein, the terms “providing,” “administering,” and “introducing,” are used interchangeably herein and refer to the placement of the compounds or compositions of the disclosure into a subject by a method or route which results in at least partial localization of the compounds or composition to a desired site. The compounds or compositions can be administered by any appropriate route which results in delivery to a desired location in the subject.

[0206] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2ndedition, University Science Books, Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rdEdition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0207] “Cycloalkyl” refers to a saturated hydrocarbon ring that is not aromatic. Cycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic or polycyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 12 carbon atoms, preferably from 3 to 7 carbon atoms, in the ring. Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring. Preferred bicyclic cycloalkyl rings comprise 4-, 5-, 6- or 7- membered rings fused to 5-, 6- or 7-membered rings. Cycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Cycloalkyl may be substituted with halogen, cyano, nitro, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, alkoxy, arylalkyl, heteroarylalkyl or any combination thereof. Examples of cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl rings.

[0208] “Heterocycloalkyl” is a saturated or unsaturated ring containing carbon atoms and from 1 to 4 (preferably 1 to 3) heteroatoms in the ring. Heterocycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic or polycyclic ring systems. Monocyclic heterocycloalkyl rings contain from about 3 to about 9 member atoms (including both carbons and heteroatoms), preferably from 5 to 7 member atoms, in the ring. Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems. Preferred bicyclic heterocycloalkyl rings comprise 5-, 6- or 7- membered rings fused to 5-, 6- or 7-membered rings. Heterocycloalkyl rings may be unsubstituted (i.e., contain hydrogen) or substituted (on either carbons or heteroatoms or both) with from 1 to 4 substituents selected from halogen, cyano, nitro, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, alkoxy, arylalkyl, heteroarylalkyl or any combination thereof.

[0209] “Aryl” refers to aromatic monocyclic or multicyclic groups containing from 3 to 16 carbon atoms. Aryl may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted aryls are mono-, di, or tri-substituted. Aryls may be substituted with halogen, cyano, nitro, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, alkoxy, arylalkyl, heteroarylalkyl or any combination thereof.

[0210] “Heteroaryl” or Het refers to a monocyclic or multicyclic aromatic ring system, of about 5 to about 15 members where one or more of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to nitrogen, oxygen or sulfur. The heteroaryl group may be optionally fused to a benzene ring. Heteroaryl may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroaryls are mono-, di, or trisubstituted. Heteroaryls may be substituted with halogen, cyano, nitro, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, alkoxy, arylalkyl, heteroarylalkyl or any combination thereof.

[0211] “Halo” or “halogen” is fluoro, chloro, bromo or iodo.

[0212] “Alkyl" means a saturated hydrocarbon radical having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms, most preferably 1 to 3 carbon atoms, that may be branched or unbranched. Non-limiting example of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like, wherein methyl, ethyl, n-propyl and isopropyl represent specifically preferred examples.

[0213] “Heteroalkyl” is a saturated or unsaturated chain carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5. For example, alkoxy (i.e., -O-alkyl or -O-heteroalkyl) radicals are included in heteroalkyl. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more carbon-carbon double bounds and / or one or more carbon-carbon triple bounds. Preferred unsaturated heteroalkyl have one or two carbon-carbon double bounds or one carboncarbon triple bound, more preferably one double bound. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di, or tri-substituted. Heteroalkyl may be substituted with halogen, cyano, nitro, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, alkoxy, arylalkyl, heteroarylalkyl or any combination thereof.

[0214] “Alkoxy” means an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl). Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, allyloxy and the like.

[0215] “Arylalkyl” alone or in combination, refers to an alkyl radical in which one hydrogen atom is replaced by an aryl radical, for example, benzyl and the like.

[0216] “Heteroarylalkyl” refers to an alkyl radical in which one hydrogen atom is replaced by a heteroaryl radical.

[0217] “Independently” groups are groups present in the same structure that need not all represent the same substitution.

[0218] As used herein, the term “substituent” refers to a group substituted on an atom of the indicated group.

[0219] When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogen atoms on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, sulfonamide, thiol, thione, thioxo, or combinations thereof.

[0220] In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl alkenyl) is indicated by the prefix “Cx-Cy”, wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, “C1-C3 alkyl” refers to an alkyl substituent containing from 1 to 3 carbon atoms.

[0221] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0222] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they optionally encompass substituents resulting from writing the structure from right to left, e.g., -CH2O- is intended to encompass -OCH2-, and -C(O)NH- is intended to encompass -NHC(O)-. “Pharmacological composition” refers to a mixture of one or more of the compounds described herein or pharmaceutically acceptable salts thereof, with other chemical components, such as pharmaceutically acceptable carriers and / or excipients. The purpose of a pharmacological composition is to facilitate administration of a compound to an organism.

[0223] “Pharmaceutically acceptable salts” is a cationic salt formed at any acidic (e.g., carboxylic acid) group, or an anionic salt formed at any basic (e.g., amino) group.

[0224] “Solvate” is a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association often includes hydrogen bonding. In certain instances, the solvate is capable of isolation, for example, when one or more solvate molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ehanolates, and methanolates.

[0225] “Prodrug” refers to a pharmacologically inactive derivative of a parent “drug” molecule which requires biotransformation within the target physiological system to release, or to convert the prodrug into the active drug. Prodrugs can address the problems associated with solubility, stability, cell permeability or bioavailability. Prodrugs usually comprise an active drug molecule and a chemical masking group. Prodrugs can be readily prepared from the parent compounds with well-known methods.

[0226] 2. Compounds

[0227] In a particular embodiment, compounds encompassed within the following formulas are provided: Formula I Formula 1-1

[0228] Formula 1-1-1 Formula 1-1 -1-1

[0229] pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, triphenylpbosphonium (TPP) tagged derivatives, proteolysis targeting chimera (PROTAC) derivatives, mitochondria tagged derivatives, biotin tagged derivatives, bomn-dipyrromethene (BODIPY) tagged derivatives, stereoisomers, and / or deuterated analogues thereof.

[0230] Formula I is not limited to a particular chemical moiety for Ri, R2, R3, R4, Rs, Re, Rg, R12, Ai, A2, A3, A4, As, Bi, B2, B3, T, U, V, X, Y, Z, o, and n. In some aspects, the particular chemical moiety for Ri, R2, R3, R4, Rs, Re, Rg, R12, Ai, A2, A3, A4, As, Bi, B2, B3, T, U, V, X, Y, Z, o, and n independently include any chemical moiety that permits the resulting compound to inhibit SIRT5 activity. In some aspects, the particular chemical moiety for Ri, R2, R3, R4, Rs, Re, Rg, R12, AI, A2, A3, A4, As, 61, 62, B3, T, U, V, X, Y, Z, o, and n independently include any chemical moiety that permits the resulting compound effective as a therapeutic for the treatment of diseases associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

[0231] In some aspects,

[0232] X, Y and T are independently selected from the group consisting of: H, O, S, halogen, NH, N-OH, N-CN, and C1-C3 alkyl; or

[0233] X and T, independently, together with the atoms to which they are attached, is a monocyclic heterocycle optionally substituted with H, alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, and having zero to two ring heteroatoms selected from the group consisting of N, O, and S ; or

[0234] X and T, independently, together with the atoms to which they are attached, is monocyclic aromatic ring optionally substituted with alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, thereby forming a bicyclic ring system; wherein the dotted line represents an optional bond in case X, Y or T selected from the group consisting of: O, S, N-OH and N-CN.

[0235] In some aspects, U and V are independently selected from the group consisting of: N, CH and C-OH.

[0236] In some aspects, Z is selected from the group consisting of: NH, CH2, O and C=O.

[0237] In some aspects, n is selected from the group consisting of: 0, 1, 2, and 3.

[0238] In some aspects, o is selected from the group consisting of: 0, 1, 2, and 3.

[0239] In some aspects,

[0240] Ri R2, R3, R4, and R5 are independently selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, halogen, tetrazole, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted Cl- C6 amino alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C6 cycloalkyl, substituted C5-C7 aryl or Het, OR?, COR?, O(CH2)mC(=O)R?, COOR?, SO3R7, ASO3R7, BOR7OR8, (CH2)mR7, NR7R8, SO2R7R8, CONR7R8, NHCOR?, NHCOCHR7Rs, SO2NR7R8, and NHSO2R7; or

[0241] Ri with R2, R2 with R3, R3 with R4, R4 with R5, independently, together with the atoms to which they are attached, is a monocyclic heterocycle optionally substituted with H, alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, and having zero to two ring heteroatoms selected from the group consisting of N, O, and S; or Ri with R2, R2with R3, R3 with R4, R4 with R5 together with the atoms to which they are attached, is monocyclic aromatic ring optionally substituted with alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, thereby forming a bicyclic ring system.

[0242] In some aspects, R, and R2are independently selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, OMe, SMe, OEt, SEt, F, Cl, Br, I, Me, Et, t-Bu, i-Pr, SO2Me, NHSO2Me, S(O)Me, S(O)Et, SO2Me, SO2Et, O(i-Pr), O(t-Bu), F, Cl, Br, I, Me, Et, n-Pr, n-Bu, t-Bu, i-Pr, Ph, SO2Me, NHSO2Me, COMe, COEt, COCF3, OC(=O)Me, OC(=O)Et,

[0243] COOMe, COOEt, CH2OH, NH2, NHMe, NHEt, NMe2, NEt2, NHCH2PH, SO2Me, SO2Et,

[0244] CONH2, CONHMe, CONHEt, CONMe2, CONEt2, NHCOMe, NHCOEt, NHCOCH3,

[0245] NHCOCH2Me, NHCOCH2Et, NHCOCHMe2, NHCOCHEb, SO2NH2, SO2NHMe, SO2NHEt,

[0246] SO2NMe2, SO2NEt2, NHSO2Me, and NHSO2Et.

[0247] In some aspects, R? and Rg are independently selected form the group consisting of: H, deuterium (D), OH, OD, OMe, NO2, CN, CF3, OCF3, halogen, C1-C6 alkyl, C1-C6 alkoxy, CORg, (CH2)mOH, (CH2)mCOORg, substituted phenyl, substituted C5-C7 aryl and Het; wherein m is selected from the group consisting of: 0, 1, 2, and 3.

[0248] In some aspects, Rg is selected from the group consisting of: H, D, and Cl-6 alkyl.

[0249] In some aspects,

[0250] Re is selected from the group consisting of: unsubstituted or substituted Cl -C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 aminoalkyl, unsubstituted or substituted Cl-C6haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C8 cycloalkyl, OR10, COR10, OC(=0)Rio, COOR10, (CH)pRioRn, NR10R11, S02Rio, CONR10R11, NHCOR10, NHCOCR10R11, S02NRioRn, NHS02RIO. unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl, Het, heteroaryloxy, arylalkyl, and heteroarylalkyl; or

[0251] Rr> and X, together with the atoms to which they are attached, may optionally form a substituted or unsubstituted monocyclic heterocycle having zero to two ring heteroatoms selected from the group consisting of N, O, and S; or a substituted or unsubstituted monocyclic aromatic ring, thereby forming a bicyclic ring system; wherein p is selected from 0, 1, 2, or 3. In some aspects, R6 is selected from the group consisting of:

[0252] In some aspects, Rw and Rn are independently selected from the group consisting of: unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 aminoalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted Cl -6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl, and Het.

[0253] In some aspects, Al , A2, A3, A4, A5, A6, and A7 are independently selected from the group consisting of: O, S, CH, CH2, N, NH, CR13, and NR13.

[0254] In some aspects, B l, B2, and B3 are independently selected from the group consisting of: O, S, CH, CH2, N, NH, CR13, and NR13.

[0255] In some aspects, R13 is independently selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, CONH2, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 amino alkyl, unsubstituted or substituted Cl-C6 haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl or Het, heteroaryloxy, arylalkyl, or heteroarylalkyl; OR14, COR14, OC(=O)Ri4, COOR14, (CH2)pRi4Ri5, NR14R15, SO2Ri4, CONR14R15, NHCOR14, NHCOCHR14R15, SO2NR14R15, and NHSO2R14; wherein p is selected from 0, 1, 2, or 3.

[0256] In some aspects, R12 and RB are independently selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, OMe, SMe, OEt, SEt, S(O)Me, S(O)Et, SO2Me,

[0257] 25 SO2Et, O(i-Pr), O(t-Bu), F, Cl, Br, I, Me, Et, n-Pr, n-Bu, t-Bu, i-Pr, Ph, SO2Me, NHSO2Me, COMe, COEt, COCF3, OC(=O)Me, OC(=O)Et, COOMe, COOEt, CH2OH, NH2, NHMe, NHEt,

[0258] NMe2, NEt2, NHCH2PH, SO2Me, SO2Et, CONH2, CONHMe, CONHEt, CONMe2, CONEt2,

[0259] NHCOMe, NHCOEt, NHCOCH3, NHCOCH2Me, NHCOCH2Et, NHCOCHMe2, NHCOCHEt2,

[0260] SO2NH2, SO2NHMe, SO2NHEt, SO2NMe2, SO2NEt2, NHSO2Me, NHSO2Et; , ,

[0261] In some aspects, R14 and R15 are independently selected from the group consisting of: H, D, and C1-C6 alkyl.

[0262] In some aspects, Ri2is selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, CONH2, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 amino alkyl, unsubstituted or substituted Cl-C6haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl or Het, heteroaryloxy, arylalkyl, or heteroarylalkyl; OR]4, COR14, OC(=O)R]4, COOR14, (CH2)pRi4Ri5, NR14R15, SO2R]4, CONR14R15, NHCOR14, NHCOCHR14R15, SO2NR14R15, and NHSO2R14; wherein p is selected from 0, 1, 2, or 3.

[0263] In some aspects, Pi, P2, P3, and P4 are independently selected from the group consisting of: O, S, C, N, CR16, and NRI6.

[0264] In some aspects, Rie is selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, CONH2, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 amino alkyl, unsuhstituted or substituted Cl -C6haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl or Het, heteroaryloxy, arylalkyl, or heteroarylalkyl; OR,?, CORie, OC(=O)Rn, COORn, (CH2)pRi?Ri8, NRnRis, SO2R17, CONR17R18, NHCOR17, NHCOCHRnRis, SO2NR17R18, and NHSO2R17; wherein p is selected from 0, 1, 2, or 3; wherein p is selected from 0, 1, 2, or 3.

[0265] In some aspects, R17 and Ris are independently selected from the group consisting of: H, D, and C1-C6 alkyl.

[0266] In some aspects, the compound encompassed within Formulas 1, 1-1, 1-1-1, 1-l-l-l, 1-1-2, I-1-2-1, 1-1-3, 1-1-3-1, 1-2, 1-2-1, 1-2-1-1, 1-2-2, L2-2-1, 1-2-3, L2-3-1, 1-3, 1-3-1, 1-3-1-1, 1-3-2, and 1-3-2- 1 is shown in Table 1. In some aspects, the new class of carbothioamide (and structurally related) small-molecule compounds described herein is shown in Table 1. Table 1 further shows the molecular weight and cLogP values for each small-molecule compound.

[0267] The compounds may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem. , 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this disclosure. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England (or more recent versions thereof), or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods.

[0268] It should be understood that the compounds may possess tautomeric forms, as well as geometric isomers, and that these also constitute embodiments of the disclosure. The present disclosure also includes isotopically-labeled compounds, which is identical to those recited in Formulas 1, 1-1 , 1-1-1 , 1-l-l-l, 1-1-2, 1-1-2-1, 1-1-3, 1-1-3-1, 1-2, 1-2-1, 1-2-1 -1 ,

[0269] 1-2-2, 1-2-2-1, 1-2-3, 1-2-3- 1 , 1-3, 1-3-1, 1-3-1-1, 1-3-2, and 1-3-2- 1 but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes include those for hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,1SN,18O,17O,31P,32P ,35S,18F, and36C1, respectively. Substitution with heavier isotopes such as deuterium, for example,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positronemitting tomography (PET) studies. Suitable positron-emitting isotopes that can be incorporated in compounds of formula (I) arenC,13N,15O, and18F. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent.

[0270] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para- toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0271] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N -methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1 -ephenamine and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0272] Compounds may be synthesized according to a variety of methods, including those illustrated in the Examples. Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.

[0273] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the disclosure can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

[0274] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0275] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[0276] It can be appreciated that the synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the disclosure as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

[0277] 3. Compositions

[0278] The disclosed compounds may be incorporated into compositions that may be suitable for administration to a subject (such as a patient, which may be a human or non-human).

[0279] 3a. Pharmaceutical Compositions

[0280] The disclosed compounds may be incorporated into pharmaceutically acceptable compositions. The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of the compound(s). A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the invention (e.g., a compound of formula (I)) are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0281] The pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material, surfactant, cyclodextrins or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, com starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; surfactants such as, but not limited to, cremophor EL, cremophor RH 60, Solutol HS 15 and polysorbate 80; cyclodextrins such as, but not limited to, alpha-CD, beta-CD, gamma-CD, HP-beta-CD, SBE-beta-CD; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0282] The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral injections) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis). In some embodiments, the composition is for oral administration. In some embodiments, the composition is for subcutaneous administration. In some embodiments, the composition is for intravenous administration.

[0283] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, cyclodextrins combinations thereof, and others. All carriers are optional in the compositions. Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.

[0284] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.

[0285] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%.

[0286] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.

[0287] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0288] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%.

[0289] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%.

[0290] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%.

[0291] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%.

[0292] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.

[0293] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethyl acetamide and phosphate (or other suitable buffer). The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.

[0294] Suitable suspending agents include AVICEL RC-591 (from EMC Corporation of Philadelphia, Pa.) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.

[0295] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Del. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington’s Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5%.

[0296] Suitable cyclodextrins include alpha-CD, beta-CD, gamma-CD, hydroxypropyl betadex (HP-beta-CD), sulfobutyl-ether [3-cyclodextrin (SBE-beta-CD). The amount of cyclodextrins in the systemic or topical composition is typically about 0% to about 40%.

[0297] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of an active compound (e.g., a compound of formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.

[0298] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.

[0299] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof. Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[0300] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.

[0301] Solid compositions may be coated by conventional methods, typically with pH or timedependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

[0302] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non- effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0303] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0304] The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (I)), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[0305] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modem Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0306] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0307] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0308] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1 ,2-diol, butane- 1 ,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%. Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95%.

[0309] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%.

[0310] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5 -carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%.

[0311] The amount of thickener(s) in a topical composition is typically about 0% to about 95%.

[0312] Suitable powders include beta-cyclodex trins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium poly acrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically -modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.

[0313] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.

[0314] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.

[0315] 3a. Additional Therapeutic Agents

[0316] Any of the above compositions or formulations disclosed herein may further comprise at least one additional therapeutic agent. In some embodiments the at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent comprises an immune modulator, a chemotherapeutic agent, a nucleic acid (e.g., mRNA, aptamers, antisense oligonucleotides, ribozyme nucleic acids, interfering RNAs, antisense and antigene nucleic acids), a decongestant, a steroid, an analgesic, an antimicrobial agent, an immunotherapy, or a combination thereof. In some embodiments, the at least one additional therapeutic agent is selected from any type or kind of therapeutic agent capable of inhibiting SIRT5 activity. In some embodiments, the at least one additional therapeutic agent is selected from any type or kind of therapeutic agent for the treatment of diseases associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer, diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

[0317] In some embodiments, the at least one additional therapeutic agent comprises at least one chemotherapeutic agent. As used herein, the term “chemotherapeutic” or “anti-cancer drug” includes any small molecule or other drug used in cancer treatment or prevention. Chemotherapeutics include, but are not limited to, cyclophosphamide, methotrexate, 5- fluorouracil, doxorubicin, docetaxel, daunorubicin, bleomycin, vinblastine, dacarbazine, cisplatin, paclitaxel, raloxifene hydrochloride, tamoxifen citrate, abemacicilib, afinitor (Everolimus), alpelisib, anastrozole, pamidronate, anastrozole, exemestane, capecitabine, epirubicin hydrochloride, eribulin mesylate, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, ixabepilone, emtansine, lapatinib, olaparib, megestrol, neratinib, palbociclib, ribociclib, talazoparib, thiotepa, toremifene, methotrexate, and tucatinib.

[0318] In some embodiments, the at least one additional therapeutic agent comprises a polynucleotide or nucleic acid (e.g., ribonucleic acid or deoxyribonucleic acid). The term “polynucleotide,” in its broadest sense, includes any compound and / or substance that is or can be incorporated into an oligonucleotide chain. Exemplary polynucleotides for use in accordance with the present disclosure include, but are not limited to, one or more of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) including messenger mRNA (mRNA), hybrids thereof, RNAi- inducing agents, RNAi agents, siRNAs, shRNAs, miRNAs, antisense RNAs, ribozymes, catalytic DNA, RNAs that induce triple helix formation, aptamers, vectors, etc.

[0319] In some embodiments, the at least one additional therapeutic agent is an RNA. RNAs useful in the compositions and methods described herein can be selected from the group consisting of, but are not limited to, shortmers, antagomirs, antisense RNAs , ribozymes, small interfering RNA (siRNA), asymmetrical interfering RNA (aiRNA), microRNA (miRNA), Dicer-substrate RNA (dsRNA), small hairpin RNA (shRNA), transfer RNA (tRNA), messenger RNA (mRNA), and mixtures thereof.

[0320] In certain embodiments, the at least one additional therapeutic agent is an mRNA. An mRNA may encode any polypeptide of interest, including any naturally or non-naturally occurring or otherwise modified polypeptide. A polypeptide encoded by an mRNA may be of any size and may have any secondary structure or activity. In some embodiments, a polypeptide encoded by an mRNA may have a therapeutic effect when expressed in a cell.

[0321] In other embodiments, the at least one additional therapeutic agent is an siRNA. An siRNA may be capable of selectively knocking down or down regulating expression of a gene of interest. For example, an siRNA could be selected to silence a gene associated with a particular disease, disorder, or condition upon administration to a subject in need thereof of a nanoparticle composition including the siRNA. An siRNA may comprise a sequence that is complementary to an mRNA sequence that encodes a gene or protein of interest. In some embodiments, the siRNA may be an immunomodulatory siRNA.

[0322] In some embodiments, the at least one additional therapeutic agent is an shRNA or a vector or plasmid encoding the same. An shRNA may be produced inside a target cell upon delivery of an appropriate construct to the nucleus. Constructs and mechanisms relating to shRNA are well known in the relevant arts.

[0323] 4. Methods of Use

[0324] The disclosure further provides methods for treating a disease or disorder comprising administration of a compound or composition as disclosed herein, to a subject in need thereof. In some embodiments, the subject is a human.

[0325] In certain aspects, methods for treating, ameliorating, or preventing of conditions associated with aberrant posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0326] In certain aspects, methods for treating, ameliorating, or preventing of conditions (e.g., disorders, diseases) associated with SIRT5 activity (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of condition associated with SIRT5 activity) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0327] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer is metastatic cancer. In some embodiments, the disclosed compounds, compositions, or methods result in suppression of elimination of metastasis. In some embodiments, the disclosed compounds, compositions, or methods result in decreased tumor growth. In some embodiments, the disclosed compounds, compositions, or methods prevent tumor recurrence.

[0328] The compounds and compositions herein may be useful to treat a wide variety of cancers including carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. The cancer may be a cancer of the bladder, blood, bone, brain, breast, cervix, colon / rectum, endometrium, head and neck, kidney, liver, lung, lymph nodes, muscle tissue, ovary, pancreas, prostate, skin, spleen, stomach, testicle, thyroid, or uterus. In some embodiments, the cancer is wherein the disease or disorder is breast cancer, pancreatic cancer, lung cancer, or lymphoma. In select embodiments, the cancer is pancreatic cancer.

[0329] In some embodiments, the cancer is invasive and / or metastatic cancer (e.g., stage II cancer, stage III cancer or stage IV cancer). In some embodiments, the cancer is an early stage cancer (e.g., stage 0 cancer, stage I cancer), and / or is not invasive and / or metastatic cancer.

[0330] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of cancer (e.g., melanoma, NSCLC, HCC, ovarian cancer, CRC, AML, Ewing’s sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of cancer) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0331] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of diabetes are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of diabetes) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0332] In some embodiments, the disease or disorder or condition is an autoimmune disease or disorder or condition. Autoimmune diseases and disorders and conditions refer to conditions in a subject characterized by cellular, tissue and / or organ injury caused by an immunologic reaction of the subject to its own cells, tissues and / or organs. Autoimmune diseases and disorders that may be treated by the methods of the present invention include, but are not limited to, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune diseases of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg- Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barre, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), irritable bowel disease (IBD), IgA neuropathy, juvenile arthritis, lichen planus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, type 1 or immune-mediated diabetes mellitus, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatics, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, Rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, lupus erythematosus, takayasu arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitides such as dermatitis herpetiformis vasculitis, vitiligo, and Wegener’s granulomatosis.

[0333] Some autoimmune disorders are also associated with an inflammatory condition. Examples of inflammatory disorders which are also autoimmune disorders that can be prevented, treated or managed in accordance with the methods of the invention include, but are not limited to, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COED), allergic disorders, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, inflammatory osteolysis, and chronic inflammation resulting from chronic viral or bacterial infections. Examples of the types of psoriasis which can be treated in accordance with the compositions and methods of the invention include, but are not limited to, plaque psoriasis, pustular psoriasis, erythrodermic psoriasis, guttate psoriasis and inverse psoriasis. Some autoimmune disorders are also associated with immune dysregulatory diseases including, for example, sinopulmonary infections, opportunistic pneumonias, inflammatory bowel disease, autoimmune hepatitis and juvenile idiopathic arthritis, and myelofibrosis.

[0334] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of an autoimmune disorder (e.g., autoimmune condition, autoimmune disease) (e.g., multiple sclerosis (MS), celiac disease, rheumatoid arthritis, diabetes (e.g., type 1 diabetes mellitus), autoimmune diseases of the thyroid (e.g., Hashimoto's thyroiditis, Graves' disease), thyroid- associated ophthalmopathy and dermopathy, hypoparathyroidism, Addison's disease, premature ovarian failure, autoimmune hypophysitis, pituitary autoimmune disease, immunogastritis, pernicious anemia, celiac disease, vitiligo, myasthenia gravis, pemphigus vulgaris and variants, bullous pemphigoid, dermatitis herpetiformis Duhring, epidermolysis bullosa acquisita, systemic sclerosis, mixed connective tissue disease, Sjogren's syndrome, systemic lupus erythematosus, Goodpasture’s syndrome, rheumatic heart disease, autoimmune polyglandular syndrome type 1 , Aicardi-Goutieres syndrome, Acute pancreatitis Age-dependent macular degeneration, Alcoholic liver disease, Liver fibrosis, Metastasis, Myocardial infarction, Nonalcoholic steatohepatitis (NASH), Parkinson’s disease, Polyarthritis / fetal and neonatal anemia, Sepsis, and inflammatory bowel disease) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from an autoimmune disorder) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0335] In some embodiments, the disease or disorder is an inflammatory disease or disorder. Inflammatory diseases are characterized by activation of the immune system in a tissue or an organ to abnormal levels that may lead to abnormal function and / or disease in the tissue or organ. The inflammatory diseases and disorders that may be treated by the methods of the present invention include, but are not limited to, arthritis, rheumatoid arthritis, asthma, inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic obstructive pulmonary disease (COPD), allergic rhinitis, vasculitis (polyarteritis nodosa, temporal arteritis, Wegener's granulomatosis, Takayasu's arteritis, or Behcet’s syndrome), inflammatory neuropathy, psoriasis, systemic lupus erythematosus (SLE), chronic thyroiditis, Hashimoto's thyroiditis, Addison's disease, polymyalgia rheumatica, Sjogren's syndrome, or Churg-Strauss syndrome.

[0336] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of an inflammatory disorder (e.g., inflammatory condition, inflammatory disease) (e.g., arthritis, rheumatoid arthritis, asthma, inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic obstructive pulmonary disease (COPD), allergic rhinitis, vasculitis (polyarteritis nodosa, temporal arteritis, Wegener's granulomatosis, Takayasu's arteritis, or Behcet’s syndrome), inflammatory neuropathy, psoriasis, systemic lupus erythematosus (SEE), chronic thyroiditis, Hashimoto's thyroiditis, Addison's disease, polymyalgia rheumatica, Sjogren’s syndrome, or Churg-Strauss syndrome) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from an inflammatory disorder) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0337] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of a fibrosis or fibrotic disorder (e.g., fibrosis or fibrotic condition, fibrosis or fibrotic disease) (e.g., collagen disease, interstitial lung disease, human fibrotic lung disease (e.g., obliterative bronchiolitis, idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, tumor stroma in lung disease, systemic sclerosis affecting the lungs, Hermansky-Pudlak syndrome, coal worker’s pneumoconiosis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS- associated pulmonary hypertension, sarcoidosis, and the like), fibrotic vascular disease, arterial sclerosis, atherosclerosis, varicose veins, coronary infarcts, cerebral infarcts, myocardial fibrosis, musculoskeletal fibrosis, post-surgical adhesions, human kidney disease (e.g., nephritic syndrome, Alport's syndrome, HIV-associated nephropathy, polycystic kidney disease, Fabry's disease, diabetic nephropathy, chronic glomerulonephritis, nephritis associated with systemic lupus, and the like), cutis keloid formation, progressive systemic sclerosis (PSS), primary sclerosing cholangitis (PSC), liver fibrosis, liver cirrhosis, renal fibrosis, pulmonary fibrosis, cystic fibrosis, chronic graft versus host disease, scleroderma (local and systemic), Grave's opthalmopathy, diabetic retinopathy, glaucoma, Peyronie's disease, penis fibrosis, urethrostenosis after the test using a cystoscope, inner accretion after surgery, scarring, myelofibrosis, idiopathic retroperitoneal fibrosis, peritoneal fibrosis from a known etiology, drug-induced ergotism, fibrosis incident to benign or malignant cancer, fibrosis incident to microbial infection (e.g., viral, bacterial, parasitic, fungal, etc.), Alzheimer's disease, fibrosis incident to inflammatory bowel disease (including stricture formation in Crohn's disease and microscopic colitis), fibrosis induced by chemical or environmental insult (e.g., cancer chemotherapy, pesticides, radiation (e.g., cancer radiotherapy), and the like)) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from a fibrosis or fibrotic disorder) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0338] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of cardiovascular disorder (e.g., cardiovascular condition, cardiovascular disease) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of cardiovascular disorder) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0339] In certain aspects, methods for treating, ameliorating, or preventing of any type or form of neurodegenerative disorder (e.g., neurodegenerative condition, neurodegenerative disease) (e.g., Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD)) are provided, wherein the methods comprise administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of neurodegenerative disorder) a therapeutically effective amount of one or more of the carbothioamide (and structurally related) small-molecule compounds described herein.

[0340] The compounds and compositions disclosed herein may be administered to a subject by a variety of methods. In any of the uses or methods described herein, administration may be by various routes known to those skilled in the art, including without limitation oral, inhalation, intravenous, intramuscular, topical, subcutaneous, systemic, and / or intraperitoneal administration to a subject in need thereof.

[0341] The amount of the compounds of the present disclosure required for use in the disclosed methods will vary not only with the particular compound selected but also with the route of administration, the nature and / or symptoms of the disease and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies, and in vitro studies. For example, useful dosages can be determined by comparing their in vitro activity, and in vivo activity in animal models. Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and / or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, FIPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0342] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the symptoms to be treated and the route of administration. Further, the dose, and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0343] The compounds and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound or a subset of the compounds sharing certain chemical moieties, or a composition thereof, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs, or monkeys, may be determined using known methods. Efficacy may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and / or regime.

[0344] A wide range of second therapies may be used in conjunction with the compounds of the present disclosure. The second therapy may be administration of an additional therapeutic agent or may be a second therapy not connected to administration of another agent. Such second therapies include, but are not limited to, surgery, immunotherapy, radiotherapy. The second therapy may be administered at the same time as the initial therapy, either in the same composition or in a separate composition administered at substantially the same time as the first composition. In some embodiments, the second therapy may precede or follow the treatment of the first therapy by time intervals ranging from hours to months.

[0345] In some embodiments, a therapeutically effective amount of a compound disclosed herein, or compositions thereof, is administered alone or in combination with a therapeutically effective amount of at least one additional therapeutic agent. In some embodiments, effective combination therapy is achieved with a single composition or pharmacological formulation that includes both agents, or with two distinct compositions or formulations, administered at the same time or separated by a time interval, wherein one composition includes a compound of this invention, and the other includes the at least one additional therapeutic agent.

[0346] In some embodiments, the at least one additional therapeutic agent comprises any type or kind of therapeutic agent capable of inhibiting SIRT5 activity. In some embodiments, the at least one additional therapeutic agent comprises any type or kind of therapeutic agent for the treatment of diseases associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer, diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

[0347] In some embodiments, the at least one additional therapeutic agent comprises at least one chemotherapeutic agent. As used herein, the term “chemotherapeutic” or “anti-cancer drug” includes any small molecule or other drug used in cancer treatment or prevention. Chemotherapeutics include, but are not limited to, cyclophosphamide, methotrexate, 5- fluorouracil, doxorubicin, docetaxel, daunorubicin, bleomycin, vinblastine, dacarbazine, cisplatin, paclitaxel, raloxifene hydrochloride, tamoxifen citrate, abemacicilib, afinitor (Everolimus), alpelisib, anastrozole, pamidronate, anastrozole, exemestane, capecitabine, epirubicin hydrochloride, eribulin mesylate, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, ixabepilone, emtansine, lapatinib, olaparib, megestrol, neratinib, palbociclib, ribociclib, talazoparib, thiotepa, toremifene, methotrexate, and tucatinib.In select embodiments, the chemotherapeutic agent comprises paclitaxel.

[0348] 5. Kits

[0349] In another aspect, the disclosure provides kits comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a composition comprising the compound or a pharmaceutically acceptable salt thereof, and instructions for using the compound or composition.

[0350] The kits can also comprise other agents and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another agent for delivery to a patient.

[0351] The kits can also comprise instructions for using the components of the kit. The instructions are relevant materials or methodologies pertaining to the kit. The materials may include any combination of the following: background information, list of components, brief or detailed protocols for using the compositions, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0352] It is understood that the disclosed kits can be employed in connection with the disclosed methods. The kit may further contain containers or devices for use with the methods or compositions disclosed herein. The kits optionally may provide additional components such as buffers and disposable single-use equipment (e.g., pipettes, cell culture plates or flasks).

[0353] The kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like. Individual member components of the kits may be physically packaged together or separately.

[0354] EXAMPLES

[0355] The following examples are illustrative, but not limiting, of the compounds, compositions, and methods of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.

[0356] Example 1.

[0357] This example provides synthesis and characterization information for compounds of the present invention. In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomer can be obtained by methods known to those skilled in the art, such as e.g. chiral chromatography or crystallization. Column chromatography was performed on a Biotage Isolera flash chromatography system on Biotage normal phase silica gel columns. Preparative-HPLC purification was performed by Shimadzu Semi-Prep EC system. Analytical thin layer chromatography was performed on Merck pre-coated plates (silica gel 60 F254). NMR spectra were recorded on a Bruker Ultrashield 300 MHz or Bruker Ascend 400 MHz spectrometer using deuterated DMSO- de or CD3OD as solvents. Chemical shifts for proton magnetic resonance spectra (1H NMR) are quoted in parts per million (ppm) referenced to the appropriate solvent peak or 0.0 ppm for tetramethylsilane (TMS). The following abbreviations are used to describe the peak-splitting patterns when appropriate: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and dd, doublet of doublets. Coupling constants, J, are reported in hertz (Hz).

[0358] Mass spectra were recorded on a Shimadzu LCMS-2020 system using the electro spray ionization (ESI) ion source. HPLC was used to determine the purity of biologically tested compounds using Shimadzu LC-2030C 3D system on Kinetex XB-C18 column (2.6 pm, 4.6x75 mm) under the following gradient elution conditions: acetonitrile / water (10-95 %) or methanol / water (10-95 %), both with 0.1% formic acid as the additive, over 7 or 15 minutes at a 0.80 mL / min flow rate at room temperature. The observed mass spectrometry value [MS (m / z)J is indicated by [M+HJ+, [M+2H]2+, [M+Na]+, or [M+2Na]2+, and time of retention is indicated by Rt (min).

[0359] The following abbreviations used herein below have the corresponding meanings:

[0360] Me Methyl

[0361] Et Ethyl

[0362] TPP Triphenylphosphine

[0363] DIPEA A,A-Diisopropylethylamine

[0364] DMF MAM huethyl formamide

[0365] DMA MMdimethylaniline

[0366] THF Tetrahydrofuran

[0367] DCM Dichioromethane

[0368] CDCh Chloroform

[0369] DMSO Dimethylsulfoxide

[0370] EA Ethyl acetate

[0371] CAN / MeCN Acetonitrile;

[0372] EtN3Triethylamine

[0373] NaOH Sodium hydroxide Na2SO4Sodium Sulfate

[0374] TFA Trifluoroacetic acid

[0375] NMP M-methylpyrrolidine

[0376] NMM / V-methylmorpholine

[0377] Boc t-butoxycarbonyl

[0378] HATH 2-(177-7-azabenzotriazol-l-yl)-l, 1 ,3,3-tetramethyluronium hexafluorophosphate;

[0379] HPLC High performance liquid chromatography

[0380] LCMS Liquid chromatography and mass spectrometry;

[0381] NMR Nuclear magnetic resonance;

[0382] TLC Thin layer chromatography m / z Mass to charge ratio; mL Milliliter(s);

[0383] (1M Micromolar; rt Room temperature; eq. Equivalent weight

[0384] General Synthetic Methods

[0385] The following schemes are intended to present typical synthetic approaches for the preparation of the compounds of the invention. In all cases, except where otherwise stated, substituents are as defined hereinabove. Substituent R is intended be equivalent to substituents RI-6 as defined hereinabove, and as such may denote any group encompassed by those variables.

[0386] While a compound obtained in each step can be used in a subsequent reaction directly as a reaction solution or as a composition, the compound can also be isolated from a reaction mixture in accordance with a conventional method. The compound can be readily purified by separation means such as recrystallization, distillation, or chromatography.

[0387] One route for preparation of compounds of formula (I) of the present invention is depicted in Scheme 1.

[0388] Scheme 1: i-i

[0389] The typical synthesis of the compounds of the invention starts from various commercially available substituted primary aniline (A). Compound A was reacted with thiophosgene (B) in water solvent in the presence of HCI to get the key intermediates C. Compound C then reacted with various commercially available piperazine derivatives (D) in the presence of a base in a suitable solvent, to yield the final products (1-1).

[0390] As the base, a basic salt such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, an aromatic amine such as DMAP, pyridine, lutidine, 4- dimethylaminopyridine, or DMA, a tertiary amine such as EtNs, tripropylamine , DIPEA, NMP, or NMM, or the like can be used, and DMAP is particularly preferred. The solvent used in this step is selected from the solvents exemplified below and the like. Examples thereof include aprotic solvents such as DMF, N-methyl-2-pyrrolidone, DMSO, CAN, and propionitrile, ether solvents such as 1,4-dioxane, halogenated hydrocarbons such as DCM and CDCh, hydrocarbons such as toluene and benzene, esters such as EA, mixtures thereof, and the like. Preferred examples thereof include DMF and DCM. The amount of D used is generally 1-2 equivalents, preferably 1 equivalent with respect to 1 equivalent of compound C. The reaction time is generally about 0.5 hours to about 48 hours, preferably about 4 hours to about 8 hours. The reaction temperature is generally about 0°C to about 100 °C, preferably at rt.

