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. Author manuscript; available in PMC: 2022 Apr 7.
Published in final edited form as: New J Chem. 2021 Mar 2;45(13):6001–6017. doi: 10.1039/D1NJ00380A

Benign Synthesis of Fused-thiazoles with Enone-based Natural Products and Drugs for Lead Discovery

Rawan Alnufaie a, Mohamad Akbar Ali b, Ibrahim S Alkhaibari a, Subrata Roy a, Victor W Day c, Mohammad A Alam a
PMCID: PMC8026163  NIHMSID: NIHMS1682569  PMID: 33840994

Abstract

In an effort to synthesize a library of bioactive molecules, we present an efficient synthesis of fused-thiazole derivatives of natural products and approved drugs by using an environmentally usable solvent, acetic acid, and without any external reagent. Cholestenone, ethisterone, progesterone, and nootkatone-derived epoxyketones have been utilized to synthesize 50 novel compounds. The plausible mechanism of the reaction has been determined by theoretical calculation using M06–2X/6–31+G(d,p). These novel molecules have been tested against cancer cell lines and pathogenic bacterial strains. Several ethisterone-based fused-thiazole compounds are found to be potent growth inhibitors of cancer cell lines at submicromolar concentrations.

Graphical Abstract

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INTRODUCTION

Thiazole ring is found in many natural and synthetic products including many approved drugs such as sulfathiazole (antimicrobial drug), nizatidine (anti-ulcer drug), dasatinib (anti-cancer drug), abafungin (anti-fungal drug), and fentiazac (anti-inflammatory drug).1 Thiazole containing drug, talipexole, and its derivatives are known as potent dopamine receptor ligands.2, 3 Pramipexole, a synthetic fused-thiazole derivative, is a drug to treat Parkinson’s disease and edoxaban is a widely used anticoagulant (Figure 1).4 Natural products containing the thiazole moiety are found in essential vitamin B1 (thiamin), firefly luciferin, erythrazole B, and a number of other compounds.5–7 The steroidal skeleton is found in a numerous natural products and molecules of this skeleton control a number of biological functions of humans, animals, plants, and microbes.8, 9 There are a number of steroidal derivatives widely used to treat different type of diseases including cancer, and coronavirus disease 2019 (Covid-19).10 Addition of small molecule heterocycles to bioactive natural products frequently leads to potent molecules.11

Figure 1.

Figure 1.

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Representative examples of thiazole-containing and heterocycle-fused approved drugs.

Cancer is an unresolved and deadly problem in the world. In 2019, an estimated 1.8 million people were diagnosed with cancer and more than 600,000 died of this disease in the United States alone. Cancer is the second leading cause of death, which accounted for 21.8% of all death in the United States in 2016. In spite of a lot of efforts, the overall death rate due to cancer has increased over the years.12 Globally, cancer caused more than 9.5 million new deaths and more than 18 million new cases were reported in 2018.13 The discovery and development of novel therapeutic agents are essential to combat this deadly disease.14 Similarly, drug-resistant infections are among the major challenges of the 21st century. Drug-resistant infections kill more than 700,000 people each year and the number could increase to 10 million per year by 2050 in the world. The menace of antimicrobial resistance could force up to 24 million people into extreme poverty.15 According to a Centers for Disease Control and Prevention (CDC) report, each year more than 2.8 million antibiotic infections occur and more than 35,000 people die because of these infections in the US alone. One of the four guidelines recommended by CDC to combat antibiotic resistance is promoting the development of new antibiotics and new diagnostic tests for dealing with drug-resistant bacteria.16

Results and Discussion

Due to the importance thiazole nucleus a number of methods have been reported over the years. Nevertheless, these methods utilize toxic reagents,17, 18 metal catalyst,18, 19 excess or strong bases,17, 20 and excess reagents.21 In our efforts to get novel small molecule heterocycles as antimicrobial22–24 and anticancer agents,25, 26 we have reported the synthesis of pyridopyrimidine, thiazoline and thiazole derivatives using a domino protocol (entry A, and B) (Scheme 1).25–29 The synthesis of thiazoline and thiazole has been achieved by the reaction of thioamides with γ-bromoenones (entry A). A similar reaction of 6β-bromoandrostenedione with thiourea derivatives has formed an unprecedented fused vinyl thiazole derivative (entry B). Several of these fused-thiazole derivatives are potent anti-neoplastic agents.25, 26 Our reported methods required toxic solvent such 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and a base to scavenge the hyrdobromic acid byproduct. Due to the potent anticancer properties of these molecules,25, 26 we tried to synthesize a series of compounds by using different γ-bromo-α,β-enones but these electrophiles are not commercially available except a few and making them from α,β-unsaturated ketones in good yield and pure form is challenging.30, 31 To circumvent this problem, we hypothesized that the reaction of thiourea and thioamide derivatives with α,β-epoxyketone derivatives would form vinyl thiourea derivatives. Although, a number of methods have been reported to synthesize substituted and fused-thiazole derivatives.32–36 We were the first to report a general method to synthesize fused-vinyl thiazole derivatives25, 26 and herein, we report the synthesis of fused-vinylthiazole derivatives with broader-substrate scope using decalin-based epoxyketones derived from natural products and approved drugs (entry C). This methodology is very significant as the reaction happens in environmentally recommended green solvent, acetic acid,37 it does not require any reagent, and water is the only by product. This two-component domino reaction is very significant to generate a library of novel thiazole-fused molecules containing natural product and approved drug components.

Scheme 1.

Scheme 1.

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Synthesis of thiazole derivatives

The epoxy derivatives were synthesized according to a literature procedure (Supporting Information).38 Based on our previous experience with HFIP as a reaction promoter and solvent for domino reactions,26–29 we planned the reaction of thiourea with α,β-epoxy ketone in HFIP, nonetheless we did not observe any detectable product (Table 1). Subsequently, we tried the same reaction with various laboratory solvents. The reaction in polar protic organic solvents, methanol and ethanol gave a mixture of products, and isopropanol and 1-propanol formed the expected product in relatively low yield. We found acetic acid as the best solvent for this synthesis of thiazole derivatives. The reaction of thiourea with epoxyethisterone (ET) in acetic acid gave the product (1) in quantitative yield (Table 1). The reaction in polar aprotic solvents such as tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) did not yield any product. After the identification and characterization of the pure product, fused-aminothiazolo-ethisterone (1), we reacted substituted thiourea derivatives with the electrophile (ET). The product (2) from phenylthiourea was also formed in an excellent yield. Dimethoxy substituted products (3 and 4) were obtained in 83% and 92% yields respectively. Very strong electron donating substituent such as hydroxyl group did not hamper the reaction and the hydroxyl phenyl product (5) was obtained in 89% yield. Moderate and strong electron withdrawing substituents on the phenyl ring of the thiourea yielded the products (6 and 7) in 94% average yield. Mixed-substitution on the phenyl ring formed the product (8) in 90% yield. Heterocycle and nitrogen enriched thioureas also reacted smoothly to give the corresponding products. Pyridine substituted products (9, 10, and 11) were obtained smoothly in 84% average yield. Pyrimidine (12) derivative was formed in 69% yield. Hence, different substituents on the thiourea moiety and this delicate electrophile (ET) formed the products without compromising the yield and the purity of the resultant compounds. To further explore the scope of nucleophile, we reacted epoxy-ethisterone (ET) with thioamide derivatives, which have slightly different electronic nature than the corresponding thioureas (Table 1). Aliphatic thioamide nucleophiles reacted with the electrophile to give the products (13 and 14) in 69% average yield. Aromatic derivative of thioamide, thiobenzamide, reacted effortlessly to give the pure product (15) in 67% yield. Methyl and methoxy substituted novel compounds (16, 17, and 18) were formed in a very good average yield.

Table 1.

The reaction of epoxy-ethisterone with thiourea derivatives.

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sn solvent T(°C) Yield (%)
1 HFIP reflux NR
2 CH3OH reflux mixture
3 CH3CH2OH reflux mixture
4 nPrOH reflux 40
5 iPrOH reflux 35
6 CH3CO2H 100 99
7 THF reflux NR
8 dioxane reflux NR
9 DMF 100 NR
10 DMSO 100 NR
graphic file with name nihms-1682569-t0053.jpg
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Very strong electron donating group on the phenyl ring, meta- and para-hydroxy derivatives, gave the expected products (19 and 20) in 60% and 91% yields, respectively. Moderate and strong electron withdrawing substituents gave the predicted products (21, 22, and 23) under the established reaction condition. Dichloro phenyl and pyridine substituted products (24 and 25) were obtained in 69% and 65% yields respectively. Thus, this the methodology is well tolerant to the reaction of different thioamide based nucleophiles with the delicate epoxyethisterone (ET) electrophile. It is worth noting that thiourea-based nucleophiles gave better average yield of products (1-12) than that of thioamide nucleophiles (13-25).

After getting products from epoxy-ethisterone, we studied the scope of this methodology on epoxy-cholestenone (EC) (Scheme 1). Reaction of thiourea with this electrophile formed the product (26) in 97% by using the established reaction condition. Methyl-substituted phenyl groups such as mono- (27), di- (28), and tri-methyl (29) substituted products formed efficiently. 2-Methoxy (30), 2,4- (31), and 2,5-dimethoxy (32) substituted products were formed in 84%, 85%, and 90% yields respectively. Moderately electron-withdrawing substituted-products such as chloro (33) and fluoro (34) were formed in ~90% yield. Strong electron-withdrawing groups such as trifluoromethyl (35 and 36) and nitro (37) did not hamper the reaction to form the products. Mixed substitution, electron-donating (methoxy) and electron-withdrawing (chloro) on the phenyl ring formed the product (38) without compromising the average yield. Pyridine- (39) and pyrimidine-substituted (40) thiourea reacted with the electrophile smoothly to form the corresponding products in 88% and 85% yields respectively. N,N-Disubstituted product (41) formed in 70% yield. Alkyl (allyl and benzyl) substituted thioureas, reacted with the epoxy-cholestenone (EC) to form the corresponding products (42 and 43) in good overall yields. Thus, a wide range of substituents on the thiourea moiety has negligible impact on the product outcome for this methodology.

To further widen the scope of this methodology, we explored the reaction on two more α,β-epoxy ketone based natural products to generate fused-thiazole chemical space (Scheme 3). Nootkatone, an enone sesquiterpenoid based natural product, is an approved insecticide and this small molecule is known for a number of pharmacological properties including anticancer, and antimicrobial activities.39, 40 Similarly, progesterone is a steroidal hormone which controls a number of human body functions.41 Epoxy derivatives (EN and EP) of both of these natural products reacted with thiourea under the established reaction conditions to give the corresponding aminothiazole derivatives (44 and 45) in 98% and 91% yields respectively.

