Synthesis of structural analogues of GGT1-DU40, a potent GGTase-1 inhibitor

Muhammad Mansha, Nisar Ullah 1  and Khalid Alhooshani 1
  • 1 Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
  • 2 Centre of Research Excellence in Nanotechnology, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
Muhammad Mansha, Nisar Ullah and Khalid Alhooshani

Abstract

A series of new substituted pyrazoles 212 have been synthesized. The synthesized compounds are structural analogues of GGT1-DU40 1, a highly potent and selective inhibitor of protein geranylgeranyltransferase I (GGTase-I) both in vitro and in vivo. The implications of GGTase-I in oncogenesis have highlighted its potential as a cancer therapeutic target. Accordingly, the development of GGTase-I inhibitors has been a subject of much interest. The synthesis of 212 stemmed from the acetylation or acylation of N-function of amino acids to produce suitably modified amino acids. Meanwhile, the substituted pyrazole subunit originated from the reaction of ethyl nicotinate with γ-butyrolactone followed by condensation of the resultant β-keto lactone with (3,4-dichlorophenyl)hydrazine. The operations of O-alkylation and thioetherification on the resultant intermediate eventually produced the substituted pyrazole fragment. The amidation of the latter with amino acid derivatives finally rendered 212 in good to excellent yields.

1 Introduction

Protein prenylation by isoprenoid lipids plays an important role in biology [1, 2]. The majority of these prenylated proteins are termed “CaaX proteins”, which are defined by a specific C-terminal motif that directs the lipid modification. The CaaX (C = cysteine, aa = aliphatic amino acids, and X = any amino acid) prenyltranferases, enzymes that catalyze the prenylation of substrate proteins, include protein farnesyltransferase (FTase), which adds the 15-carbon farnesyl group, and protein geranylgeranyltransferase type I (GGTase-I), which transfers the 20-carbon geranylgeranyl through a thioether linkage to a C terminus cysteine residue near the carboxyl terminus of a target substrate protein. The prenylation state of a protein, farnesylated or geranylgeranylated, is dictated by the nature of the terminal X-specificity residue, i.e. the substrate protein is farnesylated when “X” is methionine or serine or geranylgeranylated where the carboxyl terminal residue “X” is leucine or phenylalanine [3–5]. In addition to attachment of the isoprenoid, Ras and most other CaaX proteins undergo two subsequent prenylation-dependent processing steps, proteolytic removal of the -aaX tripeptide by the CaaX protease Rce1 and carboxymethylation of the now C-terminal prenylcysteine residue by an enzyme termed Icmt [6, 7]. This three-step modification process creates a mature form of the CaaX protein with increased hydrophobicity, facilitating its interaction with membranes. In addition, the modified C terminus can also be viewed as a motif for specific protein-protein recognition events [7, 8].

Prenylated CaaX proteins, most notably Ras family members, play critical role in a wide variety of cellular processes and have been implicated in pathologies such as cancer, inflammation, and viral infectivity. Accordingly, efforts have been devoted to develop inhibitors of CaaX processing as a rational approach to therapeutic development [8, 9].

Early studies were mostly focused on the development of FTase inhibitors (FTIs), given FTase importance in Ras maturation and oncogenic activity. FTIs showed efficacy in preclinical studies of malignancies, including those without Ras mutations [10]. However, unfortunately, clinical trials of FTIs in humans have not been particularly successful [11]. In FTI-treated cells, K-RAS and N-RAS are alternately prenylated by GGTase-I and continue to support tumorigenesis [12]. Meanwhile, GGTase-I inhibitors (GGTIs) have shown promise as therapeutic targets [4, 13–17]. In addition, the rationale for inhibiting GGTase-I is also supported by genetic studies in mice with K-RAS-induced lung cancer [18].

In ongoing efforts toward the synthesis of molecules of medicinal value [19–22], we have synthesized a series of substituted pyrazoles 212, which are structural analogues of GGTI-DU40 (1), a highly potent and selective inhibitor of GGTase-I both in vitro and in vivo (Fig. 1) [23]. Herein, we disclose the synthesis of compounds 212.

Fig. 1:
Fig. 1:

Structural analogues of GGTI-DU40 (1).