[0391] Another route for preparation of compounds of the present invention is depicted in Scheme 2.

[0392] Scheme 2:

[0393] A

[0394] 1-3

[0395] Compound 1-3 and its analogs were synthesized according to the procedures outlined in Scheme 2. Commercially available E and F were reacted through nucleophilic substitution in the presence of a base in a suitable solvent, to get an intermediate G. The intermediate then reacted with various primary or secondary amines (A) to yield the final products (1-3)

[0396] Another route for preparation of compounds of the present invention is depicted in Scheme 3.

[0397] Scheme 3:

[0398] E H J 1-3

[0399] In other situations, compound 1-3 and its analogs were synthesized according to the procedures outlined in Scheme 3. Commercially available 7-nitro-l,2,3,4-tetrahydroisoquinoline (E) was reacted with various acids (H) through a condensation reaction or reacted with various acyl chloride (J) in the presence of a base in a suitable solvent to obtain the final products (1-3) in good yield.

[0400] Another route for preparation of compounds of the present invention is depicted in Scheme 4.

[0401] Scheme 4:

[0402] In other situations, compound 1-1 and its analogs were synthesized according to the procedures outlined in Scheme 4. Commercially available substituted primary aniline (A) was reacted with 4-nitrophenyl carbonochloridate (K) through a nucleophilic substitution to obtain an intermediate (L) without further purification, the intermediate (L) was reacted with various commercially available piperazine derivatives (d) in the presence of a base in a suitable solvent to get the final products (1-1) in good yield.

[0403] Another route for preparation of compounds of the present invention is depicted in Scheme 5.

[0404] Scheme 5:

[0405] A

[0406] M TPP tagged derivatives

[0407] B

[0408] Ph3P' N H

[0409] Rl

[0410] DMF H n

[0411] M

[0412] TPP tagged derivatives

[0413] Starting from compound 1-1 or 1-3 with a NO2 substituent, the corresponding reduction product L is obtained through a basic reduction reaction. With HATU / DIEA coupling reagent / base combination, the corresponding TPP tagged derivatives are obtained.

[0414] Scheme 6:

[0415] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline- 1 ,3-dione (N) and tert-butyl 6- bromohexanoate (O) are reacted through a substitution reaction to obtain P, the corresponding intermediate Q is obtained through a basic deprotection reaction. The final SIRT5-PR0TAC derivatives are obtained with HATU / DIEA coupling reagent / base combination by reacting with the synthetic intermediate L.

[0416] These and other reaction methodologies may be useful in preparing the compounds of the invention, as recognized by one of skill in the art. Various modifications to the above schemes and procedures will be apparent to one of skill in the art, and the invention is not

[0417] 15 limited specifically by the method of preparing the compounds of the invention. In general, the synthesis methods described herein may employ a variety of commercially available starting materials, starting materials known in the literature, and readily prepared starting materials prepared by employing standard synthetic methods and procedures. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard reference textbooks in the field. Although not limited to any one or several sources, recognized reference textbooks of organic synthesis include for example: Smith, M. B.; March, J. M arch’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed.; John Wiley & Sons: New York, 2001; The foregoing descriptions of synthetic methods are designed to illustrate, but not limit, general procedures for the preparation of compounds of the invention.

[0418] 2-Hydroxy-4-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido) benzoic acid (TL283).

[0419] To a solution of commercially available A (1 eq.) in H2O, was slowly added HC1 (4 eq.) and thiophosgene (B, 1.2 eq.), the mixture was stirred at rt till the color disappeared. The resulting solids were filtered and washed with water. The intermediate C was obtained as a white product. To a mixture of compound C (108 mg, 0.55 mmol) and 7-nitro-l,2,3,4-tetrahydroisoquinoline (D, 98 mg, 0.55 mmol) in DMF (2 mL) was added DMAP (3.4 mg, 0.0275 mmol), the mixture was reacted at room temperature overnight and quenched with H2O, then filtered. The product was purified through flash chromatography as a yellow solid (165 mg, 80%).1H NMR (300 MHz, DMSO-d6) δ 13.67 (s, 1H), 11.31 (s, 1H), 9.63 (s, 1H), 8.19 - 8.03 (m, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.05 - 6.89 (m, 2H), 5.15 (s, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.09 (t, J = 6.0 Hz, 2H). MS (ESI) m / z 374.0 [M+H]+C17H15N3O5S. HPLC analysis: MeCN- H2O (95:5), 7.00 min, 99.93% pure.

[0420] 4-(4-(4-AcetylphenyI)piperazine-l-carbothioamido)-2-hydroxybenzoic acid (TL304). The product was obtained as a white solid (15 mg, 18%) using a similar procedure as described for TL283. ‘H NMR (300 MHz, DMSO-rfc) δ 13.69 (s, 1H), 11.31 (s, 1H), 9.59 (s, 1H), 7.83 (dd, J = 8.9, 2.3 Hz, 2H), 7.68 (d, J = 8.6 Hz, 1H), 7.09 - 6.81 (m, 4H), 4.04 (t, 7 = 5.2 Hz, 4H), 3.53 (d, 7 = 5.3 Hz, 4H), 2.46 (s, 3H). MS (ESI) m / z 400.2 [M+H]+C20H21N3O4S. HPLC analysis: MeCN-H2O (95:5), 6.41 min, 98.13% pure.

[0421] Methyl 2-hydroxy-4-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido) benzoate (TL328). The product was obtained as a yellow solid (96mg, 17%) using a similar procedure as described for TL283. 1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.66 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.08 (dd, 7 = 8.3, 2.4 Hz, 1H), 7.69 (d, 7 = 8.7 Hz, 1H), 7.52 (d, 7 = 8.4 Hz, 1H), 7.06 (d, 7 = 2.1 Hz, 1H), 7.00 (dd, 7 = 8.7, 2.1 Hz, 1H), 5.15 (s, 2H), 4.09 (t, 7 = 6.0 Hz, 2H), 3.87 (s, 3H), 3.09 (t, 7 = 5.9 Hz, 2H). MS (ESI) m / z 388.0 [M+H]+C18H17N3O5S. HPLC analysis: MeCN- H2O (95:5), 8.08 min, 99.31% pure.

[0422] (lH-Imidazol-l-yl)(7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)methanethione (TL334).

[0423] A mixture of 7-nitro-l,2,3,4-tetrahydroisoquinoline (E, 89 mg, 0.5 mmol) and di(lH-imidazol- 1 -yl)methanethione (F, 72 mg, 0.5 mmol) in DCM (2 mL) reacted at room temperature overnight. The resulting product (G) was concentrated and purified through HPLC as a yellow solid (52 mg, 36%). 1H NMR (300 MHz, DMSCMj 5 8.78 (s, 1H), 8.3 (s, 1H), 8.12 (dd, 7 = 8.4, 2.3 Hz, 1H), 7.85 (s, 1H), 7.57 (d, 7 = 8.4 Hz, 1H), 7.52 - 7.37 (m, 1H), 5.20 (s, 2H), 4.17 (s, 1H), 3.84 (s, 1H), 3.18 (s, 2H). MS (ESI) m / z 289.0 [M+H]+C13H12N4O2S. HPLC analysis: MeCN-H2O (95:5), 5.76 min, 97.05% pure.

[0424] (4-(Methylsulfonyl)piperazin-l-yl)(7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)methanethione (TL341).

[0425] To a mixture of TL334 (G, 280 mg, 1 mmol) and l-(methylsulfonyl)piperazine (A, 180 mg, 1.1 mmol) in CH3CN (1 mL) was added EtsN (420 pL, 3 mmol). The mixture was stirred at room temperature overnight and then concentrated. The resulting solution was purified through HPLC to give TL341 as a yellow solid (140 mg, 38%). 1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, 7 =

[0426] 2.4 Hz, 1H), 8.05 (dd, 7 = 8.4, 2.4 Hz, 1H), 7.48 (d, 7 = 8.5 Hz, 1H), 4.85 (s, 2H), 3.85 (t, 7 = 5.8 Hz, 2H), 3.60 (d, 7 = 5.2 Hz, 4H), 3.23 (t, 7 = 5.0 Hz, 4H), 3.09 (t, 7 = 5.9 Hz, 2H), 2.93 (s, 3H). MS (ESI) m / z 385.1 [M+H]+C15H20N4O4S2. HPLC analysis: MeCN-H2O (95:5), 7.25 min, 95.23% pure.

[0427] (E')-3-(lH-Imidazol-5-yl)-l-(7-nitro-3,4-dihydroisoquinoIin-2(lH)-yl)prop-2-en-l-one (TL346).

[0428] To a solution of 7-nitro-l,2,3,4-tetrahydroisoquinoline (E, 89 mg, 0.5 mmol), (E)-3-(lH- imidazoL5-yl)acrylic acid (H, 69 mg, 0.5 mmol), HATH (209 mg, 0.55 mmol) in DMF (2 mL) was added DIPEA (194 mg, 1.5 mmol). The mixture was stirred at rt overnight. The reaction was quenched with water and then filtered. The product was purified through flash chromatography as a white solid (60 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ 9.01 (d, 7 =

[0429] 9.4 Hz, 1 H), 8.26 - 7.99 (m, 2H), 7.95 (s, 1 H), 7.57 - 7.28 (m, 3H), 4.92 (d, 7 = 35.1 Hz, 2H), 3.83 (s, 2H), 3.00 (d, J = 22.7 Hz, 2H). MS (ESI) m / z 299.0 [M+H]+C15H14N4O3. HPLC analysis: MeCN-HiO (95:5), 4.51 min, 99.48% pure.

[0430] Methyl 4-(7-amino-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)-2-hydroxybenzoate (TL349).

[0431] A mixture of TL328 (1-3, 200 mg, 0.52 mmol) and Zn (336 mg, 5.2 mmol) in EtOH (20 mL) was added cone. NH4CI (3 mL). The mixture was refluxed overnight and then cooled to room temperature. The resulting solution was filtered through a layer of silica gel. The filter was concentrated and purified through flash chromatography to give the final product TL349 (N) as a yellow solid (100 mg, 55%).1H NMR (300 MHz, DMSO-d6 ) δ 10.58 (s, 1H), 9.56 (s, 1H), 7.89 - 7.72 (m, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 7.02 - 6.90 (m, 3H), 5.00 (s, 2H), 4.04 (t, J = 5.9 Hz, 2H), 3.87 (s, 2H), 2.91 (t, 7 = 5.7 Hz, 2H). MS (ESI) m / z C18H19N3O3S. HPLC analysis: MeCN-H2O (95:5), 3.77 min, 95.58% pure.

[0432] Ethyl l-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidine-4-carboxy!ate (TL357).

[0433] The product was obtained as a yellow solid (20 mg, 11%) using a similar procedure as described for TL341. 1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, 7 = 2.4 Hz, 1H), 8.03 (dd, 7= 8.4, 2.5 Hz, 1H), 7.45 (d, 7 = 8.5 Hz, 1H), 4.80 (s, 2H), 4.09 (q, 7 = 7.1 Hz, 2H), 3.91 (dt, 7 = 13.6, 3.9 Hz, 2H), 3.81 (t, 7 = 5.8 Hz, 2H), 3.27 - 2.95 (m, 4H), 2.62 (tt, 7 = 10.8, 3.8 Hz, 1H), 1.88 (dd, 7 = 13.5, 3.7 Hz, 2H), 1.72 (dd, 7 = 12.7, 9.0 Hz, 2H), 1.19 (t, 7 = 7.1 Hz, 3H). MS (ESI) m / z 378.2 [M+H]+C18H23N3O4S. HPLC analysis: MeCN-H2O (95:5), 9.79 min, 99.68% pure.

[0434] 7-Nitro-A-((6-oxo-l,6-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinoline-2(lH)- carbothioamide (TL363).

[0435] The product was obtained as a grey solid (25 mg, 15%) using a similar procedure as described for TL283.1H NMR (300 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.17 (t, 7 = 5.6 Hz, 1H), 8.12 - 8.02 (m, 2H), 7.54 - 7.44 (m, 2H), 7.29 (d, 7= 2.6 Hz, 1H), 6.30 (d, 7 = 9.4 Hz, 1H), 5.08 (s, 2H), 4.50 (d, 7 = 5.3 Hz, 2H), 3.97 (t, 7 = 5.9 Hz, 2H), 2.99 (t, 7 = 5.9 Hz, 2H). MS (ESI) m / z 342.9 [M-H]- C16H16N4O3S. HPLC analysis: MeCN-H2O (95:5), 6.78 min, 97.80% pure.

[0436] Methyl 2-hydroxy-4-(7-(3-(triphenyl-14-phosphanyl)propanamido)-l, 2,3,4- tetrahydroisoquinoline-2-carbothioamido)benzoate (TL366) .

[0437] To a solution of TL349 (N, 240 mg, 0.65 mmol), (2-carboxyethyl)triphenylphosphonium bromide (M, 260 mg, 0.65 mmol), HATU (260 mg, 0.72 mmol) in DMF was added DIPEA (310 pL, 2.0 mmol). The mixture was stirred at rt for 6h and then quenched with water. The resulting solution was filtered and purified through HPLC to give compound TL366 as a white solid (13 mg, 30%). ‘H NMR (300 MHz, Methanol-d4) δ 7.94 - 7.67 (m, 16H), 7.24 - 7.17 (m, 1H), 7.13 (d, 7 = 8.3 Hz, 1H), 6.96 (d, 7 = 2.1 Hz, 1H), 6.92 (dd, 7 = 8.6, 2.1 Hz, 1H), 4.94 (s, 2H), 4.06 (t, 7 = 5.9 Hz, 2H), 3.92 (s, 3H), 3.77 (dt, 7 = 14.2, 7.9 Hz, 2H), 2.93 (q, J = 15, 6.7 Hz, 2H), 2.83 (dd, 7 = 14.2, 7.0 Hz, 2H). MS (ESI) m / z C39H37BrN3O4PS. HPLC analysis: MeCN-H2O (95:5), 5.02 min, 97.23% pure.

[0438] Ethyl l-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidine-3-carboxylate (TL367).

[0439] The product was obtained as a yellow solid (17 mg, 27%) using a similar procedure as described for TL341. 1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, 7 = 2.5 Hz, 1H), 8.04 (dd, 7 = 8.4, 2.5 Hz, 1H), 7.46 (d, 7 = 8.4 Hz, 1H), 4.80 (d, 7 = 2.8 Hz, 2H), 4.06 (q, 7 = 7.1 Hz, 3H), 3.89 (dt, 7 = 11.7, 5.5 Hz, 1H), 3.81 - 3.66 (m, 2H), 3.11 (tdd, 7 = 29.0, 15.3, 7.9 Hz, 5H), 2.73 (td, 7= 9.7, 4.5 Hz, 1H), 2.04 - 1.90 (m, 1H), 1.81 - 1.48 (m, 3H), 1.15 (t, 7 = 7.1 Hz, 3H). MS (ESI) m / z C18H23N3O4S.

[0440] 2-Hydroxy-l-(7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)-2-(3-nitrophenyl)ethan-l-one (TL370).

[0441] The product was obtained as a grey solid (35 mg, 35%) using a similar procedure as described for TL346. 1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, 7 = 15.9 Hz, 1H), 8.17 (d, 7= 7.7 Hz,

[0442] 1H), 8.01 (ddd, 7 = 20.3, 16.0, 11.1 Hz, 2H), 7.84 (d, 7 = 7.4 Hz, 1H), 7.62 (dt, 7 = 24.6, 8.0 Hz,

[0443] 1H), 7.41 (t, 7 = 7.8 Hz, 1H), 6.34 (d, 7 = 6.6 Hz, 1H), 5.74 (d, 7 = 6.6 Hz, 1H), 5.03 - 4.61 (m,

[0444] 2H), 3.93 - 3.49 (m, 2H), 2.96 - 2.73 (m, 2H). MS (ESI) m / z 355.8 [M-H]' Ci7Hi5N3O6. HPLC analysis: MeCN-H3O (95:5), 9.66 min, 97.41% purity.

[0445] (2,4-Dihydroxyphenyl)(7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)methanone (TL373). The product was obtained as a yellowish white solid (32 mg, 36%) using a similar procedure as described for TL346.1H NMR (300 MHz, DMSO-d6 ) δ 9.77 (s, 1H), 9.62 (s, 1H), 8.18 - 7.96 (m, 2H), 7.45 (d, 7 = 8.5 Hz, 1H), 6.98 (d, 7 = 8.3 Hz, 1H), 6.33 (d, 7= 2.3 Hz, 1H), 6.27 (dd, 7 = 8.3, 2.2 Hz, 1H), 4.75 (s, 2H), 3.64 (s, 2H), 2.94 (t, 7 = 5.8 Hz, 2H). MS (ESI) m / z 315.0 [M+H]+C16H14N2O5 HPLC analysis: MeCN-H20 (95:5), 5.78 min, 96.42% pure.

[0446] Methyl l-methyl-4-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)-lH-pyrrole- 2-carboxylate (TL389).

[0447] The product was obtained as a yellow solid (90 mg, 48%) using a similar procedure as described for TL341. 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.08 (d, 7 = 6.5 Hz, 2H), 7.51 (d, 7 = 9.1 Hz, 1 H), 7.36 (d, 7 = 2.0 Hz, 1 H), 6.90 (d, 7 = 2.0 Hz, 1H), 5.15 (s, 2H), 4.06 (t, 7 = 5.9 Hz, 2H), 3.83 (s, 4H), 3.04 (t, J = 5.9 Hz, 2H). MS (ESI) m / z 375.1 [M+H]+C17H1SN4O4S. HPLC analysis: MeCN-HiO (95:5), 7.38 min, 98.90% pure.

[0448] 2-Hydroxy-5-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL390).

[0449] The product was obtained as a yellow solid (100 mg, 54%) using a similar procedure as described for TL283. 1H NMR (300 MHz, DMSO-d6) δ 13.95 (s, 1H), 11.17 (s, 1H), 9.39 (s,

[0450] 1H), 8.08 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 2.7 Hz, 1H), 7.56 - 7.43 (m, 2H), 6.91 (d, J = 8.8 Hz, 1H), 5.19 (s, 2H), 4.09 (t, J = 5.9 Hz, 2H), 3.08 (t, J = 5.9 Hz, 2H). MS (ESI) m / z 374.1 [M+H]+

[0451] C17H15N3O5S. HPLC analysis: MeCN-H2O (95:5), 6.70 min, 97.47% pure. (E)-l-(7-Nitro-3,4-dihydroisoquinoIin-2(lH)-yl)-3-(pyridin-4-yI)prop-2-en-l-one (TL391). The product was obtained as a yellow solid (85mg, 55%) using a similar procedure as described for TL346.1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J = 5.5 Hz, 2H), 8.26 - 7.95 (m, 4H), 7.76 (dd, J = 15.5, 10.3 Hz, 1H), 7.67 - 7.42 (m, 2H), 4.99 (d, J = 65.2 Hz, 2H), 3.92 (dt, 7 = 49.4, 5.9 Hz, 2H), 3.00 (dq, J = 20.7, 8.7, 7.3 Hz, 2H). MS (ESI) m / z 310.0 [M+H]+C17H15N3O3.

[0452] HPLC analysis: MeCN-H2O (95:5), 4.81 min, 97.92% pure.

[0453] 2-Hydroxy-3-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL397).

[0454] The product was obtained as a yellow solid (5 Img, 55%) using a similar procedure as described for TL283. 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 2H), 9.07 (s, 1H), 8.10 (d, J = 6.5 Hz, 2H), 7.70 (dd, J = 8.0, 1.7 Hz, 1H), 7.51 (ddd, 7 = 21.5, 6.8, 2.3 Hz, 2H), 6.90 (t, 7= 7.8 Hz, 1H), 5.22 (s, 2H), 4. 11 (t, 7 = 5.9 Hz, 2H), 3.08 (t, 7 = 6.0 Hz, 2H). MS (ESI) m / z 374.0 [M+H]+C17H15N3O5S. HPLC analysis: MeCN-H2O (95:5), 6.82 min, 96.54% pure.

[0455] 2-Methoxy-4-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL398).

[0456] The product was obtained as a yellow solid (58 mg, 60%) using a similar procedure as described for TL283. 1H NMR (300 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.61 (s, 1H), 8.29 - 8.00 (m, 2H), 7.66 (dd, 7 = 14.9, 8.3 Hz, 1H), 7.54 (d, 7 = 8.4 Hz, 1H), 7.22 (dd, 7 = 4.1, 1.9 Hz, 1H), 7.03 (ddd, 7= 8.4, 5.0, 1.9 Hz, 1H), 5.18 (s, 2H), 4.11 (t, 7 = 5.9 Hz, 2H), 3.85 - 3.74 (m, 3H), 3.10 (s, 2H). MS (ESI) m / z 388.0 [M+H]+C18H17N3O5S. HPLC analysis: MeCN-H2O (95:5), 6.67 min, 98.30% pure.

[0457] 2-FIuoro-5-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL399). The product was obtained as a yellow solid (61 mg, 65%) using a similar procedure as described for TL283. 1H NMR (300 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.19 - 8.04 (m, 2H), 7.75 (dd, J = 6.7, 2.8 Hz, 1H), 7.61 - 7.47 (m, 2H), 7.22 (dd, J = 10.5, 8.8 Hz, 1H), 6.73 (d, J = 6.5 Hz, 1H), 5.20 (s, 2H), 4.11 (t, 7 = 5.9 Hz, 2H), 3.09 (t, J = 5.9 Hz, 2H). MS (ESI) m / z 376.0 [M+H]+C17H14FN3O4S. HPLC analysis: MeCN-H20 (95:5).

[0458] 2-Methyl-4-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL407) The product was obtained as a yellow solid (50 mg, 54%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.10 (d, 7 = 2.4 Hz, 1H), 8.07 (dd, 7

[0459] = 8.3, 2.5 Hz, 1H), 7.77 (d, 7 = 8.4 Hz, 1H), 7.52 (d, 7 = 8.4 Hz, 1H), 7.28 (dd, 7 = 8.5, 2.2 Hz, 1H), 7.24 (d, 7 = 2.1 Hz, 1H), 5.15 (s, 2H), 4.09 (t, 7 = 5.9 Hz, 2H), 3.07 (t, 7 = 5.9 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 181.43, 168.58, 146.40, 144.44, 143.78, 140.09, 135.79, 131.14, 130.16, 127.00, 125.69, 122.03, 121.88, 121.70, 50.42, 46.01, 28.78, 22.01. MS (ESI) m / z 371.9 [M+H]+Ci8Hi7N3O4S. HPLC analysis: MeCN-H2O (95:5), 6.98 min, 98.43% pure.

[0460] 5-Fluoro-2-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL408).

[0461] The product was obtained as a yellow solid (22 mg, 23%) using a similar procedure as described for TL283. 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.04 (dd, 7 = 8.4, 2.5 Hz, 1H), 7.46 (d, 7 = 8.5 Hz, 1H), 7.04 (td, 7 = 8.7, 3.1 Hz, 1H), 6.96 (dd, 7 = 9.0, 3.0 Hz, 1H), 6.79 (dd, 7 = 8.9, 4.8 Hz, 1H), 4.81 (s, 2H), 3.66 (s, 2H), 2.98 (t, 7 = 5.8 Hz, 2H). MS (ESI) m / z C17H14FN3O4S. HPLC analysis: MeCN-H20 (95:5), 9.66 min, 95.77% pure.

[0462] 5- Acetyl-2-(7 -nitro- 1,2,3, 4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL409) .

[0463] The product was obtained as a yellow solid (20 mg, 29%) using a similar procedure as described for TL283. 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.04 (dd, 7 = 8.4, 2.4 Hz, 1H), 7.74 (dd, J = 8.6, 2.1 Hz, 1H), 7.68 (d, 7 = 2.1 Hz, 1H), 7.47 (d, 7 = 8.5 Hz, 1H), 6.74 (d, 7 = 8.6 Hz, 1H), 6.16 (s, 1H), 4.82 (s, 2H), 3.67 (s, 2H), 2.98 (t, 7 = 5.9 Hz, 2H), 2.42 (s, 3H). MS (ESI) m / z C19H17N3O5S. HPLC analysis: MeCN-H2O (95:5), 6.14 min, 96.47% pure.

[0464] (3,5-Bis(trifluoromethyl)piperidin-l-yl)(7-nitro-3,4-dihydroisoquinolin-2(lH)- yl)methanethione (TL416).

[0465] The product was obtained as a yellow solid (16 mg, 16%) using a similar procedure as described for TL341.1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, 7 = 16.8 Hz, 1H), 8.05 (dd, 7 = 8.4, 2.4 Hz, 1H), 7.47 (d, 7 = 8.5 Hz, 1H), 4.80 (d, 7 = 21.0 Hz, 2H), 4.22 (m, 1H), 3.85 (dd, 7 = 11.7, 7.3 Hz, 2H), 3.48 (m, 1 H), 3.00 (m, 4H), 2.13 - 1 .49 (m, 4H). MS (ESI) m / z CnHnFeNsO.S. (4-Hydroxy-4-(trifluoromethyl)piperidin-l-yl)(7-nitro-3,4-dihydroisoquinolin-2(l / / )- yl)methanethione (TL420).

[0466] The product was obtained as a yellow solid (14 mg, 20%) using a similar procedure as described for TL341. 1H NMR (300 MHz, Methanol-d4) δ 8.08 (d, J = 2.3 Hz, 1H), 8.03 (dd, J = 8.4, 2.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 4.83 (s, 2H), 4.08 (d, J = 13.6 Hz, 2H), 3.90 (t, J = 5.9 Hz, 2H), 3.41 (td, J = 13.1, 2.7 Hz, 2H), 3.13 (t, 7 = 5.9 Hz, 2H), 1.99 (td, 7 = 13.3, 3.7 Hz, 2H), 1.83 - 1.66 (m, 2H). MS (ESI) m / z 390.1 [M+H]+C16H18F3N3O3S. HPLC analysis: MeCN-H2O (95:5), 7.88 min, 95.40% pure. l-Methyl-6-((7-nitro-3,4-dihydroisoquinolin-2(l / / )-yl)suIfonyl)benzo[cd]indoL2(17 / )-one (TL465)

[0467] The product was obtained as a brown solid (60 mg, 67%) using a similar procedure as described for TL346.1H NMR (300 MHz, DMSO-d6) δ 8.68 (d, 7 = 8.4 Hz, 1H), 8.21 (d, 7 = 7.7 Hz, 1H), 8.10 (dd, 7 = 15.6, 4.7 Hz, 2H), 7.93 (dd, 7 = 9.1, 6.4 Hz, 2H), 7.40 - 7.26 (m, 2H), 4.47 (s, 2H), 3.49 (t, 7 = 6.0 Hz, 2H), 3.38 (s, 3H), 2.91 (t, 7 = 6.0 Hz, 2H). MS (ESI) m / z 421 .9 [M-H]’ C21H17N3O5S. HPLC analysis: MeCN-H20 (95:5), 9.13 min, 96.05% pure.

[0468] (3aR,4S,6aS)-4-(5-(7-Nitro-3,4-dihydroisoquinolin-2(lH)-yl)-5-oxopentyl)tetrahydro-LH- thieno[3,4-d]imidazol-2(3H)-one (TL466)

[0469] The product was obtained as a yellow solid (85 mg, 76%) using a similar procedure as described for TL346. 1H NMR (300 MHz, DMSO-d6) δ 8.15 (t, 7 = 2.8 Hz, 1H), 8.04 (dt, 7 = 7.8, 3.2 Hz, 1H), 7.46 (dd, 7 = 8.4, 2.5 Hz, 1H), 6.45 (s, 1H), 6.37 (s, 1H), 4.76 (d, 7 = 22.9 Hz, 2H), 4.30 (t,

[0470] J = 6.5 Hz, 1H), 4.14 (t, J = 6.1 Hz, 1H), 3.70 (q, J= 5.4 Hz, 2H), 3.17 - 3.04 (m, 1H), 2.98 (t, J = 5.8 Hz, 1H), 2.92 - 2.76 (m, 2H), 2.57 (d, J = 12.4 Hz, 1H), 2.41 (t, J = 7.4 Hz, 2H), 1.67 - 1.45 (m, 4H), 1.36 (s, 2H). MS (ESI) m / z 405.2 [M+H]+C19H24N4O4S. HPLC analysis: MeCN- H2O (95:5), 5.98 min, 95.31% pure.

[0471] A^-(4-(7-Nitro-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)acetamide (TL467)

[0472] The product was obtained as a yellow solid (87 mg, 92%) using a similar procedure as described for TL346. 1H NMR (300 DMSO-d6) δ 8.33 - 7.96 (m, 2H), 7.67 (d, 7 = 8.1 Hz, 2H), 7.45 (dd, J = 14.8, 8.3 Hz, 3H), 4.82 (s, 2H), 3.70 (s, 3H), 2.99 (t, J = 5.6 Hz, 2H), 2.07 (s, 3H). MS (ESI) m / z 340.1 [M+H]+C18H17N3O4. HPLC analysis: MeCN-H2O (95:5), 7.08 min, 98.15% pure.

[0473] 2-(3-((7-Nitro-3,4-dihydroisoquinolin-2(lH)-yl)sulfonyI)propyI)isoindoline-l, 3-dione

[0474] (TL468) The product was obtained as a yellow solid (55 mg, 46%) using a similar procedure as described for TL346. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J = 2.4 Hz, 1H), 8.04 (dd, 7 = 8.4, 2.5 Hz, 1H), 7.92 - 7.71 (m, 4H), 7.46 (d, 7 = 8.5 Hz, 1H), 4.54 (s, 2H), 3.67 (s, 2H), 3.52 (d, 7 = 5.9 Hz, 2H), 3.32 - 3.19 (m, 2H), 2.99 (t, 7 = 5.9 Hz, 2H), 2.00 (dd, 7 = 9.1, 6.1 Hz, 2H). MS (ESI) m / z 429.9 [M+H]+C^HigNsOeS. HPLC analysis: MeCN-H20 (95:5), 6.02 min, 97.61% pure.

[0475] 2,2,2-Trifluoro-l-(7-((7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)sulfonyl)-3,4- dihydroisoquinolin-2(lH)-yl)ethan-l-one (TL471)

[0476] The product was obtained as a pink solid (33 mg, 38%) using a similar procedure as described for TL346. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, 7 = 2.5 Hz, 1H), 7.98 (dd, 7 = 8.5, 2.5 Hz, 1H), 7.80 (dd, 7 = 17.0, 2.0 Hz, 1H), 7.72 - 7.62 (m, 1H), 7.45 (d, 7 = 8.0 Hz, 1H), 7.38 (dd, 7 = 8.6, 2.2 Hz, 1H), 4.85 (d, 7 = 8.0 Hz, 2H), 4.37 (d, 7 = 5.5 Hz, 2H), 3.80 (q, 7 = 5.8 Hz, 2H), 3.44 - 3.35 (m, 2H), 2.98 (q, 7 = 6.5 Hz, 4H). MS (ESI) m / z 467.8 [M-H]’ C20H18F3N3O5S. HPLC analysis: MeCN-H2O (95:5), 8.30 min, 90.22% pure.

[0477] (7-Nitro-3,4-dihydroisoquinolin-2(lH)-yl)(l-(trifluoromethyl)cyclopropyl) methanone (TL475)

[0478] The product was obtained as a white solid (17 mg, 19%) using a similar procedure as described for TL346. 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.05 (dd, 7 = 8.4, 2.4 Hz, 1H), 7.47 (d, 7 = 8.5 Hz, 1H), 4.80 (d, 7 = 33.3 Hz, 2H), 3.84 (s, 2H), 2.99 (d, 7 = 6.0 Hz, 2H), 1.35 (d, 7 = 5.2 Hz, 2H), 1.26 (d, 7 = 15.3 Hz, 2H). MS (ESI) m / z 356.1 [M+MeCN]+CI4HI3F3N2O3 HPLC analysis: MeCN-H20 (95:5), 7.28 min, 95.27% pure.

[0479] (£)-7-Hydroxy-5-methoxy-4-methyl-6-(3-methyl-6-(7-nitro-3,4-dihydroisoquinolin-2(l / / )- yl)-6-oxohex-2-en- l-yl)isobenzofuran- l(3H)-one (TL476)

[0480] The product was obtained as a white solid (14 mg, 10%) using a similar procedure as described for TL346. H NMR (300 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.12 (dd, 7 = 6.1, 2.5 Hz, 1H), 8.02 (dd, 7 = 8.4, 2.3 Hz, 1H), 7.42 (dd, 7 = 8.5, 3.2 Hz, 1H), 5.22 (d, 7 = 5.5 Hz, 2H), 5.18 - 5.05 (m, 1H), 4.76 (s, 1H), 4.65 (s, 1H), 3.67 (d, 7 = 4.6 Hz, 4H), 3.63 (t, 7 = 3.9 Hz, 2H), 3.26 (dd, 7 = 10.4, 6.8 Hz, 2H), 2.93 (t, 7 = 5.9 Hz, 1H), 2.82 (t, 7 = 6.0 Hz, 1H), 2.47 - 2.39 (m, 2H), 2.18 (dd, 7 = 9.2, 5.2 Hz, 2H), 2.05 (d, 7 = 4.9 Hz, 3H), 1.76 (s, 3H). MS (ESI) m / z 481.0 [M+H]+C26H28N2O7. HPLC analysis: MeCN-H20 (95:5), 7.98 min, 98.25% pure.

[0481] (2-(Furan-3-yl)quinolin-4-yl)(7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)methanone (TL477)

[0482] The product was obtained as a yellow sticky solid (18 mg, 16%) using a similar procedure as described for TL346. MS (ESI) m / z 400.1 [M+H]+CO3H17N3O4. HPLC analysis: MeCN-H20 (95:5), 7.63 min, 96.28% pure. 5-(7-Nitro-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrazin-2(l / / )-one (TL478)

[0483] The product was obtained as a white solid (15 mg, 18%) using a similar procedure as described for TL346.1H NMR (300 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.14 (s, 1H), 8.04 (dd, 7 = 8.4, 2.3 Hz, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.84 (s, 1H), 7.47 (d, J = 8.5 Hz, 1H), 4.90 (s, 2H), 3.84 (s, 2H), 3.02 (d, J = 6.4 Hz, 2H). MS (ESI) m / z 298.8 [M-H]’ C14H12N4O4. HPLC analysis: MeCN- H2O (95:5), 7.77 min, 98.42% pure.

[0484] A,'-(4-((7 -Nitro-3, 4-dihydroisoquinolin-2(lH)-yl)sulfonyl)phenyl)acetamide (TL485)

[0485] The product was obtained as a pink solid (40 mg, 42%) using a similar procedure as described for TL346. 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.12 (d, J = 2.5 Hz, 1H), 8.05 -7.93 (m, 1H), 7.87 - 7.69 (m, 4H), 7.39 (d, J = 8.6 Hz, 1H), 4.32 (s, 2H), 2.96 (d, 7 = 6.2 Hz, 2H), 2.07 (s, 3H). MS (ESI) m / z 373.8 [M-H]" C17H17N3O5S. HPLC analysis: MeCN-H2O (95:5), 6.87 min, 98.32% pure.

[0486] 5-FIuoro-6-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrimidine-2,4(lH,3H)- dione (TL486)

[0487] The product was obtained as a white solid (22 mg, 24%) using a similar procedure as described for TL346. 1H NMR (300 MHz, DMSO-d6) <5 11.70 (s, 1H), 11.14 (s, 1H), 8.20 (d, J = 26.0 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.88 (s, 2H), 3.80 (s, 2H), 2.99 (s, 2H). MS (ESI) m / z 333.0 [M-H]" C14H11FN4O5. HPLC analysis: MeCN-H20 (95:5), 5.21 min, 97.84% pure.

[0488] 4-((7-Nitro-3,4-dihydroisoquinolin-2(lH)-yl)sulfonyl)benzo[c][l,2,5]thiadiazole (TL487)

[0489] The product was obtained as a pink solid (49 mg, 52%) using a similar procedure as described for TL346. 1H NMR (300 MHz, DMSO-d6) δ 8.37 (d, 7 = 8.8 Hz, 1H), 8.30 (d, 7 = 7.1 Hz, 1H), 8.05 (d, 7 = 2.4 Hz, 1H), 7.98 - 7.81 (m, 2H), 7.27 (d, 7 = 8.5 Hz, 1H), 4.67 (s, 2H), 3.70 (t, 7 = 6.0 Hz, 2H), 2.84 (t, 7 = 6.1 Hz, 2H). MS (ESI) m / z 377.0 [M+H]+C17H17N3O5S. HPLC analysis: MeCN-HzO (95:5), 7.73 min, 98.27% pure.

[0490] 7-Nitro-2-((3-(trifluoromethyl)phenyl)sulfonyI)-l,2,3,4-tetrahydroisoquinoIine (TL490)

[0491] The product was obtained as a yellow solid (68 mg, 86%) using a similar procedure as described for TL346. 1H NMR (300 MHz, DMSO-d6) δ 8.19 - 8.11 (m, 2H), 8.05 (d, 7 = 8.0 Hz, 2H), 7.97 (dd, 7 = 8.5, 2.5 Hz, 1H), 7.85 (t, 7 = 7.8 Hz, 1H), 7.33 (d, 7 = 8.5 Hz, 1H), 4.50 (s, 2H), 3.49 (t, 7 = 6.1 Hz, 2H), 2.92 (t, 7 = 6.1 Hz, 2H). MS (ESI) m / z 384.8 [M-H]’ C16H13F3N2O4S. HPLC analysis: MeCN-H20 (95:5), 8.57 min, 99.55% pure.

[0492] (E)-3-(4-Fluorophenyl)- 1 -(7 -nitro-3,4-dihydroisoquinolin-2(l 7 / )-yl)prop-2-en- 1 -one (TL491) The product was obtained as a yellow solid (24 mg, 23%) using a similar procedure as described for TL346. 1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, 7 = 12.5 Hz, 1H), 8.05 (d, 7= 8.4 Hz, 1H), 7.83 (t, 7 = 6.9 Hz, 2H), 7.55 (d, 7 = 15.3 Hz, 1H), 7.48 (d, 7 = 8.4 Hz, 1H), 7.39 - 7.19 (m, 3H), 4.96 (d, 7 = 66.0 Hz, 2H), 3.90 (dt, 7 = 46.9, 5.8 Hz, 2H), 2.99 (dt, 7 = 21.4, 5.8 Hz, 2H). MS (ESI) m / z 368.1 [M+MeCN]+C18H15FN2O3. HPLC analysis: MeCN-H20 (95:5), 7.91 min, 97.66% pure.

[0493] 4-(7-Nitro-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)quinolin-2(l / / )-one (TL496).

[0494] The product was obtained as a yellow solid (44 mg, 45%) using a similar procedure as described for TL346. MS (ESI) m / z C19H15N3O4.