Scheme 3:

Scheme 3:

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The synthesis of fused-thiazole derivatives of nootkatone and progesterone

The scope of the methodology was further explored to generate a library of novel molecules as potential therapeutic agents. Reaction of aminothiazole derivatives (1, 26, 44, and 45) with acetic anhydride and pyridine mixture afforded the corresponding acetyl derivatives (46-49) in quantitative yield (Scheme 4). Readily available anhydrides and acyl chlorides can be used to synthesize a series of novel thiazole amide derivatives.

Scheme 4:

Scheme 4:

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Acetylation of aminothiazole derivatives

We proposed the following mechanism for the feasibility of the reaction (Scheme 5) and computed the feasibility of each step in the presence of different protic solvents i.e.,AcOH, HFIP, MeOH, EtOH, PrOH, iPrOH (see Supporting Information) using a hybrid-density functional method M06–2X/6–31+G(d,p). We have observed that the reaction in AcOH is thermodynamically more feasible than other solvents, which is consistent with our experimental observation. Therefore, we restrict the mechanistic discussion only based on AcOH. Acetic acid created the least energy barrier for the first step, nucleophilic addition of thiourea with the carbonyl carbon of epoxy ketone. Acetic acid activates the carbonyl group of EN by hydrogen bonding which is 2.88 kcal/mol. Hydrogen bond energy of acetic acid with the epoxy oxygen is 2.97 kcal/mol. Protonation on EN is completely ruled out due to very high (55 kcal/mol) energy. In addition to hydrogen bonding, acetic acid favorably interact with the epoxy ketone derivative via London dispersion forces. Nucleophilic addition of thiourea with the activated epoxy ketone (EH) formed the hemiaminal intermediate (HA). Another possibility of the reaction of EH with thiourea is the formation isothiourea derivative (IT) via intermolecular SN2 reaction and this route is preferred (2.10 kcal/mol vs 3.44 kcal/mol). Intramolecular SN2 reaction of hemiaminal (HA) and intramolecular nucleophilic addition isothiosulphide (IT) formed the same intermediate, thiazoline derivative (TZ). Again, the intramolecular nucleophilic addition route is preferred by 1.28 kcal/mol. Subsequent elimination of water to form the hydroxy thiazole derivative (HT) followed by the final product (44), the vinyl thiazole derivative. The elimination of water molecules is hydrogen bond driven unlike the formation of cation intermediates, which are very high in energy (Supporting information). As shown in Supporting Information, the protonation on all intermediates in the scheme is >50 kcal/mol, Therefore we believe that hydrogen bonded complex will be the preferred path (see Scheme 4) for the formation of 44.

Scheme 5.

Scheme 5.

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Plausible mechanism for the formation of product using M06–2X/6–31+G(d,p) + PCM (Solvent = AcOH), energy = kcal/mol

The structure of the compounds based on the proposed reaction mechanism was confirmed by the X-ray single crystal diffraction of compound 39 (Figure 2). ORTEP diagram shows that nitrogen and sulfur of fused-thiazole is attached to C-3 and C-4 of cholestenone respectively. The double bond (C-5 and C6) is vinylic to the thiazole ring.

Figure 2:

Figure 2:

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ORTEP diagram of compound 39 (CCDC number 2035523)

In vitro Anticancer Studies

Most of these synthesized molecules were submitted to the Developmental Therapeutic Program (DTP) for testing against NCI-60 cancer cell lines. None of the thiazole-fused cholestenone derivatives (26-43) showed any remarkable activity against these 60 cancer cell lines at 10μM concentration. We are delighted to find several of the ethisterone series of compounds as potent growth inhibitors of the panels of cancer cell lines with 50% growth inhibition (GI50) values at submicromolar and total growth inhibition (TGI) values at low micromolar concentrations. In this article, we are discussing the activity of two of the potent compounds. As shown in Table 2, compounds 3 and 9 inhibited the growth of several cell lines of leukemia panel with GI50 values as low as 0.182 μM. Compound 3 showed relatively higher TGI values against the leukemia panel except for RPMI-8226 cell line. Compound 9 inhibited the growth of leukemia cell line with TGI values in the range of 0.602 to 4.18 μM. These potent compounds inhibited the growth of central nervous system (CNS) cell lines with GI50 values from 0.218 to 0.770 μM concentration. TGI values for these compounds against CNS cell lines are as low as 0.489 μM. Several cell lines of melanoma and renal cancer panels were inhibited efficiently. Both the compounds (3 and 9) inhibited the growth of MALME-3M and SK-MEL-28 cell lines of melanoma panel with GI50 values <1 μM and TGI values were around 2 μM. Three cell lines (786–0, A498, and RXF 393) of renal cancer panel were inhibited efficiently with GI50 values at submicromolar concentration and TGI values were as low as 1.19 μM. Cell lines of prostate and breast cancer panels were also inhibited at low micromolar concentration.

Table 2:

NCI data for selected cell lines for compounds 3 and 9. GI50 = concentration of a compound that causes 50% growth inhibition, and TGI = Total Growth Inhibition at μM concentration.42

cancer panel cell line 3 9
GI50 TGI GI50 TGI
Leukemia CCRF-CEM 0.544 11.0 0.482 4.18
HL-60 (TB) 1.42 5.91 0.398 1.96
K-562 0.525 13.0 0.348 2.13
MOLT-4 0.460 4.69 0.344 1.70
RPMI-8226 0.248 0.804 0.182 0.602
SR 0.523 11.2 0.542 3.24
CNS SF-295 0.249 0.613 0.218 0.489
SF-539 0.374 1.70 0.185 0.744
U251 0.770 4.09 0.541 2.13
Melanoma MALME-3M 0.655 2.85 0.677 2.32
SK-MEL-2 1.23 6.39 0.603 3.08
SK-MEL-28 0.712 2.70 0.279 1.01
UACC-257 1.57 4.99 0.778 2.55
Renal 786–0 0.504 2.60 0.389 1.69
A498 0.152 1.23 0.260 1.19
RXF 393 0.262 6.08 0.218 4.69
Prostate PC-3 0.845 9.02 0.489 3.99
Breast MCF7 0.978 2.65 0.968 3.73
HS578T 0.411 2.36 0.421 2.40
BT-549 0.656 4.76 0.692 2.84
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These novel compounds were also tested against several strains of bacteria. Nootkatone derivatives are selective growth inhibitors of Staphylococcus aureus and Enterococcus faecium strains with an MIC value as low as 1.56 μg/ml. We synthesized several thiazolo-nootkatone derivative and some of these molecules are potent antimicrobial agents, and these molecules are nontoxic to NCI-60 cancer cell lines at 10 μM (data not shown).

CONCLUSIONS

In summary, we have designed and developed a new domino reaction to synthesize fused-thiazole derivatives by using readily available starting materials and mild reaction conditions. This methodology provides an alternative approach to our previous reports with a broader substrate scope to synthesize fused-thiazole derivatives. Easy availability of thiourea derivatives and epoxy ketones makes this methodology very attractive to generate a library of bioactive compounds. Natural products: cholestenone, progesterone, and nootkatone; and ethisterone, an approved drug, have been used to synthesize several fused-thiazole derivatives. Preliminary screening of these compounds against cancer cell lines and bacterial strains led to the discovery of potent lead molecules. Further anticancer and antimicrobial studies are going on and will be reported in due course.

GENERAL CONDITIONS

General conditions:

All the reactions were carried out under an air atmosphere in round-bottom flasks with magnetic stirring bars. Solvents, reagents, and substrates were purchased from Fisher Scientific (Hanover Park, IL, USA.) and Oakwood chemical (Estill, SC, USA). 1H and 13C NMR spectra were recorded in a 300 MHz TOPSPIN spectrometer (1H NMR at 300 MHz, and 13C at 75 MHz) using DMSO-d6 and CDCl3 as solvents and TMS as internal standard. High Resolution Mass Spectra (HRMS) were recorded using Shimadzu IT-TOF mass spectrometer.

General procedure for the synthesis of epoxy ketones:

Epoxy-ketones were synthesized according to a reported procedure.43

General procedure for the synthesis of fused-thiazole:

A mixture of epoxy-ketone (1 mmol) and thiourea or thioamide derivative (1.05 mmol) in acetic acid (5 ml) in a round-bottom flask was heated to 100 °C for 8 hours. The reaction mixture was brought to room temperature and water was added to precipitate the product. The solid product was filtered and washed repeatedly with water followed by drying in vacuo to get the pure product. In case of impurities, recrystalization with ethanol or methanol gave the pure products. Some reactions were done at 0.5 mmol scale.

General procedure of the acetylation:

A solution of aminothiazole derivative (0.5 mmol) in acetic anhydride (3 ml) in a round-bottom flask was sealed with a septum and cooled in an ice bath followed by the dropwise addition of pyridine (2 ml). The reaction mixure was stirred for 12 hours and 10% HCl was added to precipitate the product. The solid product was filtered and washed repeatedly with water to get the pure products in quatitative yields.

Experimental Data

(4R,4aS,6R)-6-isopropenyl-4,4a-dimethyl-3,4,5,6,7,8-hexahydro-1aH-naphtho[1,8a-b]oxiren-2-one (EN).

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Colorless viscous solid (224 mg, 96%); 1H NMR (300 MHz, CDCl3): δ 4.76 (s, 2H), 3.10 (s, 1H), 2.46– 2.26 (m, 5H), 2.00– 1.76 (m, 5H), 1.62– 1.54 (m, 1H), 1.39– 1.21 (m, 2H), 0.97 (s, 3H), 0.82 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 206.4, 149.1, 109.2, 68.7, 62.5, 41.8, 40.5, 40.0, 36.5, 32.3, 30.1, 29.0, 20.7, 14.9, 14.4. HRMS (ESI-FTMS Mass (m/z): calcd for C15H22O2 [M+H]+ = 235.1692, found 235.1690.

(1S,2R,13R,14S,17R,18S)-7-amino-17-ethynyl-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (1).

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Whitish (366 mg, 99%); 1H NMR (300MHz, CDCl3): δ 7.53 (br s, 2H), 5.35–5.33 (m, 1H), 2.55 (m, 3H), 2.34–2.16 (m, 2H), 2.00–1.94 (m, 1H), 1.84–1.63 (m, 6H), 1.58–1.31 (m, 4H), 1.16–1.10 (m, 1H), 1.00 (m, 3H), 0.88 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 167.8, 135.6, 118.8, 118.7, 87.3, 79.7, 74.0, 50.6, 47.5, 46.6, 38.8, 36.5, 33.7, 32.4, 32.1, 31.1, 23.1, 22.1, 21.4, 21.0, 18.6, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C22H28N2OS [M+H]+ = 369.1995 found 369.1981.