Citation: Zeitschrift für Naturforschung B 71, 4; 10.1515/znb-2016-0019

2 Results and discussion

The synthesis of compounds 212 required the preparation of suitably modified amino acids derivatives. To this end, l-phenylglycine was transformed to the known N-acetyl-l-phenylalanine 13 [24] and N-(methylsulfonyl)-l-phenylalanine 14 [25]. Likewise, amino acids 1517 were first transformed to their corresponding methyl esters 1820 by the action of thionyl chloride in methanol. The N-acetylation or N-acylation of 1820 with acetyl chloride or methanesulfonyl chloride followed by basic hydrolysis with LiOH furnished the desired intermediates 2126 (Scheme 1). Although this route provided straightforward access to the intermediates 21 and 22 in a moderate overall yield of 64 and 61 %, respectively, the transformation of 19 and 20 to their corresponding 2326 was low yielding (36–41 %). In the latter case, the basic hydrolysis step resulted to fewer side products. In addition, the higher water affinity of 2326 made their extraction difficult from the aqueous workup.

Scheme 1:
Scheme 1:

Synthesis of amino acid derivatives 2126.

Citation: Zeitschrift für Naturforschung B 71, 4; 10.1515/znb-2016-0019

Consequently, a direct route for the preparation of intermediates 2126 was envisioned (Scheme 2). The acetylation of 15 with acetic anhydride in MeOH under reflux followed by evaporation of the solvent and aging the obtained residues overnight in a refrigerator rendered 21 in high yield (86 %). Under identical conditions, the acetylation of 16 and 17 produced the corresponding 23 (73 %) and 25 (75 %) in good yields. Similarly, the acylation of 15 with methanesulfonyl chloride in a mixture of dichloromethane and 1 m aq. NaOH furnished 22 in good yield (80 %). By adopting a similar strategy, amino acids 16 and 17 were also transformed to the corresponding desired intermediates 24 and 26 in high yields.

Scheme 2:
Scheme 2:

Alternative synthesis of amino acid derivatives 2126.

Citation: Zeitschrift für Naturforschung B 71, 4; 10.1515/znb-2016-0019

Likewise, amino ester 27 was transformed to the known N-acetyl-(4-methoxyphenyl)alanine 28 by the operations of N-acetylation of the amine function with acetic anhydride, O-alkylation of phenolic hydroxyl group with iodomethane, and then basic hydrolysis of ester moiety with LiOH [26]. In addition, the N-Boc-protected analogue 29 was produced from 27 by N-acylation with di-tert-butyl dicarbonate followed by O-alkylation of the hydroxyl group with iodomethane and finally basic hydrolysis of the ester group [27]. Meanwhile, N-acylation of 27 with methanesulfonyl chloride in dichloromethane followed by O-alkylation of the phenolic hydroxyl moiety with iodomethane furnished intermediate 31 in a high yield (83 % for two steps). The basic hydrolysis of 31 with LiOH in a mixture of water, methanol, and THF finally produced the desired 32 in 68 % overall yield from 27 (Scheme 3).

Scheme 3:
Scheme 3:

Synthesis of amino acid derivatives 28, 29, and 32.

Citation: Zeitschrift für Naturforschung B 71, 4; 10.1515/znb-2016-0019

With suitably modified amino acids on hand, we next moved to access the synthesis of key intermediate 40 (Scheme 4). To this end, ethyl nicotinate 33 was treated with γ-butyrolactone in ethanol using sodium ethoxide as a base to produce the known α-ketobutyrolactone 34 [28], which in turn was heated with 3,4-dichlorophenylhydrazine hydrochloride in acetic acid to construct pyrazole 35 [29]. The O-alkylation of intermediate 35 with tert-butyl (3-bromopropyl)carbamate in DMF at room temperature, using K2CO3 as a base, gave the desired 36 in moderate yield (59 %). It is pertinent to mention that heating the reaction mixture at varied temperature ranging from 40 to 80 °C for different time periods resulted in sluggish reaction, leading to fewer side products. Base-induced removal of acetyl protection of 36 yielded alcohol 37, which was subjected to acylation with methanesulfonyl chloride in dichloromethane to generate mesylate 38 in 83 % yield from 36. Treatment of intermediate 38 with sodium methanethiolate in DMF furnished the thioether 39 in good yield (78 %), which was further transformed to the desired primary amine 40 by the action of acetyl chloride in MeOH (Scheme 4). Finally, to furnish the synthesis of final compounds 212, the advanced intermediate 40 was coupled with intermediates 13, 14, 2126, 28, 29, and 32, using N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and N-hydroxybenzotriazole as coupling agents to accomplish the synthesis of 212 in moderate to good yields (57–69 %) (Scheme 4). It is pertinent to mention that synthesis of 1 could also be realized from the O-alkylation of pyrazole 35 with ethyl 4-bromobutyrate followed by steps of basic hydrolysis and coupling of the resultant carboxylic acid with appropriate amino acid derivative. However, to the best of our knowledge, procedures for the synthesis of 1 are not known in the literature [30, 31].