[0495] 7-Nitro-2-((4-(thiophen-2-yl)phenyl)suIfonyl)-l,2,3,4-tetrahydroisoquinoline (TL498)

[0496] The product was obtained as a yellowish white solid (42 mg, 38%) using a similar procedure as described for TL346.1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, 7 = 2.4 Hz, 1H), 7.99 - 7.91 (m, 1H), 7.91 - 7.79 (m, 4H), 7.73 - 7.63 (m, 2H), 7.39 (d, 7 = 8.5 Hz, 1H), 7.20 (dd, 7 = 5.1, 3.7 Hz, 1H), 4.39 (s, 2H), 3.40 (d, 7 = 6.0 Hz, 2H), 2.97 (t, 7 = 6.0 Hz, 2H). MS (ESI) m / z 443.8 [M+H]+C19H16N2O4S2. HPLC analysis: MeCN-H20 (95:5), 9.05 min, 99.15% pure.

[0497] 2-Methoxy-5-(2-(7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethoxy) benzaldehyde (TL499)

[0498] The product was obtained as a yellow solid (30 mg, 29%) using a similar procedure as described for TL346. 1H NMR (300 MHz, DMSO-d6) δ 10.17 (d, 7= 0.7 Hz, 1H), 8.27 - 8.00 (m, 2H), 7.64 (d, 7 = 8.7 Hz, 1H), 7.50 (d, 7 = 8.5 Hz, 1H), 6.81 - 6.60 (m, 2H), 5.10 (d, 7= 3.7 Hz, 2H),

[0499] 4.80 (d, J = 24.1 Hz, 2H), 3.88 (d, 7= 4.7 Hz, 3H), 3.74 (t, J = 5.6 Hz, 2H), 3.00 (dt, 7= 40.3, 5.9 Hz, 2H). MS (ESI) m / z 371.1 [M+H]+C19H18N2O6 HPLC analysis: MeCN-H2O (95:5), 6.93 min, 96.62% pure.

[0500] (2-(4-Methoxyphenyl)quinolin-4-yl)(7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)methanone (TL500)

[0501] The product was obtained as a yellow solid (37 mg, 30%) using a similar procedure as described for TL346. 1H NMR (499 MHz, DMSO-d6) 6 8.32 (s, 1H), 8.30 (d, J = 5.0 Hz, 1H), 8.25 (d, J = 30.6 Hz, 1H), 8.13 (q, J = 4.6, 4.2 Hz, 1H), 8.04 (ddd, J = 25.4, 8.4, 2.4 Hz, 1H), 7.93 - 7.77 (m, 2H), 7.73 - 7.59 (m, 1H), 7.57 - 7.40 (m, 1H), 7.11 (d, J = 8.5 Hz, 2H), 5.30 - 4.96 (m, 1H), 4.75 - 4.43 (m, 1H), 3.85 (s, 4H), 3.45 (dt, J = 13.0, 6.0 Hz, 2H), 3.15 (dt, J = 11.5, 6.6 Hz, 1H), 2.79 (s, 1H). MS (ESI) m / z 440.3 [M+H]+C26H21N3O4. HPLC analysis: MeCN-H20 (95:5), 8.46 min, 99.1 1 % pure.

[0502] 2-((3,5-Difluorophenyl)sulfonyl)-7-nitro-l,2,3,4-tetrahydroisoquinoline (TL501) The product was obtained as a white solid (20 mg, 20%) using a similar procedure as described for TL346. 1H NMR (499 MHz, DMSO-d6) 8 8.13 (d, J = 2.4 Hz, 1H), 8.00 (dd, J = 8.5, 2.5 Hz, 1H), 7.67 (tt, J = 9.2, 2.3 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.41 (d, J = 8.5 Hz, 1H), 4.46 (s, 2H), 3.46 (t, J = 6.0 Hz, 2H), 2.97 (t, J = 6.1 Hz, 2H). MS (ESI) m / z 352.8 [M-H] Ci5Hi2F2N2O4S. HPLC analysis: MeCN-H20 (95:5), 8.29 min, 96.56% pure.

[0503] 2-(2-(7-Nitro-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)isoindoIine-l, 3-dione (TL502) The product was obtained as a white solid (21 mg, 21%) using a similar procedure as described for TL346. 1H NMR (499 MHz, DMSO-d6) 6 8.16 (dd, J = 4.7, 2.3 Hz, 1H), 8.08 (ddd, J = 13.1,

[0504] 8.4, 2.5 Hz, 1H), 7.98 - 7.83 (m, 4H), 7.51 (t, J = 8.8 Hz, 1H), 4.96 (s, 1H), 4.73 (s, 1H), 4.66 (s, 2H), 3.85 (t, J = 6.0 Hz, 1H), 3.69 (t, J = 6.0 Hz, 1H), 3.09 (t, J = 5.9 Hz, 1H), 2.94 (t, J = 6.0 Hz, 1H). MS (ESI) m / z 366.1 [M+H]+C19H15N3O5. HPLC analysis: MeCN-H20 (95:5), 9.79 min, 99.11% pure.

[0505] (6-Fluoroquinolin-8-yl)(7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)methanone (TL506)

[0506] The product was obtained as a white solid (24 mg, 25%) using a similar procedure as described for TL346. MS (ESI) m / z 352.2 [M+H]+C19H14FN3O3. HPLC analysis: MeCN-H20 (95:5), 9.73 min, 98.33% pure.

[0507] (6-Methylquinolin-8-yl)(7-nitro-3,4-dihydroisoquinolin-2(l / / )-yl)methanone (TL507)

[0508] The product was obtained as a white solid (17 mg, 18%) using a similar procedure as described for TL346. MS (ESI) m / z 348.0 [M+H]+Q0H17N3O3. HPLC analysis: MeCN-H20 (95:5), 9.83 min, 99.19% pure.

[0509] (9H-Fluoren-9-yl)methyl (R )-(1 -(7-nitro-3,4-dihydroisoquinolin-2(1H )-yl)-l -oxopropan-2- yl)carbamate (TL508)

[0510] The product was obtained as a yellow solid (20 mg, 15%) using a similar procedure as described for TL346. MS (ESI) m / z 472.3 [M+H]+C^H^NsOs. HPLC analysis: MeCN-H20 (95:5), 8.60 min, 95.33% pure.

[0511] (Sulfonylbis(4,l-phenylene))bis((7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)methanone) (TL514)

[0512] The product was obtained as yellowish- white solid (44 mg, 43%) using a similar procedure as described for TL346. MS (ESI) m / z C32H2eN40sS.

[0513] (9H-Fluoren-9-yl)methyl tert-butyl (6-(7-nitro-3,4-dihydroisoquinoIin-2(1H)-yI)-6- oxohexane- l,5-diyl)(S)-dicarbamate (TL515) .

[0514] The product was obtained as a yellow solid (72 mg, 41 %) using a similar procedure as described for TL346. 1H NMR (499 MHz, DMSO-d6) δ 8.15 (q, J = 5.5, 4.8 Hz, 1H), 8.06 - 7.97 (m, 1H), 7.87 (d, 7 = 7.5 Hz, 2H), 7.75 - 7.57 (m, 3H), 7.41 (dtt, 7 = 19.5, 8.3, 4.3 Hz, 3H), 7.30 (q, 7 = 8.7, 7.6 Hz, 2H), 6.76 (q, 7 = 6.5, 6.1 Hz, 1H), 4.97 - 4.71 (m, 2H), 4.68 - 4.45 (m, 2H), 4.21 (ddd, 7= 28.3, 22.0, 7.1 Hz, 3H), 3.94 - 3.56 (m, 5H), 3.00 - 2.74 (m, 4H), 1.65 - 1.52 (m, 2H), 1.36 (s, 9H). MS (ESI) m / z C35H40N4O7.

[0515] (E)-2-(5-Fluoro-2-methyl-l-(4-(methylsulfinyl)benzylidene)-lH-inden-3-yl)-l-(7-nitro-3,4- dihydroisoquinolin-2(lH)-yl)ethan-l-one (TL517)

[0516] The product was obtained as a yellow solid (63 mg, 44%) using a similar procedure as described for TL346. 1H NMR (499 MHz, DMSO-d6) δ 8.07 - 8.02 (m, 1H), 7.78 (dt, J = 8.1, 2.9 Hz,

[0517] 2H), 7.73 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.47 (dd, J = 18.6, 8.8 Hz, 1H), 7.33 (d, J = 20.6 Hz, 1H), 7.15 (ddd, J = 21.2, 8.4, 5.2 Hz, 1H), 7.02 (ddd, J = 11.0, 9.4, 2.5 Hz, 1H), 6.74 - 6.64 (m, 1H), 4.84 (d, J = 76.8 Hz, 2H), 3.84 (d, J = 5.9 Hz, 1H), 3.82 (d, J = 5.1 Hz, 2H), 3.73 (t, J = 6.0 Hz, 1H), 3.04 (t, J = 6.0 Hz, 1H), 2.91 (t, J = 6.0 Hz, 1H), 2.82 (s, 3H), 2.15 (d, J = 1.9 Hz, 3H). MS (ESI) m / z 558.2 [M+MeCN]+C29H25FN2O4S. HPLC analysis: MeCN-H20 (95:5), 7.80 min, 99.64% pure.

[0518] (7-Methoxybenzofuran-2-yl)(7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)methanone (TL535) The product was obtained as a white solid (33 mg, 34%) using a similar procedure as described for TL346. 1H NMR (499 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.07 (dd, J = 8.5, 2.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.31 (dd, J = 7.9, 1.1 Hz, 1H), 7.26 (t, I = 7.8 Hz, 1H), 7.07 (dd, J = 7.9, 1.1 Hz, 1H), 4.97 (s, 2H), 3.97 (s, 5H), 3.08 (s, 2H). MS (ESI) m / z 353.1 [M+H]+C19H16N2O5. HPLC analysis: MeCN-H20 (95:5), 7.89 min, 99.48% pure.

[0519] (7-Nitro-3,4-dihydroisoquinolin-2(lH)-yl)(2-phenylquinolin-4-yl)methanone (TL540)

[0520] The product was obtained as a yellow solid (63 mg, 55%) using a similar procedure as described for TL346. 1H NMR (499 MHz, DMSO-d6) δ 8.38 - 8.31 (m, 2H), 8.31 - 8.24 (m, 1H), 8.22 - 8.13 (m, 1H), 8.04 (ddd, J = 25.7, 8.4, 2.5 Hz, 1H), 7.93 - 7.78 (m, 2H), 7.76 - 7.63 (m, 1H), 7.60 - 7.42 (m, 4H), 5.27 - 5.02 (m, 1H), 4.77 - 4.40 (m, 1H), 4.29 - 3.82 (m, 1H), 3.46 (p, I = 6.6, 5.7 Hz, 1H), 3.15 (q, J = 6.1 Hz, 1H), 2.99 (d, J = 17.3 Hz, 1H), 2.79 (s, 1H). MS (ESI) m / z 410.1 [M+H]+C25H19N3O3. HPLC analysis: MeCN-H20 (95:5), 8.51 min, 99.55% pure.

[0521] Tert-butyl (S)-(3-(lH-indol-3-yl)-l-(7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)-l-oxopropan- 2-yl)carbamate (TL541)

[0522] The product was obtained as a yellow solid (41 mg, 32%) using a similar procedure as described for TL346. MS (ESI) m / z 465.2 [M+H]+C25H28N4O5. HPLC analysis: MeCN-H20 (95:5), 8.00 min, 99.85% pure. A) / V-Diethyl-4-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbonyl) benzenesulfonamide (TL544)

[0523] The product was obtained as a yellowish white solid (52 mg, 44%) using a similar procedure as described for TL346.1H NMR (499 MHz, DMSO-d6) δ 8.15 (d, J = 101.0 Hz, 2H), 7.91 - 7.83 (m, 2H), 7.74 - 7.61 (m, 2H), 7.48 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 123.3 Hz, 2H), 3.72 (d, J = 173.8 Hz, 2H), 3.20 (q, J = 7.1 Hz, 4H), 2.98 (s, 2H), 1.07 (t, J = 7.1 Hz, 6H). MS (ESI) m / z 459.1 [M+MeCN]+. C2oH23N305S. HPLC analysis: MeCN-H20 (95:5), 7.70 min, 98.64% pure.

[0524] 2-((2-Isopropyl-l-methyl-lH-imidazol-4-yl)sulfonyI)-7-nitro-l, 2, 3, 4- tetrahydroisoquinoline (TL545)

[0525] The product was obtained as a yellowish white solid (22 mg, 28%) using a similar procedure as described for TL346. MS (ESI) m / z 365.0 [M+H]+Ci6H2oN404S. HPLC analysis: MeCN-H20 (95:5), 7.07 min, 95.92% pure.

[0526] Tert-butyl (4-(2-(7-nitro-3,4-dihydroisoquinoIin-2(17f)-yI)-2-oxoethyl)phenyl) carbamate (TL550)

[0527] The product was obtained as a yellow solid (33 mg, 29%) using a similar procedure as described for TL346. MS (ESI) m / z 453.2 [M+MeCN]+C22H25N3O5. HPLC analysis: MeCN-H20 (95:5), 7.70 min, 97.73% pure.

[0528] 2-Methoxy-4-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL557)

[0529] The product was obtained as a yellow solid (32 mg, 32%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.15 - 8.06 (m, 2H), 7.63 (d, 7 = 8.4

[0530] Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H), 7.04 (dd, J = 8.4, 1.9 Hz, 1H), 7.01 - 6.94 (m, 2H), 4.09 (dd, J = 6.8, 4.0 Hz, 4H), 3.78 (s, 3H), 3.72 - 3.63 (m, 4H). MS (ESI) m / z 414.8 [M-H]’ C19H20N4O5S. HPLC analysis: MeCN-H2O (95:5), 6.83 min, 95.19% pure.

[0531] 2-Methoxy-4-(4-(pyrimidin-2-yl)piperazine-l-carbothioamido)benzoic acid (TL563). The product was obtained as a white solid (40 mg, 35%) using a similar procedure as described for TL2831.H NMR (499 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.56 (s, 1H), 8.40 (d, J = 4.7 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 8.5, 1.9 Hz, 1H), 6.68 (t, J = 4.7 Hz, 1H), 4.07 - 3.97 (m, 4H), 3.93 - 3.82 (m, 4H), 3.78 (s, 3H). MS (ESI) m / z 371.8 [M-H]’ C17H19N5O3S. HPLC analysis: MeCN-H20 (95:5), 8.01 min, 97.81% pure.

[0532] (E)-6-(6-(7-Bromo-3,4-dihydroisoquinolin-2(lH)-yl)-3-methyl-6-oxohex-2-en-l-yl)-7- hydroxy-5-methoxy-4-methylisobenzofuran-l(3H)-one (TL574). The product was obtained as a yellow sticky solid (110 mg, 46%) using a similar procedure as described for TL346. MS (ESI) m / z 516.1 [M+H]+C26H2SBrNO5 HPLC analysis: MeCN-H20 (95:5), 5.34 min, 96.49% pure.

[0533] (E)-. / V-(2-(6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-l,3-dihydroisobenzofuran-5-yl)-4- methylhex-4-enoyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)methanesulfonamide (TL579).

[0534] The product was obtained as a yellow sticky solid (20 mg, 34%) using a similar procedure as described for TL346. MS (ESI) m / z C27H32N2O?S.

[0535] 4-(4-(4-Hydroxyphenyl)piperazine-l-carbothioamido)-2-methylbenzoic acid (TL627)

[0536] The product was obtained as a pink solid (150 mg, 72%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.52 (s, 1H), 8.91 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.30 - 7.13 (m, 2H), 6.91 - 6.78 (m, 2H), 6.73 - 6.62 (m, 2H), 4.01 (t, J = 5.0 Hz, 4H), 3.04 (t, 7 = 5.0 Hz, 4H)., 3C NMR (126 MHz, DMSO-t / e) 8 181.57 , 168.65 , 151.79 , 144.63 , 144.05 , 140.14 , 131.20 , 126.58 , 125.49 , 121.31 , 118.69 , 115.97 , 50.39 , 48.77 , 22.04 . MS (ESI) m / z 371.9 [M+H]+Ci9H21N3O3S. HPLC analysis: MeCN-H20 (95:5), 5.03 min, 99.15% pure.

[0537] (4-Morpholinophenyl)(7-nitro-3,4-dihydroisoquinolin-2(lH)-yl)methanone (TL647).

[0538] The product was obtained as a yellow solid (30 mg, 29%) using a similar procedure as described for TL346. 1H NMR (499 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.03 (dd, 7 = 8.4, 2.4 Hz, 1H), 7.47 (d, 7 = 8.5 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.04 - 6.96 (m, 2H), 4.82 (s, 2H), 3.74 (q, 7 = 6.6, 5.7 Hz, 6H), 3.20 (dd, 7 = 5.8, 3.9 Hz, 4H), 2.99 (t, 7 = 5.9 Hz, 2H). MS (ESI) m / z 367.9 [M+H]+

[0539] Q0H21N3O4. HPLC analysis: MeCN-H20 (95:5), 6.84 min, 99.41% pure.

[0540] 2-Hydroxy-4-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL656)

[0541] The product was obtained as a yellow solid (90 mg, 46%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.13 - 8.04 (m, 2H), 7.64 (d, 7 = 8.4 Hz, 1H), 7.03 - 6.95 (m, 2H), 6.85 id, 7 = 2.0 Hz, 1H), 6.80 (dd, 7 = 8.5, 2.1 Hz, 1H), 4.12 - 4.01 (m, 4H), 3.69 - 3.59 (m, 4H). MS (ESI) m / z 402.9 [M+H]+C18H18N4O5S. HPLC analysis: MeCN-H20 (95:5), 7.03 min, 97.1% pure.

[0542] 2-Methyl-4-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL657)

[0543] The product was obtained as a yellow solid (65 mg, 34%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.60 - 9.44 (m, 1H), 8.20 - 8.01 (m, 2H), 7.77 (d, 7 = 8.3 Hz, 1H), 7.28 (dd, 7 = 8.3, 2.2 Hz, 1H), 7.24 (d, 7 = 2.2 Hz, 1H), 6.99 (d, 7 = 9.0 Hz, 2H), 4.17 - 3.97 (m, 4H), 3.75 - 3.58 (m, 4H).13C NMR (126 MHz, DMSO-76) δ 181.42 ,

[0544] 154.44 , 144.O8 , 139.77 , 137.20 , 131.01 , 126.89 , 126.19 , 121.63 , 112.42 , 47.55 , 45.60 , 22.01 . MS (ESI) m / z 400.9 [M+H]+C19H20N4O4S. HPLC analysis: MeCN-H2O (95:5), 7.07 min, 99.4% pure.

[0545] 2-Chloro-4-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL660)

[0546] The product was obtained as a yellow solid (50 mg, 50%) using a similar procedure as described for TL283. 1H NMR (499 DMSO-d6) δ 9.64 (s, 1H), 8.10 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.42 (d, 7 = 8.4 Hz, 1H), 6.99 (d, 7 = 9.0 Hz, 2H), 4.09 (t, 7 = 5.2 Hz, 5H), 3.67 (t, 7 = 5.3 Hz, 5H).13C NMR (126 MHz, DMSO-d6) δ 154.41 , 137.21 , 131.37 , 126.20 , 125.67 , 122.48 , 112.41 , 47.59 , 45.54. MS (ESI) m / z 418.8 [M-H]" C18H17CIN4O4S.

[0547] HPLC analysis: MeCN-H2O (95:5), 7.15 min, 97.76% pure.

[0548] 2-Fluoro-4-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL668 / 686)

[0549] The product was obtained as a yellow solid (104 mg, 53%) using a similar procedure as described for TL283.1H NMR (499 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.10 (d, 7 = 9.2 Hz, 2H), 7.78 (t, 7 = 8.5 Hz, 1H), 7.41 (dd, 7 = 13.1, 2.1 Hz, 1H), 7.29 (dd, 7 = 8.4, 2.0 Hz, 1H), 4.O9 (dd, 7 = 6.8, 4.0 Hz, 4H), 3.67 (dd, 7 = 6.5, 4.1 Hz, 4H). MS (ESI) m / z 404.9 [M+H]+C18H17FN4O4S. HPLC analysis: MeCN-H2O (95:5), 6.95 min, 99.3% pure.

[0550] 4-(4-Nitrophenyl)-A,-(l, 2, 3, 4-tetrahydroisoquinolin-7-yl)piperazine-l -carbothioamide (TL670)

[0551] The product was obtained as a yellow solid (15 mg, 27%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.39 (d, 7 = 3.0 Hz, 1H), 9.03 (s, 2H), 8.14 - 8.05 (m, 2H), 7.24 - 7.13 (m, 3H), 7.04 - 6.96 (m, 2H), 4.25 (s, 2H), 4.14 - 4.04 (m, 4H), 3.73 - 3.61

[0552] (m, 4H), 2.97 (t, 7 = 6.3 Hz, 2H) MS (ESI) m / z C20H23N5O2S.

[0553] Methyl 2-hydroxy-4-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoate (TL685)

[0554] The product was obtained as a yellow solid (160 mg, 80%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.59 (s, 1H), 8.14 - 8.03 (m, 2H), 7.69 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 7.03 - 6.93 (m, 3H), 4.11 - 4.02 (m, 4H), 3.87 (s, 3H), 3.69 - 3.59 (m, 4H). MS (ESI) m / z 416.9 [M+H]+C19H20N4O5S. HPLC analysis: MeCN-HiO (95:5), 8.01 min, 98.75% pure.

[0555] 2-Methoxy-4-(4-(4-nitrophenyl) piperazine-l-carbothioamido)benzoic acid (TL687)

[0556] The product was obtained as a yellow solid (45 mg, 23%) using a similar procedure as described for TL283. MS (ESI) m / z 414.9 [M-H]+C19H20N4O5S. HPLC analysis: MeCN-H2O (95:5), 6.79 min, 98.43% pure.

[0557] 2-Hydroxy-5-(4-(4-nitrophenyl)piperazine-l -carbothioamido)benzoic acid (TL688) The product was obtained as a yellow solid (97 mg, 50%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.32 (s, 1H), 8.12 - 8.05 (m, 2H), 7.67 (d, J = 2.7 Hz, 1H), 7.47 (dd, J = 8.8, 2.7 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 4.16 - 4.03 (m, 4H), 3.72 - 3.63 (m, 5H).13C NMR (126 MHz, DMSO-d6) δ 181.78 , 172.05 , 158.94 , 154.48 , 137.15 , 134.95 , 132.72 , 127.74 , 126.20 , 116.89 , 112.57 , 112.37 , 47.08 , 45.56 , 39.52 . MS (ESI) m / z 402.8 [M+H]+CI8HI8N4O5S. HPLC analysis: MeCN-H20 (95:5), 6.74 min, 99.38% pure.

[0558] 3-Hydroxy-4-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL689)

[0559] The product was obtained as a yellow solid (95 mg, 49%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 8.12 - 8.05 (m, 2H), 7.68 (dd, 7 = 8.1, 1.6 Hz, 1H), 7.64 (d, 7 = 1.5 Hz, 1H), 7.13 (d, 7 = 8.2 Hz, 1H), 7.11 - 7.05 (m, 2H), 3.65 (t, 7 = 5.2 Hz, 4H), 3.22 (t, 7 = 5.3 Hz, 4H)., 3C NMR (126 MHz, DMSO-d6) δ 185.17, 154.54 , 147.36 , 138.27 , 126.08 , 125.44 , 123.43 , 113.78 , 112.79 , 108.42 , 44.40 , 42.94 . MS (ESI) m / z CI8HI8N4O5S.

[0560] 2-Hydroxy-4-(4-(4-hydroxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL702)

[0561] The product was obtained as a white solid (60 mg, 32%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 11.30 (s, 1H), 9.60 (s, 1H), 8.91 (s, 1H), 7.67 (d, 7

[0562] = 8.6 Hz, 1H), 7.02 - 6.88 (m, 2H), 6.84 (d, 7 = 8.5 Hz, 2H), 6.71 - 6.65 (m, 2H), 4.00 (t, 7 = 4.9

[0563] Hz, 4H), 3.05 (t, 7 = 5.0 Hz, 4H).13C NMR (126 MHz, DMSO-d6) δ 181.34 , 172.13 , 161.98 ,

[0564] 151.81 , 148.17 , 143.98 , 130.51 , 118.71 , 115.98 , 114.35 , 109.93 , 108.10 , 50.38 , 49.00 .

[0565] MS (ESI) m / z 373.8 [M+H]+C18H19N3O4S. HPLC analysis: MeCN-H2O (95:5), 3.49 min, 99.32% pure.

[0566] 2-Fluoro-4-(4-(4-hydroxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL703)

[0567] The product was obtained as a pink solid (98 mg, 67%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.73 (s, 1H), 8.89 (s, 1H), 7.79 (t, 7 = 8.6 Hz, 1H), 7.38 (dd, 7 = 13.3, 2.0 Hz, 1H), 7.27 (dd, 7 = 8.6, 2.0 Hz, 1H), 6.89 - 6.78 (m, 2H), 6.72 - 6.62 (m, 2H), 4.03 (t, 7 = 5.0 Hz, 4H), 3.06 (t, 7 = 5.0 Hz, 4H).13C NMR (126 MHz, DMSO-d6) δ 181.07 , 165.15 , 165.12 , 162.55 , 151.81 , 147.46 , 147.36 , 143.96 , 132.20 , 132.18 , 118.70 , 118.67 , 115.97 , 113.62 , 110.94 , 110.73 , 50.38 , 48.94 . MS (ESI) m / z 375.9 [M+H]+CI8HI8FN3O3S. HPLC analysis: MeCN-H20 (95:5), 4.98 min, 98.65% pure.

[0568] 2-Chloro-4-(4-(4-hydroxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL704)

[0569] The product was obtained as a white solid (35 mg, 23%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 13.21 - 13.06 (m, 1H), 9.67 (s, 1H), 8.89 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.6, 2.1 Hz, 1H), 6.88 - 6.81 (m, 2H), 6.72 - 6.65 (m, 2H), 4.03 (t, 7 = 5.0 Hz, 4H), 3.05 (t, 7 = 5.1 Hz, 4H). MS (ESI) m / z 391.9 [M+H]+C18H18CIN3O3S. HPLC analysis: MeCN-H20 (95:5), 5.17 min, 96.48% pure.

[0570] 4-(4-((3-NitrophenyI)suIfonyl)piperazin-l-yl)phenol (TL706)

[0571] The product was obtained as pink- white solid (1 13 mg, 56%) using a similar procedure as described for TL346.1H NMR (499 MHz, DMSO-d6) δ 8.60 - 8.55 (m, 1H), 8.41 (t, 7 = 2.0 Hz,

[0572] 1H), 8.22 (dt, J = 7.9, 1.4 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 6.71 - 6.63 (m, 2H), 3.14 (p, J = 5.9, 4.7 Hz, 8H). MS (ESI) m / z 363.8 [M+H]+C16H17N3O5S. HPLC analysis: MeCN-H2O (95:5), 6.68 min, 98.89% pure.

[0573] 2-Hydroxy-5-(4-(4-hydroxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL707)

[0574] The product was obtained as a pink solid (80 mg, 38%) using a similar procedure as described for TL283.1H NMR (499 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.01 (s, 1H), 7.65 (t, J = 2.1 Hz, 1H), 7.46 (dd, J = 8.8, 2.7 Hz, 1H), 6.90 (dd, J = 8.7, 2.5 Hz, 3H), 6.75 - 6.64 (m, 2H), 4.05 (t, J = 5.0 Hz, 4H), 3.09 (t, J = 5.0 Hz, 4H). MS (ESI) m / z 373.8 [M+H]+C18H19N3O4S. HPLC analysis: MeCN-H20 (95:5), 4.50 min, 99.91% pure.

[0575] 4-(4-Hydroxyphenyl)-A'-(2-methyl-4-mtrophenyl)piperazine-l -carbothioamide (TL712)

[0576] The product was obtained as a yellow solid (54 mg, 52%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.73 (s, 1H), 8.13 (d, J = 2.7 Hz, 1H), 8.05 (dd, J = 8.7, 2.8 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 8.5 Hz, 2H), 6.86 - 6.80 (m, 1H), 6.75 - 6.66 (m, 3H), 4.09 (s, 4H), 3.14 (dt, 7 = 7.4, 4.1 Hz, 5H), 2.31 (s, 3H). MS (ESI) m / z 373.0 [M+H]+C18H20N4O3S. HPLC analysis: MeCN-H20 (95:5), 6.28 min, 98.42% pure.

[0577] A'-(2-Hydroxy-4-nitrophenyl)-4-(4-hydroxyphenyl)piperazine-l -carbothioamide (TL714)

[0578] The product was obtained as a yellow solid (16 mg, 15%) using a similar procedure as described for TL283. MS (ESI) m / z [M+H]+C17H18N4O4S. HPLC analysis: MeCN-H20 (95:5), 5.95 min, 99.06% pure.

[0579] A-(3-Fluoro-4-nitrophenyl)-4-(4-hydroxyphenyl)piperazine-l-carbothioamide (TL717)

[0580] The product was obtained as a yellow solid (20 mg, 16%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.94 (s, 1H), 8.12 (t, J = 9.0 Hz, 1H), 7.63 (dd, J = 14.2, 2.3 Hz, 1H), 7.40 (dd, J = 9.1, 2.3 Hz, 1H), 6.90 - 6.80 (m, 2H), 6.73 - 6.64 (m, 2H), 4.06 (t, J = 4.9 Hz, 4H), 3.09 (t, 7 = 5.1 Hz, 4H).13C NMR (126 MHz, DMSO-76) 5 180.65 , 156.56 , 151 .96 , 149.42 , 149.33 , 143.70 , 126.99 , 1 18.80 , 1 17.96 , 1 17.94 , 1 16.03 , 115.99 , 1 10.50 , 1 10.30 , 50.44 , 49. 12 .MS (ESI) m / z 376.9 [M+H]+C17H17FN4O3S. HPLC analysis: MeCN-H2O (95:5), 6.68 min, 99.48% pure.

[0581] A'-(2,5-Dimethoxy-4-nitrophenyl)-4-(4-hydroxyphenyl)piperazine-l-carbothioamide

[0582] (TL720)

[0583] The product was obtained as a yellow solid (38 mg, 27%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.88 (s, 1H), 7.58 (s, 1H), 7.49 (s,

[0584] 1H), 6.89 - 6.79 (m, 2H), 6.71 - 6.63 (m, 2H), 4.04 (t, J = 5.0 Hz, 4H), 3.84 (s, 3H), 3.82 (s, 3H), 3.09 - 3.02 (m, 4H).13C NMR (126 MHz, DMSO-O 5 181.61 , 151.79 , 146.52 , 144.01 ,

[0585] 136.50 , 135.18 , 118.65 , 115.98 , 113.09 , 108.74 , 57.48 , 56.94 , 50.27 , 48.64 . MS (ESI) m / z 419.1 [M+H]+C19H22N4O5S. HPLC analysis: MeCN-H2O (95:5), 6.41 min, 95.70% pure.

[0586] 3-Methyl-4-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL738)

[0587] The product was obtained as a yellow solid (108 mg, 70%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.12 - 8.05 (m, 2H), 7.81 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 8.1, 2.0 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.05 - 6.94 (m, 2H),

[0588] 3.73 - 3.62 (m, 4H), 2.24 (s, 3H).13C NMR (126 MHz, DMSO-J6) δ 181.64 , 167.73 , 154.50 , 144.10 , 137.22 , 135.90 , 131.67 , 129.17 , 128.87 , 127.61 , 126.18 , 112.44 , 47.24 , 45.61 , 18.39 . MS (ESI) m / z 400.9 [M+H]+C19H20N4O4S. HPLC analysis: MeCN-H2O (95:5), 6.91 min, 98.65% pure.

[0589] 4-Methyl-3-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL739)

[0590] The product was obtained as a yellow solid (110 mg, 71%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.10 (d, J = 9.0 Hz, 2H),

[0591] 7.73 (d, J = 7.9 Hz, 1H), 7.64 (s, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 9.0 Hz, 2H), 4.11 (t, 7 = 5.1 Hz, 4H), 3.68 (t, 7 = 5.3 Hz, 4H), 2.24 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 181.79 , 154.54 , 141.47 , 140.15 , 137.21 , 130.75 , 130.22 , 127.64 , 126.19 , 112.45 , 47.13 , 45.63 , 18.55 . MS (ESI) m / z 400.9 [M+H]+C19H20N4O4S. HPLC analysis: MeCN-H2O (95:5), 6.94 min, 97.2% pure.

[0592] 4-Ethyl-3-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL740)

[0593] The product was obtained as a yellow solid (60 mg, 43%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 12.77 (s, 1H), 9.22 (s, 1H), 8.14 - 8.05 (m, 2H), 7.78 (dd, 7= 7.9, 1.8 Hz, 1H), 7.64 (d, 7 = 1.8 Hz, 1H), 7.38 (d, 7 = 8.1 Hz, 1H), 7.06 - 6.95 (m, 2H), 4.24 - 3.99 (m, 4H), 3.75 - 3.60 (m, 4H), 2.61 (q, 7 = 7.6 Hz, 2H), 1.15 (t, 7 = 7.5 Hz, 3H).13C NMR ( 126 MHz, DMSO-d6) δ 182.13 , 167.48 , 154.55 , 147.07 , 139.65 , 137.22 , 130.91 , 129.21 , 128.94 , 127.99 , 126.19 , 1 12.47 , 47.13 , 45.65 , 24.49 , 14.26 . MS (ESI) m / z 414.9 [M+H]+C20H22N4O4S. HPLC analysis: MeCN-H2O (95:5), 7.27 min, 96.7% pure.

[0594] 3-Ethyl-4-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL741)

[0595] The product was obtained as a yellow solid (90 mg, 64%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.09 (d, J = 8.9 Hz, 2H), 7.83 (s, 1H), 7.76 (d, 7 = 8.2 Hz, 1H), 7.20 (d, 7= 8.1 Hz, 1H), 7.00 (d, 7 = 9.0 Hz, 2H), 4.11 (t, 7 = 5.3 Hz, 4H), 3.67 (s, 4H), 2.61 (q, J = 7.5 Hz, 2H), 1.15 (t, 7 = 7.6 Hz, 3H).13C NMR (126 MHz, DMSO-d6) δ 181.97 , 167.68 , 154.52 , 143.67 , 141.53 , 137.23 , 129.73 , 129.71 , 129.36 ,

[0596] 127.49 . 126.18 , 112.47 , 47.22 , 45.65 , 24.24 , 14.30 . MS (ESI) m / z 414.9 [M+HJ+C20H22N4O4S. HPLC analysis: MeCN-H2O (95:5), 7.14 min, 96.96% pure.

[0597] N-(2-fluoro-4-hydroxyphenyl)-4-(4-nitrophenyl)piperazine-l -carbothioamide (TL742 / TL748)

[0598] The product was obtained as a yellow solid (50 mg, 52%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.82 (d, 7 = 0.8 Hz, 1H), 8.99 (s, 1H), 8.13 - 8.05 (m, 2H), 7.06 - 6.95 (m, 3H), 6.63 - 6.53 (m, 2H), 4.19 - 3.99 (m, 4H), 3.76 - 3.58 (m, 4H), 2.07 (s, 2H).13C NMR (126 MHz, DMSO-d6) δ 182.75 , 159.41 , 157.57 , 157.49 , 157.46 , 154.47 , 137.17 , 131.46 , 131.44 , 126.18 , 120.16 , 112.37 , 111.25 , 111.23 , 103.24 , 103.06 ,

[0599] 47.11 . 45.52 , 1.60 .MS (ESI) m / z 376.9 [M+H]+C17H17FN4O3S. HPLC analysis: MeCN-H2O (95:5), 6.77 min, 99.86% pure.

[0600] 3,5-Dimethyl-4-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL747)

[0601] The product was obtained as a yellow solid (95 mg, 60%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.66 (s, 2H), 7.07 - 6.93 (m, 2H),

[0602] 4.18 - 3.99 (m, 4H), 3.72 - 3.62 (m, 4H).13C NMR (126 MHz, DMSO-d6) δ 180.87 , 167.73 , 154.58 , 142.90 , 137.29 , 137.12 , 129.25 , 129.13 , 126.16 , 112.54 , 47.10 , 45.75 , 39.87 , 18.50 . MS (ESI) m / z 414.9 [M+H]+C20H22N4O4S. HPLC analysis: MeCN-H2O (95:5), 7.01 min, 99.73% pure.

[0603] 2V-(2-fluoro-4-methoxyphenyl)-4-(4-nitrophenyl)piperazine-l-carbothioamide (TL749)

[0604] The product was obtained as a yellow solid (45 mg, 34%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.12 - 8.04 (m, 2H), 7. 15 (t, J = 8.9 Hz, 1H), 7.03 - 6.96 (m, 2H), 6.85 (dd, J = 11.9, 2.8 Hz, 1H), 6.78 - 6.71 (m, 1H), 4.18 - 4.05 (m, 4H), 3.77 (s, 3H), 3.71 - 3.60 (m, 4H).13C NMR (126 MHz, DMSO-d6) δ 126.19 , 112.39 ,

[0605] 47.15 . 45.52 . MS (ESI) m / z 390.9 [M+H]+C18H19FN4O3S. HPLC analysis: MeCN-H2O (95:5), 7.56 min, 97.35% pure. 3-(4-(4-Hydroxyphenyl)piperazine-l-carbothioamido)-4-methylbenzoic acid (TL750)

[0606] The product was obtained as a white solid (53 mg, 36%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.26 (s, 1H), 8.89 (s, 1H), 7.72 (dd, 7 = 7.9, 1.8 Hz, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.34 (d, 7 = 7.9 Hz, 1H), 6.85 (d, 7 = 8.4 Hz, 2H), 6.73 - 6.65 (m, 2H), 4.05 (t, 7 = 4.8 Hz, 4H), 3.05 (t, 7 = 4.9 Hz, 4H), 2.23 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 181.92, 167.43, 141.64, 140.33, 130.81, 130.09, 129.21, 127.54, 118.69, 115.95, 50.41, 48.33, 18.52. MS (ESI) m / z 371.9 [M+H]+C19H21N3O3S. HPLC analysis: MeCN-H20 (95:5), 4.98 min, 99.54% pure.

[0607] 4-(4-(4-Hydroxyphenyl)piperazine-l-carbothioamido)-3-methylbenzoic acid (TL757)

[0608] The product was obtained as a pink solid (123 mg, 85%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.80 (d, 7 = 2.0 Hz, 1H), 7.74 (dd, 7 = 8.1, 2.0 Hz, 1H), 7.17 (d, 7 = 8.1 Hz, 1H), 6.88 - 6.80 (m, 2H), 6.71 - 6.63 (m, 2H), 4.03 (t, 7 = 5.0 Hz, 4H), 3.04 (t, 7 = 5.1 Hz, 4H), 2.23 (s, 3H).13C NMR (126 MHz, DMSO-76) δ 181.79, 167.84, 151.76, 144.17, 144.08, 135.77, 131.64, 129.28, 128.73, 127.60, 118.65, 115.96, 50.37, 48.45, 18.36. MS (ESI) m / z 372.1 [M+H]+C19H21N3O3S. HPLC analysis: MeCN-H20 (95:5), 4.76 min, 99.26% pure.