(1S,2R,13R,14S,17R,18S)-7-anilino-17-ethynyl-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (2).

graphic file with name nihms-1682569-f0004.jpg

White solid (422 mg, 95%); 1H NMR (300MHz, CDCl3): δ 7.36–7.31 (m, 4H), 7.12–7.06 (m, 1H), 5.46 (s, 1H), 2.72–2.69 (m, 2H), 2.60 (s, 1H), 2.38–2.20 (m, 2H), 2.08–2.00 (m, 2H), 1.84–1.31 (m, 12H), 1.25–1.15 (m, 1H), 1.06 (s, 3H), 0.91 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 177.3, 163.0, 143.4, 139.9, 136.1, 129.4, 123.2, 119.4, 118,4, 118.3, 87.5, 79.7, 50.7, 47.6, 46.6, 38.9, 36.6, 34.1, 32.5, 32.1, 31.2, 23.3, 23.1, 21.0, 18.7, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C28H32N2OS [M+H]+ = 445.2308 found 445.2310.

(1S,2R,13R,14S,17R,18S)-7-(2,4-dimethoxyanilino)-17-ethynyl-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (3).

graphic file with name nihms-1682569-f0005.jpg

Brown solid (418 mg, 83%); 1H NMR (300MHz, CDCl3): δ 7.60 (d = 8.3 Hz, 1H), 6.51–6.48 (m, 2H), 5.42–5.40 (m, 1H), 3.85–3.81 (m, 6H), 2.73–2.62 (m, 1H), 2.58 (s, 1H), 2.36–2.18 (m, 2H), 2.08–1.97 (m, 4H), 1.82–1.65 (m, 6H), 1.60–1.29 (m, 5H), 1.21–1.14 (m, 1H), 1.05 (s, 3H), 0.90 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 163.9, 156.9, 150.8, 143.2, 136.1, 122.6, 120.2, 119.4, 118.3, 103.8, 99.2, 87.4, 97.7, 74.0, 55.7, 55.6, 50.7, 47.6, 46.6, 38.9, 36.6, 34.1, 32.5, 32.1, 31.1, 23.4, 23.1, 21.0, 18.7, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C30H36N2O3S [M+H]+ = 505.2519 found 505.2518.

(1S,2R,13R,14S,17R,18S)-7-(2,5-dimethoxyanilino)-17-ethynyl-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (4).

graphic file with name nihms-1682569-f0006.jpg

Brown solid (230 mg, 92%); 1H NMR (300MHz, CDCl3): δ 7.59 (d, J = 2.8 Hz, 1H), 6.80 (d, 8.7 Hz, 1H), 6.47 (dd, J = 2.8, 8.7 Hz, 1H), 5.49–5.48 (m, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2.75–2.70 (m, 2H), 2.59 (s, 1H), 2.37–2.25 (m, 2H), 2.21 (t, J = 4.3 Hz, 1H), 2.08–1.99 (m, 3H), 1.82–1.31 (m, 10H), 1.23–1.15 (m, 1H), 1.06 (s, 3H), 0.91 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 160.3, 154.0, 145.5, 141.9, 136.5, 130.5, 121.0, 118.2, 110.8, 105.1, 103.5, 87.4, 79.8, 74.0, 56.3, 55.7, 50.7, 47.6, 46.7, 38.9, 36.6, 34.3, 32.5, 32.2, 31.2, 24.1, 23.1, 21.0, 18.7, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C30H36N2O3S [M+H]+ = 505.2519 found 505.2505.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-7-(4-hydroxyanilino)-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (5).

graphic file with name nihms-1682569-f0007.jpg

Yellowish solid (204 mg, 89%); 1H NMR (300MHz, DMSO-d6): δ 10.03 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H), 5.70 (s, 1H), 5.36 (1H), 3.34 (s, 1H), 2.85–2.68 (2H), 2.50 (s, 2H), 2.24–2.01 (m, 3H), 1.90–1.27 (m, 10 H), 1.13–1.06 (m, 1H), 0.97 (s, 3H), 0.77 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 161.6, 152.7, 146.0, 136.8, 133.5, 119.8, 118.8, 117.5, 115.8, 89.3, 78.5, 75.5, 50.8, 47.9, 46.6, 36.4, 34.3, 32.7, 32.2, 31.3, 24.4, 23.2, 21.5, 21.0, 19.0, 13.2. HRMS (ESI-FTMS Mass (m/z): calcd for C28H32N2O2S [M+H]+ = 461.2257 found 461.2252.

(1S,2R,13R,14S,17R,18S)-7-(2,4-difluoroanilino)-17-ethynyl-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (6).

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Whitish solid (457 mg, 95%); 1H NMR (300MHz, DMSO-d6): δ 7.99–7.91 (m, 1H), 7.02–6.86 (m, 2H), 5.47–5.45 (m, 1H), 2.74–2.72 (m, 2H), 2.61–2.58 (m, 1H), 2.35–2.20 (m, 2H), 2.07–2.02 (m, 2H), 1.78–1.68 (m, 7H), 1.61–1.34 (m, 5H), 1.26–1.19 (m, 1H), 1.06–1.00 (m, 3H), 0.91–0.89 (m, 3H); 13C NMR (75 MHz, DMSO-d6): δ 161.4, 158.0 (dd, J = 11.1, 243.6 Hz), 152.6 (dd, J = 11.9, 245.7 Hz), 144.7, 136.1, 124.9 (d, J = 7.2 Hz), 121.3, 120.9 (d, J = 10.9 Hz), 118.9, 111.3 (dd, J = 3.8, 21.8 Hz), 104.1 (d, J = 22.9 Hz), 103.9 (d, J = 22.9 Hz), 87.4, 79.8,74.3, 74.0, 50.7, 48.5, 47.6, 38.9, 36.6, 34.2, 32.5, 32.1, 31.2. 23.9, 23.1, 21.0, 18.7, 12.6. HRMS (ESI-FTMS Mass (m/z): calcd for C28H30F2N2OS [M+H]+ = 481.2120 found 481.2113.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-(2-nitroanilino)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (7).

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Red solid (455 mg, 93%); 1H NMR (300MHz, DMSO-d6): δ 8.66 (d, J = 8.5 Hz, 1H), 8.25 (dd, 1.2, 8.4 Hz, 1H), 7.63 (t, J = 8.5 Hz, 1H), 7.03 (t, J = 8.0 Hz, 1H), 5.58–5.57 (m, 1H), 2.89–2.76 (m, 2H), 2.60 (s, 1H), 2.38–2.22 (m, 2H), 2.10–1.99 (m, 3H), 1.86–1,28 (m, 11H), 1.24–1.15 (m, 1H), 1.07 (s, 3H), 0.92 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 157.7, 146.3, 137.9, 136.4, 136.1, 133.9, 126.2, 124.6, 120.4, 120.3, 119.1, 87.7, 79.8, 74.1, 50.7, 47.6, 46.6, 38.9, 36.6, 34.2, 32.5, 32.1, 31.3, 24.2, 23.1, 21.0, 18.7, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C28H31N3O3S [M+H]+ = 490.2159 found 490.2154.

(1S,2R,13R,14S,17R,18S)-7-(5-chloro-2-methoxy-anilino)-17-ethynyl-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (8):

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Light brown solid (229 mg, 90%); 1H NMR (300MHz, CDCl3): δ 7.99 (d, J = 2.2 Hz, 1H), 6.95 (dd, J = 2.4, 8.6 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 5.52 (s, 1H), 3.89 (s, 3H), 2.83–2.72 (m, 2H), 2.60 (s, 1H), 2.38–2.22 (m, 2H), 2.07–2.00 (m, 3H), 1.83–1.16 (m, 12H), 1.06 (s, 3H), 0.91 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 160.4, 146.3, 143.9, 136.0, 130.1, 126.0, 121.8, 121.0, 119.2, 116.6, 110.9, 87.4, 79.8, 74.1, 56.0, 50.7, 47.6, 46.6, 38.9, 36.6, 34.1, 32.5, 32.1, 31.2, 23.7, 23.1, 21.0, 18.7, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C29H33N2O2SCl [M+H]+ = 509.2024 found 509.2014.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-(2-pyridylamino)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (9).

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Whitish solid (378 mg, 85%); 1H NMR (300MHz, DMSO-d6): δ 8.35 (d, J = 4.1 Hz, 1H), 7.61 (t, J = 7.0 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.90 (t, J = 7.0 Hz, 1H), 5.69 (s, 1H), 2.70–2.68 (m, 2H), 2.60 (s, 1H), 2.35–2.19 (m, 2H), 2.14 (s, 1H), 2.08–2.02 (m, 3H), 1.87–1.36 (m, 10H), 1.22–1.17 (m, 1H), 1.04 (s, 3H), 0.91 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 159.2, 150.9, 146.7, 140.3, 137.8, 136.1, 122.1, 118.5, 116.7, 111.3, 87.4, 79.8, 74.0, 50.7, 47.6, 46.6, 38.9, 36.4, 34.0, 32.5, 32.1, 31.2, 23.1, 22.5, 21.9, 18.6, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C27H31N3OS [M+H]+ = 446.2261 found 446.2264.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-[(4-methyl-2-pyridyl)amino]-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (10):

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Brownish solid, (192 mg, 84%), 1H NMR (300MHz, CDCl3): δ 8.21 (d, J = 5.0 Hz, 1H), 6.72–6.69 (m, 2H), 5.68 (s, 1H), 2.74–2.41 (m, 2H), 2.60 (s, 1H), 2.30 (s, 3H), 2.39–2.22 (m, 3H), 2.15 (s, 1H), 2.04–2.01 (m, 2H), 1.87–1.17 (m, 11H), 1.05 (s, 3H), 0.92 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 158.7, 151.4, 149.0, 146.5, 142.0, 136.4, 122.6, 118.1, 118.0, 111.0, 87.5, 79.8, 77.2, 74.0, 50.7, 47.6, 46.7, 38.9, 36.4, 34.3, 32.5, 32.1, 31.0, 23.3, 23.1, 21.1, 18.6, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C28H33N3OS [M+H]+ = 460.2417 found 460.2408.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-[(6-methyl-2-pyridyl)amino]-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (11).

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Brownish solid, (192 mg, 84%); 1H NMR (300MHz, CDCl3): δ 7.52 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 7.3 Hz, 1H), 5.70 (s, 1H), 2.71–2.70 (m, 2H), 2.60 (s, 1H), 2.54 (s, 3H), 2.48–2.19 (m, 2H), 2.13 (s, 3H), 2.07–1.99 (m, 2H), 1.87–1.32 (m, 10H), 1.24–1.10 (m, 1H), 1.03 (s, 3H), 0.91 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 177.6, 159.6, 156.0, 149.7, 138.5, 138.2, 135.9, 121.7, 118.9, 116.4, 108.3, 87.4, 79.8, 74.0, 50.7, 47.5, 46.6, 38.9, 36.4, 33.9, 32.5, 31.2, 23.6, 23.1, 22.1, 21.9, 18.6, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C28H33N3OS [M+H]+ = 460.2417 found 460.2411.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-(pyrimidin-2-ylamino)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (12).