Scheme 4:
Scheme 4:

Synthesis of compounds 212.

Citation: Zeitschrift für Naturforschung B 71, 4; 10.1515/znb-2016-0019

3 Conclusion

We synthesized a series of substituted pyrazoles 212, structural analogues of GGTI-DU40, in good to excellent yields.

4 Experimental section

4.1 (S)-2-acetamido-3-(4-fluorophenyl)propanoic acid (21)

To a solution of compound 15 (1.00 g, 5.46 mmol) in MeOH (7 mL) was added acetic anhydride (1.40 mL, 14.75 mmol), and the mixture was refluxed for 6 h. The reaction was cooled to room temperature, and all the volatiles were removed at reduced pressure. The residue was kept in a refrigerator overnight and then warmed up to the room temperature to allow the recrystallization of the title compound as a colorless crystalline solid (yield 86 %). M.p. 139–140 °C. – IR (neat): ν = 3367, 3025, 2953, 1720, 1625, 1581, 1451, 1360, 1028 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.89 (s, 3 H, COCH3), 2.92 (dd, J = 9.1, 14.0 Hz, 1 H, CH2CH), 3.16 (dd, J = 5.5, 14.1 Hz, 1 H, CH2CH), 4.61 (m, 1 H, CH2CH), 6.98 (t, J = 8.5 Hz, 2 H, 3′-H, 5′-H), 7.22 (m, 2 H, 2′-H, 6′-H), 8.09 (d, J = 6.2 Hz, 1 H, NH) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 22.27 (COCH3), 37.63 (CH2CH), 55.10 (CH2CH), 115.99 (d, J = 21.8 Hz, C-3′, C-5′), 131.95 (d, J = 8.3 Hz, C-2′, C-6′), 134.45 (C-1′), 162.60 (d, J = 247 Hz, C-4′), 173.10 (C=O), 174.54 (C=O) ppm. – C11H12FNO3 (225.22): calcd. C 58.66, H 5.37, N 6.22; found C 58.61, H 5.41, N 6.14.

4.2 (S)-3-(4-fluorophenyl)-2-(methylsulfonamido)propanoic acid (22)

To a cold solution of compound 15 (0.50 g, 2.73 mmol) in 1 m aq. NaOH (10 mL) at 0 °C was added CH2Cl2 (2 mL) followed by the dropwise addition of methanesulfonyl chloride (0.25 mL, 3.28 mmol). The reaction mixture was stirred for 3 h at 0 °C, transferred into a separatory funnel, and washed with diethyl ether (10 mL). The aqueous layer was acidified to pH 3 with 1 n aq. HCl and extracted with EtOAc (2 × 10 mL). The organic layer was dried over Na2SO4 and evaporated to get compound 22 as a colorless gummy solid (yield 80 %). – IR (neat): ν = 3538, 3034, 2930, 1733, 1605, 1512, 1412, 1225 cm−1. – 1H NMR (500 MHz, CD3OD): δ = 2.70 (s, 3 H, SO2CH3), 2.91 (dd, J = 8.5, 13.7 Hz, 1 H, CH2CH), 3.13 (dd, J = 5.2, 13.7 Hz, 1 H, CH2CH), 4.20 (m, 1 H, CH2CH), 7.01 (m, 2 H, 3′-H, 5′-H), 7.28 (m, 2 H, 2′-H, 6′-H) ppm. – 13C NMR (125.7 MHz, CD3OD): δ = 39.11 (SO2CH3), 41.28 (CH2CH), 58.90 (CH2CH), 116.03 (d, J = 21.8 Hz, C-3′, C-5′), 132.40 (d, J = 8.3 Hz, C-2′, C-6′), 134.27 (C-1′), 162.56 (d, J = 247 Hz, C-4′), 174.59 (C=O) ppm. – C10H12FNO4S (261.27): calcd. C 45.97, H 4.63, N 5.36; found C 45.92, H 4.67, N 5.30.