[0609] 2,6-DimethyI-4-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL758)

[0610] The product was obtained as yellow solid (15 mg, 15%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.09 (d, 7 = 9.1 Hz, 2H), 7.03 (s, 2H), 6.99 (d, 7 = 9.1 Hz, 2H), 4.13 - 3.97 (m, 4H), 3.65 (t, 7 = 5.3 Hz, 4H), 2.25 (s, 6H). MS (ESI) m / z 414.9 [M+H]+C20H22N4O4S. HPLC analysis: MeCN-H20 (95:5), 6.99 min, 98.5% pure.

[0611] Methyl 2-hydroxy-4-(4-(4-hydroxyphenyl)piperazine-l-carbothioamido)benzoate (TL762)

[0612] The product was obtained as a violet solid (141 mg, 81%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.62 (s, 1H), 8.89 (s, 1H), 7.69 (d, 7 = 8.7 Hz, 1H), 7.03 (d, 7 = 2.0 Hz, 1H), 6.97 (dd, 7 = 8.7, 2.1 Hz, 1H), 6.88 - 6.79 (m, 2H), 6.73 - 6.63 (m, 2H), 4.00 (t, 7 = 4.9 Hz, 4H), 3.04 (t, 7 = 4.9 Hz, 4H).13C NMR (126 MHz, DMSO- 7e) δ 181.25, 169.59, 161.07, 151.79, 148.33, 143.97, 130.24, 118.68, 115.96, 114.51, 109.98, 107.66, 52.66, 50.37, 49.03. MS (ESI) m / z 388.1 [M+H]+C19H21N3O4S. HPLC analysis: MeCN-H20 (95:5), 6.40 min, 99.72% pure.

[0613] 4-Ethyl-3-(4-(4-hydroxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL765)

[0614] The product was obtained as a pink solid (88 mg, 58%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 12.82 (s, 1H), 9.23 (s, 1H), 8.89 (s, 1H), 7.77 (dd, 7 = 8.0, 1.8 Hz, 1 H), 7.61 (d, 7 = 1.7 Hz, 1 H), 7.37 (d, 7 = 8.0 Hz, 1 H), 6.90 - 6.81 (m, 2H), 6.71 - 6.62 (m, 2H), 4.06 (t, 7 = 4.9 Hz, 4H), 3.04 (dd, 7= 6.3, 3.9 Hz, 4H), 2.60 (q, 7 = 7.6 Hz, 2H), 1.14 (1, 7= 7.6 Hz, 3H).13C NMR (126 MHz, DMSO-d6) δ 182.22, 167.47, 151.74, 147.03, 144.11, 139.77, 130.82, 129.16, 128.98, 127.90, 118.65, 115.95, 50.41, 48.36, 24.55, 14.27. MS (ESI) m / z 386.2 [M+H]+C20H23N3O3S. HPLC analysis: MeCN-H20 (95:5), 5.43 min, 99.23% pure.

[0615] A-(3-Fluoro-4-hydroxyphenyl)-4-(4-hydroxyphenyl)piperazine-l -carbothioamide (TL766)

[0616] The product was obtained as a violet solid (120 mg, 77%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.99 (s, 1H), 8.88 (s, 1H), 7.00 (td, J = 9.0, 3.3 Hz, 1H), 6.84 (d, 7 = 8.8 Hz, 2H), 6.73 - 6.64 (m, 2H), 6.57 (dq, 7 = 9.6, 3.7, 3.2 Hz, 2H), 4.08 - 3.93 (m, 4H), 3.02 (t, 7 = 4.8 Hz, 4H).13C NMR (126 MHz, DMSO-76) δ 182.92, 159.38, 157.48, 157.43, 157.39, 151.72, 144.10, 131.43, 131.41, 120.33, 120.23, 118.63, 115.95, 111.22, 111.20, 103.22, 103.04, 50.29, 48.31. MS (ESI) m / z 348.0 [M+H]+C17H18FN3O2S. HPLC analysis: MeCN-H2O (95:5), 4.40 min, 99.60% pure.

[0617] A-(2-Fluoro-4-methoxyphenyl)-4-(4-hydroxyphenyl)piperazine-l -carbothioamide (TL767) The product was obtained as a pink solid (129 mg, 100%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.88 (s, 1H), 7.13 (t, 7 = 8.9 Hz, 1H), 6.89 - 6.80 (m, 3H), 6.76 - 6.71 (m, 1H), 6.68 (d, 7 = 2.3 Hz, 1H), 6.67 (d, 7 = 2.2 Hz, 1H), 4.03 (t, 7 = 4.9 Hz, 4H), 3.77 (s, 3H), 3.03 (t, 7 = 5.1 Hz, 4H).13C NMR (126 MHz, DMSO-d6) δ 182.83, 159.42, 159.09, 159.01, 157.46, 151.74, 144.09, 131.37, 131.34, 121.87, 121.77, 118.64,

[0618] 115.94, 109.96, 109.93, 102.21, 102.02, 56.10, 50.29, 48.34. MS (ESI) m / z 361.9 [M+H]+C18H20FN3O2S. HPLC analysis: MeCN-H20 (95:5), 5.69 min, 99.82% pure.

[0619] A?-(4-Hydroxy-2-nitrophenyl)-4-(4-hydroxyphenyl)piperazine-l -carbothioamide (TL769)

[0620] The product was obtained as a yellow solid (126 mg, 75%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.38 (s, 1H), 8.89 (s, 1H), 7.32 (d, 7 = 2.7 Hz, 1H), 7.21 (d, 7 = 8.7 Hz, 1H), 7.08 (dd, 7= 8.7, 2.8 Hz, 1H), 6.87 - 6.81 (m, 2H), 6.72 - 6.64 (m, 2H), 4.02 (t, 7 = 4.9 Hz, 4H), 3.12 - 2.98 (m, 4H).13C NMR (126 MHz, DMSO-d6) δ 182.00, 156.08, 151.74, 146.55, 144.07, 132.36, 126.68, 120.94, 118.62, 115.96, 111.00, 50.39, 48.54. MS (ESI) m / z 374.9 [M+H]+C17H18N4O4S. HPLC analysis: MeCN-H2O (95:5), 4.91 min, 99.62% pure.

[0621] 4-(4-Hydroxyphenyl)-A'-(2-methoxy-4-nitrophenyl)piperazine-I-carbothioamide (TL770)

[0622] The product was obtained as a yellow solid (128 mg, 74%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.89 (s, 1H), 7.84 (dd, 7 = 8.7, 2.5 Hz, 1H), 7.81 (d, 7 = 2.5 Hz, 1 H), 7.64 (d, 7 = 8.6 Hz, 1 H), 6.88 - 6.80 (m, 2H), 6.73 - 6.63 (m, 2H), 4.04 (dd, 7 = 6.7, 3.5 Hz, 4H), 3.92 (s, 3H), 3.05 (dd, 7= 6.2, 4.0 Hz, 4H).13C NMR (126 MHz, DMSO-d6) δ 181.75, 153.04, 151.77, 144.83, 143.99, 137.15, 127.11, 118.66, 116.10, 115.95, 106.89, 56.75, 50.29, 48.74. MS (ESI) m / z 389.0 [M+H]+C18H20N4O4S. HPLC analysis: MeCN-H20 (95:5), 6.52 min, 99.21% pure.

[0623] 2-Fluoro-5-(4-(4-hydroxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL771)

[0624] The product was obtained as a grey solid (108 mg, 64%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.89 (s, 1H), 7.78 (dd, 7 = 6.6, 2.8

[0625] Hz, 1H), 7.59 (ddd, J = 8.8, 4.2, 2.8 Hz, 1H), 7.24 (dd, J = 10.5, 8.8 Hz, 1H), 6.91 - 6.79 (m, 2H), 6.74 - 6.61 (m, 2H), 4.04 (t, J = 5.0 Hz, 4H), 3.12 - 2.98 (m, 4H).13C NMR (126 MHz, DMSO-d6) δ 181.73, 165.25, 165.22, 159.44, 157.41, 151.75, 144.06, 137.59, 137.57, 132.26, 132.18, 128.75, 118.97, 118.88, 118.66, 116.88, 116.69, 115.95, 50.34, 48.42. MS (ESI) m / z 376.0 [M+H]+C18H18FN3O3S. HPLC analysis: MeCN-H2O (95:5), 4.75 min, 99.99% pure. 4-(4-(4-Hydroxyphenyl)piperazine-l-carbothioamido)-2-methoxybenzoic acid (TL772) The product was obtained as a pink solid (118 mg, 68%) using a similar procedure as described for TL283. H NMR (499 MHz, DMSO-d6) δ 9.58 (s, 1H), 7.61 (d, 7 = 8.4 Hz, 1H), 7.18 (d, 7 = 2.0 Hz, 1H), 7.00 (dd, 7 = 8.4, 1.9 Hz, 1H), 6.88 - 6.78 (m, 2H), 6.71 - 6.60 (m, 2H), 4.02 (t, 7 = 5.1 Hz, 4H), 3.77 (s, 3H), 3.04 (t, 7 = 5.1 Hz, 4H).13C NMR (126 MHz, DMSO-76) δ 181.36, 167.29, 158.97, 151.78, 146.09, 144.01, 131.48, 118.67, 115.96, 115.33, 107.84, 56.10, 50.39, 48.78. MS (ESI) m / z 387.9 [M+H]+C19H21N3O4S. HPLC analysis: MeCN-H20 (95:5), 4.78 min, 99.72% pure.

[0626] 2-FIuoro-5-(4-(4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL774)

[0627] The product was obtained as a yellow solid (86 mg, 44%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.14 - 8.05 (m, 2H), 7.79 (dd, 7 = 6.7, 2.8 Hz, 1H), 7.60 (ddd, 7 = 8.8, 4.2, 2.8 Hz, 1H), 7.24 (dd, 7 = 10.5, 8.8 Hz, 1H), 7.02 - 6.91 (m, 2H), 4. 19 - 4.03 (m, 4H), 3.77 - 3.59 (m, 4H).13C NMR (126 MHz, DMSO-d6) δ 181.60, 165.37, 159.50, 157.47, 154.44, 137.39, 137.37, 137.17, 132.21, 132.14, 128.97, 126.19, 116.84, 116.66, 112.36, 47.23, 45.54. MS (ESI) m / z 405.0 [M+HFC18H17FN4O4S. HPLC analysis: MeCN-H20 (95:5), 6.85 min, 99.06% pure.

[0628] 2-Chloro-4-(7 -nitro- l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL775).

[0629] The product was obtained as yellow solid (22 mg, 13%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.70 (s, 1H), 8.13 (s, 1H), 8.09 (d, 7 = 8.4 Hz, 1 H), 7.79 (d, J = 8.5 Hz, 1 H), 7.60 (s, 1 H), 7.53 (d, 7 = 8.4 Hz, 1H), 7.45 (d, 7 = 8.6 Hz, 1H), 5.18 (s, 2H), 4.11 (t, 7 = 5.8 Hz, 2H), 3.10 (t, 7 = 5.9 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 181.11, 166.52, 146.42, 145.22, 143.75, 135.65, 132.26, 131.68, 130.12, 125.68, 125.60, 122.40, 122.08, 121.92, 50.46, 46.13, 28.77. MS (ESI) m / z 391.9 [M+H]+C17H14CIN3O4S. HPLC analysis: MeCN-H2O (95:5), 7.15 min, 97.80% pure.

[0630] 3-Ethyl-4-(7-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL776).

[0631] The product was obtained using a similar procedure as described for TL283. MS (ESI) m / z 385.9 [M+H]+C17H14CIN3O4S. HPLC analysis: MeCN-H20 (95:5), 7.12 min, 95.58% pure.

[0632] 4-(4-(4-Hydroxyphenyl)piperazine-l-carbothioamido)-3,5-dimethylbenzoic acid (TL777) The product was obtained as a yellow solid (78 mg, 45%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.88 (s, 1H), 7.66 (s, 2H), 6.95 - 6.78 (m, 2H), 6.70 - 6.66 (m, 2H), 4.06 (t, 7 = 4.9 Hz, 4H), 3.10 - 2.98 (m, 4H), 2.19 (s, 6H).13C NMR (126 MHz, DMSO-d6) δ 180.91, 167.71, 151.75, 144.12, 143.04, 137.08, 129.11, 118.63, 115.95, 50.47, 48.32, 36.23, 18.46. MS (ESI) m / z 385.9 |M+H|+G0H23N3O3S. HPLC analysis: MeCN-H2O (95:5), 4.96 min, 99.38% pure.

[0633] 3-Ethyl-4-(4-(4-hydroxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL778)

[0634] The product was obtained as a brown solid (98 mg, 57%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.91 (s, 1H), 7.82 (d, 7 = 1.9 Hz, 1H), 7.75 (dd, 7 = 8.1, 2.0 Hz, 1H), 7.18 (d, 7 = 8.1 Hz, 1H), 6.94 - 6.78 (m, 2H), 6.73 - 6.58 (m, 2H), 4.04 (t, 7 = 4.9 Hz, 4H), 3.04 (t, 7 = 4.9 Hz, 4H), 2.60 (q, 7 = 7.5 Hz, 2H), 1.15 (t, 7 = 7.5 Hz, 3H).13C NMR (126 MHz, DMSO-d6) δ 182.06, 167.67, 151.75, 144.08, 143.82, 141.45, 129.76, 129.65, 129.23, 127.49, 118.64, 115.95, 50.40, 48.43, 24.30, 14.31. MS (ESI) m / z 386.1 [M+H]+C20H23N3O3S. HPLC analysis: MeCN-H2O (95:5), 5.14 min, 99.75% pure.

[0635] 4-(4-(3-Chlorophenyl)piperazine-l-carbothioamido)-2-methylbenzoic acid (TL779)

[0636] The product was obtained as a pink solid (175 mg, 63%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.54 (s, 1H), 7.78 (d, 7 = 8.4 Hz, 1H), 7.27 (dd, 7 = 8.4, 2.2 Hz, 1H), 7.26 - 7.18 (m, 2H), 6.97 (t, 7 = 2.2 Hz, 1H), 6.91 (dd, 7 = 8.4, 2.4 Hz, 1H), 6.80 (dd, 7 = 7.9, 1.8 Hz, 1H), 4.O3 (t, 7= 5.1 Hz, 4H), 3.31 (t, 7 = 5.1 Hz, 4H).13C NMR (126 MHz, DMSO-d6) δ 181.56, 168.96, 152.01, 144.32, 139.92, 134.31, 131.09, 130.92, 126.73, 121.46, 118.59, 114.87, 113.90, 48.17, 47.47, 22.03. MS (ESI) m / z 389.9 [M+H]+CI9H20C1N3O2S. HPLC analysis: MeCN-H2O (95:5), 7.94 min, 98.67% pure.

[0637] 2-Methyl-4-(4-(m-tolyl) piperazine- 1-carbothioamido) benzoic acid (TL780) The product was obtained as a white solid (122 mg, 73%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.43 (s, 1H), 7.78 (d, 7 = 8.4 Hz,

[0638] 1H), 7.25 (dd, 7 = 8.4, 2.2 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.10 - 6.97 (m, 3H), 4.84 (d, 7 = 13.1

[0639] Hz, 2H), 3.14 (td, 7 = 13.0, 2.4 Hz, 2H), 2.82 (tt, 7 = 12.1, 3.7 Hz, 1H), 2.28 (s, 3H), 1.87 - 1.75 (m, 2H), 1.64 (qd, 7 = 12.7, 3.9 Hz, 2H).13C NMR (126 MHz, DMSO-cZe) δ 181.11, 168.70, 145.71, 144.80, 140.08, 137.89, 131.17, 128.77, 127.84, 127.33, 126.34, 125.32, 124.23, 121.08,

[0640] 49.53, 42.00, 33.31, 22.07, 21.53. MS (ESI) m / z 368.9 [M-H]’ C20H23N3O2S. HPLC analysis: MeCN-H2O (95:5), 8.11 min, 98.90% pure.

[0641] 4-(4-(3-Bromophenyl)piperazine-l-carbothioamido)-2-methylbenzoic acid (TL781)

[0642] The product was obtained as a white solid (75 mg, 42%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.76 (d, 7 = 8.4 Hz, 1H), 7.28 - 7.03 (m, 4H), 6.94 (t, J = 7.9 Hz, 2H), 3.36 - 3.20 (m, 4H).,3C NMR (126 MHz, DMSO-d6) δ 181.63, 152.18, 143.45, 139.20, 131.22, 130.83, 126.79, 123.01, 121.56, 121.51, 117.70, 114.30,

[0643] 48.11, 47.48, 22.01. MS (ESI) m / z 435.8 [M+H]+Ci9H2oBrN302S. HPLC analysis: MeCN-H20 (95:5), 8.06 min, 97.52% pure.

[0644] 4-(4-(2,5-Dimethylphenyl)piperazine-l-carbothioamido)-2-methylbenzoic acid (TL782)

[0645] The product was obtained as a yellowish white solid (130 mg, 81%) using a similar procedure as described for TL283.1H NMR (499 MHz, DMSO-d6) δ 9.54 (s, 1H), 7.78 (d, 7 = 8.4 Hz, 1H), 7.30 - 7.20 (m, 2H), 7.05 (d, 7 = 7.6 Hz, 1H), 6.85 (d, 7 = 1.6 Hz, 1H), 6.82 - 6.75 (m, 1H), 4.01 (t, 7 = 4.7 Hz, 4H), 2.88 (t, 7 = 4.8 Hz, 4H), 2.50 (s, 4H), 2.24 (d, 7 = 4.0 Hz, 6H).13C NMR (126 MHz, DMSO-d6) δ 181.82, 168.66, 150.86, 144.59, 140.12, 135.98, 131.20, 131.13,

[0646] 129.11, 126.46, 125.54, 124.30, 121.19, 120.19, 51.59, 49.36, 22.06, 21.30, 17.66. MS (ESI) m / z 384.0 [M+H]+C19H20FN3O2S. HPLC analysis: MeCN-H2O (95:5), 8.37 min, 99.57% pure.

[0647] 2-Methyl-4-(4-phenylpiperazine-l-carbothioamido)benzoic acid (TL783)

[0648] The product was obtained as a yellowish white solid (122 mg, 80%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 9.54 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.33 - 7.19 (m, 4H), 6.97 (d, 7 = 8.1 Hz, 2H), 6.81 (t, 7 = 7.2 Hz, 1H), 4.04 (t, 7 = 5.1 Hz, 4H), 3.24 (d, 7 = 10.4 Hz, 4H), 2.50 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 181.57, 150.88, 144.40, 139.97, 131.11, 129.46, 126.66, 121.40, 119.58, 115.92, 48.44, 48.27, 22.04. MS (ESI) m / z 355.9 [M+H]+C19H21N3O2S. HPLC analysis: MeCN-H20 (95:5), 7.17 min, 99.6% pure.

[0649] 4-(4-(5-Chloro-2-methoxyphenyl)piperazine-l-carbothioamido)-2-methylbenzoic acid (TL784) The product was obtained as a pink-white solid (52 mg, 36%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) 3 12.58 (s, 1H), 9.55 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.29 - 7.16 (m, 3H), 7.03 (d, J = 6.8 Hz, 2H), 4.02 (t, J = 4.7 Hz, 4H), 2.92 (t, J =

[0650] 4.9 Hz, 4H), 2.26 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 181.92, 168.66, 152.41, 144.59, 140.14, 132.72, 131.34, 131.22, 131.1 1, 126.54, 125.58, 123.34, 121.27, 119.77, 51.24, 49.15, 22.07, 17.71. MS (ESI) m / z 420.0 [M+H]+C20H22CIN3O3S. HPLC analysis: MeCN-H2O (95:5), 8.51 min, 99.14% pure.

[0651] 4-(4-(3,4-Dichlorophenyl)piperazine-l-carbothioamido)-2-methylbenzoic acid (TL785)

[0652] The product was obtained as a white solid (105 mg, 72%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.54 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.26 (dd, J = 8.4, 2.2 Hz, 1H), 7.22 (d, 7= 2.2 Hz, 1H), 7.16 (d, 7 = 2.9 Hz, 1H), 6.95 (dd, 7= 9.0, 2.9 Hz, 1H), 4.03 (t, 7= 5.3 Hz, 4H), 3.33 (t, 7 = 5.2 Hz, 4H).,3C NMR (126 MHz, DMSO-d6) δ 181.58, 150.51, 144.12, 139.77, 132.00, 131.02, 130.96, 126.79, 121.53, 120.07, 116.51, 115.50, 48.02, 47.30, 22.01. MS (ESI) m / z 423.9 [M+H]+C19H19CI2N3O2S. HPLC analysis: MeCN-H2O (95:5), 8.45 min, 98.28% pure.

[0653] 2-Methyl-4-(4-(4-(trifluoromethyl)phenyl)piperazine-l-carbothioamido)benzoic acid (TL786)

[0654] The product was obtained as a white solid (104 mg, 71%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.77 (d, 7 = 8.4 Hz, 1H), 7.52 (d, 7 = 8.7 Hz, 2H), 7.26 (dd, 7 = 8.4, 2.2 Hz, 1H), 7.23 (d, 7= 2.1 Hz, 1H), 7.06 (d, 7 = 8.7 Hz, 2H), 4.14 - 4.00 (m, 4H), 3.44 (dd, 7 = 6.6, 4.1 Hz, 4H).13C NMR (126 MHz, DMSO-d6) δ 181.54, 152.97, 143.99, 139.66, 130.97, 126.79, 126.70, 126.67, 126.64, 126.61, 126.53, 124.38, 121.53, 1 18.35, 118.09, 114.22, 47.96, 46.58, 22.01. MS (ESI) m / z 424.0 [M+H]+C20H20F3N3O2S. HPLC analysis: MeCN-H2O (95:5), 8.14 min, 99.07% pure.

[0655] 4-(4-(4-Chlorophenyl)piperazine-l-carbothioamido)-2-methylbenzoic acid (TL787)

[0656] The product was obtained as a white solid (112 mg, 71 %) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.62 - 9.48 (m, 1H), 7.75 (d, 7 = 8.4 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.24 - 7.20 (m, 1H), 7.18 (d, 7 = 2.2 Hz, 1H), 7.01 - 6.94 (m, 2H), 4.03 (t, 7 = 5.1 Hz, 4H), 3.31 - 3.21 (m, 4H), 2.50 (s, 4H).13C NMR (126 MHz, DMSO-t / e) 8 181.62, 149.67, 130.82, 129.12, 126.75, 122.98, 121.52, 117.26, 48.20, 47.98, 22.00. MS (ESI) m / z

[0657] 389.9 [M+H]+C19H20CIN3O2S. HPLC analysis: MeCN-H20 (95:5), 7.90 min, 99.57% pure.

[0658] 2-Methyl-4-(4-(3-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL788) The product was obtained as a yellow solid (95 mg, 62%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.56 (s, 1H), 7.78 (d, 7 = 8.4 Hz,

[0659] 1H), 7.67 (s, 1H), 7.59 (dd, 7 = 8.0, 2. 1 Hz, 1H), 7.49 (t, 7 = 8.2 Hz, 1H), 7.40 (dd, 7 = 8.3, 2.5

[0660] Hz, 1H), 7.28 (dd, 7 = 8.3, 2.2 Hz, 1H), 7.25 (d, 7 = 2.2 Hz, 1H), 4.07 (t, 7 = 5.1 Hz, 4H), 3.43 (t,

[0661] 7 = 5.1 Hz, 4H).13C NMR (126 MHz, DMSO-d6) δ 181.58, 168.83, 151.33, 149.29, 144.38,

[0662] 140.00, 131.12, 130.64, 126.77, 121.50, 121.37, 113.09, 108.63, 48.04, 47.17, 22.03. MS (ESI) m / z 400.9 [M+H]+C19H20N4O4S. HPLC analysis: MeCN-H20 (95:5), 7.40 min, 99.92% pure.

[0663] 4-(4-(2,4-Difluorophenyl)piperazine-l-carbothioamido)-2-methylbenzoic acid (TL789)

[0664] The product was obtained as a white solid (120 mg, 76%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSOvL) δ 9.56 (s, 1H), 7.78 (d, 7 = 8.4 Hz, 1H), 7.28 - 7.19

[0665] (m, 3H), 7.12 (td, 7 = 9.4, 5.9 Hz, 1H), 7.05 - 6.99 (m, 1H), 4.05 (t, 7 = 4.9 Hz, 4H), 3.10 - 2.99 (m, 4H).13C NMR (126 MHz, DMSO-d6) δ 181.74, 158.74, 156.82, 156.72, 154.38, 154.28,

[0666] 144.31, 139.91, 136.61, 136.52, 131.09, 126.61, 121.35, 121.03, 120.99, 120.95, 120.92, 111.63,

[0667] 1 11.48, 111.46, 105.35, 105.15, 104.94, 50.68, 50.66, 48.74, 22.03. MS (ESI) m / z 391.9 [M+H]+C19H19F2N3O2S. HPLC analysis: MeCN-H2O (95:5), 7.57 min, 99.93% pure.

[0668] 4-(4-(4-(Tert-butyl)phenyl)piperazine-l-carbothioamido)-2-methylbenzoic acid (TL790)

[0669] The product was obtained as a white solid (105 mg, 70%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 12.58 (s, 1H), 9.54 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.36 - 7.12 (m, 4H), 6.94 - 6.87 (m, 2H), 4.03 (t, J = 5.0 Hz, 4H), 3.19 (t, J = 5.1 Hz, 4H), 2.50 (s, 3H), 1.24 (s, 9H). MS (ESI) m / z 412.1 [M+H]+C23H29N3O2S. HPLC analysis: MeCN- H2O (95:5), 8.74 min, 97.82% pure.

[0670] 2-Methyl-4-(4-(pyridin-3-yl)piperazine-l-carbothioamido)benzoic acid (TL791)

[0671] The product was obtained as a yellowish white solid (90 mg, 59%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 12.57 (s, 1H), 9.56 (s, 1H), 8.39 - 8.31 (m, 1H), 8.02 (d, 7 = 4.5 Hz, 1H), 7.79 (d, 7 = 8.4 Hz, 1H), 7.35 (ddd, 7 = 8.6, 3.1, 1.3 Hz, 1H), 7.28 (dd, 7 = 8.4, 2.2 Hz, 1H), 7.26 - 7.20 (m, 2H), 4.05 (t, 7 = 5.1 Hz, 4H), 2.50 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 181.56, 168.59, 146.55, 144.54, 140.32, 140.12, 138.06, 131.18, 126.71, 125.56, 123.99, 122.18, 121.44, 48.20, 47.48, 22.04. MS (ESI) m / z 357.1 [M+H]+C18H20N4O2S. HPLC analysis: MeCN-H20 (95:5), 4.38 min, 98.94% pure.

[0672] 4-(4-(4-FIuorophenyl)piperazine-l-carbothioamido)-2-methylbenzoic acid (TL792)

[0673] The product was obtained as a white solid (120 mg, 83%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.55 (s, 1H), 7.77 (d, 7 = 8.4 Hz, 1H), 7.26 (dd, 7

[0674] = 8.4, 2.2 Hz, 1H), 7.23 (d, 7 = 2.1 Hz, 1H), 7.11 7.04 (m, 2H), 7.03 - 6.95 (m, 2H), 4.03 (t, J = 5.1 Hz, 4H), 3.24 - 3.12 (m, 4H).13C NMR (126 MHz, DMSOvL) δ 181.59, 169.14, 157.60, 155.72, 147.81, 147.79, 144.25, 139.85, 131.06, 126.67, 121.41, 117.84, 117.78, 115.89, 115.71, 49.14, 48.46, 22.03. MS (ESI) m / z 373.9 [M+H]+C19H20FN3O2S. HPLC analysis: MeCN-H20 (95:5), 7.29 min, 99.98% pure.

[0675] 4-(4-(5-Chloro-2-methylphenyl)piperazine-l-carbothioamido)-2-methylbenzoic add (TL794)

[0676] The product was obtained as a yellowish white solid (85 mg, 56%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 12.58 (s, 1H), 9.55 (s, 1H), 7.78 (d, 7 =

[0677] 8.4 Hz, 1H), 7.29 - 7.16 (m, 3H), 7.03 (d, J = 6.8 Hz, 2H), 4.02 (t, J = 4.7 Hz, 4H), 2.92 (t, J = 4.9 Hz, 4H), 2.26 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 181.92, 168.66, 152.41, 144.59, 140.14, 132.72, 131.34, 131.22, 131.11, 126.54, 125.58, 123.34, 121.27, 119.77, 51.24, 49.15, 22.07, 17.71. MS (ESI) m / z 403.9 [M+H]+C20H22CIN3O2S. HPLC analysis: MeCN-H2O (95:5), 8.51 min, 99.14% pure.

[0678] 4-(4-(4-Cyanophenyl)piperazine-l-carbothioamido)-2-methylbenzoic add (TL795)

[0679] The product was obtained as a white solid (48 mg, 34%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 12.59 (s, 1H), 9.51 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.29 (dd, J = 8.5, 2.2 Hz, 1H), 7.26 (d, J = 2. 1 Hz, 1H), 7.03 - 6.97 (m, 2H), 4.05 (dd, J = 6.8, 4.0 Hz, 4H), 3.56 - 3.47 (m, 4H). MS (ESI) m / z 380.9 [M+H]+C20H20N4O2S. HPLC analysis: MeCN-H20 (95:5), 6.88 min, 99.64% pure.

[0680] 4-(4-(3,5-Dichlorophenyl)piperazine-l-carbothioamido)-2-methylbenzoic add (TL796)

[0681] The product was obtained as a yellowish white solid (100 mg, 68%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 9.65 - 9.34 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.25 (dd, 7 = 8.3, 2.2 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 6.95 (d, J = 1.7 Hz, 2H), 6.86 (t, J = 1.7 Hz, 1H), 3.44 - 3.33 (m, 4H), 2.50 (s, 3H). MS (ESI) m / z 423.9 [M+H]+C19H19CI2N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.69 min, 98.83% pure.

[0682] 4-(4-(3,4-Dimethylphenyl)piperazine-l-carbothioamido)-2-methylbenzoic add (TL797)

[0683] The product was obtained as a white solid (126 mg, 78%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) 8 9.53 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.4, 2.2 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 6.69 (dd, 7 = 8.3, 2.6 Hz, 1H), 4.02 (t, 7= 5.1 Hz, 4H), 3.20 - 3.10 (m, 4H), 2.50 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H).13C NMR (126 MHz, DMSO-76) δ 181.57, 149.18, 144.33, 139.88, 136.93, 131.08, 130.36, 127.45, 126.64, 121.38, 1 17.87, 1 13.72, 48.96, 48.54, 22.04, 20.30, 18.89. MS (ESI) m / z 384.0 [M+H]+C2IH25N3O2S. HPLC analysis: MeCN-H20 (95:5), 7.80 min, 99.21 % pure.

[0684] 2-Methyl-4-(4-(p-tolyl)piperazine-l-carbothioamido)benzoic acid (TL798)

[0685] The product was obtained as a white solid (136 mg, 93%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.77 (d, 7 = 8.4 Hz, 1H), 7.25 (dd, 7 = 8.4, 2.2 Hz, 1H), 7.21 (d, 7 = 2.2 Hz, 1H), 7.05 (d, 7 = 8.2 Hz, 2H), 6.87 (d, 7 = 8.5 Hz, 2H),

[0686] 4.02 (d, J = 5.2 Hz, 4H), 3.17 (t, 7 = 5.1 Hz, 4H), 2.50 (s, 3H), 2.21 (s, 3H). MS (ESI) m / z 369.9 [M+H]+C20H23N3O2S. HPLC analysis: MeCN-H2O (95:5), 7.53 min, 99.70% pure.

[0687] 4-(4-(2,4-Dimethylphenyl)piperazine- l-carbothioamido)-2-methylbenzoic acid (TL800)

[0688] The product was obtained as a white solid (105 mg, 74%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.54 (s, 1H), 7.78 (d, 7 = 8.4 Hz, 1H), 7.26 (dd, 7 = 8.4, 2.2 Hz, 1H), 7.23 (d, 7 = 2.1 Hz, 1H), 6.99 (d, 7 = 1.9 Hz, 1H), 6.98 - 6.91 (m, 2H), 4.02 (t, 7 = 4.6 Hz, 4H), 2.85 (t, 7 = 4.9 Hz, 4H), 2.26 (s, 3H), 2.21 (s, 3H). MS (ESI) m / z 383.9 [M+H]+C2iH25N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.45 min, 99.52% pure.

[0689] 4-(4-(3-Hydroxyphenyl)piperazine-l-carbothioamido)-2-methylbenzoic acid (TL819)

[0690] The product was obtained as a beige solid (85 mg, 59%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 12.56 (s, 1H), 9.52 (s, 1H), 9.17 (s, 1H), 7.78 (d, 7 = 8.4 Hz, 1H), 7.28 (dd, 7 = 8.5, 2.2 Hz, 1H), 7.25 (d, 7 = 2.2 Hz, 1H), 7.00 (t, 7 = 8.1 Hz, 1H), 6.40 (dd, 7 = 8.1, 2.3 Hz, 1H), 6.33 (t, 7= 2.3 Hz, 1H), 6.24 (dd, 7 = 7.9, 2.1 Hz, 1H), 4.01 (t, 7 = 5.1 Hz, 4H), 3.26 - 3.12 (m, 4H), 2.50 (s, 3H). MS (ESI) m / z 371.9 [M+H]+CI9H2IN3O3S.

[0691] HPLC analysis: MeCN-H2O (95:5), 5.99 min, 99.95% pure.

[0692] 2-Chloro-4-(4-(3-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL820)

[0693] The product was obtained as a yellow solid (45 mg, 32%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.73 (d, 7 = 8.5 Hz, 1H), 7.67 (t, 7 = 2.4 Hz, 1H), 7.60 (dd, J = 8.0, 2.0 Hz, 1H), 7.55 (d, 7 = 2.1 Hz, 1H), 7.50 (t, 7 = 8.2 Hz, 1H), 7.40 (dt, 7 = 8.5, 2.5 Hz, 2H), 4.09 (t, 7 = 5.2 Hz, 4H). MS (ESI) m / z 421.0 [M+H]+C18H17CIN4O4S. HPLC analysis: MeCN-H20 (95:5), 4.72 min, 93.21% pure.

[0694] 2-Chloro-4-(4-(2-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL821)

[0695] The product was obtained as a yellow solid (82 mg, 58%) using a similar procedure as described for TL283. 'H NMR (499 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.86 (dd, 7 = 8.1, 1.6 Hz, 1H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.59 (d, 7 = 2.3 Hz, 1H), 7.42 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.38 (dd, 7 = 8.4, 1.2 Hz, 1H), 7.19 - 7.12 (m, 1 H), 4.03 (t, 7 = 4.9 Hz, 4H), 3.19 - 3.1 1 (m, 5H). MS (ESI) m / z 420.8 [M+H]+C18H17CIN4O4S. HPLC analysis: MeCN-H2O (95:5), 7.39 min, 99.53% pure.

[0696] 2-Chloro-4-(4-(4-nitrophenyl)-l,4-diazepane-l-carbothioamido)benzoic acid (TL822)

[0697] The product was obtained as a yellow solid (75 mg, 55%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.07 - 7.96 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 35.6 Hz, 2H), 6.98 - 6.87 (m, 2H), 4.11 (s, 2H), 3.89 (s, 2H), 3.69 (t, 7 =

[0698] 6.1 Hz, 2H), 2.04 (p, 7 = 6.4, 6.0 Hz, 2H). MS (ESI) m / z 434.9 [M+H]+C19H19CIN4O4S. HPLC analysis: MeCN-H20 (95:5), 6.99 min, 98.10% pure.

[0699] 2-Chloro-4-(4-(3-nitrophenyl)-3-oxopiperazine-l-carbothioamido)benzoic acid (TL823)

[0700] The product was obtained as a white solid (65 mg, 47%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.68 (s, 1H), 8.36 (t, 7 = 2.2 Hz, 1H), 8.14 (ddd, 7 = 8.3, 2.3, 0.9 Hz, 1H), 7.89 (ddd, 7 = 8.1, 2.2, 1.0 Hz, 1H), 7.80 (d, 7 = 8.5 Hz, 1H), 7.73 (t, 7 = 8.2 Hz, 1H), 7.65 (d, 7 = 2.1 Hz, 1H), 7.48 (dd, 7 = 8.5, 2.1 Hz, 1H), 4.69 (s, 2H), 4.30 (t, 7 = 5.3 Hz, 2H), 3.98 (dd, 7 = 6.3, 4.2 Hz, 2H). MS (ESI) m / z 434.8 [M+H]+C18H15CIN4O5S. HPLC analysis: MeCN-H20 (95:5), 6.37 min, 99.37% pure.

[0701] 2-Chloro-4-(4-(2-(methylthio)phenyl)piperazine-l-carbothioamido)benzoic acid (TL824)

[0702] The product was obtained as a white solid (68 mg, 48%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.73 (d, 7 = 8.4 Hz, 1H), 7.54 (d, 7 =

[0703] 2.1 Hz, 1H), 7.38 (dd, 7 = 8.4, 2.1 Hz, 1H), 7.18 - 7.15 (m, 1H), 7.15 - 7.08 (m, 3H), 4.12 - 3.93 (m, 5H), 2.96 (s, 4H), 2.39 (s, 3H). MS (ESI) m / z 421.9 [M+H]+CI9H20C1N3O2S2. HPLC analysis: MeCN-H20 (95:5), 8.04 min, 99.14% pure.

[0704] 2-Chloro-4-(4-(4-nitrobenzyl)piperazine- l-carbothioamido)benzoic acid (TL825)

[0705] The product was obtained as a yellow solid (20 mg, 15%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.65 (d, 7 =

[0706] 8.2 Hz, 2H), 7.56 (s, 1H), 7.40 (d, 7 = 8.6 Hz, 1H), 4.03 - 3.85 (m, 4H), 3.70 (s, 2H). MS (ESI) m / z 434.9 [M+H]+C19H19CIN4O4S. HPLC analysis: MeCN-H2O (95:5), 5.47 min, 96.29% pure.

[0707] 2-Chloro-4-(4-(3-(trifluoromethyl)phenyl)piperazine-l-carbothioamido)benzoic acid (TL827)

[0708] The product was obtained as a white solid (50 mg, 25%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 8.28 - 7.72 (m, 2H), 7.47 - 7.38 (m, 2H), 7.35 (d, 7 = 2.0 Hz, 1H), 7.25 - 7.20 (m, 2H), 7.19 (s, 1H), 7.08 (d, 7 = 7.6 Hz, 1H), 4.07 (t, 7 = 5.1 Hz, 4H), 3.37 (t, 7 = 5.2 Hz, 4H). MS (ESI) m / z 444.4 [M+H]+C19H17C1F3N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.20 min, 98.48% pure. 2-Chloro-4-(4-((4-chIorophenyl)(phenyl)methyl)piperazine-l-carbothioamido)benzoic acid (TL828)

[0709] The product was obtained as a white solid (20 mg, 11%) using a similar procedure as described for TL283. H NMR (499 MHz, DMSO-d6) δ 9.58 (s, 1H), 7.71 (d, 7 = 8.5 Hz, 1H), 7.51 - 7.44 (m, 3H), 7.42 (d, 7 = 7.6 Hz, 2H), 7.37 (d, 7 = 8.3 Hz, 2H), 7.35 - 7.28 (m, 3H), 7.22 (t, 7 = 7.3 Hz, 1H), 4.44 (s, 1H), 3.91 (t, 7 = 4.8 Hz, 5H), 2.37 (t, 7 = 5.0 Hz, 4H). MS (ESI) m / z 500.1 [M+H]+C25H23CI2N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.53 min, 97.07% pure.