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White solid (308 mg, 69%); 1H NMR (300MHz, CDCl3+DMSO-d6): δ 8.64 (s, 2H), 7.05–6.90 (m, 1H), 5.70 (s, 1H), 3.09–2.79 (m, 2H), 2.59 (s, 1H), 2.29–2.03 (m, 7H), 1.78–1.47 (m, 9H), 1.19–1.04 (m, 1H), 1.04 (s, 3H), 0.90 (s, 3H) ; APT NMR (75 MHz, CDCl3+DMSO-d6): δ 181.3, 158.0, 157.8, 157.1, 136.6, 123.4, 118.2, 115.6, 113.6, 79.0, 73.8, 50.6, 47.7, 46.6, 39.1, 36.3, 34.3, 32.6, 32.1, 31.3, 23.6, 23.2, 21.0, 18.7, 12.9. HRMS (ESI-FTMS Mass (m/z): calcd for C26H30N4OS [M+H]+ = 447.2213 found 447.2207.

(1S,2R,13R,14S,17R,18S)-7-cyclopropyl-17-ethynyl-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (13).

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White powder (137 mg, 70%); 1H NMR (300 MHz, CDCl3): δ 5.64 (s, 1H), 2.88–2.75 (m, 2H), 2.59 (s, 1H), 2.35–2.18 (m, 4H), 2.08–1.99 (m, 3H), 1.78–1.65 (m, 6H), 1.60–1.34 (m, 5H), 1.21–1.09 (m, 3H), 1.02 (s, 3H), 0.90 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 170.7, 148.1, 136.3, 129.1, 120.8, 87.4, 79.7, 74.0, 50.7, 47.6, 46.6, 38.9, 36.6, 34.3, 32.5, 32.1, 31.3, 23.9, 23.1, 21.0, 18.6, 14.7, 12.7, 11.2, 11.1. HRMS (ESI-FTMS Mass (m/z): calcd for C25H31NOS [M+H]+ = 394.2199, found = 394.2200.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-tetrahydropyran-4-yl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (14).

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White powder (147 mg, 68%); 1H NMR (300 MHz, CDCl3): δ 5.70 (s, 1H), 4.05 (d, J = 9.6 Hz, 2H), 3.50 (t, J = 11.5 Hz, 2H), 3.19–3.11 (m, 1H), 2.91–2.56 (m, 5H), 2.29–2.19 (m, 2H), 2.01–1.59 (m, 11H), 1.55–1.32 (m, 4H), 1.23–1.11 (m, 1H), 1.01 (s, 3H), 0.88 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 171.3, 148.3, 136.3, 130.4, 121.3, 87.6, 79.5, 73.9, 67.5, 50.6, 47.6, 39.8, 38.9, 36.6, 34.3, 33.1, 33.0, 32.5, 32.1, 31.3, 29.6, 23.1, 21.0, 18.6, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C27H35NO2S [M+H]+ = 438.2461, found = 438.2470.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-phenyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (15).

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Deep champagne powder (143 mg, 67%), 1H NMR (300 MHz, CDCl3): δ 7.92 (s, 2H), 7.41 (s, 3H), 5.83 (s, 1H), 3.04–2.83 (m, 2H), 2.60 (s, 1H), 2.32–2.00 (m, 6H), 1.85–1.41 (m, 9H), 1.26–1.17 (m, 1H), 1.07 (s, 3H), 0.92 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 164.1, 150.1, 136.3, 133.6, 131.8, 129.8, 128.8, 126.4, 122.1, 87.4, 79.7, 74.1, 50.7, 47.6, 46.6, 38.9, 36.6, 34.3, 32.5, 32.1, 31.4, 24.1, 23.1, 21.1, 18.7, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C28H31NOS [M+H]+ = 430.2199, found = 430.2187.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-(o-tolyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (16).

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Blond powder (190 mg, 86%); 1H NMR (300 MHz, CDCl3): δ 7.71 (s, 1H), 7.28 (s, 3H), 5.84 (s, 1H), 3.04–2.84 (m, 2H), 2.60 (s, 4H), 2.31–1.40 (m, 15H), 1.24–1.21 (m, 1H), 1.09 (s, 3H), 0.92 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 163.6, 149.5, 136.4, 136.3, 133.2, 132.2, 131.3, 129.8, 129.1, 126.0, 121.9, 87.4, 79.7, 74.0, 50.7, 47.7, 46.7, 38.9, 36.6, 34.4, 32.5, 32.1, 31.4, 24.1, 23.1, 21.5, 21.1, 18.7, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C29H33NOS [M+H]+ = 444.2355, found = 444.2362.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-(p-tolyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (17).

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White powder (163 mg, 74%); 1H NMR (300 MHz, CDCl3): δ 7.81 (d, J = 8.0 Hz, 2H), 7.24 (t, J = 9.8 Hz, 2H), 5.82 (s, 1H), 2.99–2.87 ( m, 2H), 2.60 (s, 1H), 2.39–2.26 (m, 4H), 2.08–2.02 (m, 3H), 1.85–1.38 (m, 11H), 1.21 (m, 1H), 1.07 (s, 3H), 0.92 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 164.6, 149.3, 140.5, 136.2, 131.3, 130.3, 129.6,126.4, 122.2, 87.3, 79.7, 74.1, 50.7, 47.6, 46.6, 38.9, 36.6, 34.2, 32.4, 32.1, 31.4, 23.9, 23.1, 21.4, 21.0, 18.7, 12.7; HRMS (ESI-FTMS Mass (m/z): calcd for C29H33NOS [M+H]+ = 444.2356, found = 444.2352.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-(4-methoxyphenyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (18).

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Beige powder (388 mg, 84% ); 1H NMR (300 MHz, CDCl3): δ 7.89 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 5.80 (s, 1H), 3.87 (s, 3H), 3.04–2.87 (m, 2H), 2.61 (s, 1H), 2.34–2.26 (m, 2H), 2.12–1.36 (m, 13H), 1.25–1.20 (m, 1H), 1.07 (s, 3H), 0.92 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 164.3, 161.1, 149.3, 136.3, 130.8, 128.0, 126.1, 121.8, 114.2, 87.3, 79.7, 74.1, 55.4, 50.7, 47.5, 46.6, 38.9, 36.6, 34.2, 32.5, 32.1, 31.4, 23.9, 23.0, 21.0, 18.7, 12.7; HRMS (ESI-FTMS Mass (m/z): calcd for C29H33NO2S[M+H]+ = 460.2305, found = 460.2310.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-7-(3-hydroxyphenyl)-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (19).

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White powder (0.133g , 60%); 1H NMR (300 MHz, DMSO): δ 9.74 (s, 1H), 7.27 (s, 3H), 6.83 (s, 1H), 5.78 (s, 1H), 5.34 (s, 1H), 2.88–2.76 ( m, 2H), 2.49 (s, 1H), 2.30–2.06 (m, 2H), 1.98–1.14 (m, 12H), 1.07–0.97 (m, 4H), 0.77 (s, 3H) ; 13C NMR (75 MHz, DMSO): δ 163.2, 158.2, 150.6, 136.2, 134.8, 131.5, 130.7, 122.8, 117.6, 117.3, 112.7, 89.3, 78.5, 75.5, 50.7, 47.9, 46.6, 36.5, 34.1, 32.7, 32.0, 31.5, 24.2, 23.2, 21.5, 21.1, 18.9, 13.2; HRMS (ESI-FTMS Mass (m/z): calcd for C28H31NO2S [M+H]+ = 446.2148, found = 446.2153.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-7-(4-hydroxyphenyl)-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (20).

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Gray solid (202 mg, 91%); 1H NMR (300 MHz, DMSO): δ 10.08 (br s, 1H), 7.68 (d, J = 7.92 Hz, 2H), 6.82 (d, J = 6.93Hz, 2H), 5.68 (s, 1H), 5.33 (s, 1H), 2.78–2.72 (m, 2H), 2.49 (s, 1H), 2.21–1.99 (m, 4H), 1.89–1.16 (m, 11H), 1.12–0.95 (m, 4H), 0.75 (s, 3H); 13C NMR (75 MHz, DMSO): δ 163.7, 159.7, 150.2, 136.4, 130.1, 128.0, 125.0, 121.9, 116.2, 89.3, 78.5, 75.5, 50.7, 49.9, 46.6, 36.5, 39.0, 34.2, 32.7, 32.1, 31.5, 24.2, 23.2, 21.1, 18.9, 13.1; HRMS (ESI-FTMS Mass (m/z): calcd for C28H31NO2S[M+H]+ = 446.2148, found = 446.2153.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-7-(3-fluorophenyl)-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (21).

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Brown powder (143 mg, 64%), 1H NMR (300 MHz, CDCl3): δ 7.67 (t, J = 7.8 Hz, 2H), 7.39–7.35 (m, 1H), 7.11–7.00 (m, 1H), 5.84 (s, 1H), 3.03–2.83 (m, 2H), 2.60 (s, 1H), 2.34–2.02 (m, 5H), 1.89–1.34 (m, 10H), 1.23–1.17 (m, 1H), 1.07 (s, 3H), 0.92–0.88 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 163.0 (1J = 245.0 Hz), 162.5, 150.1, 136.2, 135.5, 132.5, 130.5 (3J = 8.2 Hz), 122.7, 122.1, 116.7 (2J = 20.1 Hz), 113.2 (2J = 23.2 Hz), 87.3, 79.7, 74.1, 50.7, 47.6, 46.6, 38.9, 36.6, 34.2, 32.4, 32.1, 31.4, 24.0, 23.1, 21.1, 18.7, 12.7; HRMS (ESI-FTMS Mass (m/z): calcd for C28H30FNOS [M+H]+ = 448.2105, found = 448.2113.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-7-(4-chlorophenyl)-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (22).

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Beige powder (155 mg, 65%); 1H NMR (300 MHz, CDCl3): δ 7.88 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H ), 5.85 (s, 1H), 3.07–2.84 (m, 2H), 2.60 (s, 1H), 2.37–1.36 (m, 15H), 1.25–1.18 (m, 1H), 1.07 (s, 3H), 0.92 ( s, 3H); 13C NMR (75 MHz, CDCl3): δ 162.8, 149.8, 136.1, 135.9, 132.3, 131.7, 129.1, 127.6, 122.7, 87.3, 79.7, 74.1, 50.7, 47.6, 46.6, 38.9, 36.6, 34.2, 32.4, 32.1, 31.4, 23.9, 23.1, 21.0, 18.7, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C28H30ClNOS [M+H]+ = 464.1809, found = 464.1810.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-[4-(trifluoromethyl)phenyl]-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (23).