4.3 (S)-2-acetamido-3-(pyridin-3-yl)propanoic acid (23)

Following the same procedure adopted for the synthesis of 21, acetylation of compound 16 gave compound 23 as a colorless sticky solid (yield 73 %). – IR (neat): ν = 3428, 3050, 2946, 1732, 1668, 1606, 1512, 1370, 1226, 1060 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.82 (s, 3 H, COCH3), 2.90 (dd, J = 8.5, 14.0 Hz, 1 H, CH2CH), 3.17 (dd, J = 5.2, 14.0 Hz, 1 H, CH2CH), 4.54 (m, 1 H, CH2CH), 7.29 (m, 1 H, 5′-H), 7.67 (m, 1 H, 6′-H), 8.30 (m, 1 H, 4′-H), 8.41 (d, J = 1.1 Hz, 1 H, 2′-H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 22.39 (COCH3), 35.91 (CH2CH), 55.34 (CH2CH), 125.10 (C-5′), 135.67 (C-6′), 139.26 (C-1′), 148.12 (C-4′), 150.68 (C-2′), 172.92 (C=O) ppm. – C10H12N2O3 (208.21): calcd. C 57.68, H 5.81, N 13.45; found C 57.62, H 5.86, N 13.38.

4.4 (S)-2-(methylsulfonamido)-3-(pyridin-3-yl)propanoic acid (24)

Following the same procedure adopted for the synthesis of 22, acylation of 16 produced compound 24 as a light yellow gum (yield 82 %). – IR (neat): ν = 3475, 3427, 3062, 2955, 1750, 1582, 1435, 1322, 1150 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 2.69 (s, 3 H, SO2CH3), 2.85 (dd, J = 7.3, 13.7 Hz, 1 H, CH2CH), 3.05 (dd, J = 5.2, 13.7 Hz, 1 H, CH2CH), 3.46 (m, 1 H, CH2CH), 7.34 (m, 1 H, 5′-H), 7.76 (m, 1 H, 6′-H), 8.36 (m, 1 H, 4′-H), 8.43 (d, J = 1.3 Hz, 1 H, 2′-H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 39.42 (SO2CH3), 39.75 (CH2CH), 58.71 (CH2CH), 125.04 (C-5′), 136.77 (C-6′), 139.26 (C-1′), 147.86 (C-4′), 150.89 (C-2′), 181.15 (C=O) ppm. – C9H12N2O4S (244.27): calcd. C 44.25, H 4.95, N 11.47; found C 44.20, H 4.99, N 11.40.

4.5 (S)-2-acetamido-3-(pyridin-4-yl)propanoic acid (25)

Following the same procedure adopted for the synthesis of 21, acetylation of 17 gave compound 25 as a brown gum (yield 75 %). – IR (neat): ν = 3441, 3054, 2926, 1738, 1664, 1609, 1508, 1378, 1223, 1066 cm−1. – 1H NMR (500 MHz, CD3OD): δ = 1.85 (s, 3 H, COCH3), 3.01 (dd, J = 8.8, 13.7 Hz, 1 H, CH2CH), 3.26 (dd, J = 5.5, 13.7 Hz, 1 H, CH2CH), 4.72 (m, 1 H, CH2CH), 7.35 (d, J = 6.1 Hz, 2 H, 2′-H, 6′-H), 8.44 (d, J = 6.1 Hz, 2 H, 3′-H, 5′-H) ppm. – 13C NMR (125.7 MHz, CD3OD): δ = 22.29 (COCH3), 37.92 (CH2CH), 54.21 (CH2CH), 126.50 (C-2′, C-6′), 149.38 (C-1′), 150.29 (C-3′, C-5′), 173.11 (C=O), 175.27 (C=O) ppm. – C10H12N2O3 (208.21): calcd. C 57.68, H 5.81, N 13.45; found C 57.63, H 5.86, N 13.39.

4.6 (S)-2-(methylsulfonamido)-3-(pyridin-4-yl)propanoic acid (26)

Following the same procedure adopted for the synthesis of 22, acylation of 17 rendered compound 26 as a light yellow gum (yield, 85 %). – IR (neat): ν = 3500, 3073, 2923, 1702, 1607, 1393, 1297, 1153 cm−1. – 1H NMR (500 MHz, CD3OD): δ = 2.85 (s, 3 H, SO2CH3), 2.98 (dd, J = 8.2, 13.7 Hz, 1 H, CH2CH), 3.15 (dd, J = 5.2, 13.7 Hz, 1 H, CH2CH), 4.02 (m, 1 H, CH2CH), 7.36 (d, J = 6.8 Hz, 2 H, 2′-H, 6′-H), 8.43 (d, J = 6.8 Hz, 2 H, 3′-H, 5′-H) ppm. – 13C NMR (125.7 MHz, CD3OD): δ = 37.35 (CH2CH), 40.29 (SO2CH3), 60.32 (CH2CH), 126.96 (C-2′, C-6′), 149.47 (C-1′), 150.49 (C-3′, C-5′), 176.85 (C=O) ppm. – C9H12N2O4S (244.27): calcd. C 44.25, H 4.95, N 11.47; found C 44.19, H 5.00, N 11.41.