[0710] 2-Chloro-4-(4-(2-fluorophenyl)piperazine-l-carbothioamido)benzoic acid (TL829)

[0711] The product was obtained as a while solid (90 mg, 59%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.73 (d, 7 = 8.4 Hz, 1H), 7.54 (d, 7 = 2.0 Hz, 1H), 7.39 (dd, 7 = 8.4, 2.1 Hz, 1H), 7.21 - 7.11 (m, 2H), 7.07 (td, 7= 8.5, 1.8 Hz, 1H), 7.01 (tdd, 7 = 7.4, 4.7, 1.7 Hz, 1H), 4.07 (t, 7 = 4.9 Hz, 4H), 3.14 - 3.04 (m, 4H). MS (ESI) m / z 393.8 [M+H]+C18H17CIFN3O2S. HPLC analysis: MeCN-H20 (95:5), 7.58 min, 98.76% pure.

[0712] 2-Chloro-4-(4-(4-chlorophenyl)piperidine-l-carbothioamido)benzoic acid (TL830)

[0713] The product was obtained as a yellowish solid (32 mg, 22%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.70 (d, 7 = 8.4 Hz, 1H), 7.51 (d, 7 = 2.1 Hz, 1H), 7.35 (td, 7 = 5.4, 2.6 Hz, 3H), 7.30 (d, 7 = 6.6 Hz, 2H), 4.88 (d, 7 = 13. 1 Hz, 2H), 3.16 (td, 7 = 13.1, 2.4 Hz, 2H), 2.89 (qd, 7 = 10.0, 9.2, 3.7 Hz, 1H), 1.85 (dd, 7 = 13.8, 3.7 Hz, 2H), 1.64 (qd, 7 = 12.8, 3.9 Hz, 2H). MS (ESI) m / z 408.8 [M+H]+C19H18G2N2O2S. HPLC analysis: MeCN-H2O (95:5), 8.31 min, 95.15% pure.

[0714] 2-Chloro-4-(4-((4-fluorophenyl)(phenyl)methyl)piperazine-l-carbothioamido)benzoic acid (TL831)

[0715] The product was obtained as a while solid (16 mg, 9%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.57 (s, 1H), 7.73 (d, 7 = 8.5 Hz, 1H), 7.51 (d, 7 = 2.1 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.45 - 7.41 (m, 2H), 7.35 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.32 (t, 7 = 7.6 Hz, 2H), 7.24 - 7.19 (m, 1H), 7.17 - 7.10 (m, 2H), 4.44 (s, 1H), 3.91 (t, 7 = 4.9 Hz, 4H), 2.37 (t, 7 = 5.3 Hz, 4H). MS (ESI) m / z 484.0 [M+H]+C25H23CIFN3O2S. HPLC analysis: MeCN- H2O (95:5), 7.72 min, 97.64% pure.

[0716] 2-Chloro-4-(4-(2-chlorophenyl)piperazine-l-carbothioamido)benzoic acid (TL832)

[0717] The product was obtained as a white solid (105 mg, 72%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.77 (d, 7 = 8.5 Hz, 1H), 7.58 (d, 7 = 2.1 Hz, 1 H), 7.43 (ddd, 7 = 14.3, 8.2, 1.8 Hz, 2H), 7.32 (td, 7 = 7.7, 1.6 Hz, 1 H), 7.19 (dd, 7 =

[0718] 8.1, 1.6 Hz, 1H), 7.08 (td, 7 = 7.6, 1.5 Hz, 1H), 4.07 (t, 7 = 4.8 Hz, 4H), 3.06 (t, 7 = 4.9 Hz, 4H). MS (ESI) m / z 409.8 [M+H]+CISHI7C12N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.04 min, 99.72% pure.

[0719] 4-(4-([l,l'-biphenyl]-4-yl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL833)

[0720] The product was obtained as a white solid (100 mg, 66%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.66 (d, 7 = 8.4 Hz, 1H), 7.61 (d, 7 = 7.6 Hz, 2H), 7.56 (d, 7 = 8.4 Hz, 2H), 7.50 (d, 7= 2.1 Hz, 1H), 7.41 (t, 7 = 7.6 Hz, 2H), 7.36 (dd,

[0721] 7 = 8.3, 2.2 Hz, 1H), 7.27 (t, J = 7.3 Hz, 1H), 7.05 (d, 7 = 8.3 Hz, 2H), 4.08 (t, 7 = 5.0 Hz, 4H), 3.33 (t, 7 = 5. 1 Hz, 4H). MS (ESI) m / z C24H22C1N3O2S.

[0722] 4-(4-(5-Bromopyridin-3-yl)piperazine-l-carbothioamido)-2-chIorobenzoic acid (TL834)

[0723] The product was obtained as a pink- white solid (90 mg, 47 %) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.31 (d, 7 = 2.5 Hz, 1H), 8.06 (d, 7 = 1.8 Hz, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.56 (t, 7 = 2.3 Hz, 1H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 4.06 (dd, 7 = 6.6, 3.9 Hz, 4H), 3.46 - 3.39 (m, 5H). MS (ESI) m / z 454.8 [M+H]+Ci7Hi6BrClN4O2S. HPLC analysis: MeCN-H20 (95:5), 6.48 min, 99.75% pure.

[0724] 2-Chloro-4-(4-(2-cyanophenyl)piperazine-l-carbothioamido)benzoic acid (TL835)

[0725] The product was obtained as a white solid (70 mg, 47%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.77 (d, 7 = 8.5 Hz, 1H), 7.73 (dd, 7 = 7.7, 1.6 Hz, 1H), 7.62 (td, 7 = 8.0, 1.7 Hz, 1H), 7.59 (d, 7= 2.1 Hz, 1H), 7.42 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.21 (d, 7= 8.3 Hz, 1H), 7.13 (t, 7 = 7.5 Hz, 1H), 4.10 (t, 7 = 4.9 Hz, 4H), 3.27 (t, 7 = 5.0 Hz, 5H). MS (ESI) m / z 400.9 [M+H]+C19H17CIN4O2S. HPLC analysis: MeCN-H20 (95:5), 7.22 min, 98.55% pure.

[0726] 4-(4-(4-Bromo-2-methylphenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL836)

[0727] The product was obtained as an off-white solid (138 mg, 94%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) δ 9.74 (s, 1H), 7.70 (d, 7 = 8.4 Hz, 1H), 7.52 (d, 7 = 2.1 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.32 (dd, 7 = 8.4, 2.5 Hz, 1H), 6.98 (d, 7 = 8.6 Hz, 1H), 4.04 (t, 7 = 4.8 Hz, 4H), 2.94 - 2.83 (m, 4H), 2.29 (s, 3H).13C NMR (151 MHz, DMSO-d6) 5 181.50, 166.78, 150.39, 145.24, 135.50, 133.68, 132.22, 131.65, 129.73, 125.33, 122.10, 121.87, 115.91, 51.40, 49.26, 17.84, 17.75. MS (ESI) m / z 469.9 [M+H]+Ci9Hi9BrClN3O2S. HPLC analysis: MeCN-H2O (95:5), 8.91 min, 95.44% pure.

[0728] 2-Chloro-4-(4-(2-chloropyridin-4-yI)piperazine-l -carbothioamido)benzoic acid (TL837) The product was obtained as a white solid (27 mg, 19%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.69 (s, 1H), MS (ESI) m / z 410.8 [M+H]+C17H16C12N4O2S. HPLC analysis: MeCN-H2O (95:5), 5.03 min, 99.68% pure.

[0729] 4-(4-([l,l'-biphenyl]-2-yl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL838)

[0730] The product was obtained as a white solid (18 mg, 16%) using a similar procedure as described for TL283. MS (ESI) m / z 452.1 [M+H]+C24H22C1N3O2S. HPLC analysis: MeCN-H20 (95:5), 5.41 min, 94.08% pure.

[0731] 4-(4-Benzhydrylpiperazine-l-carbothioamido)-2-chlorobenzoic acid (TL839)

[0732] The product was obtained as a while solid (55 mg, 27%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.56 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.48 - 7.43 (m, 4H), 7.35 (dd, J = 8.5, 2.1 Hz, 1H), 7.31 (t, J = 7.6 Hz, 4H), 7.23 - 7.18 (m, 2H), 4.39 (s, 1H), 3.91 (t, J = 4.8 Hz, 4H), 2.38 (t, 7 = 5.0 Hz, 4H). MS (ESI) m / z 466.1 [M+H]+C20H22CIN3O2S. HPLC analysis: MeCN-H20 (95:5), 7.28 min, 97.18% pure.

[0733] 2-Chloro-4-(4-(pyrazin-2-yl)piperazine-l-carbothioamido)benzoic acid (TL840)

[0734] The product was obtained as a white solid (79 mg, 49%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 13.12 (s, 1H), 9.66 (s, 1H), 8.34 (d, 7 = 1.6 Hz, 1H), 8.16 - 8.04 (m, 1H), 7.88 (d, 7 = 2.7 Hz, 1H), 7.79 (d, 7 = 8.4 Hz, 1H), 7.61 (d, 7 = 2.1 Hz, 1H), 7.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 4.06 (dd, 7 = 6.9, 3.9 Hz, 4H), 3.80 - 3.66 (m, 4H). MS (ESI) m / z 377.8 [M+HfCieHieClNsChS. HPLC analysis: MeCN-H20 (95:5), 5.65 min, 98.78% pure.

[0735] 2-Chloro-4-(4-(quinolin-2-yl)piperazine-l-carbothioamido)benzoic acid (TL841)

[0736] The product was obtained as a yellow solid (128 mg, 80%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-t / e) 5 9.63 (d, 7 = 33.6 Hz, 1H), 8.04 (d, 7 = 34.4 Hz, 1H), 7.58 (h, 7 = 36.5, 35.9 Hz, 6H), 7.20 (d, 7 = 34.0 Hz, 2H), 4.05 (d, 7 = 33.7 Hz, 4H), 3.81 (d, 7 = 33.7 Hz, 4H). MS (ESI) m / z 426.9 [M+H]+C21H19CIN4O2S. HPLC analysis: MeCN-H20 (95:5), 5.33 min, 94.38% pure.

[0737] 2-Chloro-4-(4-(5-phenylpyridiii-3-yl)piperazine-l-carbothioamido)benzoic acid (TL842)

[0738] The product was obtained as a pink solid (122 mg, 72%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.33 (d, 7 = 8.2 Hz, 2H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.73 (d, 7 = 7.6 Hz, 2H), 7.60 (d, 7 = 2.1 Hz, 1H), 7.56 (s, 1H), 7.49 (t, 7 = 7.5 Hz, 2H), 7.47 - 7.39 (m, 2H), 4.11 (t, 7 = 4.9 Hz, 4H), 3.46 (t, 7 = 5.1 Hz, 4H).13C NMR (151 MHz, DMSO-d6) δ 181.28, 166.57, 166.55, 147.56, 145.45, 138.26, 136.1 1 , 132.26, 131.65, 129.60,

[0739] 129.57, 129.50, 127.86, 127.83, 127.78, 127.75, 125.64, 125.48, 123.54, 122.39, 47.99, 46.64. MS (ESI) m / z 453.1 [M+H]+C23H21CIN4O2S. HPLC analysis: MeCN-H2O (95:5), 6.29 min, 95.82% pure.

[0740] 2-Chloro-4-(4-(4-(methylsulfonyl)phenyl)piperazine-l-carbothioamido)benzoic acid

[0741] (TL843)

[0742] The product was obtained as a yellow solid (1 10 mg, 65%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.74 (d, 7 = 8.5 Hz, 1H),

[0743] 7.71 (d, J = 8.8 Hz, 2H), 7.57 (d, 7 = 2.1 Hz, 1H), 7.41 (dd, 7 = 8.4, 2.1 Hz, 1H), 7.12 - 7.03 (m, 2H), 4.08 (t, 7 = 5.4 Hz, 4H), 3.59 - 3.49 (m, 4H). MS (ESI) m / z 453.8 [M+H]+

[0744] C19H20CIN3O4S2. HPLC analysis: MeCN-H2O (95:5), 6.20 min, 98.30% pure.

[0745] 2-Chloro-4-(4-(7-chloroquinoIin-4-yl)piperazine-l-carbothioamido)benzoic acid (TL844)

[0746] The product was obtained as a white solid (130 mg, 87%) using a similar procedure as described for TL283. 'H NMR (499 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.73 (d, 7 = 5.0 Hz, 1H), 8.15 (d, 7 = 9.1 Hz, 1H), 8.01 (d, 7 = 2.2 Hz, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 1.6 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.42 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.06 (d, 7 = 5.1 Hz, 1H), 4.2O (t, 7 = 4.9 Hz, 4H), 3.32 (d, 7 = 4.9 Hz, 4H). MS (ESI) m / z C21H18CI2N4O2S.

[0747] 4-(4-(lH-indol-4-yl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL845)

[0748] The product was obtained as an off-white solid (94 mg, 57%) using a similar procedure as described for TL283.1H NMR (499 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.71 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.4, 2.1 Hz, 1H), 7.27 (t, 7 = 2.8 Hz, 1H), 7.06 (d, 7 = 8.1 Hz, 1H), 6.98 (t, 7 = 7.8 Hz, 1H), 6.48 (d, 7 = 7.3 Hz, 2H), 4. 14 (t, 7 = 4.6 Hz, 4H), 3.22 (t, 7 = 5.0 Hz, 5H). MS (ESI) m / z 414.9 [M+H]+C20H19CIN4O2S. HPLC analysis: MeCN-H20 (95:5), 6.67 min, 99.21% pure.

[0749] 2-Chloro-4-(4-(4-nitro-3-(piperidin-l-yl)phenyl)piperazine-l-carbothioamido)benzoic acid (TL846)

[0750] The product was obtained as a yellow solid (17 mg, 11%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.92 (d, 7 = 9.3 Hz, 1H), 7.73 (d, 7 = 8.4 Hz, 1H), 7.57 (d, 7 = 2.1 Hz, 1H), 7.41 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.54 (dd, 7 = 9.5, 2.6 Hz, 1H), 6.35 (d, 7 = 2.7 Hz, 1H), 4.07 (dd, 7 = 6.9, 4.0 Hz, 4H), 3.60 (dd, 7 = 6.9, 4.0 Hz, 4H), 2.97 (t, 7 = 5.2 Hz, 4H), 1.68 - 1.52 (m, 5H). MS (ESI) m / z 504.1 [M+H]+C23H26CIN5O4S. HPLC analysis: MeCN-H20 (95:5), 7.89 min, 96.35% pure.

[0751] 2-Chloro-4-(4-(2-methyIquinolin-4-yI)piperazine- l-carbothioamido)benzoic acid (TL847) The product was obtained as a white solid (88 mg, 51 %) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 11.29 - 10.59 (m, 1H), 9.76 (s, 1H), 8.08 (d, 7 = 8.3 Hz, 1 H), 7.88 (d, J = 8.3 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.60 (d, 7 = 2.1 Hz, 1H), 7.52 (t, 7 = 7.6 Hz, 1H), 7.44 (dd, 7 = 8.6, 2.1 Hz, 1H), 6.95 (s, 1H), 4.29 - 4.15 (m, 4H), 3.41 - 3.28 (m, 5H), 2.60 (s, 3H). MS (ESI) m / z C22H21CIN4O2S.

[0752] 2-Chloro-4-(4-(4-fluorophenyl)-3-oxopiperazine-l-carbothioamido)benzoic acid (TL848) The product was obtained as a white solid (33 mg, 31 %) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 7.77 (s, 6H), 7.43 (ddd, 7 = 13.2, 6.1, 3.4 Hz, 4H),

[0753] 7.32 - 7.20 (m, 3H), 4.64 (s, 2H), 4.27 (t, 7 = 5.3 Hz, 2H), 3.84 (t, 7 = 5.3 Hz, 2H). MS (ESI) m / z 407.9 [M+H]+C18H15CIFN3O3S. HPLC analysis: MeCN-H20 (95:5), 6.24 min, 97.95% pure.

[0754] 2-Chloro-4-(4-(2,3-dihydro-lH-inden-2-yl)piperazine-l-carbothioamido)benzoic acid (TL849)

[0755] The product was obtained as a white solid (139 mg, 85%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.77 (d, 7 = 8.5 Hz, 1H), 7.56 (d, 7 = 2.1 Hz, 1H), 7.40 (dd, 7 = 8.6, 2.1 Hz, 1H), 7.19 (dt, 7 = 7.4, 3.6 Hz, 2H), 7.12 (dd, 7 = 5.6, 3.2 Hz, 2H), 3.93 (t, 7 = 4.8 Hz, 5H), 3.18 (q, 7 = 7.9 Hz, 1H), 3.04 (dd, 7 = 15.4, 7.4 Hz, 2H), 2.81 (dd, 7 = 15.4, 8.4 Hz, 2H), 2.54 (t, 7= 4.9 Hz, 4H). MS (ESI) m / z 416.0 [M+H]+C21H22CIN3O2S. HPLC analysis: MeCN-H20 (95:5), 4.01 min, 100% pure.

[0756] 2-Chloro-4-(4-(3,5-dimethoxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL850)

[0757] The product was obtained as a white solid (138 mg, 78%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.72 (d, 7 = 8.5 Hz, 1H), 7.54 (d, 7 =

[0758] 2.1 Hz, 1H), 7.39 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.10 (d, 7= 2.1 Hz, 2H), 5.99 (t, 7 = 2.0 Hz, 1H), 4.03 (t, 7 = 5.1 Hz, 4H), 3.71 (s, 6H), 3.26 (t, 7 = 5.2 Hz, 4H). MS (ESI) m / z 435.9 [M+H]+C20H22CIN3O4S. HPLC analysis: MeCN-H20 (95:5), 7.34 min, 96.24% pure.

[0759] 4-(4-(3-(Benzylamino)-4-nitrophenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL851)

[0760] The product was obtained as a yellow solid (156 mg, 93%) using a similar procedure as described for TL283. H NMR (499 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.85 (t, 7 = 5.9 Hz, 1H), 7.94 (d, 7 = 9.6 Hz, 1H), 7.70 (d, 7 = 8.4 Hz, 1H), 7.53 (s, 1H), 7.38 (dt, 7 = 21.6, 7.6 Hz, 4H), 7.27 (t, J = 13 Hz, 1H), 6.37 (d, 7= 9.8 Hz, 1H), 5.92 (s, 1H), 4.59 (d, 7 = 5.9 Hz, 2H), 4.03 (t, 7 = 5.4 Hz, 4H), 3.55 (s, 4H). MS (ESI) m / z 526.1 [M+H]+C25H24CIN5O4S. HPLC analysis: MeCN-H20 (95:5), 8.09 min, 97.54% pure.

[0761] 2-Chloro-4-(4-(4-(pyrimidin-2-yl)phenyl)piperazine-l-carbothioamido)benzoic acid (TL852) The product was obtained as a yellow solid (104 mg, 62%) using a similar procedure as described for TL283. 1H NM (R499 MHz, DMSO-d6) 3 9.71 (s, 1H), 8.95 - 8.64 (m, 2H), 8.28 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.6 Hz, 1H), 7.60 (s, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.34 - 7.22 (m, 1H), 7.04 (d, J = 8.6 Hz, 2H), 4.09 (s, 4H). MS (ESI) m / z C22H20CIN5O2S.

[0762] 4-(4-( Benzo| / ?]thiophen-4-yl)piperazine- 1 -carhothioainido)-2-chlorohenzoic acid (TL853)

[0763] The product was obtained as a white solid (149 mg, 73%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.79 - 7.58 (m, 2H), 7.54 (d, 7 = 6.8 Hz, 2H), 7.43 (s, 1H), 7.29 (d, 7 = 8.7 Hz, 2H), 6.95 (d, 7= 7.6 Hz, 1H), 4.16 (s, 4H), 3.15 (s, 4H). MS (ESI) m / z 431.9 [M+HJ+C20H18CIN3O2S2. HPLC analysis: MeCN-H2O (95:5), 8.21 min, 99.62% pure.

[0764] 2-Chloro-4-(4-(2,3-dichlorophenyl)piperazine-l-carbothioamido)benzoic acid (TL854)

[0765] The product was obtained as a white solid (219 mg, 100%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-76) δ 9.30 (s, 1H), 7.44 (d, 7 = 8.2 Hz, 1H), 7.40 - 7.30 (m, 3H), 7.20 (ddd, 7 = 11 .8, 7.1, 2.8 Hz, 2H), 4.07 (t, 7 = 4.8 Hz, 4H), 3.06 (t, 7 = 5.0 Hz, 4H). MS (ESI) m / z 445.8 [M+H]+C18H16C13N3O2S. HPLC analysis: MeCN-H2O (95:5), 8.56 min, 99.70% pure.

[0766] 2-Chloro-4-(4-(3-chlorophenyl)-3-oxopiperazine-l-carbothioainido)benzoic acid (TL855)

[0767] The product was obtained as a white solid 30 mg, 18%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) 3 8.14 - 7.63 (m, 3H), 7.55 (d, 7 = 2.2 Hz, 1H), 7.45 (t, 7 = 8.0 Hz, 1H), 7.43 - 7.36 (m, 3H), 7.35 (dd, 7 = 8.0, 2.0 Hz, 1H), 7.24 (dd, 7 = 8.1,

[0768] 2.1 Hz, 1H), 4.65 (s, 2H), 4.26 (t, 7 = 5.3 Hz, 2H), 3.88 (t, 7 = 5.3 Hz, 2H). MS (ESI) m / z 423.8 [M+H]+C18H15CI2N3O3S. HPLC analysis: MeCN-H20 (95:5), 6.75 min, 99.58% pure.

[0769] 4-(4-(5-Bromo-3-nitropyridin-2-yl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL856)

[0770] The product was obtained as a yellow solid (131 mg, 63%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) 3 9.62 (s, 1H), 8.56 (d, 7 = 2.2 Hz, 1H), 8.51 (d, 7 = 2.3 Hz, 1H), 7.76 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.0 Hz, 1H), 7.42 (dd, 7 = 8.6, 2.1 Hz, 1H), 4.04 (dd, 7 = 6.8, 3.9 Hz, 4H), 3.60 - 3.55 (m, 5H). MS (ESI) m / z 501.7 [M+H]+CnHisBrCINsCriS. HPLC analysis: MeCN-H2O (95:5), 7.91 min, 96.75% pure.

[0771] 2-Chloro-4-(4-(2-fluoro-4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL857) The product was obtained as a yellow solid (82 mg, 47%) using a similar procedure as described for TL283. MS (ESI) m / z 438.8 [M+H]+C18H16CIFN4O4S. HPLC analysis: MeCN-H2O (95:5), 7.65 min, 97.87% pure. (7?)-2-Chloro-4-(4-((4-chlorophenyl)(phenyl)methyl)piperazine-l-carbothioamido)benzoic acid (TL858)

[0772] The product was obtained as a white solid (86 mg, 41%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.69 (d, 7 = 8.5 Hz, 1H), 7.52 - 7.44 (m, 3H), 7.41 (d, 7 = 7.6 Hz, 2H), 7.33 (dt, 7 = 23.9, 7.9 Hz, 5H), 7.21 (t, 7 = 7.4 Hz, 1H), 4.42 (s, 2H), 2.36 (t, 7 = 5.0 Hz, 4H). MS (ESI) m / z 500.1 [M+H]+C25H23CI2N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.57 min, 96.88% pure.

[0773] 4-(4-(5-Bromo-3-methyIpyridin-2-yl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL859)

[0774] The product was obtained as a pink solid (111 mg, m°Zo^ using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.21 (d, 7 = 2.3 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.57 (d, 7 = 2.1 Hz, 1H), 7.41 (dd, 7 = 8.5, 2.1 Hz, 1H), 4.06 - 3.99 (m, 4H), 3.20 - 3.12 (m, 5H), 2.28 (s, 3H). MS (ESI) m / z 470.8 [M+H]+Ci8Hi8BrClN4O2S. HPLC analysis: MeCN-H20 (95:5), 8.08 min, 99.03% pure.

[0775] 4-(4-(5-Bromo-4-methylpyridin-2-yl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL860)

[0776] The product was obtained as a yellowish white solid (100 mg, 55%) using a similar procedure as described for TL283.1H NMR (499 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.21 (d, 7 = 2.3 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.57 (d, 7 = 2.1 Hz, 1H), 7.41 (dd, 7 = 8.5, 2.1 Hz, 1H), 4.06 - 3.99 (m, 4H), 3.20 - 3.12 (m, 5H), 2.28 (s, 3H). MS (ESI) m / z Cl 8Hi8BrCIN4O2S.

[0777] 4-(4-Benzyl-3-phenylpiperazine-l-carbothioamido)-2-chIorobenzoic acid (TL861)

[0778] The product was obtained as a white solid (41 mg, 22%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 7.7 Hz, 3H), 7.42 (q, 7 = 9.7, 8.6 Hz, 3H), 7.38 - 7.18 (m, 7H), 4.73 (dd, J = 41.3, 13.3 Hz, 2H), 3.65 (d, 7 = 13.5 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.24 (t, 7 = 12.5 Hz, 1H), 3.14 (dd, 7 = 19.6, 7.8 Hz, 1H), 2.97 (d, 7 = 13.6 Hz, 1H), 2.85 (d, 7 = 11.7 Hz, 1H), 2.19 (t, 7 = 11.6 Hz, 1H). MS (ESI) m / z 466.1 [M+HrCis^ClNsChS. HPLC analysis: MeCN-H20 (95:5), 7.31 min, 95.40% pure.

[0779] 4-(4-(4-Bromophenyl)-4-hydroxypiperidine-l-carbothioamido)-2-chlorobenzoic acid

[0780] (TL862)

[0781] The product was obtained as a yellow solid (46 mg, 25%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.57 (s, 1H), 7.77 (d, 7 = 8.5 Hz,

[0782] 1H), 7.58 (d, 7 = 2.1 Hz, 1H), 7.53 (d, 7 = 8.5 Hz, 2H), 7.47 (d, 7 = 8.5 Hz, 2H), 7.40 (dd, 7 = 8.5, 2.1 Hz, 1H), 5.37 (s, 1H), 4.81 - 4.58 (m, 2H), 3.56 - 3.44 (m, 2H), 1.97 (td, 7 = 13.3, 4.4 Hz, 2H), 1.76 - 1.64 (m, 2H). MS (ESI) m / z 470.8 [M+H]+Ci9Hi8BrClN2O2S. HPLC analysis: MeCN-H2O (95:5), 7.21 min, 98.22% pure.

[0783] 4-(4-(5-Bromopyridin-2-yl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL863)

[0784] The product was obtained as a white solid (175 mg, 94%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.20 (d, J = 2.6 Hz, 1H), 7.72 (dd, J

[0785] = 9.0, 2.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.37 (dd, 7 = 8.4, 2.1 Hz, 1H), 6.84 (d, 7 = 9.1 Hz, 1H), 4.03 (dd, 7 = 6.8, 3.9 Hz, 4H), 3.67 - 3.60 (m, 5H). MS (ESI) m / z 456.8 LM+HJ+Ci7Hi6BrClN4O2S. HPLC analysis: MeCN-H20 (95:5), 4.77 min, 90.40% pure.

[0786] 4-(7-Bromo-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)-2-chlorobenzoic acid (TL864).

[0787] The product was obtained as a white solid (90 mg, 45%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.70 (d, 7 = 8.4 Hz, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.42 - 7.35 (m, 2H), 7.20 (d, 7 = 8.1 Hz, 1H), 5.05 (s, 2H), 4.05 (t, 7 = 6.0 Hz, 3H), 2.92 (t, J = 5.9 Hz, 2H). MS (ESI) m / z 426.7 [M+H]+C]7Hi4BrClN2O2S. HPLC analysis: MeCN-H20 (95:5), 8.02 min, 96.55% pure.

[0788] 4-(4-(4-Bromobenzyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL865)

[0789] The product was obtained as a white solid (125 mg, 68%) using a similar procedure as described for TL283. 1H NMR (499 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.74 (d, 7 = 8.5 Hz, 1H), 7.56 - 7.48 (m, 3H), 7.37 (dd, 7 = 8.6, 2.1 Hz, 1H), 7.32 - 7.27 (m, 2H), 3.90 (s, 4H), 3.50 (s, 2H), 2.43 (t, 7 = 4.9 Hz, 4H). MS (ESI) m / z 469.8 [M+H]+Ci9Hi9BrClN3O2S. HPLC analysis: MeCN-H20 (95:5), 6.21 min, 97.13% pure.

[0790] 2-Chloro-4-(7-chloro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL866).

[0791] The product was obtained as a pink-white solid (101 mg, 55%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.72 (d, 7 = 8.4 Hz, 1H), 7.55 (s, 1H), 7.39 (d, 7 = 8.1 Hz, 1H), 7.29 (s, 1H), 7.25 (s, 2H), 5.02 (s, 2H), 4.04 (t, 7 = 6.0 Hz, 2H). MS (ESI) m / z 380.8 [M+H]+CI7HI4C12N2O2S. HPLC analysis: MeCN-H2O (95:5), 7.86 min, 95.40% pure.

[0792] 2-Chloro-4-(2,3-dihydrospiro[indene-l,4'-piperidine]-l'-carbothioamido)benzoic acid (TL867)

[0793] The product was obtained as a yellowish white solid ( 132 mg, 77%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.71 (d, 7 = 8.4 Hz, 1H), 7.53 (d, 7 = 2.1 Hz, 1H), 7.37 (dd, 7 = 8.4, 2.1 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.16 (hd, 7 = 6.8, 1.6 Hz, 2H), 4.76 (d, 7 = 13.1 Hz, 2H), 3.37 - 3.24 (m, 2H), 2.89 (t, 7 = 7.3 Hz, 2H), 2.10 (t, 7 = 7.3 Hz, 2H), 1.83 (td, 7 = 13.2, 4.2 Hz, 2H), 1.64 - 1.50 (m, 2H). MS (ESI) m / z 400.9 [M+H]+C21H21CIN2O2S. HPLC analysis: MeCN-H2O (95:5), 8.22 min, 97.99% pure.

[0794] 2-Chloro-4-(4-(4-(methylsulfonyl)-2-nitrophenyl)piperazine-l-carbothioamido) benzoic acid (TL868)

[0795] The product was obtained as a yellow solid (98 mg, 56%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.31 (d, 7 = 2.3 Hz, 1H), 8.03 - 7.95

[0796] (m, 1H), 7.75 (d, 7 = 8.5 Hz, 1H), 7.59 (s, 1H), 7.44 (dd, 7 = 20.7, 8.7 Hz, 2H), 4.07 (t, 7 = 5.1 Hz, 4H), 3.45 (t, 7 = 5.1 Hz, 4H), 3.25 (s, 3H). MS (ESI) m / z C19H19CIN4O6S2.

[0797] 2-Chloro-4-(6-chloro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL869).

[0798] The product was obtained as a white solid (116 mg, 64%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.75 (d, 7 = 8.5 Hz, 1H), 7.57 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.34 (d, 7= 2.2 Hz, 1H), 7.29 - 7.20 (m, 2H), 5.02 (s, 2H), 4.05 (t, 7 = 5.9 Hz, 3H), 2.96 (t, 7 = 5.9 Hz, 2H). MS (ESI) m / z 380.8 [M+H]+C17H14CI2N2O2S. HPLC analysis: MeCN-H2O (95:5), 7.92 min, 98.61% pure.

[0799] 4-(4-(4-Bromophenyl)piperidine-l-carbothioamido)-2-chlorobenzoic acid (TL870)

[0800] The product was obtained as a yellow solid (142 mg, 76%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.59 (s, 1H), 7.75 (d, 7 = 8.5 Hz, 1H),

[0801] 7.55 (d, 7 = 2.0 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.38 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.30 - 7.21 (m, 2H), 4.86 (d, 7 = 13.2 Hz, 2H), 3.16 (td, 7 = 13.1, 2.4 Hz, 2H), 2.92 - 2.86 (m, 1H), 1.91 - 1.79 (m, 2H), 1.63 (qd, 7 = 12.7, 3.9 Hz, 2H). MS (ESI) m / z 454.8 [M+H]+Ci9Hi8BrClN2O2S. HPLC analysis: MeCN-H20 (95:5), 8.48 min, 95.22% pure.

[0802] 2-Chloro-4-(6-hydroxy-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL872).

[0803] The product was obtained as a white solid (103 mg, 61%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.36 (s, 1H), 7.77 (d, 7= 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.6, 2.1 Hz, 1H), 6.99 (d, 7 = 8.0 Hz, 1H), 6.63 (d, 7 = 7.5 Hz, 2H), 4.89 (s, 2H), 4.00 (t, 7 = 6.0 Hz, 2H), 2.86 (t, 7 = 5.9 Hz, 2H). MS (ESI) m / z 362.8 [M+H]+Ci7Hi5ClN2O3S. HPLC analysis: MeCN-H2O (95:5), 5.96 min, 95.23% pure.

[0804] (7?)-2-Chloro-4-(l-(hydroxymethyl)-l,2,3,4-tetrahydroisoquinoline-2- carbothioamido)benzoic acid (TL873). The product was obtained as a white solid (60 mg, 37%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 10.07 - 9.82 (m, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.63 (d, 7 = 2.1 Hz, 1H), 7.40 (dd, 7 = 8.6, 2.1 Hz, 1H), 7.23 (d, 7 = 4.1 Hz, 4H), 5.23 (s, 1H), 5.17 - 4.95 (m, 1H), 4.6O (d, 7 = 16.7 Hz, 1H), 3.57 (dd, 7 = 11.6, 6.3 Hz, 1H), 3.17 (d, 7 = 5.3 Hz, 1H), 3.06 (dd, 7 = 16.0, 5.7 Hz, 1H), 2.92 (dd, 7 = 15.9, 3.2 Hz, 1H). MS (ESI) m / z 376.9 [M+H]+C18H17C1N2O3S. HPLC analysis: MeCN-H20 (95:5), 6.84 min, 97.47% pure.

[0805] 4-(4-([l,l'-Biphenyl]-3-yl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL874)

[0806] The product was obtained as a white solid (167 mg, 88%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.71 (d, 7 = 8.4 Hz, 1H), 7.66 (d, 7 = 7.6 Hz, 2H), 7.57 (s, 1H), 7.43 (dt, 7 = 16.7, 8.0 Hz, 3H), 7.33 (dt, 7 = 16.5, 7.6 Hz, 2H), 7.20 (s, 1H), 7.08 (d, 7 = 7.6 Hz, 1H), 6.96 (d, 7= 8.4 Hz, 1H), 4.10 (t, 7 = 5.1 Hz, 4H), 3.35 (d, 7 = 10.2 Hz, 4H). MS (ESI) m / z 452.0 [M+H]+C24H22C1N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.62 min, 95.28% pure.

[0807] 4-(2-(4-Bromophenyl)pyrrolidine-l-carbothioainido)-2-chlorobenzoic acid (TL875)

[0808] The product was obtained as a white solid (70 mg, 40%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.81 - 7.57 (m, 2H), 7.51 (d, 7 = 8.0 Hz, 3H), 7.12 (d, 7 = 8.1 Hz, 2H), 5.60 (s, 1H), 4.02 (t, 7 = 9.9 Hz, 1H), 3.79 (q, 7 = 10.2, 8.9 Hz, 1H), 2.39 (s, 1H), 1.91 (d, 7 = 83.3 Hz, 3H). MS (ESI) m / z 440.7 [M+H]+CisHi6BrClN2O2S. HPLC analysis: MeCN-H2O (95:5), 7.97 min, 97.94% pure.

[0809] 2-Chloro-4-(4-(pyridin-2-yl)piperazine-l-carbothioamido)benzoic acid (TL876)

[0810] The product was obtained as a white solid (165 mg, 100%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.14 (dd, 7 = 5.0, 1.9 Hz, 1H), 7.77 (d, 7 = 8.5 Hz, 1H), 7.60 (d, 7 = 2.0 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.43 (dd, 7 = 8.6, 2.1 Hz, 1H), 6.84 (d, 7 = 8.6 Hz, 1H), 6.67 (dd, 7 = 7.1, 4.9 Hz, 1H), 4.04 (dd, 7 = 6.7, 4.0 Hz, 4H), 3.64 (dd, 7 = 6.5, 4.0 Hz, 4H). MS (ESI) m / z 376.8 [M+H]+Ci7H]7ClN4O2S. HPLC analysis: MeCN-H20 (95:5), 4.28 min, 98.22% pure.

[0811] 2-Chloro-4-(4-(pyrimidin-4-yl)piperazine-l-carbothioamido)benzoic acid (TL877)

[0812] The product was obtained as a yellowish white solid (87 mg, 54%) using a similar procedure as described for TL283. ’H NMR (599 MHZ, DMSO-d6) δ 11.10 - 10.25 (m, 1H), 9.65 (s, 1H), 8.54 (s, 1H), 8.23 (d, 7 = 6.2 Hz, 1H), 7.79 (d, 7 = 8.4 Hz, 1H), 7.61 (d, 7 = 2.1 Hz, 1H), 7.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.84 (d, 7 = 6.2 Hz, 1H), 4.15 - 4.00 (m, 4H), 3.89 - 3.69 (m, 4H). MS (ESI) m / z 377.8 [M+H]+CI6HI6C1N5O2S. HPLC analysis: MeCN-H2O (95:5), 4.27 min, 95.15% pure. 4-(4-(5-Bromo-6-methylpyridin-2-yl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL878)

[0813] The product was obtained as a white solid (78 mg, 41%) using a similar procedure as described for TL283. MS (ESI) m / z 470.8 [M+H]+Ci8Hi8BrClN4O2S. HPLC analysis: MeCN-H20 (95:5), 8.19 min, 95.37% pure.

[0814] 2-Chloro-4-(6-methoxy-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL879).

[0815] The product was obtained as a white solid (126 mg, 78%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.56 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.12 (d, 7 = 8.4 Hz, 1H), 6.83 (d, 7 = 2.6 Hz, 1H), 6.80 (dd, 7 = 8.3, 2.7 Hz, 1H), 4.95 (s, 2H), 4.03 (t, 7 = 5.9 Hz, 2H), 2.93 (t, 7 = 6.0 Hz, 2H). MS (ESI) m / z 376.8 [M+H]+Ci8Hi7ClN2O3S. HPLC analysis: MeCN-H20 (95:5), 7.23 min, 98.77% pure.