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Blond powder ( 154 mg, 62% ); 1H NMR (300 MHz, CDCl3): δ 8.04 (d, J = 6.6 Hz, 2H), 7.68 (d, J = 6.5 Hz, 2H), 5.88 (s, 1H), 3.17–2.90 (m, 2H), 2.61 ( s, 1H), 2.33–2.28 (m, 2H), 2.15–1.39 (m, 13H), 1.25–1.21 (m, 1H), 1.08 (s, 3H), 0.93 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 162.0, 150.5, 136.5, 136.1, 133.2, 131.3 (J = 32.9 Hz), 126.5, 125.9, 123.1, 87.3, 79.7, 74.1, 50.7, 47.6, 46.6, 38.9, 36.6, 34.2, 32.4, 32.1, 31.5, 24.0, 23.1, 21.1, 18.7, 12.7, HRMS (ESI-FTMS Mass (m/z): calcd for C29H30F3NOS [M+H]+ = 498.2072, found = 498.2067.

(1S,2R,13R,14S,17R,18S)-7-(2,6-dichlorophenyl)-17-ethynyl-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (24).

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Gray powder (171 mg, 69% ); 1H NMR (300 MHz, CDCl3): δ 7.40–7.27 (m, 3H), 5.85 (s, 1H), 3.07–2.92 (m, 2H), 2.61 (s, 1H), 2.30–1.42 (m, 15H), 1.26–1.18 (m, 1H), 1.11 (s, 3H), 0.93 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 157.3, 148.8, 136.0, 135.9, 134.3, 131.9, 131.2, 128.1, 123.1, 87.3, 79.7, 74.1, 50.7, 47.7, 46.7, 38.9, 36.7, 34.1, 32.5, 32.1, 31.4, 23.8, 23.1, 21.1, 18.8, 12.7; HRMS (ESI-FTMS Mass (m/z): calcd for C28H29Cl2NOS [M+H]+ = 498.1419, found = 498.1420.

(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-(2-pyridyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-ol (25).

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Gray powder (139 mg, 65%), 1H NMR (300 MHz, CDCl3): δ 8.60 (d, J = 4.7 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.78 (t, J = 6.3 Hz, 1H), 7.31–7.28 (m, 1H), 5.93 (s, 1H), 3.04–2.85 (m, 2H), 2.60 (s, 1H), 2.33–1.36 (m, 15H), 1.25–1.20 (m, 1H), 1.07 (s, 3H), 0.92 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 164.6, 151.3, 150.5, 149.4, 136.9, 136.3, 134.2, 124.1, 122.9, 119.5, 87.4, 79.7, 74.1, 50.7, 47.6, 46.6, 38.9, 36.5, 34.3, 32.5, 32.1, 31.5, 24.1, 23.1, 21.1, 18.7, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C27H30N2OS [M+H]+ = 431.2151, found = 431.2161.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (26).

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White solid (427 mg, 97%); 1H NMR (300MHz, CDCl3): δ 5.40–5.38 (m, 1H), 4.92 (s, 2H), 2.65–2.62 (m, 2H), 2.20–2.16 (m, 1H), 2.07–1.94 (m, 2H), 1.87–1.03 (m, 26H), 0.93 (d, J = 6.4 Hz, 3H), 0.89–0.86 (m, 6H), 0.71 (s, 2H); 13C NMR (75 MHz, CDCl3): δ 167.6, 155.7, 142.7, 136.0, 125.8, 56.7, 56.1, 47.9, 42.3, 39.7, 39.5, 36.4, 36.1, 35.8, 34.3, 31.7, 31.4, 28.2, 28.0, 24.2, 23.8, 23.3, 22.8, 22.5, 21.4, 18.7, 18.5. HRMS (ESI-FTMS Mass (m/z): calcd for C28H44N2S [M+H]+ = 441.3298, found 441.3294.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-(p-tolyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (27).

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Yellow solid (478 mg, 90%); 1H NMR (300MHz, CDCl3): δ 7.24–7.14 (m, 4H), 5.44–5.42 (m, 1H), 2.68–2.66 (m, 2H), 2.34 (s, 3H), 2.22–2.16 (m, 1H), 2.07–1.96 (m, 2H), 1.85–1.04 (m, 24H), 0.94 (d, J = 6.4 Hz, 3H), 0.89–0.87 (m, 7H), 0.72 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 162.8, 145.1, 137.8, 136.5, 133.0, 129.9, 129.7, 120.9, 119.3, 118.3, 56.8, 56.1, 48.0, 42.3, 39.7, 39.5, 36.5, 36.1, 35.8, 34.3, 31.7, 31.5, 28.2, 28.0, 24.2, 24.0, 23.8, 22.8, 22.5, 21.3, 20.8, 18.7, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C35H50N2S [M+H]+ = 531.3767, found 531.3767.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-(2,4-dimethylphenyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (28).

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Brown solid (495 mg, 91%); 1H NMR (300MHz, DMSO-d6): δ 7.41 (d, J = 7.8 Hz, 1H), 6.83–6.81 (m, 2H), 5.39–5.38 (m, 1H), 2.68–2.66 (m, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 2.20–1.21 (m, 17H), 1.18–1.10 (m, 6H), 1.04 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.89–0.86 (m, 8H), 0.72 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 164.4, 145.4, 136.5, 136.0, 134.7, 131.7, 130.3, 127.6, 121.8, 120.5, 118.0, 56.8, 56.1, 48.0, 42.3, 39.7. 39.5, 36.5, 36.1, 35.8, 34.3, 31.6, 31.5, 28.3, 28.0, 24.2, 24.0, 23.8, 22.8, 22.5, 21.3, 20.8, 18.7, 17.7, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C36H52N2S [M+H]+ = 545.3924, found 545.3927.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-(2,4,6-trimethylphenyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (29).

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White solid (390 mg, 70%); 1H NMR (300MHz, CDCl3): δ 7.62 (br s, 1H), 6.96 (s, 2H), 5.27 (s, 1H), 2.57–2.50 (m, 2H), 2.32–2.28 (m, 9H), 2.22–1.02 (m, 27H), 0.93–0.86 (m, 10H), 0.70 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 167.8, 145.8, 137.6, 136,7, 134.7, 129.4, 128.8, 119.9, 117.3, 56.8, 56.0, 48.0, 42.3, 39.7, 39.5, 36.5, 36.1, 35.7, 34.3, 31.6, 31.5, 28.2, 28.0, 24.2, 24.0, 23.8, 22.8, 22.5, 21.3, 21.0, 18.77, 18.70, 18.1, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C37H54N2S [M+H]+ = 559.4080, found 559.4080.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-(2-methoxyphenyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (30).

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Brown solid (458 mg, 84%); 1H NMR (300MHz, CDCl3): δ 7.94–7.90 (br s, 1H), 7.02–6.96 (m, 2H), 6.90–6.87 (m, 1H), 5.49 (s,1H), 3.87 (s, 3H), 2.75 (s, 2H), 2.24–2.18 (m, 1H), 2.04 (t, J = 12.2 Hz, 2H), 1.88–1.22 (m, 11H), 1.18–1.08 (m, 7H), 1.05 (s, 4H), 0.94 (d, J = 6.3 Hz, 4H), 0.88 (d, J = 6.5 Hz, 8H), 0.73 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 160.5, 147.3, 145.5, 136.5, 129.8, 121.7, 121.0, 118.6, 116.0, 110.0, 56.8, 56.1, 55.7, 48.0, 42.3, 39.7, 39.5, 36.6, 36.1, 35.8, 34.2, 31.7, 31.5, 28.2, 28.0, 24.2, 24.1, 23.8, 22.8, 22.5, 21.3, 18.7, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C35H50N2OS [M+H]+ = 547.3717, found 547.3711.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-(2,4-dimethoxyphenyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (31).

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Brownish solid (489 mg, 85%); 1H NMR (300MHz, CDCl3): δ 7.75 (d, J = 9.3 Hz, 1H), 6.51 (s, 1H), 5.44 (s, 1H), 3.83 (d, J = 12.3 Hz, 6H), 2.72–2.70 (m, 2H), 2.22–2.16 (m, 1H), 2.03 (t, J = 12.6 Hz, 2H), 1.84–1.80 (m, 2H), 1.76–1.22 (m, 10H), 1.13–1.11 (m, 7H), 1.04 (s, 5H), 0.94 (d, J = 6.1 Hz, 4H), 0.88 (d, J = 6.5 Hz. 7H), 0.72 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 162.2, 155.7, 149.6, 145.6, 136.6, 123.6, 120.3, 118.5, 118.2, 103.6, 99.0, 56.8, 56.1, 55.7, 55.6, 48.0, 42.3, 39.7, 39.5, 36.5, 36.1, 35.8, 34.6, 34.4, 31.7, 31.5, 28.2, 28.0, 24.23, 24.20, 23.8, 22.8, 22.5, 21.3, 18.7, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C36H52N2O2S [M+H]+ = 577.3822, found 577.3812.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-(2,5-dimethoxyphenyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (32).

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Whitish solid (518 mg, 90%): 1H NMR (300MHz, CDCl3): δ 7.64–7.63 (m, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.48–6.44 (m, 1H), 5.49 (s, 1H), 3.85–3.81 (m, 6H), 2.75–2.73 (m, 2H), 2.24–2.18 (m, 1H), 2.03 (t, J = 12.8 Hz, 2H), 1.84–1.22 (m, 14H), 1.13–1.11 (m, 7H), 1.05 (s, 4H), 0.94 (d, J = 6.3 Hz, 3H), 0.88 (d, J = 6.3 Hz, 6H), 0.72 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 159.6, 153.6, 145.1, 141.3, 136.0, 130.1, 120.8, 118.3, 110.3, 104.6, 103.1, 56.3, 56.1, 55.8, 55.7, 55.3, 47.6, 41.9, 39.3, 39.1, 36.2, 35.7, 35.4, 33.9, 31.3, 31.1, 27.8, 27.6, 23.8, 23.4, 22.4, 22.1, 20.9, 18.3, 11.5. HRMS (ESI-FTMS Mass (m/z): calcd for C36H52N2O2S [M+H]+ = 577.3822, found 577.3824.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-(2-chlorophenyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (33).

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Yellow solid (512 mg, 93%); 1H NMR (300MHz, CDCl3): δ 8.07 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.31–7.27 (m, 1H), 6.95 (t, J = 7.4 Hz, 1H), 5.52 (s, 1H), 2.76–2.71 (m, 2H), 2.25–2.19 (m, 1H), 2.04 (t, J = 12.3 Hz, 2H), 1.88–1.78 (m, 2H), 1.72–1.61 (m, 4H), 1.56–1.42 (m, 3H), 1.39–1.32 (m, 3H), 1.28 (br s, 1H), 1.23 (d, J = 4.7 Hz, 1H), 1.17–1.12 (m, 7H), 1.06 (s, 4H), 0.94 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.5 Hz, 6H), 0.73 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 159.6, 145.6, 136.8, 136.3, 129.4, 127.8, 122.5, 122.2, 121.5, 119.4, 117.7, 56.7, 56.1, 48.0, 42.3, 39.7, 39.5, 36.6, 36.1, 35.8, 34.3, 31.7, 31.5, 28.2, 28.0, 24.23, 24.20, 23.8, 22.8, 22.5, 21.3, 18.7, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C34H47ClN2S [M+H]+ = 551.3221, 553.3195, found 551.3229, 553.3208.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-(2,4-difluorophenyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (34).