[0816] 4-(4-(4-Bromobenzoyl)piperidine-l-carbothioainido)-2-chlorobenzoic acid (TL880)

[0817] The product was obtained as a white solid (88 mg, 56%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 7.96 (d, 7 = 8.2 Hz, 2H), 7.76 (d, 7 = 8.1 Hz, 2H), 7.45 (d, 7 = 7.9 Hz, 1H), 7.33 (s, 1H), 7.20 (d, 7 = 7.9 Hz, 1H), 4.73 (d, 7 = 13.2 Hz, 2H), 3.79 (tt, 7 = 11.1, 4.1 Hz, 1H), 3.30 (t, 7 = 12.5 Hz, 2H), 1.94 - 1.77 (m, 2H), 1.69 - 1.49 (m, 2H). MS (ESI) m / z 482.8 [M+H]+C2oHi8BrClN203S. HPLC analysis: MeCN-H20 (95:5), 8.01 min, 97.45% pure.

[0818] 2-Chloro-4-(4-(l-phenylethyl)piperazine-l-carbothioamido)benzoic acid (TL881)

[0819] The product was obtained as a while solid (127 mg, 71%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.57 (s, 1H), 7.74 (d, 7 = 8.5 Hz, 1H), 7.52 (d, 7 = 2.1 Hz, 1H), 7.40 - 7.29 (m, 5H), 7.25 (td, J = 6.7, 2.0 Hz, 1H), 3.88 (t, 7 = 5.1 Hz, 4H), 3.50 (q, 7 = 6.7 Hz, 1H), 2.46 (dt, 7 = 10.8, 5.0 Hz, 2H), 2.38 (dt, 7 = 11.1, 5.1 Hz, 2H), 1.33 (d, 7 = 6.7 Hz, 3H). MS (ESI) m / z 404.0 [M+H]+C20H22ClN3O2S. HPLC analysis: MeCN-H20 (95:5), 5.28 min, 96.59% pure.

[0820] 4-(4-(4-Bromophenyl)-l,2,3,6-tetrahydropyridine-l-carbothioamido)-2-chlorobenzoic acid (TL882)

[0821] The product was obtained as a white solid (92 mg, 56%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.55 (d, 7 = 8.3 Hz, 2H), 7.51 (d, 7 = 8.3 Hz, 1 H), 7.44 (d, 7 = 8.3 Hz, 2H), 7.39 (d, 7 = 2.1 Hz, 1 H), 7.26 (dd, 7 = 8.3, 2. 1 Hz, 1 H),

[0822] 6.27 (d, 7 = 3.6 Hz, 1H), 4.59 - 4.43 (m, 2H), 4.12 (t, 7 = 5.6 Hz, 2H), 3.28 (t, 7 = 10.5 Hz, 1H), 2.74 (d, J = 10.3 Hz, 1 H), 2.61 (d, 7 = 6.2 Hz, 2H), 1.1 1 (d, 7= 6.7 Hz, 8H). MS (ESI) m / z 452.8 [M+H]+Ci9Hi6BrClN2O2S. HPLC analysis: MeCN-H2O (95:5), 8.66 min, 98.01% pure.

[0823] 2-Chloro-4-(4-(2-hydroxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL883)

[0824] The product was obtained as a pink- white solid (150 mg, 86%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.65 (s, 1H), 9.12 - 8.98 (m, 1H), 7.79 (d, 7= 8.5 Hz, 1H), 7.58 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.92

[0825] (dd, 7 = 7.9, 1.6 Hz, 1H), 6.87 (td, 7 = 7.5, 1.5 Hz, 1H), 6.81 (dd, 7 = 7.9, 1.6 Hz, 1H), 6.75 (td, 7 = 7.5, 1.6 Hz, 1H), 4.06 (t, 7 = 5.0 Hz, 4H), 3.01 (t, 7 = 4.9 Hz, 4H). MS (ESI) m / z 391.9 |M+HJ+C18H18CIN3O3S. HPLC analysis: MeCN-H2O (95:5), 6.43 min, 95.49% pure.

[0826] 2-Chloro-4-(6-nitro-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)benzoic acid (TL884).

[0827] The product was obtained as a yellowish-brown solid (126 mg, 78%) using a similar procedure as described for TL283. MS (ESI) m / z C17H14CIN3O4S.

[0828] 4-(4-(2,3-Dihydro-lH-inden-2-yl)piperazine-l-carbothioamido)-2-fluorobenzoic acid (TL888)

[0829] The product was obtained as a yellowish white solid (156 mg, 79%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.78 (t, 7 = 8.5 Hz, 1H), 7.37 (d, 7 = 13.2 Hz, 1H), 7.25 (d, 7 = 8.6 Hz, 1H), 7.23 - 7.16 (m, 2H), 7.16 - 7.07 (m, 2H), 3.93 (t, 7 = 4.8 Hz, 4H), 3.17 (q, 7= 7.9 Hz, 1H), 3.04 (dd, 7 = 15.4, 7.4 Hz, 2H), 2.81 (dd, 7 = 15.4, 8.5 Hz, 2H).13C NMR (151 MHz, DMSO-d6) δ 180.84, 165.28, 165.25, 162.40, 160.71,

[0830] 147.43, 147.35, 141.72, 141.55, 132.20, 132.19, 126.84, 124.75, 118.67, 118.65, 113.76, 113.69, 110.91, 110.73, 66.37, 51.03, 48.77, 36.81. MS (ESI) m / z 400.1 [M+H]+C21H22FN3O2S. HPLC analysis: MeCN-H2O (95:5), 5.33 min, 97.95% pure.

[0831] 4-(4-(5-Bromo-3-methylpyridin-2-yl)piperazine-l-carbothioamido)-2-fluorobenzoic acid (TL889)

[0832] The product was obtained as a pink solid (133 mg, 66%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 12.93 (s, 1H), 9.75 (s, 1H), 8.27 - 8. 16 (m, 1H), 7.85 - 7.71 (m, 2H), 7.38 (d, 7 = 13.2 Hz, 1H), 7.27 (d, 7 = 8.6 Hz, 1H), 4.13 - 3.94 (m, 4H), 3.18 (t, 7= 4.9 Hz, 4H), 2.28 (s, 3H).13C NMR (151 MHz, DMSO-d6) δ 181.45, 165.25, 165.23,

[0833] 162.43, 160.74, 159.84, 147.42, 147.34, 145.60, 141.87, 132.25, 127.45, 118.71, 118.69, 113.69,

[0834] 113.62, 113.29, 110.95, 110.77, 49.10, 48.90, 18.22. MS (ESI) m / z 454.8 [M+H]+CisHisBrFNaChS. HPLC analysis: MeCN-H20 (95:5), 7.89 min, 97.64% pure.

[0835] 4-(4-(4-Bromobenzyl)piperazine-l-carbothioamido)-2-fluorobenzoic acid (TL890) The product was obtained as a white solid (55 mg, 26%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.76 (t, J = 8.5 Hz, 1H), 7.52 (d, 7 = 8.0 Hz, 2H), 7.33 (dd, 7 = 13.2, 2.1 Hz, 1H), 7.29 (d, 7 = 8.1 Hz, 2H), 7.22 (dd, 7 = 8.5, 2.1 Hz, 1H), 3.90 (t, 7 = 4.9 Hz, 4H), 2.43 (t, 7 = 4.9 Hz, 4H). MS (ESI) m / z 453.8 [M+H]+Ci9Hi9BrFN3O2S. HPLC analysis: MeCN-H20 (95:5), 6.08 min, 99.83% pure.

[0836] 4-(4-(2-Bromophenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL891)

[0837] The product was obtained as a yellowish white solid (144 mg, 67%) using a similar procedure as described for TL283. 'H NMR (599 MHz, DMSO-d6) δ 11.51 (s, 1H), 9.70 (s, 1H), 7.62 (d, 7 =

[0838] 7.9 Hz, 1H), 7.52 (d, 7 = 8.3 Hz, 1H), 7.41 (s, 1H), 7.37 (t, 7 = 7.7 Hz, 1H), 7.28 (d, 7 = 8.2 Hz, 1H), 7.21 (d, 7 = 7.9 Hz, 1H), 7.02 (t, 7 = 7.6 Hz, 1H), 4.07 (t, 7 = 4.7 Hz, 4H), 3.04 (t, 7 = 4.9 Hz, 4H), 2.81 (s, 2H). MS (ESI) m / z 455.7 [M+H]+Ci8H]7BrClN3O2S. HPLC analysis: MeCN- H2O (95:5), 8.18 min, 99.96% pure.

[0839] 4-(4-(4-Bromophenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL892).

[0840] The product was obtained as a white solid (53 mg, 26%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.76 (s, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 7.46 - 7.27 (m, 3H), 6.91 (d, 7 = 8.5 Hz, 2H), 4.06 (s, 4H), 3.27 (s, 4H).13C NMR (151 MHz, DMSO- d6) 5 181.29, 149.94, 144.73, 132.03, 125.51, 122.40, 117.68, 110.71, 48.27, 47.82. MS (ESI) m / z 455.7 [M+H]+Ci8Hi7BrClN3O2S. HPLC analysis: MeCN-H2O (95:5), 5.01 min, 99.23% pure.

[0841] 2-Chloro-4-(4-(4-chlorophenyl)piperazine-l-carbothioamido)benzoic acid (TL894).

[0842] The product was obtained as a brown solid (101 mg, 61%) using similar procedure as described for TL283.1H NMR (599 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.72 (d, 7 = 8.4 Hz, 1H), 7.55 (s, 1H), 7.39 (d, 7 = 8.4 Hz, 1H), 7.26 (d, 7 = 8.5 Hz, 2H), 6.97 (d, 7 = 8.5 Hz, 2H), 4.05 (t, 7 = 4.9 Hz, 4H), 3.27 (t, 7 = 5.0 Hz, 4H).13C NMR (151 MHz, DMSO-d6) δ 181.27, 167.35, 149.58, 144.61, 131.83, 131.27, 129.18, 125.58, 123.12, 122.45, 117.32, 48.29, 47.98. MS (ESI) m / z 407.8 [M- H]+CisHi7Cl2N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.03 min, 95.07% pure.

[0843] 4-(4-(4-Bromo-2-methylphenyl)piperazine-l-carbothioainido)-2-fluorobenzoic acid (TL896).

[0844] The product was obtained as a yellowish solid (65mg, 52%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.74 (t, 7 = 8.5 Hz, 1H), 7.38 (d, 7 = 2.5 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.23 - 7.15 (m, 1H), 6.98 (d, 7 = 8.5 Hz, 1H), 4.04 (t, 7 = 4.8 Hz, 4H), 2.89 (t, 7 = 4.8 Hz, 4H), 2.28 (s, 3H). MS (ESI) m / z 453.8 [M+H]+

[0845] Ci9Hi9BrFN3O2S. HPLC analysis: MeCN-H20 (95:5), 8.69 min, 95.17% pure. Methyl 4-(4-(4-bromo-2-methylphenyl)piperazine-l-carbothioamido)-2-chlorobenzoate (TL898).

[0846] The product was obtained as a white solid (102 mg, 60%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.63 (d, J =

[0847] 2.1 Hz, 1H), 7.45 (dd, J = 8.5, 2.1 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.33 (dd, J = 8.5, 2.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 4.05 (t, J = 4.9 Hz, 4H), 3.83 (s, 3H), 2.91 (t, J = 4.8 Hz, 4H), 2.29 (s, 3H). MS (ESI) m / z 483.8 [M+H]+C2oH2iBrClN302S. HPLC analysis: MeCN-H2O (95:5), 9.83 min, 96.72% pure.

[0848] 2-Chloro-4-(4-(4-chloro-2-methyIphenyl)piperazine-l-carbothioamido)benzoic acid (TL899).

[0849] The product was obtained as a white solid (131 mg, 65%) using a similar procedure as described for TL283. 'H NMR (599 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.56 (d, 7 =

[0850] 2.2 Hz, 1H), 7.40 (dd, 7 = 8.4, 2.1 Hz, 1H), 7.26 (d, 7 = 2.6 Hz, 1H), 7.20 (dd, 7 = 8.6, 2.6 Hz, 1H), 7.05 (dd, 7 = 8.6, 1.8 Hz, 1H), 4.15 - 3.97 (m, 4H), 2.90 (q, 7 = 5.1 Hz, 4H), 2.30 (s, 3H). MS (ESI) m / z 423.8 [M+H]+C19H19CI2N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.74 min, 96.33% pure.

[0851] 2-Chloro-4-(4-(2,3-dihydro-lH-inden-l-yl)piperazine-l-carbothioamido)benzoic acid (TL903).

[0852] The product was obtained as a yellowish solid (98 mg, 48%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 12.98 (s, 1H), 9.56 (s, 1H), 7.76 (d, 7 =

[0853] 8.4 Hz, 1H), 7.54 (d, 7 = 2.0 Hz, 1H), 7.38 (dd, 7 = 8.6, 2.1 Hz, 1H), 7.35 - 7.29 (m, 1H), 7.27 - 7.16 (m, 3H), 4.35 (t, 7 = 6.8 Hz, 1H), 3.89 (h, 7 = 9.4 Hz, 4H), 2.89 (dt, 7 = 14.9, 7.0 Hz, 1H), 2.77 (dt, 7 = 15.6, 7.5 Hz, 1H), 2.63 - 2.53 (m, 2H), 2.46 - 2.37 (m, 2H), 2.03 (q, 7 = 7.4 Hz, 2H). MS (ESI) m / z 416.0 [M+H]+C21H22CIN3O2S. HPLC analysis: MeCN-H20 (95:5), 5.55 min, 98.10% pure.

[0854] 4-(4-(5-Bromo-3-methyIpyridin-2-yl)piperazine-l-carbothioamido)-2, 3,5,6- tetrafluorophenyl hypofluorothioite (TL920).

[0855] The product was obtained as a white solid (11 1 mg, 70%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.21 (d, 7 = 2.5 Hz, 1H), 7.83 - 7.79 (m, 2H), 7.78 (d, 7 = 2.5 Hz, 1H), 7.56 (d, 7 = 8.8 Hz, 2H), 4.09 - 3.99 (m, 4H), 3.24 - 3.15 (m, 4H), 2.28 (s, 3H). MS (ESI) m / z 518.8 [M+H]+Ci7Hi4BrF5N4S2. HPLC analysis: MeCN-H20 (95:5), 9.72 min, 97.35% pure. 4-(5-Bromo-3-methylpyridin-2-yl)- / V-(4-chloro-3-fluorophenyl)piperazine-l- carbothioamide (TL922).

[0856] The product was obtained as a white solid (115 mg, 83%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.40 (s, 1H), 8.16 (s, 1H), 7.57 (ddd, 7 = 12.6, 6.8, 2.5 Hz, 2H), 7.41 - 7.25 (m, 3H), 6.89 (s, 1H), 4.05 - 3.99 (m, 4H), 3.68 - 3.59 (m, 4H), 2.28 (s, 3H). MS (ESI) m / z Ci7Hi7BrClFN4S.

[0857] 4-(5-Bromo-3-methylpyridin-2-yl)-A,-(6-(trifluoromethyl)pyridin-3-yl)piperazine-l- carbothioamide (TL923).

[0858] The product was obtained as a white solid (100 mg, 62%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.74 (d, J = 2.7 Hz, 1H), 8.21 (t, J = 2.9 Hz, 1H), 8.04 (dd, J = 8.4, 2.8 Hz, 1H), 7.83 (dd, J = 9.6, 5.2 Hz, 1H), 7.82 - 7.75 (m, 1H), 4.09 (dd, 7 = 6.7, 3.5 Hz, 4H), 3.21 (dq, 7 = 4.8, 2.3 Hz, 4H), 2.29 (d, 7 = 3.4 Hz, 3H). MS (ESI) m / z 461.8 [M+H]+CnHnBrFsNsS. HPLC analysis: MeCN-H2O (95:5), 8.75 min, 99.75% pure.

[0859] 4-(4-(2,3-Dihydro-lH-inden-2-yl)piperazine-l-carbothioamido)-2,3,5,6-tetrafluorophenyl hypofluorothioite (TL924).

[0860] The product was obtained as a white solid (65 mg, 38%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.83 - 7.76 (m, 2H), 7.55 (d, 7 = 8.8 Hz, 2H), 7.20 (dd, 7 = 5.3, 3.3 Hz, 2H), 7. 12 (dd, 7 = 5.5, 3.2 Hz, 2H), 3.94 (t, 7 = 4.9 Hz, 4H), 3.16 (p, 7 = 8.0 Hz, 1H), 3.04 (dd, 7 = 15.3, 7.4 Hz, 2H), 2.81 (dd, 7 = 15.3, 8.5 Hz, 2H), 2.53 (t, 7 = 5.0 Hz, 4H). MS (ESI) m / z 463.9 [M+H]+C20H18F5N3S2. HPLC analysis: MeCN-H20 (95:5), 7.77 min, 99.72% pure.

[0861] 4-(4-(4-Bromobenzyl)piperazine-l-carbothioamido)-2,3,5,6-tetrafluorophenyl hypofluorothioite (TL925).

[0862] The product was obtained as a white solid (67 mg, 48%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.79 id, 7 = 9.0 Hz, 2H), 7.53 (d, 7 = 8.2 Hz, 4H), 7.30 (d, 7 = 8.0 Hz, 2H), 3.91 (t, 7 = 4.7 Hz, 4H), 3.51 (s, 2H), 2.44 (t, 7 = 5.0 Hz, 5H). MS (ESI) m / z CisHisBrFsN^.

[0863] 4-(4-Bromobenzyl)-A / -(5-chloro-4-fluoro-2-nitrophenyl)piperazine-l -carbothioamide (TL926).

[0864] The product was obtained as a yellow solid (81 mg, 61%) using a similar procedure as described for TL283. MS (ESI) m / z CsHnBrClFN^FS.

[0865] 4-(4-Bromobenzyl)-A / -(4-chloro-3-fluorophenyl)piperazine-l -carbothioamide (TL927). The product was obtained as a white solid (65 mg, 42%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.55 - 7.50 (m, 3H), 7.33 (t, J = 9.0 Hz, 1H), 7.31 - 7.28 (m, 2H), 7.27 (ddd, J = 8.9, 4.4, 2.5 Hz, 1H), 3.89 (t, J = 4.9 Hz, 4H), 3.50 (s, 2H), 2.43 (t, J = 5.0 Hz, 4H). MS (ESI) m / z 443.8 [M+H]+CisHigBrCIFNgS. HPLC analysis: MeCN-H20 (95:5), 7.44 min, 97.78% pure.

[0866] 4-(4-Bromobenzyl)- / V-(6-(trifluoromethyl)pyridin-3-yl)piperazine-l-carbothioamide (TL928).

[0867] The product was obtained as a white solid (93 mg, 65%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.70 (d, J = 2.7 Hz, 1H), 8.00 (dd, J = 8.6, 2.5 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 4.08 - 3.82 (m, 4H), 3.52 (s, 2H), 2.46 (t, J = 5.0 Hz, 4H). MS (ESI) m / z 460.8 [M+H]+Ci8Hi8BrF3N4S. HPLC analysis: MeCN-H20 (95:5), 6.62 min, 99.48% pure.

[0868] 2-Chloro-4-(4-(4-hydroxyphenyl)piperazine- l-carbothioamido)benzoic acid (TL933) .

[0869] The product was obtained as a white solid (89 mg, 82%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.89 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.58 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.87 - 6.79 (m, 2H), 6.71 - 6.64 (m, 2H), 4.03 (t, 7 = 5.1 Hz, 4H), 3.05 (t, 7 = 5.0 Hz, 4H). MS (ESI) m / z 389.9 [M-H]+C18H18CIN3O3S. HPLC analysis: MeCN-H2O (95:5), 5.26 min, 99.51% pure.

[0870] 2-Chloro-4-(4-(4-(trifluoromethyl)phenyl)piperazine-l-carbothioamido)benzoic acid (TL934).

[0871] The product was obtained as a white solid (89 mg, 77%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13. 12 (s, 1H), 9.67 (s, 1H), 7.83 - 7.76 (m, 1H), 7.61 (d, 7 = 2.2 Hz, 1H), 7.53 (d, 7 = 8.6 Hz, 2H), 7.44 (dd, 7 = 8.5, 2.3 Hz, 1H), 7.06 (d, 7 = 8.6 Hz, 2H), 4.16 - 4.00 (m, 4H), 3.47 (dd, 7 = 6.4, 4.2 Hz, 4H). MS (ESI) m / z 443.9 [M+H]+CI9HI7C1F3N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.26 min, 99.58% pure.

[0872] 2-Chloro-4-(4-(4-cyanophenyl)piperazine-l-carbothioamido)benzoic acid (TL935).

[0873] The product was obtained as a white solid (58 mg, 55%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.25 - 13.03 (m, 1H), 9.64 (s, 1H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.69 - 7.57 (m, 3H), 7.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.00 (d, 7 = 8.7 Hz, 2H), 4.07 (t, 7 = 5.3 Hz, 4H), 3.53 (t, 7 = 5.3 Hz, 4H). MS (ESI) m / z 400.9 [M+H]+CI9HI7C1N4O2S. HPLC analysis: MeCN-H2O (95:5), 6.95 min, 95.04% pure.

[0874] 2-Chloro-4-(4-(3,4-dichlorophenyl)piperazine-l-carbothioamido)benzoic acid (TL939). The product was obtained as a white solid (95 mg, 82%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.14 (s, 1H), 9.68 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.46 - 7.37 (m, 2H), 7.16 (d, 7 = 2.9 Hz, 1H), 6.94 (dd, 7 = 9.0,

[0875] 2.9 Hz, 1H), 4.05 (t, J = 5.2 Hz, 4H), 3.47 - 3.29 (m, 4H). MS (ESI) m / z 445.7 [M+H]+C18H16CI3N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.57 min, 98.36% pure.

[0876] 2-Chloro-4-(4-(5-chloro-2-methylphenyl)piperazine-l-carbothioamido)benzoic acid (TL940).

[0877] The product was obtained as a white solid (100 mg, 83%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.71 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.56 (d, 7 = 2.1 Hz, 1H), 7.40 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.04 (d, 7 = 7.1 Hz, 2H), 4.05 (t, 7 = 4.8 Hz, 4H), 2.94 (d, 7 = 9.9 Hz, 4H), 2.27 (s, 3H). MS (ESI) m / z 423.9 [M+H]+C19H19CI2N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.66 min, 97.62% pure.

[0878] 2-Chloro-4-(4-(2,4-dimethyIphenyl)piperazine-l-carbothioamido)benzoic acid (TL941).

[0879] The product was obtained as a white solid (102 mg, 80%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.70 (s, 1H), 7.73 (d, 7 = 8.4 Hz, 1H), 7.55 (q, 7 = 1.7 Hz, 1H), 7.39 (dt, 7 = 8.5, 1.5 Hz, 1H), 7.00 (d, 7 = 2.1 Hz, 1H), 6.98 - 6.90 (m, 2H), 4.17 - 3.91 (m, 4H), 2.86 (t, 7 = 4.9 Hz, 4H), 2.26 (s, 3H), 2.21 (s, 4H). MS (ESI) m / z

[0880] 403.9 [M+H]+C20H22CIN3O2S. HPLC analysis: MeCN-H2O (95:5), 8.56 min, 98.55% pure.

[0881] 2-Chloro-4-(4-(3-hydroxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL943).

[0882] The product was obtained as a grey solid (111 mg, 85%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.66 (s, 1H), 9.18 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.01 (t, 7 = 8.1 Hz, 1H), 6.41 (dd, 7 = 8.2, 2.3 Hz, 1H), 6.33 (t, 7= 2.3 Hz, 1H), 6.24 (dd, 7 = 8.0, 2.1 Hz, 1H), 4.04 (t, 7 = 5.2 Hz, 4H), 3.26 - 3.14 (m, 4H). MS (ESI) m / z 391.8 [M+H]+C18H18CIN3O3S. HPLC analysis: MeCN-H20 (95:5), 6.13 min, 99.01% pure.

[0883] 2-Chloro-4-(4-(3-chlorophenyl)piperazine-l-carbothioamido)benzoic acid (TL944).

[0884] The product was obtained as a yellowish solid (56 mg, 54%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.69 (s, 1H), 7.76 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.24 (t, 7 = 8.1 Hz, 1H), 6.98 (t, 7 = 2.2 Hz, 1H), 6.92 (dd, 7 = 8.5, 2.4 Hz, 1H), 6.81 (dd, 7 = 7.9, 1.9 Hz, 1H), 4.05 (dd, 7 = 6.6, 3.8 Hz, 4H), 3.34 (dd, 7 = 4.3, 2.6 Hz, 4H). MS (ESI) m / z C18H17CI2N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.07 min, 98.62% pure.

[0885] 2-Chloro-4-(4-(3,5-dichlorophenyl)piperazine-l-carbothioamido)benzoic acid (TL945). The product was obtained as a white solid (78 mg, 68%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.07 (s, 1H), 9.67 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.95 (d, 7 = 1.8 Hz, 2H), 6.87 (t, 7 = 1.7 Hz, 1H), 4.03 (dd, 7 = 6.6, 4.0 Hz, 4H), 3.48 - 3.35 (m, 4H).

[0886] MS (ESI) m / z 445.7 [M+H]+C18H16CI3N3O2S. HPLC analysis: MeCN-H20 (95:5), 8.83 min, 97.66% pure.

[0887] 4-(4-(3-Bromophenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL946).

[0888] The product was obtained as a pink solid (75 mg, 67%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.14 (s, 1H), 9.67 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.60 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.17 (1, 7 = 8.1 Hz, 1H), 7.11 (t, 7 = 2.1 Hz, 1H), 6.94 (td, 7 = 8.2, 7.7, 2.1 Hz, 2H), 4.04 (dd, 7 = 6.6, 3.9 Hz, 4H), 3.42 - 3.24 (m, 4H). MS (ESI) m / z 455.8 [M+H]+CisHpBrChSfeChS. HPLC analysis: MeCN-H2O (95:5), 8.18 min, 98.42% pure.

[0889] 2-Chloro-4-(4-(4-fluorophenyl)piperazine-l-carbothioamido)benzoic acid (TL947).

[0890] The product was obtained as a white solid (66 mg, 61%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.12 (s, 1H), 9.68 (s, 1H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.13 - 7.03 (m, 2H), 7.03 - 6.96 (m, 2H), 4.05 (t, 7 = 5.1 Hz, 4H), 3.29 - 3.09 (m, 4H). MS (ESI) m / z 393.9 [M+H]+C18H17CIFN3O2S. HPLC analysis: MeCN-H20 (95:5), 4.64 min, 100% pure.

[0891] 2-Chloro-4-(4-(3,4-dimethylphenyl)piperazine-l-carbothioamido)benzoic acid (TL948).

[0892] The product was obtained as a white solid (71 mg, 56%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.67 (s, 1H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.99 (d, 7 = 8.2 Hz, 1H), 6.79 (d, 7 = 2.6 Hz, 1H), 6.69 (dd, 7 = 8.3, 2.6 Hz, 1H), 4.04 (t, 7 = 5.1 Hz, 4H), 3.17 (t, 7 = 5.2 Hz, 4H), 2.18 (s, 3H), 2.12 (s, 3H). MS (ESI) m / z 403.9 [M+H]+C20H22CIN3O2S. HPLC analysis: MeCN-H20 (95:5), 7.99 min, 98.29% pure.

[0893] 2-Chloro-4-(4-(p-tolyl)piperazine-l-carbothioamido)benzoic acid (TL952).

[0894] The product was obtained as a yellowish solid (60 mg, 54%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.6, 2.1 Hz, 1H), 7.05 (d, 7 = 8.3 Hz, 2H), 6.88 (d, 7 = 8.4 Hz, 2H), 4.05 (t, 7 = 5.0 Hz, 4H), 3.18 (t, 7 = 5.1 Hz, 4H), 2.21 (s, 3H). MS (ESI) m / z 389.9 [M+H]+C19H20CIN3O2S. HPLC analysis: MeCN-H20 (95:5), 7.70 min, 99.62% pure.

[0895] 2-Chloro-4-(4-(pyrimidin-2-yl)piperazine-l-carbothioamido)benzoic acid (TL954). The product was obtained as a white solid (75 mg, 65%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.66 (s, 1H), 8.40 (dd, J = 4.8, 1.7 Hz, 2H), 7.79 (d, 7 = 8.3 Hz, 1H), 7.61 (t, 7 = 1.6 Hz, 1H), 7.44 (dt, J = 8.6, 1.6 Hz, 1H), 6.74 - 6.65 (m, 1H), 4. 12 - 3.98 (m, 4H), 3.98 - 3.79 (m, 4H). MS (ESI) m / z 377.8 [M+H]+C16H16CIN5O2S. HPLC analysis: MeCN-H20 (95:5), 5.91 min, 99.84% pure.

[0896] 2-Chloro-4-(4-(3-methylquinolin-2-yI)piperazine-l-carbothioamido)benzoic add (TL955).

[0897] The product was obtained as a white solid (124 mg, 92%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.71 (s, 1H), 8.06 - 7.99 (m, 1H),

[0898] 7.80 (dd, J = 8.8, 2.6 Hz, 1H), 7.75 (dd, J = 11.4, 7.8 Hz, 2H), 7.61 (d, J = 2.9 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 4.11 (dd, J = 6.5, 3.6 Hz, 4H), 3.30 (d, J = 12.5 Hz, 4H), 2.45 (d, 7 = 2.7 Hz, 3H). MS (ESI) m / z 441.0 [M+H]+C22H21CIN4O2S. HPLC analysis: MeCN-H20 (95:5), 6.37 min, 98.02% pure.

[0899] 2-Chloro-4-(4-(pyridin-3-yl)piperazine-l-carbothioamido)benzoic acid (TL958).

[0900] The product was obtained as a yellowish solid (81 mg, 59%) using a similar procedure as described for TL283.1H NMR (599 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.34 (d, 7 = 3.0 Hz, 1H), 8.03 (dd, 7 = 4.6, 1.3 Hz, 1H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.60 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 =

[0901] 8.5, 2.1 Hz, 1H), 7.35 (ddd, 7 = 8.6, 3.1, 1.3 Hz, 1H), 7.24 (dd, 7 = 8.4, 4.5 Hz, 1H), 4.08 (t, 7 = 5.2 Hz, 4H), 3.34 (d, 7 = 10.4 Hz, 4H). MS (ESI) m / z 376.8 [M+H]+C17H17CIN4O2S. HPLC analysis: MeCN-H20 (95:5), 4.45 min, 98.67% pure.

[0902] 2-Chloro-4-(4-(3-nitropyridin-2-yl)piperazine- l-carbothioamido)benzoic acid (TL960) .

[0903] The product was obtained as a yellow solid (110 mg, 91%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-76) δ 13.11 (s, 1H), 9.60 (s, 1H), 8.46 (dt, 7 =

[0904] 4.6, 1.4 Hz, 1H), 8.31 (dt, 7 = 8.1, 1.6 Hz, 1H), 7.79 (d, 7= 8.5 Hz, 1H), 7.61 (d, 7 = 2.1 Hz, 1H), 7.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.95 (ddd, 7 = 8.1, 4.6, 1.6 Hz, 1H), 4.17 - 3.96 (m, 4H), 3.67 - 3.50 (m, 4H). MS (ESI) m / z 421.8 [M+H]+C17H16CIN5O4S. HPLC analysis: MeCN-H20 (95:5), 6.90 min, 99.85% pure.

[0905] 2-Chloro-4-(4-(3-cyanopyrazin-2-yl)piperazine-l-carbothioamido)benzoic acid (TL961).

[0906] The product was obtained as a yellow solid (79 mg, 62%) using a similar procedure as described for TL283. MS (ESI) m / z 402.8 [M+H]+C17H15CIN6O2S. HPLC analysis: MeCN-H20 (95:5), 6.42 min, 96.59% pure.

[0907] 2-Chloro-4-(4-(5-chloropyridin-2-yl)piperazine-l-carbothioamido)benzoic acid (TL962).

[0908] The product was obtained as a pink solid (53 mg, 42%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.14 (d, 7 = 2.7 Hz, 1H), 7.79 (d, 7 = 8.5 Hz, 1 H), 7.64 (dd, J = 9.1 , 2.7 Hz, 1H), 7.61 (d, 7 = 2.1 Hz, 1 H), 7.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.89 (d, 7 = 9.1 Hz, 1H), 4.12 - 3.99 (m, 4H), 3.72 - 3.63 (m, 4H). MS (ESI) m / z 410.8 [M+H]+C17H16CI2N4O2S. HPLC analysis: MeCN-H2O (95:5), 7.31 min, 99.56% pure.

[0909] (R)-2-ChIoro-4-(4-(5-cyanopyridin-2-yl)-2-methyIpiperazine-l-carbothioamido)benzoic acid (TL963).

[0910] The product was obtained as a white solid (75 mg, 61%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.06 (s, 1H), 9.55 (s, 1H), 8.55 - 8.47 (m, 1H), 7.89 (dt, 7 = 9.0, 2.3 Hz, 1H), 7.78 (d, 7= 8.5 Hz, 1H), 7.58 (d, 7 = 2.0 Hz, 1H), 7.42 (dd, 7 =

[0911] 8.5, 2.1 Hz, 1H), 6.96 (dd, 7 = 9.1, 2.2 Hz, 1H), 5.14 (s, 1H), 4.47 (s, 1H), 4.26 (dd, 7 = 22.0, 13.5 Hz, 2H), 3.60 (ddd, 7= 14.0, 10.3, 3.8 Hz, 1H), 3.50 (dd, 7 = 13.7, 3.9 Hz, 1H), 3.34 - 3.29 (m, 1H), 1.20 (d, 7 = 6.6 Hz, 3H). MS (ESI) m / z 415.9 [M+H]+CI9HI8C1N5O2S. HPLC analysis: MeCN-H20 (95:5), 6.90 min, 99.57% pure.

[0912] / V-(4-(lfi-tetrazol-5-yl)phenyI)-4-(5-bromo-3-methylpyridin-2-yI)piperazine-l- carbothioamide (TL965).

[0913] The product was obtained as a yellow solid (91 mg, 85%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.20 (d, 7 = 2.4 Hz, 1H), 8.01 - 7.89 (m, 2H), 7.76 (d, 7 = 2.5 Hz, 1H), 7.60 - 7.47 (m, 2H), 4. 15 - 3.89 (m, 4H), 3.24 - 3. 13 (m, 4H), 2.28 (s, 3H). MS (ESI) m / z 460.8 [M+H]+Ci8Hi9BrN8S. HPLC analysis: MeCN-H2O (95:5), 7.44 min, 96.70% pure.

[0914] 4-(5-Bromo-3-methylpyridin-2-yl)-Ar-(4-(5-methyl-4H-l,2,4-triazol-3-yl)phenyl)piperazine- 1-carbothioamide (TL967).

[0915] The product was obtained as a pink solid (91 mg, 83%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.59 (s, 1H), 9.49 (s, 1H), 8.21 (d, 7 = 2.5 Hz, 1H), 7.89 (t, 7 = 8.7 Hz, 2H), 7.78 (d, 7 = 2.4 Hz, 1H), 7.38 (d, 7 = 8.2 Hz, 2H), 4.04 (dd, 7 = 6.7, 3.5 Hz, 4H), 3.26 - 3.13 (m, 4H), 2.28 (s, 3H). MS (ESI) m / z 473.8 [M+H]+C20H22BrN7S. HPLC analysis: MeCN-H2O (95:5), 7.20 min, 98.60% pure.

[0916] 2V-(3-(2H-tetrazol-5-yl)phenyl)-4-(5-bromo-3-methylpyridin-2-yl)piperazine-l- carbothioamide (TL968).

[0917] The product was obtained as a white solid (81 mg, 76%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.21 (d, 7 = 2.7 Hz, 1H), 8.09 - 8.02 (m, 1H), 7.77 (ddd, 7 = 10.4, 4.9, 2.2 Hz, 2H), 7.53 (d, 7 = 6.9 Hz, 2H), 4.07 (t, 7 = 4.9 Hz, 4H), 3.31 - 3.07 (m, 5H), 2.29 (d, 7 = 2.4 Hz, 3H). MS (ESI) m / z 460.8 [M+H]+Ci8Hi9BrN8S. HPLC analysis: MeCN-H20 (95:5), 7.46 min, 99.90% pure. 2-Chloro-4-(4-(2,5-dimethylphenyl)piperazine-l-carbothioamido)benzoic acid (TL970).

[0918] The product was obtained as a white solid (98 mg, 77%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.68 (s, 1H), 7.79 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.59 (q, J = 2.4 Hz, 1H), 7.46 - 7.38 (m, 1H), 7. 11 - 7.03 (m, 1H), 6.85 (s, 1H), 6.80 (d, J = 7.6 Hz, 1H), 4.04 (t, J = 4.7 Hz, 4H), 2.90 (t, J = 4.8 Hz, 4H), 2.24 (d, J = 2.3 Hz, 6H). MS (ESI) m / z 403.9 [M+H]+C20H22CIN3O2S. HPLC analysis: MeCN-H2O (95:5), 8.50 min, 99.58% pure.

[0919] 4-(4-(4-(Tert-butyl)phenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL971).

[0920] The product was obtained as a yellow solid (62 mg, 52%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-J6) δ 9.69 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.59 (d, J =

[0921] 2.1 Hz, 1H), 7.43 (dd, J = 8.5, 2.0 Hz, 1H), 7.30 - 7.20 (m, 2H), 6.95 - 6.83 (m, 2H), 4.05 (t, J =

[0922] 5.1 Hz, 4H), 3.20 (d, 7 = 10.3 Hz, 4H), 1.24 (s, 9H). MS (ESI) m / z 432.0 [M+H]+C22H26CIN3O2S. HPLC analysis: MeCN-H20 (95:5), 8.87 min, 97.13% pure.

[0923] 4-(5-Bromo-3-methylpyridin-2-yl)- / V-(3,5-dichloro-6-fluoro-2-oxo-l,2-dihydropyridin-4- yl)piperazine- 1-carbothioamide (TL974) .

[0924] The product was obtained using a similar procedure as described for TL283 as a white solid (35 mg, 30%). MS (ESI) m / z CieHuBrChFNsOS.

[0925] 2-Chloro-4-(4-(3,5-dichIoropyridin-2-yl)piperazine-l-carbothioamido)benzoic acid (TL976).

[0926] The product was obtained as a white solid (112 mg, 73%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13. 11 (s, 1H), 9.68 (s, 1H), 8.30 (t, 7 = 2.7 Hz, 1H), 8.12 - 8.04 (m, 1H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.5,

[0927] 2.1 Hz, 1H), 4.14 - 3.94 (m, 4H), 3.49 - 3.37 (m, 5H). MS (ESI) m / z 444.7 [M+H]+C17H15CI3N4O2S. HPLC analysis: MeCN-H20 (95:5), 8.38 min, 99.24% pure.

[0928] N-(4-(l / / -tetrazol-5-yl)phenyl)-4-(4-bromo-2-methylphenyl)piperazine-l-carbothioamide (TL977).