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Yellow solid (496 mg, 90%); 1H NMR (300MHz, CDCl3): δ 8.06–7.98 (m, 1H), 6.92–6.87 (m, 2H), 5.48 (s, 1H), 2.72 (s, 2H), 2.23–2.17 (m, 1H), 2.04 (t, J = 12.2 Hz, 2H), 1.85-(m, 11H), 1.13–1.11 (m, 8H), 1.04 (s, 4H), 0.93 (d, J = 6.4 Hz, 5H), 0.88 (d, J = 6.4 Hz, 6H), 0.72 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 160.9, 157.6 (dd, J = 10.9, 243.2Hz), 152.3 (dd, J = 11.7, 245.0 Hz), 145.5, 136.3, 125.3–125.1 (m), 121.6, 120.5 (d, 3J = 9.1 Hz), 119.2, 111.4–111.0 (m), 104.2, 103.6 (m), 56.7, 56.1, 48.0, 42.3, 39.4, 39.5, 36.5, 36.1, 35.8, 34.2, 31.7, 31.5, 28.2, 28.0, 24.2, 24.1, 23.8, 22.8, 22.5, 21.3, 18.7, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C34H46F2N2S [M+H]+ = 553.3423, found 553.3416.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-[2-(trifluoromethyl)phenyl]-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (35).

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Yellowish solid (438 mg, 75%): 1H NMR (300MHz, CDCl3): δ 8.04 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 5.49 (s, 1H), 2.74 (s, 2H), 2.24–2.18 (m, 1H), 2.04 (t, J = 12.3 Hz, 2H), 1.85–1.23 (m, 13H), 1.18–1.08 (m, 8H), 1.06 (s, 3H), 0.94 (d, J = 6.3 Hz, 3H), 0.88 (d, J = 6.5 Hz, 7H), 0.73 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 160.64, 145.4, 138.5, 136.2, 133.1, 126.7–126.6 (m), 125.9, 122.7, 122.3, 120.6, 119.5, 118.6 (d, 2J = 29.5 Hz), 56.7, 56.1, 48.0, 42.3, 39.7, 39.5, 36.6, 36.1, 35.8, 34.2, 31.7, 31.5, 28.2, 28.0, 24.2, 24.0, 23.8, 22.8, 22.5, 21.3, 18.7, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C35H47F3N2S [M+H]+ = 585.3485, found 585.3482.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-[3,5-bis(trifluoromethyl)phenyl]-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (36).

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Whitish solid (581 mg, 89%); 1H NMR (300 MHz, CDCl3): δ 7.88 (s, 2H), 7.48 (s, 1H), 5.55 (s, 1H), 2.76 (s, 2H), 2.26–2.16 (m, 1H), 2.05 (t, J = 12.3 Hz, 2H), 1.86–1.22 (m, 13H), 1.14–1.11 (m, 8H), 1.05 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.1 Hz, 7H), 0.73 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 159.5, 145.2, 141.8, 136.0, 133.2–131.9 (m), 123.1 (d, 1J = 270 Hz), 122.6, 120.2, 117.0, 115.2, 56.7, 57.1, 47.9, 42.3, 39.6, 39.5, 36.6, 36.1, 35.8, 34.2, 31.7, 31.5, 28.2, 28.0, 24.2, 24.1, 23.8, 22.8, 22.5, 21.3, 18.7, 18.6, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C36H46F6N2S [M+H]+ = 653.3359, found 653.3350.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-(2-nitrophenyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (37).

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Red solid (393 mg, 70%); 1H NMR (300MHz, CDCl3): δ 8.71 (d, J = 8.6 Hz, 1H), 8.26 (dd, J = 1.4, 8.5 Hz, 1H), 7.63 (dt, J = 1.5, 7.1 Hz, 1H), 7.01 (dt, J = 1.1, 8.4 Hz, 1H), 5.59 (s, 1H), 2.87–2.80 (m, 2H), 2.28–2.19 (m, 1H), 2.09–2.02 (m, 2H), 1.88–1.79 (m, 2H), 1.73–1.62 (m, 4H), 1.58–1.47 (m, 3H), 1.44–1.35 (m, 4H), 1.28–1.27 (m, 1H), 1.23 (d, J = 4.2 Hz, 1H), 1.18–1.08 (m, 7H), 1.06 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.90–0.87 (m, 6H), 0.73 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 157.6, 146.3, 138.0, 136.3, 136.0, 133.8, 126.2, 124.8, 120.8, 120.3, 119.1, 56.7, 56.1, 48.0, 42.3, 39.7, 39.5, 36.6, 36.1, 35.8, 34.2, 31.8, 31.5, 28.2, 28.0, 24.3, 24.2, 23.8, 22.8, 22.5, 21.3, 18.7, 18.6, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C34H47N3O2S [M+H]+ = 562.3462, found 562.3453.

(1S,2R,13S,14S,17R,18R)-N-(5-chloro-2-methoxy-phenyl)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (38).

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Whitish solid (476 mg, 82%); 1H NMR (300MHz, CDCl3): δ 8.10 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 2.4, 8.4 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 5.52 (s, 1H), 3.88 (s, 3H), 2.77–2.71 (m, 2H), 2.24–2.18 (m,1H), 2.08–2.04 (m, 3H), 1.84–1.13 (m, 20H), 1.05 (s, 3H), 0.94 (d, J = 6.3 Hz, 3H), 0.88 (d, J = 6.5 Hz, 7H), 0.72 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 159.3, 145.8, 145.6, 136.4, 130.8, 126.1, 121.8, 120.7, 119.2, 115.9, 110.6, 77.2, 56.7, 56.1, 55.9, 48.0, 42.3, 39.7, 39.5, 36.6, 36.1, 35.8, 34.3, 31.7, 31.5, 28.2, 28.0, 24.26, 24.24, 23.8, 22.8, 22.5, 21.3, 18.7, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C35H49ClN2OS [M+H]+ = 581.3327, 583.3301, found 581.3321, 583.3307.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-(2-pyridyl)-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (39).

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Whitish solid (455 mg, 88%); 1H NMR (300MHz, CDCl3): δ 8.35 (d, J = 3.9 Hz, 1H), 7.72–7.42 (m, 1H), 6.88–6.83 (m, 2H), 5.70–5.68 (m, 1H), 2.75–2.74 (m, 2H), 2.26–2.21(m, 1H), 2.04(t, J = 12.0 Hz, 2H), 1.87–1.05 (m, 24H), 0.94 (d, J = 6.4 Hz, 3H), 0.90–0.80 (m, 7H), 0.703(s, 3H); 13C NMR (75 MHz, CDCl3): δ 158.2, 151.6, 147.0, 143.1, 137.5, 136.6, 123.2, 118.5, 116.1, 110.6, 56.8, 56.1,48.0, 42.3, 39.7, 39.5, 36.4, 36.1, 35.8, 34.4, 31.7, 31.5, 28.2, 28.0, 24.2, 24.0, 23.8, 22.8, 22.5, 21.4, 18.7, 11.9 . HRMS (ESI-FTMS Mass (m/z): calcd for C33H47N3S [M+H]+ = 518.3563, found 518.3550.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-N-pyrimidin-2-yl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (40).

graphic file with name nihms-1682569-f0042.jpg

Brownish solid (441 mg, 85%); 1H NMR (300MHz, CDCl3): δ 8.67–8.65 (m, 2H), 6.90–6.86 (m, 1H), 5.69 (s, 1H), 2.90–2.75 (m, 2H), 2.25–2.19 (m, 1H), 2.08–2.01 (m, 2H), 1.94–1.81(m, 2H), 1.79–1.22 (m, 11H), 1.14–1.11 (m, 8H), 1.04 (s, 3H), 0.94 (d, J = 6.2 Hz, 3H), 0.88 (d, J = 6.5 Hz, 7H), 0.73 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 157.9, 157.0, 156.7, 144.2, 136.7, 124.4, 118.6, 113.5, 56.8, 56.1, 48.0, 42.3, 39.7, 39.5, 36.4, 36.2, 35.8, 34.4, 31.7, 31.5, 28.2, 28.0, 24.2, 23.9, 22.8, 22.5, 21.4, 18.7, 18.6, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C32H46N4S [M+H]+ = 519.3516, found 519.3518.

(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-N,2,18-trimethyl-N-phenyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (41).

graphic file with name nihms-1682569-f0043.jpg

Whitish solid (371 mg, 70%); 1H NMR (300MHz, CDCl3): δ 7.44–7.33 (m, 4H), 7.30–7.24 (m, 1H), 5.31–5.29 (m, 1H), 3.53 (s, 3H), 2.74–2.69 (m, 2H), 2.16–2.11 (m, 1H), 2.07–1.97 (m, 2H), 1.86–1.74 (m, 2H), 1.66–1.58 (m, 3H), 1.55–1.43 (m, 3H), 1.40–1.29 (m, 4H), 1.25–1.24 (m, 1H), 1.20 (d, J = 4.5 Hz, 1H), 1.14–1.07 (m, 7H), 1.03 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.89–0.86 (m, 6H), 0.71 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 166.9, 146.4, 146.0, 136.7, 129.6, 126.4, 125.2, 120.5, 117.8, 56.8, 56.1, 48.0, 42.3, 40.0, 39.7, 39.5, 36.4, 36.1, 35.8, 34.4, 31.6, 31.5, 28.2, 28.0, 24.3, 24.2, 23.8, 22.8, 22.5, 21.3, 18.7, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C35H50N2S [M+H]+ = 531.3767, found 531.3753.

(1S,2R,13S,14S,17R,18R)-N-allyl-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (42).

graphic file with name nihms-1682569-f0044.jpg

Yellow solid (433 mg, 90%); 1H NMR (300MHz, CDCl3): δ 5.95–5.86 (m, 1H), 5.67 (br s, 1H), 5.37–5.16 (m, 3H), 3.89 (s, 2H), 2.63–2.60 (m, 2H), 2.20–2.14 (m, 1H), 2.04–1.92 (m, 3H), 1.85–1.01 (m, 26H), 0.91 (d, J = 6.3 Hz, 3H), 0.86 (d, J = 6.3 Hz, 3H), 0.69 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 166.4, 145.2, 136.3, 133.3, 119.4, 117.0, 116.6, 56.4, 55.7, 47.7, 47.6, 41.9, 39.3, 39.1, 36.1, 35.7, 35.4, 33.9, 31.2, 31.1, 27.8, 27.6, 23.8, 23.7, 23.4, 22.4, 22.1, 20.9, 18.3, 11.5. HRMS (ESI-FTMS Mass (m/z): calcd for C31H48N2S [M+H]+ = 481.3611, found 481.3599.

(1S,2R,13S,14S,17R,18R)-N-benzyl-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-amine (43).

graphic file with name nihms-1682569-f0045.jpg

Yellowish solid (387 mg, 73%); 1H NMR (300MHz, CDCl3): δ 7.37–7.28 (m, 5H), 5.38–5.36 (m, 1H), 4.48 (s, 2H), 2.64–2.61 (m, 1H), 2.26–2.15 (m, 1H), 2.07–1.94 (m, 4H), 1.87–1.02 (m, 22H), 0.93 (d, J = 6.4 Hz, 3H), 0.89–0.86 (m, 8H), 0.71 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 166.9, 144.1, 137.1, 136.3, 128.7, 127.8, 127.6, 119.6, 118.1, 76.6, 56.7, 56.1, 49.8, 47.9, 42.3, 39.7, 39.5, 36.5, 36.1, 35.8, 34.2, 31.6, 31.5 28.2, 28.0, 24.2, 23.8, 23.7, 22.8, 22.5, 21.3, 18.7, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C35H50N2S [M+H]+ = 531.3767, found 531.3765.

(5R,5aS,7R)-7-isopropenyl-5,5a-dimethyl-5,6,7,8,9,9a-hexahydro-4H-benzo[g][1,3]benzothiazol-2-amine (44).

graphic file with name nihms-1682569-f0046.jpg

Brown solid (270 mg, 98%); 1H NMR (300MHz, DMSO-d6): δ 5.42–5.40 (m, 1H), 4.76 (s, 2H), 2.61–2.21 (m, 5H), 2.07–1.98 (m, 1H), 1.77–1.72 (m, 5H), 1.31–1.10 (m, 2H), 0.98–0.95 (m, 6H); 13C NMR (75 MHz, DMSO-d6): δ 164.9, 149.9, 145.4, 136.8, 121.2, 118.1, 108.8, 40.0, 39.6, 37.5, 37.0, 32.8, 31.0, 20.7, 17.3, 14.9. HRMS (ESI-FTMS Mass (m/z): calcd for C16H22N2S [M+H]+ = 275.1576 found 275.1582.

1-[(1S,2R,13S,14S,17S,18S)-7-amino-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-17-yl]ethanone (45).

graphic file with name nihms-1682569-f0047.jpg

Yellowish solid (336 mg, 91%); 1H NMR (300MHz, DMSO-d6): δ 5.17 (s, 1H), 2.64–2.44 (m, 3H), 2.16–1.87 (m, 8H), 1.76–0.99 (m, 12H), 0.93 (s, 3H), 0.54 (s, 3H); 13C NMR (300MHz, DMSO-d6): δ 209.1, 165.7, 146.0, 137.1, 118.5, 116.2, 62.9, 56.5, 47.8, 43.7, 38.3, 36.4, 31.6, 31.4, 31.4, 24.3, 24.1, 22.6, 21.3, 19.0, 13.4. HRMS (ESI-FTMS Mass (m/z): calcd for C22H30N2OS [M+H]+ = 371.2152, found 371.2150.

N-[(1S,2R,13S,14S,17R,18R)-17-[(1R)-1,5-dimethylhexyl]-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-yl]acetamide (46).

graphic file with name nihms-1682569-f0048.jpg

Gray powder (239 mg, 99%); 1H NMR (300 MHz, CDCl3): δ 5.73 ( s, 1H), 2.71 (s, 2H), 2.25 (s, 3H), 2.08–2.00 (m, 2H), 1.85–0.87 (m, 35H), 0.72 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 167.7, 156.04, 141.8, 135.7, 125.7, 120.8, 56.7, 56.1, 47.9, 42.3, 39.7, 39.5, 36.4, 36.1, 35.7, 34.2, 31.7, 31.4, 28.2, 28.0, 24.2, 23.8, 23.5, 23.3, 22.8, 22.5, 21.3, 18.7, 18.5, 11.9. HRMS (ESI-FTMS Mass (m/z): calcd for C30H46N2OS[M+H]+ = 483.3403, found = 483.3402.

1H NMR Spectrum of Compound 47.

N-[(1S,2R,13R,14S,17R,18S)-17-ethynyl-17-hydroxy-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-yl]acetamide (47).

graphic file with name nihms-1682569-f0049.jpg

White solid (205 mg, 99%); 1H NMR (300MHz, CDCl3): δ 5.72 (s, 1H), 2.73–2.68 (m, 2H), 2.59 (s, 1H), 2.34–2.22 (m, 5H), 2.06–2.03 (m, 2H), 1.85–1.14 (m, 12H), 1.02 (s, 3H), 0.91 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 167.9, 156.2, 141.7, 135.7, 125.5, 120.3, 87.5, 79.7, 74.0, 50.7, 47.6, 46.6, 38.9, 36.4, 34.2, 32.5, 32.1, 31.3, 23.5, 23.3, 23.1, 21.0, 18.5, 12.7. HRMS (ESI-FTMS Mass (m/z): calcd for C24H30N2O2S [M+H]+ = 411.2100 found 411.2094.

N-[(5R,5aS,7R)-7-isopropenyl-5,5a-dimethyl-5,6,7,8,9,9a-hexahydro-4H-benzo[g][1,3]benzothiazol-2-yl]acetamide (48).

graphic file with name nihms-1682569-f0050.jpg

Yellowish powder (113 mg, 98%); 1H NMR (300 MHz, CDCl3): δ 5.75 (t, J = 2.16 Hz, 1H), 4.78 (s, 2H), 2.72–2.65 (m, 1H), 2.49–2.43 (m, 2H), 2.39–2.24 (m, 4H), 2.13–2.01 (m, 1H), 1.78 (s, 5H), 1.28 (t, J = 12.54 Hz, 1H), 1.01 (d, J = 6.7 Hz, 3H), 0.96 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 167.9, 156.2, 149.7, 142.6, 136.1, 125.4, 120.6, 109.0, 40.0, 39.6, 37.3, 36.9, 32.6, 31.1, 23.3, 20.7, 17.1, 15.0; HRMS (ESI-FTMS Mass (m/z): calcd for C18H24N2OS [M+H]+ = 317.1682, found = 317.1677.

N-[(1S,2R,13S,14S,17S,18S)-17-acetyl-2,18-dimethyl-8-thia-6-azapentacyclo[11.7.0.02,10.05,9.014,18]icosa-5(9),6,10-trien-7-yl]acetamide (49).

graphic file with name nihms-1682569-f0051.jpg

Brownish solid (205 mg, 99%); 1H NMR (300MHz, CDCl3): δ 5.75 (s, 1H), 2.80–2.70 (m, 2H), 2.63–2.53 (m, 1H), 2.31 (s, 3H), 2.25–2.03 (m, 3H), 2.14 (s, 3H), 1.83–1.73 (m, 5H), 1.58–1.18 (m, 7H), 0.99 (s, 3H), 0.94–0.89 (m, 1H), 0.67 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 209.5, 168.1, 156.8, 139.0, 135.1, 125.0, 121.4, 63.5, 56.7, 47.7, 43.9, 38.6, 36.4, 33.8, 31.5, 31.4, 24.4, 23.3, 22.8, 22.4, 21.3, 18.5, 13.3. HRMS (ESI-FTMS Mass (m/z): calcd for C24H32N2O2S [M+H]+ = 413.2257 found 413.2250.

Supplementary Material

Supporting Information

Scheme 2.

Scheme 2.

Open in a new tab

Reaction of epoxy-cholestenone (EC) with thiourea derivatives.

ACKNOWLEGGMENTS

This manuscript was made possible by the support from the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences (UAMS). This publication was made possible by Arkansas INBRE program and the Research Technology Core of the Arkansas INBRE program, supported by a grant from the National Institute of General Medical Sciences, (NIGMS), P20 GM103429 from the National Institutes of Health. NSF-MRI grant CHE-0923449 that was used to purchase the x-ray diffractometer and software used in this study.

Footnotes

Conflicts of interest

There are no conflicts of interest to declare.