[0929] The product was obtained as an off-white solid (78 mg, 72%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.99 - 7.92 (m, 2H), 7.58 - 7.51 (m, 2H), 7.39 (d, 7 = 2.5 Hz, 1H), 7.33 (dd, 7 = 8.5, 2.5 Hz, 1H), 7.00 (d, 7 = 8.5 Hz, 1H), 4.15 - 3.96 (m, 4H), 2.91 (d, 7 = 9.8 Hz, 4H), 2.30 (s, 3H). MS (ESI) m / z 459.8 [M+H]+Ci9H2oBrN7S. HPLC analysis: MeCN-H20 (95:5), 8.34 min, 98.92% pure.

[0930] 4-(4-(4-Bromo-2-methylphenyl)piperazine-l-carbothioamido)-2,3,5,6-tetrafluorophenyl hypofluorothioite (TL921=TL978). The product was obtained as a white solid (105 mg, 88%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.85 - 7.76 (m, 2H), 7.56 (d, 7 = 8.9 Hz, 2H), 7.44 - 7.37 (m, 1H), 7.33 (dd, J = 8.5, 2.5 Hz, 1H), 7.00 (d, 7 = 8.5 Hz, 1H), 4.06 (t, 7 = 4.7 Hz, 4H), 2.91 (t, 7 = 4.9 Hz, 4H), 2.29 (s, 3H). MS (ESI) m / z CisHisBrFsNsSz. HPLC analysis: MeCN-H20 (95:5), 10.34 min, 97.89% pure.

[0931] 4-(4-Bromo-2-methylphenyl)-A,-(4-(5-methyl-4 / / -l,2,4-triazol-3-yl)phenyl)piperazine-l- carbothioamide (TL979).

[0932] The product was obtained as a yellow solid (103 mg, 94%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.68 (s, 1H), 9.52 (s, 1H), 7.98 - 7.80 (m, 2H), 7.49 - 7.35 (m, 3H), 7.32 (dd, 7 = 8.5, 2.5 Hz, 1H), 6.99 (d, 7 = 8.5 Hz, 1H), 4.13 - 3.93 (m, 4H), 2.90 (t, 7 = 4.9 Hz, 4H), 2.38 (s, 3H), 2.29 (s, 3H). MS (ESI) m / z 472.8 [M+H]+C2iH23BrN6S. HPLC analysis: MeCN-H20 (95:5), 8.18 min, 98.94% pure.

[0933] / V-(3-(2 / / -tetrazol-5-yl)phenyl)-4-(4-bromo-2-methylphenyl (piperazine- 1-carbothioamide (TL980).

[0934] The product was obtained as an off-white solid (76 mg, 70%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.25 - 8. 18 (m, 1H), 7.99 (q, 7 = 1.4 Hz, 1H), 7.75 (ddt, 7 = 6.1, 4.4, 2.2 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.39 (d, 7 = 2.6 Hz, 1H), 7.37 - 7.30 (m, 1H), 7.01 (d, 7 = 8.6 Hz, 1H), 6.97 - 6.92 (m, 1H), 4.07 (t, 7 = 4.8 Hz, 4H), 2.91 (t, 7 = 4.9 Hz, 4H), 2.30 (s, 3H). MS (ESI) m / z 459.9 [M+H]+Ci9H20BrN7S. HPLC analysis: MeCN-H20 (95:5), 8.35 min, 95.19% pure.

[0935] 4-(4-Bromo-2-methylphenyl)-Af-(4-bromo-3-fluoro-2-methylphenyl)piperazine-l- carbothioamide (TL981).

[0936] The product was obtained as a white solid (82 mg, 64%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.32 (dd, 7 = 8.4, 2.5 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.95 - 6.89 (m, 1H), 4.11 - 3.95 (m, 4H), 2.90 (t, J = 4.9 Hz, 4H), 2.29 (s, 3H), 2.12 (d, J = 2.3 Hz, 3H). MS (ESI) m / z 501.8 [M+H]+Ci9H2oBr2FN3S. HPLC analysis: MeCN-H20 (95:5), 10.10 min, 98.02% pure.

[0937] 4-(4-Bromo-2-methylphenyl)-A,-(3-chloro-4-hydroxyphenyl)piperazine-l-carbothioamide (TL982).

[0938] The product was obtained as a brown solid (83 mg, 81%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.27 (s, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 8.5, 2.5 Hz, 1 H), 7.24 (d, 7 = 2.5 Hz, 1H), 7.04 (dd, 7 = 8.6, 2.5 Hz, 1H), 6.99

[0939] (d, 7 = 8.5 Hz, 1H), 6.90 (d, 7 = 8.6 Hz, 1H), 4.01 (t, 7 = 4.7 Hz, 4H), 2.88 (t, 7= 4.9 Hz, 4H), 2.29 (s, 3H). MS (ESI) m / z 439.7 [M+H]+CisHigBrCMOS. HPLC analysis: MeCN-H2O (95:5), 8.84 min, 95.73% pure.

[0940] 4-(4-Bromo-2-methylphenyl)- / V-(3-chloro-4-cyanophenyl)piperazine-l-carbothioamide (TL983).

[0941] The product was obtained as an off-white solid (71 mg, 62%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-t / e) 5 9.85 (s, 1H), 7.84 (d, 7 = 8.5 Hz, 1H),

[0942] 7.78 (d, J = 2.0 Hz, 1H), 7.52 (dd, 7 = 8.6, 2.1 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.32 (dd, 7 = 8.5, 2.5 Hz, 1H), 6.99 (d, 7 = 8.5 Hz, 1H), 4.05 (t, 7= 4.8 Hz, 4H), 2.91 (t, 7 = 4.9 Hz, 4H), 2.29 (s, 3H). MS (ESI) m / z 450.8 [M+HJ+Ci9HisBrClN4S. HPLC analysis: MeCN-H2O (95:5), 9.85 min, 98.61% pure.

[0943] 4-(4-Bromo-2-methylphenyl)-A,-(6-bromo-5-fluoropyridin-3-yl)piperazine-l- carbothioamide (TL984).

[0944] The product was obtained as an off-white solid (107 mg, 86%) using a similar procedure as described for TL283.1H NMR (599 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.25 (d, 7 = 2.2 Hz, 1H), 7.98 (dd, 7 = 9.9, 2.2 Hz, 1H), 7.39 (d, 7 = 2.5 Hz, 1H), 7.33 (dd, 7 = 8.5, 2.5 Hz, 1H), 7.00 (d, 7 = 8.5 Hz, 1H), 4.07 (t, 7 = 4.8 Hz, 4H), 2.92 (t, 7 = 4.9 Hz, 4H), 2.30 (s, 3H). MS (ESI) m / z 488.7 [M+H]+Ci7Hi7Br2FN4S. HPLC analysis: MeCN-H2O (95:5), 9.72 min, 98.85% pure.

[0945] Methyl 4-(4-(5-bromo-3-methyIpyridin-2-yl)piperazine-l-carbothioainido)-2- chlorobenzoate (TL987).

[0946] The product was obtained as a pink solid (94 mg, 83%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.24 - 8.19 (m, 1H), 7.80 (d, 7 = 8.5 Hz, 1H), 7.79 - 7.76 (m, 1H), 7.63 (d, 7 = 2.1 Hz, 1H), 7.45 (dd, 7 = 8.6, 2.1 Hz, 1H), 4.11 - 3.97 (m, 4H), 3.83 (s, 3H), 3.24 - 3.11 (m, 4H), 2.28 (s, 3H). MS (ESI) m / z 484.8 [M+H]+Ci9H2oBrClN402S. HPLC analysis: MeCN-H2O (95:5), 9.10 min, 99.36% pure.

[0947] Methyl 4-(4-(4-bromobenzyl)piperazine-l-carbothioamido)-2-chlorobenzoate (TL988).

[0948] The product was obtained as a white solid (102 mg, 90%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 11.07 - 9.91 (m, 1H), 9.62 (s, 1H), 7.78 (d, 7 = 8.6 Hz, 1H), 7.60 (d, 7 = 2.1 Hz, 1H), 7.58 - 7.49 (m, 2H), 7.42 (dd, 7 = 8.6, 2.1 Hz, 1H), 7.33 - 7.25 (m, 2H), 3.95 - 3.87 (m, 4H), 3.83 (s, 3H), 3.51 (s, 2H), 2.44 (t, 7 = 5.0 Hz, 4H). MS (ESI) m / z 483.8 [M+H]+C20H2iBrClN3O2S. HPLC analysis: MeCN-H2O (95:5), 6.83 min, 97.92% pure.

[0949] Ar-(4-(l / / -tetrazol-5-yl)phenyl)-4-(4-bromobenzyl)piperazine-l-carbothioamide (TL989). The product was obtained as an off-white solid (62 mg, 58%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) 3 10.01 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.68 (s, 1H), 7.67 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.57 (d, 7= 8.1 Hz, 2H), 4.30 (s, 6H). MS (ESI) m / z 459.8 [M+H]+Ci9H2oBrN7S. HPLC analysis: MeCN-H20 (95:5), 5.66 min, 99.69% pure.

[0950] / V-(4-(lH-tetrazol-5-yl)phenyI)-4-(2,3-dihydro-lH-inden-2-yl)piperazine-l-carbothioamide (TL990).

[0951] The product was obtained as a white solid (18 mg, 60%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.57 (s, 1H), 7.98 - 7.87 (m, 2H), 7.57 - 7.47 (m, 2H), 7.20 (dt, 7 = 7.3, 3.7 Hz, 2H), 7.13 (dd, 7 = 5.5, 3.2 Hz, 2H), 3.97 (t, 7 = 4.9 Hz, 4H), 3.24 (p, 7 = 8.0 Hz, 1H), 3.07 (dd, 7 = 15.4, 7.5 Hz, 2H), 2.84 (dd, 7 = 15.4, 8.5 Hz, 2H), 2.61 (t, 7 = 5.0 Hz, 4H). MS (ESI) m / z 406.0 [M+H]+C21H23N7S. HPLC analysis: MeCN-H20 (95:5), 5.33 min, 97.67% pure.

[0952] 4-(4-Bromoisoindoline-2-carbothioamido)-2-chlorobenzoic acid (TL991).

[0953] The product was obtained as a brown solid (72 mg, 58%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.48 (d, 7 = 30.8 Hz, 1H), 7.84 - 7.77 (m, 2H), 7.62 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.39 (s, 1H), 7.28 (td, 7 = 8.2, 3.3 Hz, 1H), 5.12 (s, 2H), 4.97 (s, 2H). MS (ESI) m / z 412.7 [M+H]+CieH^BrCl^ChS. HPLC analysis: MeCN-H20 (95:5), 7.98 min, 98.97% pure.

[0954] 4-(5-Bromoisoindoline-2-carbothioamido)-2-chlorobenzoic acid (TL992).

[0955] The product was obtained as a pink solid (116 mg, 94%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.83 - 7.75 (m, 2H), 7.71 - 7.61 (m, 1H), 7.60 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.51 (dd, 7 = 8.2, 1.9 Hz, 1H), 7.36 (s, 1H), 5.03 (s, 2H), 4.99 (s, 2H). MS (ESI) m / z 412.7 [M+H]+Ci6Hi2BrClN2O2S. HPLC analysis: MeCN-H20 (95:5), 8.00 min, 98.92% pure.

[0956] 4-(6-Bromo-l,2,3,4-tetrahydroquinoline-l-carbothioamido)-2-chlorobenzoic acid (TL993).

[0957] The product was obtained as an off-white solid (62 mg, 44%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) 3 13.11 (s, 1H), 10.12 (s, 1H), 7.76 (d, 7 = 8.5 Hz, 1H), 7.63 (d, 7= 2.1 Hz, 1H), 7.47 (d, 7 = 2.4 Hz, 1H), 7.41 (dd, 7 = 8.6, 2.1 Hz, 1H), 7.29 (dd, 7 = 8.7, 2.4 Hz, 1H), 7.21 (d, 7 = 8.7 Hz, 1H), 4.05 (t, 7 = 6.4 Hz, 2H), 2.75 (t, 7 = 6.7 Hz, 2H), 1.94 (p, 7 = 6.6 Hz, 2H). MS (ESI) m / z 426.7 [M+H]+Ci7Hi4BrClN2O2S. HPLC analysis: MeCN-H20 (95:5), 8.22 min, 95.54% pure.

[0958] 4-(5-Bromoindoline-l-carbothioamido)-2-chlorobenzoic acid (TL997). The product was obtained as a white solid (85 mg, 69%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.02 (d, 7 = 8.8 Hz, 1H), 7.80 (d, 7 = 8.5 Hz, 1H), 7.65 (d, 7 = 2.1 Hz, 1H), 7.56 - 7.44 (m, 2H), 7.35 (dd, 7 = 8.8, 2.2 Hz, 1H), 4.32 (t, 7 = 8.2 Hz, 2H), 3.20 - 3.05 (m, 2H). MS (ESI) m / z 412.7 [M+H]+Ci6Hi2BrClN2O2S. HPLC analysis: MeCN-H20 (95:5), 8.12 min, 97.30% pure.

[0959] 4-(5-Bromo-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)-2-chlorobenzoic acid (TL998).

[0960] The product was obtained as a white solid (72 mg, 70%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.13 (s, 1H), 9.69 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.60 (d, 7 = 2.1 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.45 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.25 (d, 7 = 7.6 Hz, 1H), 7.18 (t, 7 = 7.8 Hz, 1H), 5.09 (s, 2H), 4.13 (t, 7 = 6.0 Hz, 2H), 2.95 (t, 7= 6.0 Hz, 2H). MS (ESI) m / z 426.7 [M+H]+Ci7Hi4BrClN2O2S. HPLC analysis: MeCN-H2O (95:5), 8.07 min, 99.96% pure.

[0961] 4-(6-Bromoindoline-l-carbothioamido)-2-chlorobenzoic acid (TL999).

[0962] The product was obtained as a white solid (87 mg, 70%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.20 (s, 1H), 10.08 (s, 1H), 8.34 (d, 7 = 1.8 Hz, 1H), 7.82 (d, 7 = 8.4 Hz, 1H), 7.66 (d, 7 = 2.1 Hz, 1H), 7.49 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.26 (d, 7 = 7.9 Hz, 1H), 7.21 (dd, 7 = 8.0, 1.8 Hz, 1H), 4.33 (t, 7 = 8.2 Hz, 2H), 3.08 (t, 7 = 8.2 Hz, 2H). MS (ESI) m / z 412.7 [M+H]+Ci6Hi2BrClN2O2S. HPLC analysis: MeCN-H20 (95:5), 7.92 min, 99.73% pure.

[0963] 2-Chloro-4-(6-chloro-4-methyl-l,2,3,4-tetrahydroisoquinoIine-2-carbothioamido)benzoic acid (TL1000).

[0964] The product was obtained as a white solid (58 mg, 44%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.60 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.60 id, 7 = 2.1 Hz, 1H), 7.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.38 (d, 7 = 2.2 Hz, 1H), 7.29 (dd, 7 = 8.2, 2.2 Hz, 1H), 7.25 (d, 7 = 8.2 Hz, 1H), 5.18 (d, 7 = 16.7 Hz, 1H), 4.93 (d, 7 = 16.7 Hz, 1H), 4.10 (dd, 7 = 13.0, 4.5 Hz, 1H), 3.82 (dd, 7 = 13.0, 7.7 Hz, 1H), 3.20 - 3.09 (m, 1H), 1.28 (d, 7 = 6.9 Hz, 3H). MS (ESI) m / z 394.8 [M+H]+CI8HI6C12N2O2S. HPLC analysis: MeCN-H20 (95:5), 8.26 min, 96.75% pure.

[0965] 4-(8-Bromo-l,2,3,4-tetrahydroisoquinoline-2-carbothioamido)-2-chIorobenzoic acid (TL1003).

[0966] The product was obtained as a yellowish solid (98 mg, 81 %) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.77 (s, 1H), 7.76 (d, 7 = 8.4 Hz, 1H), 7.57 (d, 7 = 2.1 Hz, 1H), 7.51 (d, 7 = 7.9 Hz, 1H), 7.42 (dd, 7= 8.5, 2.1 Hz, 1H), 7.27 (d, 7 = 7.6 Hz, 1H), 7.19 (q, 7= 7.7, 7.1 Hz, 1H), 5.07 (s, 2H), 4.07 (t, 7 = 5.9 Hz, 2H), 2.99 (t, 7 = 5.9 Hz, 2H). MS (ESI) m / z 426.7 [M+H]+Ci7Hi4BrClN2O2S. HPLC analysis: MeCN-H2O (95:5), 7.91 min, 99.63% pure.

[0967] 4-(4-Bromoindoline-l-carbothioamido)-2-chlorobenzoic acid (TL1004).

[0968] The product was obtained as a white solid (92 mg, 74%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.18 (s, 1H), 10.14 (s, 1H), 8.01 (d, 7 = 8.2 Hz, 1H), 7.81 (d, 7 = 8.5 Hz, 1H), 7.67 (d, 7 = 2.0 Hz, 1H), 7.50 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.24 (d, 7

[0969] = 8.0 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 4.35 (t, J = 8.2 Hz, 2H), 3.09 (t, J = 8.1 Hz, 2H). MS (ESI) m / z 412.7 [M+H]+Ci6Hi2BrClN2O2S. HPLC analysis: MeCN-H2O (95:5), 8.18 min, 96.75% pure.

[0970] 4-(4-(4-Acetylphenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL1009).

[0971] The product was obtained as a yellow solid (110 mg, 89%) using a similar procedure as described for TL283.1H NMR (599 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.66 (s, 1H), 7.87 - 7.82 (m, 2H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.61 (d, 7 = 2.1 Hz, 1H), 7.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.99 - 6.92 (m, 2H), 4.08 (dd, 7 = 6.8, 4.0 Hz, 4H), 3.60 - 3.50 (m, 4H), 2.46 (s, 3H). MS (ESI) m / z 417.9 [M+H]+C20H20CIN3O3S. HPLC analysis: MeCN-H2O (95:5), 6.64 min, 100% pure.

[0972] 2-Chloro-4-(4-phenylpiperazine-l-carbothioamido)benzoic acid (TL1013).

[0973] The product was obtained as a white solid (55 mg, 43%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.12 (s, 1H), 9.68 (s, 1H), 7.79 (d, 7 = 8.5 Hz,

[0974] 1H), 7.60 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.30 - 7.17 (m, 2H), 7.04 - 6.93

[0975] (m, 2H), 6.81 (t, 7 = 7.2 Hz, 1H), 4.06 (t, 7 = 5.1 Hz, 4H), 3.27 (dd, 7 = 6.4, 4.0 Hz, 4H). MS

[0976] (ESI) m / z 375.9 [M+H]+C18H18CIN3O2S. HPLC analysis: MeCN-H2O (95:5), 7.35 min, 99.95% pure.

[0977] 2-Chloro-4-(4-(4-(methoxycarbonyl)phenyl)piperazine-l-carbothioamido)benzoic acid (TL1014).

[0978] The product was obtained as a yellowish solid (30 mg, 25%) using a similar procedure as described for TL283. MS (ESI) m / z 431.8 [M-H]+C20H20CIN3O4S. HPLC analysis: MeCN-H20 (95:5), 7.22 min, 88.61% pure.

[0979] 4-(4-(4-Acetyl-2-nitrophenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL1016).

[0980] The product was obtained as a yellow solid (17 mg, 15%) using a similar procedure as described for TL283. NMR (599 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.66 (s, 1H), 7.78 (d, J = 8.5 Hz,

[0981] 1H), 7.58 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.03 - 6.95 (m, 2H), 6.95 - 6.85 (m, 2H), 4.04 (t, J = 4.9 Hz, 4H), 3.80 (s, 3H), 3.04 (d, J = 10.0 Hz, 4H). MS (ESI) m / z 462.9 [M+H]+C20H19CIN4O5S. HPLC analysis: MeCN-H2O (95:5), 6.95 min, 99.89% pure.

[0982] 2-Chloro-4-(4-(2-methoxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL1022).

[0983] The product was obtained as a white solid (76 mg, 60%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.66 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.58 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, J = 8.5, 2.1 Hz, 1H), 7.03 - 6.95 (m, 2H), 6.95 - 6.85

[0984] (m, 2H), 4.04 (t, 7 = 4.9 Hz, 4H), 3.80 (s, 3H), 3.04 (d, 7 = 10.0 Hz, 4H). MS (ESI) m / z 405.9 [M+H]+C19H20CIN3O3S. HPLC analysis: MeCN-H20 (95:5), 7.01 min, 99.88% pure.

[0985] 2-Chloro-4-(4-(4-methoxyphenyl)piperazine-l-carbothioainido)benzoic acid (TL1023).

[0986] The product was obtained as a yellowish solid (55 mg, 43%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.68 (s, 1H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.6, 2.1 Hz, 1H), 6.99 - 6.90 (m, 2H), 6.90 - 6.81 (m, 2H), 4.05 (t, 7 = 5.0 Hz, 4H), 3.69 (s, 3H), 3.11 (t, 7 = 5.1 Hz, 4H). MS (ESI) m / z 405.9 [M+H]+C19H20CIN3O3S. HPLC analysis: MeCN-H20 (95:5), 6.83 min, 99.32% pure.

[0987] 2-Chloro-4-(4-(3-methoxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL1024).

[0988] The product was obtained as a brown solid (81 mg, 55%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13. 10 (s, 1H), 9.68 (s, 1H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.60 (d, 7 = 2. 1 Hz, 1H), 7.43 (dd, 7 = 8.5, 2. 1 Hz, 1H), 7.13 (t, 7 = 8.2 Hz, 1H), 6.55 (dd, 7 = 8.3, 2.3 Hz, 1H), 6.49 (t, 7 = 2.3 Hz, 1H), 6.40 (dd, 7 = 8.1, 2.3 Hz, 1H), 4.05 (t, 7 = 5.1 Hz, 4H), 3.72 (s, 3H), 3.27 (t, 7 = 5.2 Hz, 4H). MS (ESI) m / z 405.9 [M+H]+C19H20CIN3O3S. HPLC analysis: MeCN-H20 (95:5), 7.29 min, 97.05% pure.

[0989] 4-(4-(4-Acetyl-3-hydroxyphenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL1025).

[0990] The product was obtained as a white solid (106 mg, 77%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 12.81 (s, 1H), 9.63 (s, 1H), 7.77 (d, 7 = 8.5 Hz, 1H), 7.71 (dd, 7 = 9.1, 1.4 Hz, 1H), 7.60 (d, 7 = 2.0 Hz, 1H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.51 (dd, 7 = 9.1, 2.4 Hz, 1H), 6.27 (d, 7 = 2.5 Hz, 1H), 4.06 (dd, 7 = 6.9, 3.9 Hz, 4H), 3.68 - 3.52 (m, 4H), 2.49 (s, 3H).13C NMR (151 MHz, DMSO-d6) δ 201.96, 181.07, 166.68, 164.53, 155.79, 145.18, 133.45, 132.24, 131.64, 125.89, 125.62, 122.35, 111.09, 105.59, 99.02, 47.80, 45.51, 26.29. MS (ESI) m / z 431.8 [M-H]+C20H20CIN3O4S. HPLC analysis: MeCN-H20 (95:5), 7.07 min, 95.87% pure.

[0991] 2-Chloro-4-(4-(2-((2,6-dimethylphenyl)amino)-2-oxoethyI)piperazine-l- carbothioamido)benzoic acid (TL1026). The product was obtained as a white solid (72 mg, 92%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.62 (s, 1H), 9.31 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.57 (d, 7 = 2.1 Hz, 1H), 7.41 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.08 (s, 3H), 4.08 - 3.96 (m, 4H), 3.23 (s, 2H), 2.73 - 2.61 (m, 4H), 2.15 (s, 6H). MS (ESI) m / z 461.1 [M+H]+C22H25CIN4O3S. HPLC analysis: MeCN-H20 (95:5), 5.86 min, 99.69% pure.

[0992] 2-Chloro-4-(4-(m-toiyI)piperazine-l-carbothioamido)benzoic acid (TL1027).

[0993] The product was obtained as a white solid (120 mg, 90%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.71 (d, 7 = 8.4 Hz, 1H), 7.55 (d, 7 =

[0994] 2.1 Hz, 1H), 7.39 (dd, J = 8.4, 2.1 Hz, 1H), 7.14 - 7.09 (m, 1H), 6.79 (q, J = 2.7 , 1.8 Hz, 1H), 6.76 (dd, 7 = 8.2, 2.6 Hz, 1H), 6.63 (dd, 7 = 7.5, 1.4 Hz, 1H), 4.16 - 3.93 (m, 4H), 3.30 - 3.18 (m, 4H), 2.26 (d, 7 = 2.6 Hz, 3H). MS (ESI) m / z 389.9 [M+H]+C19H20CIN3O2S. HPLC analysis: MeCN-H2O (95:5), 7.73 min, 95.52% pure.

[0995] 2-Chloro-4-(4-(3-cyanophenyI)piperazine-l-carbothioamido)benzoic acid (TL1031).

[0996] The product was obtained as a yellow solid (40 mg, 31 %) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.77 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.36 (dd, 7 = 2.6, 1.4 Hz, 1H), 7.28 (dd, 7 = 8.5, 2.6 Hz, 1H), 7.18 (dd, 7 = 7.5, 1.2 Hz, 1H), 4.06 (t, 7= 5.2 Hz, 4H), 3.44 - 3.33 (m, 5H). MS (ESI) m / z 401.0 [M+H]+C19H17CIN4O2S. HPLC analysis: MeCN-H2O (95:5), 7.20 min, 98.57% pure.

[0997] A;-(4-(l / / -tetrazol-l-yl)phenyl)-4-(5-bromo-3-methylpyridin-2-yl)piperazine-l- carbothioamide (TL1032).

[0998] The product was obtained as a white solid (54 mg, 50%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.64 (s, 1H), 8.22 (dd, 7 = 2.4, 0.8 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.79 (dd, 7 = 2.4, 0.9 Hz, 1H), 7.63 - 7.56 (m, 2H), 4.16 - 3.99 (m, 4H), 3.26 - 3.17 (m, 4H), 2.29 (s, 3H). MS (ESI) m / z 460.8 [M+H]+CisHigBrNsS. HPLC analysis: MeCN-H20 (95:5), 7.95 min, 99.15% pure.

[0999] 4-(4-(2-Bromo-4-(methylsuIfonyl)phenyI)piperazine-l-carbothioamido)-2-chIorobenzoic acid (TL1033).

[1000] The product was obtained as a white solid (64 mg, 55%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.10 (d, 7 = 2.2 Hz, 1H), 7.88 (dd, 7 = 8.5, 2.2 Hz, 1H), 7.80 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7= 8.5, 2.1 Hz, 1H), 7.38 (d, 7 = 8.5 Hz, 1H), 4.10 (t, 7 = 4.8 Hz, 4H), 3.24 (s, 3H), 3.21 (t, 7 = 5.0 Hz, 4H). MS (ESI) m / z 533.8 [M+H]+C19H19B1-CIN3O4S2. HPLC analysis: MeCN-H20 (95:5), 6.98 min, 99.55% pure. 2-Chloro-4-(4-(2-chloro-4-(methylsulfonyl)phenyl)piperazine-l-carbothioamido)benzoic acid (TL1035).

[1001] The product was obtained as a white solid (77 mg, 62%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 12.93 (s, 1H), 9.69 (s, 1H), 7.86 (d, 7 = 2.6 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.68 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.5, 2.1 Hz, 1H), 4.07 (s, 4H), 3.46 (s, 3H), 3.06 (t, 7 = 4.8 Hz, 4H). MS (ESI) m / z 489.7 [M+H]+

[1002] C19H19CI2N3O4S2. HPLC analysis: MeCN-H2O (95:5), 7.37 min, 99.33% pure. 2-Chloro-4-(4-(o-tolyl)piperazine-l-carbothioamido)benzoic acid (TL1036). The product was obtained as a yellowish solid (78 mg, 59%) using a similar procedure as described for TL283.1H NMR (599 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.40 (dd, 7 = 8.5, 2.2 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.04 (d, 7 = 8.0 Hz, 1H), 6.99 (td, 7 = 7.4, 1.2 Hz, 1H), 4.11 - 3.94 (m, 4H), 2.91 (t, 7 = 4.9 Hz, 4H), 2.30 (s, 3H).

[1003] MS (ESI) m / z 389.8 [M+H]+C19H20CIN3O2S. HPLC analysis: MeCN-H2O (95:5), 8.13 min, 97.99% pure.

[1004] 2-Chloro-4-(4-(3-methoxybenzoyl)piperazine-l-carbothioamido)benzoic acid (TL1037).

[1005] The product was obtained as a white solid (66 mg, 48%) using a similar procedure as described for TL283. MS (ESI) m / z 433.9 [M+H]+C20H20CIN3O4S. HPLC analysis: MeCN-H20 (95:5), 4.08 min, 93.54% pure.

[1006] 2-Chloro-4-(4-(3-fluorophenyl)piperazine-l-carbothioamido)benzoic acid (TL1038).

[1007] The product was obtained as a yellowish solid (68 mg, 52%) using a similar procedure as described for TL283. 'H NMR (599 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.68 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.60 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.24 (q, 7 = 7.9 Hz, 1H), 6.82 - 6.72 (m, 2H), 6.57 (td, 7 = 8.6, 2.0 Hz, 1H), 4.05 (t, 7 = 5.2 Hz, 4H), 3.34 - 3.29 (m, 4H). MS (ESI) m / z 393.8 [M+H]+C18H17CIFN3O2S. HPLC analysis: MeCN-H20 (95:5), 7.64 min, 99.52% pure.

[1008] 2-Chloro-4-(4-(4-(methylsulfonyl)-3-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL1042).

[1009] The product was obtained as a yellow solid (82 mg, 59%) using a similar procedure as described for TL283. ’H NMR (599 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.64 (s, 1H), 7.80 (dd, 7 = 11.6, 8.8 Hz, 2H), 7.61 (d, 7 = 2.1 Hz, 1H), 7.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.42 (dd, 7 = 2.6, 1.3 Hz, 1H), 7.20 (dt, 7 = 9.2, 2.8 Hz, 1H), 4.16 - 4.02 (m, 4H), 3.73 - 3.62 (m, 4H), 3.33 (s, 3H). MS (ESI) m / z 498.8 [M+H]+C19H19CIN4O6S2. HPLC analysis: MeCN-H20 (95:5), 6.73 min, 98.30% pure. 2-Chloro-4-(4-(4-chloro-2-(methylsulfonyl)phenyl)piperazine-l-carbothioamido)benzoic acid (TL1043).

[1010] The product was obtained as a yellowish solid (76mg, 54%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 13.12 (s, 1H), 9.73 (s, 1H), 7.94 (d, 7 = 2.2 Hz, 1H), 7.83 (dd, 7 = 8.5, 2.2 Hz, 1H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.38 (d, 7 = 8.5 Hz, 1H), 4.18 - 4.00 (m, 4H), 3.24 (s, 3H), 3.22 (d, 7 = 5.1 Hz, 4H). MS (ESI) m / z 487.8 [M+H]+C19H19CI2N3O4S2. HPLC analysis: MeCN-H20 (95:5), 6.87 min, 99.59% pure.

[1011] 4-(4-(2-CarbamoyIphenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL1044).

[1012] The product was obtained as a white solid (86 mg, 70%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.69 (s, 1H), 8.32 (d, 7 = 3.0 Hz, 1H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.68 (dd, 7 = 7.7, 1.7 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.53 (d, 7 = 2.9 Hz, 1H), 7.43 (ddd, 7 = 8.6, 6.3, 1.9 Hz, 2H), 7.18 (d, 7 = 8.1 Hz, 1H), 7.13 (td, 7 = 7.5, 1.0 Hz, 1H), 4.09 (t, 7 = 4.9 Hz, 4H), 3.12 - 2.98 (m, 4H). MS (ESI) m / z 418.8 [M+H]+C19H19C1N4O3S. HPLC analysis: MeCN-H2O (95:5), 5.89 min, 96.24% pure.

[1013] 2-Chloro-4-(4-(3-(methylsulfonyl)-4-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL1047).

[1014] The product was obtained as a yellow solid (96 mg, 79%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.66 (s, 1H), 8.03 (dd, 7 = 9.1, 1.6 Hz, 1H), 7.77 (dd, 7 = 8.5, 1.3 Hz, 1H), 7.61 (d, 7 = 2.1 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.20 (dt, 7

[1015] = 9.2, 2.6 Hz, 1H), 4.11 (dd, 7 = 6.9, 4.0 Hz, 4H), 3.78 - 3.66 (m, 4H), 3.54 (s, 3H). MS (ESI) m / z 498.9 [M+H]+C19H19CIN4O6S2. HPLC analysis: MeCN-H20 (95:5), 6.71 min, 96.70% pure.

[1016] 2-Chloro-4-(6-fluoro-2-methyl-l,2,3,4-tetrahydroquinoline-l-carbothioamido)benzoic acid (TL1051).

[1017] The product was obtained using a similar procedure as described for TL283.1H NMR (599 MHz, DMSO-d6) δ 13.07 (s, 1H), 9.79 (s, 1H), 7.73 (d, 7 = 8.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.38 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.21 (dd, 7 = 8.9, 5.1 Hz, 1H), 7.15 (dd, 7 = 9.1, 3.0 Hz, 1H), 6.99 (td, 7 = 8.7, 3.0 Hz, 1H), 6.67 (t, 7 = 8.0 Hz, 1H), 5.30 (td, 7 = 6.9, 5.1 Hz, 1H), 2.82 - 2.71 (m, 1H), 2.64 (dt, 7 = 15.8, 7.4 Hz, 1H), 2.32 (dq, 7 = 13.6, 6.9 Hz, 1H), 1.62 - 1.52 (m, 1H), 1.11 (dd, 7 = 6.4, 1.9 Hz, 3H). MS (ESI) m / z 378.9 [M+H]+CisHieCIFNsChS. HPLC analysis: MeCN-H20 (95:5), 8.02 min, 95.95% pure. 4-(4-Bromo-2-methylphenyl)-N-(3-chloro-4-cyanophenyl)piperazine-l-carbothioaniide (TL1052).

[1018] The product was obtained as a yellowish solid (79 mg, 801%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.77 (s, 1H), 7.54 - 7.47 (m, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.33 (dd, J = 8.5, 2.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 4.18 - 3.98 (m, 4H), 2.91 (t, J = 4.9 Hz, 4H), 2.29 (s, 3H). MS (ESI) m / z 450.7 [M+H]+C19H18BrClN4S. HPLC analysis: MeCN-H20 (95:5), 9.88 min, 97.18% pure.

[1019] N-((4-(4-(4-Bromo-2-methylphenyl)piperazine-l- carbothioamido)phenyl)sulfonyl)acetamide (TL1053) .

[1020] The product was obtained as a white solid (69 mg, 69%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.76 (s, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.57 (d, 7 = 8.7 Hz, 2H), 7.39 (d, 7 = 2.5 Hz, 1H), 7.32 (dd, 7 = 8.4, 2.5 Hz, 1H), 6.99 (d, 7 = 8.5 Hz, 1H), 4.18 - 3.98 (m, 4H), 2.91 (t, 7 = 4.8 Hz, 4H), 2.29 (s, 3H), 1.92 (s, 3H). MS (ESI) m / z 512.8 [M+H]+C2oH23BrN403S2. HPLC analysis: MeCN-H20 (95:5), 8.53 min, 98.41% pure.

[1021] 2-Chloro-4-(4-(4-fluoro-2-(methylsulfonyl)phenyl)piperazine-l-carbothioamido)benzoic acid (TL1054).

[1022] The product was obtained as a white solid (62 mg, 68%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.72 - 7.63 (m, 2H), 7.60 - 7.51 (m, 2H), 7.39 (dd, 7 = 2.5, 0.8 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.00 (d, 7 = 8.5 Hz, 1H), 4.05 (t, 7 = 4.7 Hz, 4H), 2.91 (d, 7 = 4.9 Hz, 4H), 2.29 (s, 3H). MS (ESI) m / z 471.9 [M+H]+CI9HI9C1FN3O4S2. HPLC analysis: MeCN-H2O (95:5), 4.42 min, 98.44% pure.

[1023] 4-(4-Bromo-2-methylphenyl)-A,-(4-(jV-methylsulfamoyl)phenyl)piperazine-l- carbothioamide (TL1056).

[1024] The product was obtained as a white solid (72 mg, 64%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.72 - 7.63 (m, 2H), 7.60 - 7.51 (m, 2H), 7.39 (dd, 7 = 2.5, 0.8 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.00 (d, 7 = 8.5 Hz, 1H), 4.05 (t, 7 = 4.7 Hz, 4H), 2.91 (d, 7 = 4.9 Hz, 4H), 2.29 (s, 3H). MS (ESI) m / z 484.9 [M+H]+Ci9H23BrN4O2S2. HPLC analysis: MeCN-H2O (95:5), 8.73 min, 99.38% pure.

[1025] 2-Chloro-4-(4-(4-cyano-2,6-difluorophenyl)piperazine-l-carbothioamido)benzoic acid (TL1058).

[1026] The product was obtained as a white solid (98 mg, 72%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-ric) δ 13.72 (s, 1H), 9.69 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1 H), 7.75 - 7.67 (m, 2H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.5, 2.1 Hz, 1H), 4.18 - 3.94 (m, 4H), 3.36 (d, 7 = 9.9 Hz, 4H). MS (ESI) m / z 436.9 [M+H]+C19H15CIF2N4O2S. HPLC analysis: MeCN-H2O (95:5), 7.53 min, 99.60% pure.

[1027] 2-Chloro-4-(4-(4-cyano-2-methoxyphenyl)piperazine-l-carbothioamido)benzoic acid (TL1062).

[1028] The product was obtained as a yellowish solid (78 mg, 66%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.68 (s, 1H), 7.79 (d, 7 = 8.5 Hz, 1H), 7.58 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.6, 2.2 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.01

[1029] (d, 7 = 8.5 Hz, 1H), 4.04 (t, 7 = 4.8 Hz, 4H), 3.86 (s, 3H), 3.20 (t, 7 = 4.9 Hz, 4H). MS (ESI) m / z 430.9 [M+H]+C20H19CIN4O3S. HPLC analysis: MeCN-H20 (95:5), 7.07 min, 100% pure.

[1030] 4-(4-Bromo-2-methylphenyl)-A,-(4-cyanophenyl)piperazine-l -carboxamide (TL1063).

[1031] The product was obtained as a white solid (47 mg, 55%) using a similar procedure as described for TL283. MS (ESI) m / z 400.7 [M+H]+Ci9Hi9BrN4O. HPLC analysis: MeCN-H2O (95:5), 5.43 min, 93.28% pure.

[1032] 2-Chloro-4-(4-(5-cyanopyridin-2-yl)piperazine-l-carbothioamido)benzoic acid (TL1064).

[1033] The product was obtained as a white solid (80 mg, 63%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.52 (d, 7 = 2.3 Hz, 1H), 7.90 (dd, 7 = 9.1, 2.4 Hz, 1H), 7.76 (dd, 7 = 8.5, 1.5 Hz, 1H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 6.92 (d, 7 = 9.1 Hz, 1H), 4.12 - 3.97 (m, 4H), 3.92 - 3.75 (m, 5H). MS (ESI) m / z 401.8 [M+H]+C18H16CIN5O2S. HPLC analysis: MeCN-H20 (95:5), 6.54 min, 95.27% pure.