References

  • 1.Ayati A, Emami S, Asadipour A, Shafiee A and Foroumadi A, Recent applications of 1,3-thiazole core structure in the identification of new lead compounds and drug discovery, Eur. J. Med. Chem, 2015, 97, 699–718. [DOI] [PubMed] [Google Scholar]
  • 2.Stank L, Frank A, Hagenow S and Stark H, Talipexole variations as novel bitopic dopamine D2 and D3 receptor ligands, Med.Chem. Comm, 2019, 10, 1926–1929. [Google Scholar]
  • 3.Zhao H, Ning Y, Cooper J, Refoios Camejo R, Ni X, Yi B and Parks D, Indirect Comparison of Ropinirole and Pramipexole as Levodopa Adjunctive Therapy in Advanced Parkinson’s Disease: A Systematic Review and Network Meta-Analysis, Adv. Ther, 2019, 36, 1252–1265. [DOI] [PubMed] [Google Scholar]
  • 4.Takahashi N, Mukai Y, Kimura T, Yamaguchi K, Matsumoto T, Origasa H, Okumura K and K. Y. U. R. I. on behalf of the, Efficacy and Safety of Uninterrupted Periprocedural Edoxaban in Patients Undergoing Catheter Ablation for Atrial Fibrillation — The Prospective KYU-RABLE Study —, Cir. J, 2019, 83, 2017–2024. [DOI] [PubMed] [Google Scholar]
  • 5.Rouf A and Tanyeli C, Bioactive thiazole and benzothiazole derivatives, Eur. J. Med. Chem, 2015, 97, 911–927. [DOI] [PubMed] [Google Scholar]
  • 6.Chhabria MT, Patel S, Modi P and Brahmkshatriya PS, Thiazole: A Review on Chemistry, Synthesis and Therapeutic Importance of its Derivatives, Curr. Top. Med. Chem, 2016, 16, 2841–2862. [DOI] [PubMed] [Google Scholar]
  • 7.Hu Y and MacMillan JB, Erythrazoles A–B, Cytotoxic Benzothiazoles from a Marine-Derived Erythrobacter sp, Org. Lett, 2011, 13, 6580–6583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Bode HB, Zeggel B, Silakowski B, Wenzel SC, Reichenbach H and Müller R, Steroid biosynthesis in prokaryotes: identification of myxobacterial steroids and cloning of the first bacterial 2,3(S)-oxidosqualene cyclase from the myxobacterium Stigmatella aurantiaca, Molecul Microbiol, 2003, 47, 471–481. [DOI] [PubMed] [Google Scholar]
  • 9.Desmond E and Gribaldo S, Phylogenomics of sterol synthesis: insights into the origin, evolution, and diversity of a key eukaryotic feature, Genome Biol. Evol, 2009, 1, 364–381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh M.-d., Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S and Lane HC, Remdesivir for the Treatment of Covid-19 — Preliminary Report, New Eng. J. Med, 2020, DOI: 10.1056/NEJMoa2007764. [DOI] [PubMed] [Google Scholar]
  • 11.Nicolaou KC, Rhoades D, Wang Y, Bai R, Hamel E, Aujay M, Sandoval J and Gavrilyuk J, 12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents, J. Am. Chem. Soc, 2017, 139, 7318–7334. [DOI] [PubMed] [Google Scholar]
  • 12.CDC, Cancer Stat Facts: Common Cancer Sites, https://seer.cancer.gov/statfacts/html/common.html, (accessed 2/29/2020, 2020).
  • 13.WHO, Cancer Fact Sheets, https://gco.iarc.fr/today/fact-sheets-cancers, (accessed 3/4/2020, 2020).
  • 14.NCI, Enhancing Drug Discovery and Development, https://www.cancer.gov/research/areas/treatment/enhancing-drug-discovery, (accessed 2/29/2020, 2020).
  • 15.WHO, New report calls for urgent action to avert antimicrobial resistance crisis, https://www.who.int/news-room/detail/29-04-2019-new-report-calls-for-urgent-action-to-avert-antimicrobial-resistance-crisis, (accessed 2/28/2020, 2020).
  • 16.CDC, Antibiotic / Antimicrobial Resistance (AR / AMR), https://www.cdc.gov/drugresistance/biggest-threats.html, (accessed 2/28/2020, 2020).
  • 17.Sheldrake PW, Matteucci M and McDonald E, Facile Generation of a Library of 5-Aryl-2-arylsulfonyl-1,3-thiazoles, Synlett, 2006, 2006, 0460–0462. [Google Scholar]
  • 18.Tang X, Yang J, Zhu Z, Zheng M, Wu W and Jiang H, Access to Thiazole via Copper-Catalyzed [3+1+1]-Type Condensation Reaction under Redox-Neutral Conditions, J. Org. Chem, 2016, 81, 11461–11466. [DOI] [PubMed] [Google Scholar]
  • 19.Wang X, Qiu X, Wei J, Liu J, Song S, Wang W and Jiao N, Cu-Catalyzed Aerobic Oxidative Sulfuration/Annulation Approach to Thiazoles via Multiple Csp(3)-H Bond Cleavage, Org. Lett, 2018, 20, 2632–2636. [DOI] [PubMed] [Google Scholar]
  • 20.Lingaraju GS, Swaroop TR, Vinayaka AC, Sharath Kumar KS, Sadashiva MP and Rangappa KS, An Easy Access to 4,5-Disubstituted Thiazoles via Base-Induced Click Reaction of Active Methylene Isocyanides with Methyl Dithiocarboxylates, Synthesis, 2012, 44, 1373–1379. [Google Scholar]
  • 21.Fu R-G, Wang Y, Xia F, Zhang H-L, Sun Y, Yang D-W, Wang Y-W and Yin P, Synthesis of 2-Amino-5-acylthiazoles by a Tertiary Amine-Promoted One-Pot Three-Component Cascade Cyclization Using Elemental Sulfur as a Sulfur Source, J. Org. Chem, 2019, 84, 12237–12245. [DOI] [PubMed] [Google Scholar]
  • 22.Zakeyah AA, Whitt J, Duke C, Gilmore DF, Meeker DG, Smeltzer MS and Alam MA, Synthesis and antimicrobial studies of hydrazone derivatives of 4-[3-(2,4-difluorophenyl)-4-formyl-1H-pyrazol-1-yl]benzoic acid and 4-[3-(3,4-difluorophenyl)-4-formyl-1H-pyrazol-1-yl]benzoic acid, Bioorg Med. Chem. Lett, 2018, 28, 2914–2919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Whitt J, Duke C, Sumlin A, Chambers SA, Alnufaie R, Gilmore D, Fite T, Basnakian AG and Alam MA, Synthesis of Hydrazone Derivatives of 4-[4-Formyl-3-(2-oxochromen-3-yl)pyrazol-1-yl]benzoic acid as Potent Growth Inhibitors of Antibiotic-resistant Staphylococcus aureus and Acinetobacter baumannii, Molecules, 2019, 24, 2051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Whitt J, Duke C, Ali MA, Chambers SA, Khan MMK, Gilmore D and Alam MA, Synthesis and Antimicrobial Studies of 4-[3-(3-Fluorophenyl)-4-formyl-1H-pyrazol-1-yl]benzoic Acid and 4-[3-(4-Fluorophenyl)-4-formyl-1H-pyrazol-1-yl]benzoic Acid as Potent Growth Inhibitors of Drug-Resistant Bacteria, ACS Omega, 2019, 4, 14284–14293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Ali MA, Okolo C, Alsharif ZA, Whitt J, Chambers SA, Varma RS and Alam MA, Benign Synthesis of Thiazolo-androstenone Derivatives as Potent Anticancer Agents, Org. Lett, 2018, 20, 5927–5932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Okolo C, Ali MA, Newman M, Chambers SA, Whitt J, Alsharif ZA, Day VW and Alam MA, Hexafluoroisopropanol-Mediated Domino Reaction for the Synthesis of Thiazolo-androstenones: Potent Anticancer Agents, ACS Omega, 2018, 3, 17991–18001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Alsharif ZA and Alam MA, Modular synthesis of thiazoline and thiazole derivatives by using a cascade protocol, RSC Advances, 2017, 7, 32647–32651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Alam MA, Alsharif Z, Alkhattabi H, Jones D, Delancey E, Gottsponer A and Yang T, Hexafluoroisopropyl alcohol mediated synthesis of 2,3-dihydro-4H-pyrido[1,2-a]pyrimidin-4-ones, Sci. Rep, 2016, 6, 36316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Alsharif Z, Ali MA, Alkhattabi H, Jones D, Delancey E, Ravikumar PC and Alam MA, Hexafluoroisopropanol mediated benign synthesis of 2H-pyrido[1,2-a]pyrimidin-2-ones by using a domino protocol, New J. Chem, 2017, 41, 14862–14870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Roleira FMF, Varela C, Amaral C, Costa SC, Correia-da-Silva G, Moraca F, Costa G, Alcaro S, Teixeira NAA and Tavares da Silva EJ, C-6α- vs C-7α-Substituted Steroidal Aromatase Inhibitors: Which Is Better? Synthesis, Biochemical Evaluation, Docking Studies, and Structure-Activity Relationships, J. Med. Chem, 2019, 62, 3636–3657. [DOI] [PubMed] [Google Scholar]
  • 31.Akagi S and Tsuda K, Steroid studies. XXIV. Bromo derivatives of cholestenone. 1, Chem. Pharm. Bull, 1961, 9, 464–469. [Google Scholar]
  • 32.Zhang N, Ayral-Kaloustian S, Niu C, Nguyen T, Upeslacis E, Mansour TS, Ragunathan S and Rosfjord E, 2-Aryl-4,5,6,7-tetrahydro-1,3-benzothiazol-7-ols as a class of antitumor agents selectively active in securin−/− cells, Bioorg. Med. Chem. Lett, 2010, 20, 3903–3905. [DOI] [PubMed] [Google Scholar]
  • 33.Liu P, Shen H, Shao X, Li Z and Xu X, Multipathways for the Synthesis of Fused Bicyclic 2-Aminothiazolyl Compounds Tuned by Ring Size, Synlett, 2014, 25, 2797–2801. [Google Scholar]
  • 34.Wu W, Sun Z, Wang X, Lu X and Dai D, Construction of Thiazole-Fused Dihydropyrans via Formal [4 + 2] Cycloaddition Reaction on DNA, Org. Letts, 2020, 22, 3239–3244. [DOI] [PubMed] [Google Scholar]
  • 35.Mishra S, Monir K, Mitra S and Hajra A, FeCl3/ZnI2-Catalyzed Synthesis of Benzo[d]imidazo[2,1-b]thiazole through Aerobic Oxidative Cyclization between 2-Aminobenzothiazole and Ketone, Org. Lett, 2014, 16, 6084–6087. [DOI] [PubMed] [Google Scholar]
  • 36.Liu X-W, Shi J-L, Wei J-B, Yang C, Yan J-X, Peng K, Dai L, Li C-G, Wang B-Q and Shi Z-J, Diversified syntheses of multifunctionalized thiazole derivatives via regioselective and programmed C–H activation, Chem Commun, 2015, 51, 4599–4602. [DOI] [PubMed] [Google Scholar]
  • 37.Welton T, Solvents and sustainable chemistry, Proc Math Phys Eng Sci, 2015, 471, 20150502–20150502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Alarcon-Manjarrez C, Arcos-Ramos R, Alamo MF and Iglesias-Arteaga MA, Synthesis, NMR and crystal characterization of dimeric terephthalates derived from epimeric 4,5-seco-cholest-3-yn-5-ols, Steroids, 2016, 109, 66–72. [DOI] [PubMed] [Google Scholar]
  • 39.Qi Y, Cheng X, Gong G, Yan T, Du Y, Wu B, Bi K and Jia Y, Synergistic neuroprotective effect of schisandrin and nootkatone on regulating inflammation, apoptosis and autophagy via the PI3K/AKT pathway, Food Funct., 2020, 11, 2427–2438. [DOI] [PubMed] [Google Scholar]
  • 40.Rodrigues Dantas L. Bezerra, Silva ALM, da Silva Júnior CP, Alcântara IS, Correia de Oliveira MR, Martins A. Oliveira Brito Pereira Bezerra, Ribeiro-Filho J, Coutinho HDM, Passos F. Rocha Santos, Quintans-Junior LJ, de Menezes I. R. Alencar, Pezzani R and Vitalini S, Nootkatone Inhibits Acute and Chronic Inflammatory Responses in Mice, Molecules, 2020, 25, 2181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Spitz IM, Progesterone antagonists and progesterone receptor modulators: an overview, Steroids, 2003, 68, 981–993. [DOI] [PubMed] [Google Scholar]
  • 42.Holbeck SL, Collins JM and Doroshow JH, Analysis of Food and Drug Administration-approved anticancer agents in the NCI60 panel of human tumor cell lines, Mol. Cancer Ther, 2010, 9, 1451–1460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Alarcón-Manjarrez C, Arcos-Ramos R, Álamo MF and Iglesias-Arteaga MA, Synthesis, NMR and crystal characterization of dimeric terephthalates derived from epimeric 4,5-seco-cholest-3-yn-5-ols, Steroids, 2016, 109, 66–72. [DOI] [PubMed] [Google Scholar]

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Supporting Information
NIHMS1682569-supplement-Supporting_Information.docx (11.6MB, docx)

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