[1034] 4-(4-(4-Carbamoyl-2,6-difluorophenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL1066).

[1035] The product was obtained as a yellowish solid (67 mg, 59%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.01 (s, 1H), 7.73 (dd, 7 = 8.5, 2.3 Hz, 1H), 7.60 - 7.54 (m, 3H), 7.51 (s, 1H), 7.40 (dd, 7 = 8.4, 2.1 Hz, 1H), 4.04 (t, 7 = 4.8 Hz, 4H), 3.28 (t, 7 = 4.8 Hz, 4H). MS (ESI) m / z 454.9 [M+H]+C19H17CIF2N4O3S. HPLC analysis: MeCNTHO (95:5), 6.09 min, 95.65% pure.

[1036] 2-Chloro-4-(4-(4-cyano-2-fluorophenyl)piperazine-l-carbothioamido)benzoic acid (TL1070).

[1037] The product was obtained as a white solid (65 mg, 53%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.12 (s, 1H), 9.70 (s, 1H), 7.79 (d, 7 = 8.5 Hz, 1 H), 7.73 (dd, 7 = 13.3, 2.0 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.43 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.15 (t, J = 8.7 Hz, 1 H), 4.07 (t, 7 = 5.0 Hz, 4H), 3.34 (t, J = 3.3 Hz, 4H). MS (ESI) m / z 418.9 [M+H]+C19H16CIFN4O2S. HPLC analysis: MeCN-H2O (95:5), 7.30 min, 99.41% pure.

[1038] 4-(4-(4-Carbamoylphenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL1072).

[1039] The product was obtained as a yellow solid (51 mg, 84%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.67 (s, 1H), 7.78 (t, J = 7.5 Hz, 3H), 7.72 (s, 1H), 7.60 (s, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.03 (s, 1H), 6.95 (d, J = 8.6 Hz, 2H), 4.19 - 3.99 (m, 4H), 3.43 (d, J = 5.3 Hz, 4H). MS (ESI) m / z 418.9 [M+H]+C19H19CIN4O3S. HPLC analysis: MeCN-H2O (95:5), 5.47 min, 95.74% pure.

[1040] 2-Chloro-4-(4-(isoquinolin-l-yl)piperazine-l-carbothioamido)benzoic acid (TL1073).

[1041] The product was obtained as a yellowish solid (67 mg, 61%) using a similar procedure as described for TL283. 'H NMR (599 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.16 (dd, 7 = 27.5, 7.1 Hz, 2H), 7.90 (d, 7 = 8.2 Hz, 1H), 7.78 (d, 7= 8.4 Hz, 1H), 7.73 (t, 7 = 7.5 Hz, 1H), 7.68 - 7.53 (m, 2H), 7.52 - 7.34 (m, 2H), 4.38 - 3.93 (m, 4H), 3.45 (d, 7 = 10.0 Hz, 4H). MS (ESI) m / z 426.9 [M+H]+C21H19CIN4O2S. HPLC analysis: MeCN-H20 (95:5), 5.67 min, 97.84% pure.

[1042] Methyl 4-(4-(4-bromo-2-methylphenyl)piperazine-l-carboxamido)benzoate (TL1077).

[1043] The product was obtained as a white solid (50 mg, 59%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.85 (d, 7 = 8.6 Hz, 2H), 7.64 (d, 7 = 8.6 Hz, 2H), 7.37 (d, 7 = 2.5 Hz, 1H), 7.31 (dd, 7 = 8.5, 2.5 Hz, 1H), 6.98 (d, 7 = 8.5 Hz, 1H), 3.80 (s, 3H), 3.71 - 3.57 (m, 4H), 2.83 (t, 7 = 4.8 Hz, 4H), 2.27 (s, 3H). MS (ESI) m / z 433.8 [M+H]+C2oH22BrN303. HPLC analysis: MeCN-H20 (95:5), 8.98 min, 98.78% pure.

[1044] 4-(4-Bromo-2-methylphenyl)-Af-(4-(4-methyl-6-oxo-l, 4,5,6- tetrahydropyridazin-3- yl)phenyl)piperazine-l-carbothioamide (TL1083).

[1045] The product was obtained as a white solid (88 mg, 75%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.54 (s, 1H), 7.78 - 7.68 (m, 2H), 7.44 > 7.37 (m, 3H), 7.32 (dd, 7 = 8.5, 2.5 Hz, 1H), 7.00 (d, 7= 8.5 Hz, 1H), 4.04 (t, 7= 4.9 Hz, 4H), 3.38 (qd, 7 = 7.1, 1.6 Hz, 1H), 2.90 (t, 7 = 4.9 Hz, 4H), 2.68 (dd, 7 = 16.7, 6.8 Hz, 1H), 2.29 (s, 3H), 2.24 (dd, 7 = 16.6, 1.7 Hz, 1H), 1.09 (d, 7 = 7.3 Hz, 3H). MS (ESI) m / z 501.9 [M+H]+C23H26BrN5OS. HPLC analysis: MeCN-H20 (95:5), 8.62 min, 98.72% pure.

[1046] 4-(4-(4-Bromo-2-methylphenyl)piperazine-l-carbothioamido)-2-fluoro-Ar- methylbenzamide (TL1084).

[1047] The product was obtained as a white solid (89 mg, 82%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.14 - 8.04 (m, 1H), 7.62 - 7.53 (m,

[1048] 1H), 7.39 (t, 7 = 1.9 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.27 - 7.17 (m, 1H), 7.04 - 6.94 (m, 1H), 4.16 - 3.96 (m, 4H), 2.90 (t, 7 = 4.9 Hz, 4H), 2.77 (dd, 7 = 4.7, 1.9 Hz, 3H), 2.29 (s, 3H). MS (ESI) m / z 466.8 [M+H]+C20H22BrFN4OS. HPLC analysis: MeCN-H2O (95:5), 8.47 min, 99.98% pure.

[1049] 4-(4-(4-Carbamoyl-2-fluorophenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL1087).

[1050] The product was obtained as a white solid (48 mg, 81%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 12.97 (s, 1H), 9.71 (s, 1H), 7.90 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.59 (d, 7 = 2.1 Hz, 1H), 7.42 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.31

[1051] (s, 1H), 7.10 (t, J = 8.6 Hz, 1H), 4.08 (t, J = 4.9 Hz, 4H), 3.27 - 3.14 (m, 4H). MS (ESI) m / z 436.9 [M+H]+C19H18CIFN4O3S. HPLC analysis: MeCN-H2O (95:5), 5.77 min, 95.00% pure.

[1052] 4-(4-Bromo-2-methylphenyl)-Ar-(4-(5-oxo-4,5-dihydro-lH-pyrazol-3-yl)phenyl)piperazine- 1-carbothioamide (TL1088).

[1053] The product was obtained as a brown solid (72 mg, 65%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.59 (d, 7 = 8.5 Hz, 2H), 7.38 (d, 7 = 2.5 Hz, 1H), 7.35 (d, 7= 8.5 Hz, 2H), 7.32 (dd, 7 = 8.5, 2.5 Hz, 1H), 6.99 (d, 7 = 8.5 Hz, 1H), 5.86 (s, 1H), 4.15 - 3.95 (m, 4H), 2.89 (q, 7 = 4.9 Hz, 4H), 2.29 (s, 3H). MS (ESI) m / z 473.9 [M+H]+C2iH22BrN5OS. HPLC analysis: MeCN-H20 (95:5), 8.25 min, 96.61% pure.

[1054] 2-Chloro-4-(4-(4-cyano-3-nitrophenyl)piperazine-l-carbothioamido)benzoic acid (TL1093).

[1055] The product was obtained as a yellow solid (92 mg, 80%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.87 (d, 7 = 8.8 Hz, 1H), 7.75 (d, 7 = 8.4 Hz, 1H), 7.68 (d, 7 = 2.6 Hz, 1H), 7.59 (d, 7 = 2. 1 Hz, 1H), 7.43 (dd, 7 = 8.5, 2. 1 Hz, 1H), 7.29 (dd, 7 = 8.9, 2.7 Hz, 1H), 4.09 (dd, 7 = 6.9, 4.1 Hz, 4H), 3.69 (dd, 7 = 6.5, 4.1 Hz, 4H). MS (ESI) m / z 446.0 [M+H]+C19H16CIN5O4S. HPLC analysis: MeCN-H20 (95:5), 7.11 min, 96.31% pure.

[1056] 2-Chloro-4-(4-(2-(methoxycarbonyl)phenyl)piperazine-l-carbothioamido)benzoic acid (TL1095).

[1057] The product was obtained as a pink solid (76 mg, 64%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.67 (s, 1H), 7.79 (dd, 7 = 8.5, 1.3 Hz, 1H), 7.65 (dd, 7 = 7.7, 1.7 Hz, 1H), 7.60 (d, 7 = 2.0 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.43 (dt, 7 = 8.5, 1.8 Hz, 1H), 7.14 (d, 7 = 8.2 Hz, 1H), 7.09 - 7.02 (m, 1H), 4.03 (t, 7= 5.0 Hz, 4H), 3.83 (s, 3H), 3.16 - 3.05 (m, 4H). MS (ESI) m / z 433.9 [M+H]+C20H20CIN3O4S. HPLC analysis: MeCN-H20 (95:5), 7.26 min, 98.61% pure. 2-Chloro-4-(4-(4-cyano-2-fluoro-3-methylphenyI)piperazine-l-carbothioamido)benzoic acid (TL1099).

[1058] The product was obtained as a white solid (78 mg, 66%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.77 (d, 7 = 8.5 Hz, 1H), 7.58 (d, 7 = 2.1 Hz, 1H), 7.52 (d, 7 = 8.5 Hz, 1H), 7.42 (dd, 7 = 8.5, 2.2 Hz, 1H), 7.00 (t, 7 = 8.5 Hz, 1H), 4.07 (t, 7 = 5.0 Hz, 4H), 3.30 (t, 7 = 5.0 Hz, 4H), 2.35 (d, 7 = 2.4 Hz, 3H). MS (ESI) m / z 432.9 [M+H]+C20HI8C1FN4O2S. HPLC analysis: MeCN-H2O (95:5), 7.66 min, 97.91% pure.

[1059] 4-(4-(4-Carbamoyl-3-methoxyphenyl)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL1100).

[1060] The product was obtained as a yellow solid (72 mg, 63%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.07 (s, 1H), 9.67 (s, 1H), 7.95 (s, 1H), 7.79 (d, 7 = 2.3 Hz, 1H), 7.78 (d, 7 = 2.0 Hz, 1H), 7.60 (d, 7 = 2.1 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.22 (d, 7 = 3.0 Hz, 1H), 6.58 (dd, 7 = 8.9, 2.3 Hz, 1H), 6.52 (d, 7 = 2.3 Hz, 1H), 4.07 (dd, 7 = 6.7, 4.0 Hz, 4H), 3.91 (s, 3H), 3.52 - 3.43 (m, 4H). MS (ESI) m / z 448.9 [M+H]+C20H2IC1N4O4S. HPLC analysis: MeCN-H2O (95:5), 5.80 min, 95.69% pure.

[1061] 2-Chloro-4-(4-(4-cyanobenzyl)piperazine-l-carbothioamido)benzoic acid (TL1103).

[1062] The product was obtained as a white solid (79 mg, 64%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.82 - 7.79 (m, 2H), 7.75 (d, 7 = 8.5 Hz, 1H), 7.55 (s, 1H), 7.53 (d, 7= 2.3 Hz, 2H), 7.37 (dd, 7 = 8.5, 2.1 Hz, 1H), 3.91 (t, 7 = 4.9 Hz, 5H), 3.62 (s, 2H), 2.45 (t, 7 = 5.0 Hz, 4H). MS (ESI) m / z 414.9 [M+H]+C20HI9C1N4O2S.

[1063] HPLC analysis: MeCN-H2O (95:5), 5.00 min, 99.89% pure.

[1064] 4-(4-(4-Carbamoyl-3-nitrophenyI)piperazine-l-carbothioamido)-2-chlorobenzoic acid (TL1107).

[1065] The product was obtained as a yellow solid (54 mg, 49%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.12 (s, 1H), 9.67 (s, 1H), 7.95 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 2. 1 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.40 (s, 1H), 7.32 (d, 7 = 2.5 Hz, 1H), 7.15 (dd, J = 8.7, 2.6 Hz, 1H), 4.18 - 3.95 (m, 4H), 3.51 (t, 7 = 5.3 Hz, 4H). MS (ESI) m / z 464.7 [M+H]+C19H18CIN5O5S. HPLC analysis: MeCN-H2O (95:5), 5.69 min, 95.13% pure.

[1066] 2-Chloro-4-(4-(4-cyano-3-fluoro-2-methylphenyl)piperazine-l-carbothioamido)benzoic acid (TL1109).

[1067] The product was obtained as a white solid (49 mg, 83%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.73 (s, 1H), 7.79 (d, 7 = 8.5 Hz, 1 H), 7.68 (t, 7 = 8.1 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 8.5, 2.1 Hz, 1H), 6.99 (d, J

[1068] = 8.5 Hz, 1H), 4.14 - 4.02 (m, 4H), 3.09 (t, J = 5.0 Hz, 4H), 2.23 (d, J = 2.5 Hz, 3H). MS (ESI) m / z 432.8 [M+H]+C20H18CIFN4O2S. HPLC analysis: MeCN-H20 (95:5), 7.79 min, 96.66% pure.

[1069] 2-Chloro-4-(4-(6-cyanopyridin-3-yl)piperazine-l-carbothioamido)benzoic acid (TL1111).

[1070] The product was obtained as a yellowish solid (77 mg, 60%) using a similar procedure as described for TL283. 1H NM (R599 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.40 (d, 7 = 3.0 Hz, 1H), 7.78 (dd, 7 = 8.7, 7.6 Hz, 2H), 7.60 (d, 7 = 2.1 Hz, 1H), 7.44 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.33 (dd,

[1071] J = 8.9, 3.0 Hz, 1H), 4.08 (dd, J = 6.8, 4.0 Hz, 4H), 3.69 - 3.57 (m, 4H). MS (ESI) m / z 401.8 [M+H]+C18H16CIN5O2S. HPLC analysis: MeCN-H2O (95:5), 6.23 min, 99.56% pure.

[1072] 2-Chloro-4-(4-(3-chloro-4-cyano-2-methylphenyl)piperazine-l-carbothioamido)benzoic acid (TL1115).

[1073] The product was obtained as a yellowish solid (79 mg, 66%) using a similar procedure as described for TL283.1H NMR (599 MHz, DMSO-d6) δ 12.90 (s, 1H), 9.84 - 9.68 (m, 1H), 7.77

[1074] (dd, 7 = 8.5, 6.1 Hz, 2H), 7.58 (d, 7 = 2.1 Hz, 1H), 7.41 (dd, 7 = 8.5, 2.1 Hz, 1H), 7.16 (d, 7 = 8.5

[1075] Hz, 1H), 4.08 (t, J = 4.7 Hz, 4H), 3.06 (t, J = 4.9 Hz, 4H), 2.38 (s, 3H). MS (ESI) m / z 450.7 [M+H]+C20H18CI2N4O2S. HPLC analysis: MeCN-H20 (95:5), 8.05 min, 98.87% pure.

[1076] 4-(4-(4-CarbamoyI-2-fluoro-3-methylphenyI)piperazine-l-carbothioamido)-2- chlorobenzoic acid (TL1117).

[1077] The product was obtained as a white solid (80 mg, 70%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 13. 11 (s, 1H), 9.71 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.59 (d, J = 2. 1 Hz, 1H), 7.43 (dd, J = 8.6, 2. 1 Hz, 1H), 7.33 (s, 1H), 7. 19 (d, J

[1078] = 8.3 Hz, 1H), 6.91 (t, J = 8.3 Hz, 1H), 4.08 (t, J = 5.0 Hz, 4H), 3.22 - 3.06 (m, 4H), 2.29 (d, J = 2.5 Hz, 3H). MS (ESI) m / z 450.9 [M+H]+C2OH2OC1FN403S. HPLC analysis: MeCN-H20 (95:5), 5.85 min, 99.87% pure.

[1079] Methyl 2-chloro-4-(4-(2,4-dimethyIphenyl)piperazine-l-carbothioamido)benzoate (TL1121).

[1080] The product was obtained using a similar procedure as described for TL283.1H NMR (599 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.46 (dd, 7 =

[1081] 8.6, 2.1 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.98 - 6.90 (m, 2H), 4.15 - 3.97 (m, 4H), 3.83 (s, 3H), 2.87 (t, 7 = 4.9 Hz, 4H), 2.26 (s, 3H), 2.22 (s, 3H). MS (ESI) m / z 418.0 [M+H]+

[1082] C2IH24C1N3O2S. HPLC analysis: MeCN-H2O (95:5), 9.61 min, 99.96% pure. Methyl 2-chloro-4-(4-(4-(trifluoromethyl)phenyI)piperazine-l-carbothioamido)benzoate (TL1122).

[1083] The product was obtained as a white solid (86 mg, 65%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.53 (d, 7 = 8.7 Hz, 2H), 7.48 (dd, 7 = 8.6, 2.1 Hz, 1H), 7.06 (d, 7 = 8.6 Hz, 2H), 4.08 (t, 7 = 5.2 Hz, 4H), 3.83 (s, 3H), 3.54 - 3.39 (m, 4H). MS (ESI) m / z 457.9 [M+H]+

[1084] C20H19CIF3N3O2S. HPLC analysis: MeCN-H20 (95:5), 9.12 min, 97.28% pure.

[1085] 2-Chloro-4-(4-(4-cyanonaphthalen-l-yl)piperazine-l-carbothioamido)benzoic acid (TL1124).

[1086] The product was obtained as a yellow solid (58 mg, 61%) using a similar procedure as described for TL283. MS (ESI) m / z 451.1 [M+H]+C23H19CIN4O2S.

[1087] Methyl 2-chloro-4-(4-(3-methylquinolin-2-yl)piperazine-l-carbothioamido)benzoate (TL1125).

[1088] The product was obtained as a yellowish solid (68 mg, 77%) using a similar procedure as described for TL283.1H NMR (599 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.03 (s, 1H), 7.81 (d, 7 = 8.5 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.66 (d, 7 = 2.1 Hz, 1H), 7.58 (ddd, 7 = 8.3, 6.9, 1.5 Hz, 1H), 7.48 (dd, 7 = 8.5, 2.2 Hz, 1H), 7.39 (ddd, 7 = 8.0, 6.9, 1.2 Hz, 1H), 4.16 - 4.07 (m, 4H), 3.84 (s, 3H), 3.42 - 3.35 (m, 4H), 2.45 (s, 3H). MS (ESI) m / z 455.0 [M+H]+C23H23CIN4O2S. HPLC analysis: MeCNTLO (95:5), 7.65 min, 98.41% pure.

[1089] Methyl 2-chloro-4-(4-(4-chlorophenyl)piperazine-l-carbothioamido)benzoate (TL1127).

[1090] The product was obtained as a white solid (71 mg, 53%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.80 (d, 7 = 8.5 Hz, 1H), 7.65 (d, 7 =

[1091] 2.1 Hz, 1H), 7.47 (dd, 7 = 8.6, 2.1 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.02 - 6.93 (m, 2H), 4.06 (t, 7 =

[1092] 5.1 Hz, 4H), 3.83 (s, 3H), 3.27 (d, 7 = 10.4 Hz, 4H). MS (ESI) m / z 425.8 [M+H]+C19H19CI2N3O2S. HPLC analysis: MeCN-H20 (95:5), 9.01 min, 99.81% pure.

[1093] Methyl 2-chloro-4-(4-(4-nitrophenyl)piperazine- l-carbothioamido)benzoate (TL1130) .

[1094] The product was obtained as a yellow solid (400 mg, 70%) using a similar procedure as described for TL283. 1H NMR (599 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.14 - 8.03 (m, 2H), 7.81 (d, 7 = 8.5 Hz, 1H), 7.67 (d, 7 = 2.1 Hz, 1H), 7.49 (dd, 7 = 8.6, 2.1 Hz, 1H), 7.01 - 6.94 (m, 2H), 4.18 - 4.04 (m, 4H), 3.84 (s, 3H),...

Claims

What Is Claimed Is:

1. A compound encompassed within one of the following formulas:Formula 1-1 -1-1 Formula 1-1-2A3A4Formula 1-1 -3-1 Formula I-2Formula 1-3-1 -1 Formula I-3-2 , andFormula I-3-2-1 ; including pharmaceutically acceptable salts, hydrates, solvates, polymorphs, prodrugs, triphenylphosphonium (TPP) tagged derivatives, proteolysis targeting chimera (PROTAC) derivatives, mitochondria tagged derivatives, biotin tagged derivatives, boron-dipyrromethene (BODIPY) tagged derivatives, stereoisomers, and / or deuterated analogues thereof; wherein each of Ri, R2, R3, R4, Rs, Re, R9, R12, Ai, A2, A3, A4, As, Bi, B2, B3, T, U, V, X,Y, Z, o, and n independently include any chemical moiety that permits the resulting compound to SIRT5 activity.

2. The compound of Claim 1, wherein each of Ri, R2, R3, R4, Rs, Re, R9, R12, Ai, A2, A3, A4, As, Bi, B2, B3, T, U, V, X, Y, Z, o, and n independently include any chemical moiety that permits the resulting compound effective as a therapeutic for the treatment of diseases associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

3. The compound of Claim 1, wherein:X, Y and T are independently selected from the group consisting of: H, O, S, halogen, NH, N-OH, N-CN, and C1-C3 alkyl; orX and T, independently, together with the atoms to which they are attached, is a monocyclic heterocycle optionally substituted with H, alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, and having zero to two ring heteroatoms selected from the group consisting of N, O, and S ; orX and T, independently, together with the atoms to which they are attached, is monocyclic aromatic ring optionally substituted with alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, thereby forming a bicyclic ring system;wherein the dotted line represents an optional bond in case X, Y or T selected from the group consisting of: O, S, N-OH and N-CN.

4. The compound of Claim 1 , wherein U and V are independently selected from the group consisting of: N, CH and C-OH.

5. The compound of Claim 1, wherein Z is selected from the group consisting of: NH, CH2, O and C=O.

6. The compound of Claim 1, wherein n is selected from the group consisting of: 0, 1, 2, and 3.

7. The compound of Claim 1, wherein o is selected from the group consisting of: 0, 1, 2, and 3.

8. The compound of Claim 1 , wherein:Ri R?, R3, R4, and Rs are independently selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, halogen, tetrazole, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted Cl- C6 amino alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C6 cycloalkyl, substituted C5-C7 aryl or Het, OR?, COR?, O(CH2)mC(=O)R?, COOR?, SO3R7, ASO3R7, BOR7OR8, (CH2)mR?, NR?R8, SO2R7R8, CONR7R8, NHCOR?, NHCOCHR?R8, SO2NR7R8, and NHSO2R7; orRi with R?, R2 with R3, R3 with R4, R4 with Rs, independently, together with the atoms to which they are attached, is a monocyclic heterocycle optionally substituted with H, alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, and having zero to two ring heteroatoms selected from the group consisting of N, O, and S; orRi with R2, R2 with R3, R3 with R4, R4 with Rs together with the atoms to which they are attached, is monocyclic aromatic ring optionally substituted with alkyl, alkoxy, NO2, CN, CF3, OCF3, or halogen, thereby forming a bicyclic ring system;wherein R? and Rs are independently selected form the group consisting of: H, deuterium (D), OH, OD, OMe, NO2, CN, CF3, OCF3, halogen, C1-C6 alkyl, C1-C6 alkoxy, CORg, (CH2)mOH, (CH2)mCOORg, substituted phenyl, substituted C5-C7 aryl and Het; wherein m is selected from the group consisting of: 0, 1, 2, and 3; and wherein Rg is selected from the group consisting of: H, D, and Cl -6 alkyl.

9. The compound of Claim 1, wherein Ri and R2are independently selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, OMe, SMe, OEt, SEt, F, Cl, Br, 1, Me, Et, t-Bu, i-Pr, SO2Me, NHSO2Me, S(O)Me, S(O)Et, SO2Me, SO2Et, O(i-Pr), O(t-Bu), F, Cl, Br, I, Me, Et, n-Pr, n-Bu, t-Bu, i-Pr, Ph, SO2Me, NHSO2Me, COMe, COEt, COCF3,OC(=O)Me, OC(=O)Et, COOMe, COOEt, CH2OH, NH2, NHMe, NHEt, NMe2, NEt2,NHCH2PH, SO2Me, SO2Et, CONH2, CONHMe, CONHEt, CONMe2, CONEt2, NHCOMe,NHCOEt, NHCOCH3, NHCOCH2Me, NHCOCH2Et, NHCOCHMe2, NHCOCHEb, SO2NH2,SO2NHMe, SO2NHEt, SO2NMe2, SO2NEt2, NHSO2Me, and NHSO2Et.

10. The compound of Claim 1 , wherein:Re is selected from the group consisting of: unsubstituted or substituted Cl -C 6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 aminoalkyl, unsubstituted or substituted Cl-C6haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C8 cycloalkyl, OR10, COR10, OC(=0)Rio, COOR10, (CH)pRioRn, NR10R11, S02Rio, CONR10R11, NHCOR10, NHCOCR10R11, S02NRioRn, NHSO2R10. unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl, Het, heteroaryloxy, arylalkyl, and heteroarylalkyl; orRe and X, together with the atoms to which they are attached, may optionally form a substituted or unsubstituted monocyclic heterocycle having zero to two ring heteroatoms selected from the group consisting of N, O, and S; or a substituted or unsubstituted monocyclic aromatic ring, thereby forming a bicyclic ring system; wherein p is selected from 0, 1, 2, or 3; wherein Rio and Rn are independently selected from the group consisting of: unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1 -C6 aminoalkyl, unsubstituted or substituted C2-C6 alkenyl,unsubstituted or substituted Cl -6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl, and Het.

11. The compound of Claim 1 , wherein R6 is selected from the group consisting of:wherein Al, A2, A3, A4, A5, A6, and A7 are independently selected from the group consisting of: O, S, CH, CH2, N, NH, CRB, and NRB; wherein Bl, B2, and B3 are independently selected from the group consisting of: O, S, CH, CH2, N, NH, CRB, and NRB; wherein RB is independently selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, CONH2, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 amino alkyl, unsubstituted or substituted Cl-C6 haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl or Het, heteroaryloxy, arylalkyl, or heteroarylalkyl; OR14, COR14, OC(=O)Ri4, COOR14, (CH2)PRi4Ris, NR14R15, SO2R14, CONR14R15, NHCOR14, NHCOCHR14R15, SO2NR14R15, and NHSO2R14; wherein RM and Ris are independently selected from the group consisting of: H, D, and C1-C6 alkyl; wherein p is selected from 0, 1, 2, or 3.2512. The compound of Claim 1 1 , wherein RB is selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, OMe, SMe, OEt, SEt, S(O)Me, S(O)Et, SO2Me, SO2Et, O(i-Pr), O(t-Bu), F, Cl, Br, I, Me, Et, n-Pr, n-Bu, t-Bu, i-Pr, Ph, SO2Me, NHSO2Me, COMe, COEt, COCF3, OC(=O)Me, OC(=O)Et, COOMe, COOEt, CH2OH, NH2, NHMe, NHEt, NMe2, NEt2, NHCH2PH, SO2Me, SO2Et, CONH2, CONHMe, CONHEt, CONMe2, CONEt2,NHCOMe, NHCOEt, NHCOCH3, NHCOCH2Me, NHCOCH2Et, NHCOCHMe2, NHCOCHEt2,SO2NH2, SO2NHMe, SO2NHEt, SO2NMe2, SO2NEt2, NHSO2Me, NHSO2Et; VNNO2X NCl , and13. The compound of Claim 1 , wherien Al, A2, A3, A4, A5, A6, and A7 are independently selected from the group consisting of: O, S, CH, CH2, N, NH, CRB, and NR13; wherein Bl , B2, and B3 are independently selected from the group consisting of: O, S, CH, CH2, N, NH, CRB, and NRB; wherein RB is independently selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, CONH2, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 amino alkyl, unsubstituted or substituted Cl-C6 haloalkyl, unsubstituted or substituted C2-C6 alkenyl,unsubstituted or substituted C1 -C6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl or Het, heteroaryloxy, arylalkyl, or heteroarylalkyl; OR14, COR14, OC(=O)Ri4, COOR14, (CH2)PRi4Ri5, NR14R15, SO2R14, CONR14R15, NHCOR14, NHCOCHR14R15, SO2NR14R15, and NHSO2R14; wherein R14 and R15 are independently selected from the group consisting of: H, D, and Cl -C6 alkyl; wherein p is selected from 0, 1, 2, or 3.

14. The compound of Claim 13, wherein R13 is selected H, deuterium (D), OH, OD, NO2,CN, CF3, OCF3, OMe, SMe, OEt, SEt, S(O)Me, S(O)Et, SO2Me, SO2Et, O(i-Pr), O(t-Bu), F, Cl,Br, I, Me, Et, n-Pr, n-Bu, t-Bu, i-Pr, Ph, SO2Me, NHSO2Me, COMe, COEt, COCF3, OC(=O)Me,OC(=O)Et, COOMe, COOEt, CH2OH, NH2, NHMe, NHEt, NMe2, NEt2, NHCH2PH, SO2Me,SO2Et, CONH2, CONHMe, CONHEt, CONMe2, CONEt2, NHCOMe, NHCOEt, NHCOCH3,NHCOCH2Me, NHCOCH2Et, NHCOCHMe2, NHCOCHEh, SO2NH2, SO2NHMe, SO2NHEt,NO2NCl , and15. The compound of Claim 1 , wherien R12 is selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, CONH2, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted orsubstituted C 1-C6 hydroxyalkyl, unsubstituted or substituted C1-C6 amino alkyl, unsubstituted or substituted Cl-C6haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted Cl -C6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl or Het, heteroaryloxy, arylalkyl, or heteroarylalkyl; OR14, COR14, 0C(=0)RM, COOR14, (CH2)PRI4RI5, NR14R15, SO2R14, CONR14R15, NHCOR14, NHCOCHR14R15, SO2NR]4Ri5, and NHSO2RI4; wherein R14 and R15 are independently selected from the group consisting of: H, D, and C1-C6 alkyl; wherein p is selected from 0, 1, 2, or 3.

16. The compound of Claim 15, wherein Rn is selected H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, OMe, SMe, OEt, SEt, S(O)Me, S(O)Et, SO2Me, SO2Et, O(i-Pr), O(t-Bu), F, Cl, Br, I, Me, Et, n-Pr, n-Bu, t-Bu, i-Pr, Ph, SO2Me, NHSO2Me, COMe, COEt, COCF3, OC(=O)Me, OC(=O)Et, COOMe, COOEt, CH2OH, NH2, NHMe, NHEt, NMe2, NEt2, NHCH2PH, SO2Me, SO2Et, CONH2, CONHMe, CONHEt, CONMe2, CONEt2, NHCOMe, NHCOEt, NHCOCH3,NHCOCH2Me, NHCOCH2Et, NHCOCHMe2, NHCOCHEt2, SO2NH2, SO2NHMe, SO2NHEt,O NH , SO2NEt2, NHSO2Me, NHSO2Et; VVNVN SO2NMe2NN i N .0X N Br CN 1 V „U317. The compound of Claim 1 ,wherein Pi, P2, P3, and P4 are independently selected from the group consisting of: O, S, C, N, CR16, and NRie; wherein Rie is selected from the group consisting of: H, deuterium (D), OH, OD, NO2, CN, CF3, OCF3, CONH2, halogen, unsubstituted or substituted Cl -C6 alkyl, unsubstituted or substituted Cl -C6 hydroxyalkyl, unsubstituted or substituted C1-C6 amino alkyl, unsubstituted or substituted Cl-C6haloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C1-C6 alkoxy C3-C6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C5-C7 Aryl or Het, heteroaryloxy, arylalkyl, or heteroarylalkyl; OR17, CORie, OC(=O)Ri7, COOR17, (CH2)PRi7Ri8, NR17R18, SO2R17, CONRnRis, NHCOR17, NHCOCHRnRis, SO2NR17R18, and NHSO2R17; wherein p is selected from 0, 1, 2, or 3; wherein p is selected from 0, 1, 2, or 3; wherein R17 and Ris are independently selected from the group consisting of: H, D, and C1-C6 alkyl.

18. The compound of Claim 1 , wherein Rg is selected from the group consisting of: H, D, and Cl -6 alkyl.

19. The compound of Claim 1, wherein the compound is recited in Table 1.

20. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition of claim 20, wherein the composition further comprises at least one additional therapeutic agent.

22. The pharmaceutical composition of claim 21, wherein the at least one additional therapeutic agent comprises any type or kind of therapeutic agent capable of inhibiting SIRT5 activity; and / or any type or kind of therapeutic agent for the treatment of diseases associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer, diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

23. A method for treating, ameliorating, or preventing of a condition associated with aberrant posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases), comprising administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of condition associated with aberrant posttranslational modification functions) a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions recited in Claims 1-22.

24. A method for treating, ameliorating, or preventing of conditions (e.g., disorders, diseases) associated with SIRT5 activity (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases), comprising administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of condition associated with SIRT5 activity) a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions recited in Claims 1 -22.

25. A method for treating, ameliorating, or preventing of any type or form of cancer (e.g., melanoma, NSCLC, HCC, ovarian cancer, CRC, AML, Ewing's sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), comprising administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of cancer) a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions recited in Claims 1 - 22.

26. A method for treating, ameliorating, or preventing of any type or form of diabetes, comprising administering to a subject (e.g., a human subject) (e.g., a human subject sufferingfrom or at risk of suffering from any type or form of diabetes) a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions recited in Claims 1-22.

27. A method for treating, ameliorating, or preventing of any type or form of an autoimmune disorder (e.g., autoimmune condition, autoimmune disease) (e.g., multiple sclerosis (MS), celiac disease, rheumatoid arthritis, diabetes (e.g., type 1 diabetes mellitus), autoimmune diseases of the thyroid (e.g., Hashimoto’s thyroiditis, Graves' disease), thyroid-associated ophthalmopathy and dermopathy, hypoparathyroidism, Addison’s disease, premature ovarian failure, autoimmune hypophysitis, pituitary autoimmune disease, immunogastritis, pernicious anemia, celiac disease, vitiligo, myasthenia gravis, pemphigus vulgaris and variants, bullous pemphigoid, dermatitis herpetiformis Duhring, epidermolysis bullosa acquisita, systemic sclerosis, mixed connective tissue disease, Sjogren's syndrome, systemic lupus erythematosus, Goodpasture's syndrome, rheumatic heart disease, autoimmune polyglandular syndrome type 1 , Aicardi-Goutieres syndrome, Acute pancreatitis Age-dependent macular degeneration, Alcoholic liver disease, Liver fibrosis, Metastasis, Myocardial infarction, Nonalcoholic steatohepatitis (NASH), Parkinson’s disease, Polyarthritis / fetal and neonatal anemia, Sepsis, and inflammatory bowel disease), comprising administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from an autoimmune disorder) a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions recited in Claims 1 - 22.

28. A method for treating, ameliorating, or preventing of any type or form of an inflammatory disorder (e.g., inflammatory condition, inflammatory disease) (e.g., arthritis, rheumatoid arthritis, asthma, inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic obstructive pulmonary disease (COPD), allergic rhinitis, vasculitis (polyarteritis nodosa, temporal arteritis, Wegener's granulomatosis, Takayasu’s arteritis, or Behcet’s syndrome), inflammatory neuropathy, psoriasis, systemic lupus erythematosus (SEE), chronic thyroiditis, Hashimoto's thyroiditis, Addison's disease, polymyalgia rheumatica, Sjogren's syndrome, or Churg-Strauss syndrome), comprising administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from an inflammatory disorder) a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions recited in Claims 1 -22.

29. A method for treating, ameliorating, or preventing of any type or form of a fibrosis or fibrotic disorder (e.g., fibrosis or fibrotic condition, fibrosis or fibrotic disease) (e.g., collagen disease, interstitial lung disease, human fibrotic lung disease (e.g., obliterative bronchiolitis, idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, tumor stroma in lung disease, systemic sclerosis affecting the lungs, Hermansky-Pudlak syndrome, coal worker's pneumoconiosis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS -associated pulmonary hypertension, sarcoidosis, and the like), fibrotic vascular disease, arterial sclerosis, atherosclerosis, varicose veins, coronary infarcts, cerebral infarcts, myocardial fibrosis, musculoskeletal fibrosis, post-surgical adhesions, human kidney disease (e.g., nephritic syndrome, Alport's syndrome, HIV-associated nephropathy, polycystic kidney disease, Fabry's disease, diabetic nephropathy, chronic glomerulonephritis, nephritis associated with systemic lupus, and the like), cutis keloid formation, progressive systemic sclerosis (PSS), primary sclerosing cholangitis (PSC), liver fibrosis, liver cirrhosis, renal fibrosis, pulmonary fibrosis, cystic fibrosis, chronic graft versus host disease, scleroderma (local and systemic), Grave's opthalmopathy, diabetic retinopathy, glaucoma, Peyronie's disease, penis fibrosis, urethrostenosis after the test using a cystoscope, inner accretion after surgery, scarring, myelofibrosis, idiopathic retroperitoneal fibrosis, peritoneal fibrosis from a known etiology, drug-induced ergotism, fibrosis incident to benign or malignant cancer, fibrosis incident to microbial infection (e.g., viral, bacterial, parasitic, fungal, etc.), Alzheimer's disease, fibrosis incident to inflammatory bowel disease (including stricture formation in Crohn's disease and microscopic colitis), fibrosis induced by chemical or environmental insult (e.g., cancer chemotherapy, pesticides, radiation (e.g., cancer radiotherapy), and the like)), comprising administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from a fibrosis or fibrotic disorder) a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions recited in Claims 1 - 22.

30. A method for treating, ameliorating, or preventing of any type or form of cardiovascular disorder (e.g., cardiovascular condition, cardiovascular disease), comprising administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of cardiovascular disorder) a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions recited in Claims 1 -22.

31. A method for treating, ameliorating, or preventing of any type or form of neurodegenerative disorder (e.g., neurodegenerative condition, neurodegenerative disease) (e.g., Alzheimer’s disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD)), comprising administering to a subject (e.g., a human subject) (e.g., a human subject suffering from or at risk of suffering from any type or form of neurodegenerative disorder) a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions recited in Claims 1 -22.

32. Use of a compound of any one of Claims 1-22, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder.

33. The use of Claim 32, wherein the disease is associated with posttranslational modification functions (e.g., diseases associated with SIRT5 activity) (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing’s sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

34. The use of Claim 32, wherein the disease is associated with SIRT5 activity (e.g., cancer (e.g., melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), ovarian cancer, colorectal cancer (CRC), acute myeloid leukemia (AML), Ewing’s sarcoma, brain cancer, pancreatic cancer, renal cancer, breast cancer, prostate cancer, lung cancer, leukemia and lymphoma), diabetes, autoimmune diseases, inflammatory diseases, fibrotic diseases, cardiovascular diseases, and neurodegenerative diseases).

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