4.7 (S)-methyl 3-(4-hydroxyphenyl)-2-(methylsulfonamido)propanoate (30)

To a cold suspension of compound 27 (0.50 g, 2.16 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.20 mL, 8.6 mmol) followed by the dropwise addition of a solution of methanesulfonyl chloride (0.25 mL, 3.24 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred overnight at room temperature and quenched with water (10 mL) followed by the addition of dilute hydrochloric acid to adjust pH 4–5. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to get the title compound 30 as a white solid (yield 90 %). M.p. 102–103 °C. – IR (neat): ν = 3310, 3022, 2941, 1738, 1506, 1451, 1367, 973 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 2.76 (s, 3 H, SO2CH3), 3.06 (dd, J = 7.0, 14.0 Hz, 1 H, CH2CH), 3.18 (dd, J = 5.5, 14.0 Hz, 1 H, CH2CH), 3.79 (s, 3 H, OCH3), 4.41 (m, 1 H, CH2CH), 4.93 (d, J = 9.15 Hz, 1 H, NH), 6.70 (d, J = 8.5 Hz, 2 H, 3′-H, 5′-H), 6.96 (d, J = 8.5 Hz, 2 H, 2′-H, 6′-H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 38.80 (SO2CH3), 41.31 (CH2CH), 52.95 (OCH3), 56.84 (CH2CH), 122.37 (C-3′, C-5′), 131.14 (C-1′), 134.80 (C-2′, C-6′), 148.40 (C-4′), 171.53 (C=O) ppm. – C11H15NO5S (271.31): calcd. C 48.34, H 5.53, N 5.12; found C 48.28, H 5.47, N 5.05.

4.8 (S)-methyl 3-(4-methoxyphenyl)-2-(methylsulfonamido)propanoate (31)

To a solution of compound 30 (0.70 g, 2.56 mmol) in DMF (15 mL) was added NaHCO3 (0.43 g, 5.12 mmol) at room temperature, and after the mixture was stirred for 10 min, CH3I (0.32 mL, 5.12 mmol) was added. The reaction mixture was stirred overnight at room temperature followed by the addition of H2O (10 mL) and 1 m aq. HCl (10 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to obtain the title compound 31 as a colorless thick gum (yield 92 %). – IR (neat): ν = 3033, 2971, 2936, 1738, 1660, 1506, 1362, 1146 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 2.72 (s, 3 H, SO2CH3), 3.00 (dd, J = 7.3, 13.9 Hz, 1 H, CH2CH), 3.10 (dd, J = 5.8, 13.9 Hz, 1 H, CH2CH), 3.78 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 4.37 (m, 1 H, CH2CH), 6.85 (d, J = 8.5 Hz, 2 H, 3′-H, 5′-H), 7.10 (d, J = 8.5 Hz, 2 H, 2′-H, 6′-H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 38.57 (SO2CH3), 41.35 (CH2CH), 52.72 (OCH3), 55.23 (OCH3), 57.15 (CH2CH), 114.17 (C-3′, C-5′), 127.09 (C-1′), 130.49 (C-2′, C-6′), 158.94 (C-4′), 171.9 (C=O) ppm. – C12H17NO5S (287.33): calcd. C 50.16, H 5.96, N 4.87; found C 50.12, H 6.03, N 4.81.

4.9 (S)-3-(4-methoxyphenyl)-2-(methylsulfonamido)propanoic acid (32)

To a solution of 31 (0.86 g, 3 mmol) in a mixture of THF-MeOH-H2O (6:2:1, 15 mL) was added LiOH·H2O (0.38 g, 9 mmol), and the mixture was stirred overnight at room temperature followed by the addition of 1 m aq. HCl to adjust the pH of the reaction to 6. The mixture was extracted with EtOAc (20 mL), and the organic layer was washed with brine, dried over Na2SO4, and evaporated. Column chromatography on silica gel, eluting with ethyl acetate-hexane (1:1) and then changing to (2:1), gave the title compound 32 as a thick brown gum (yield 86 %). – IR (neat): ν = 3541, 3281, 3025, 2936, 1735, 1609, 1513, 1307, 1149 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 12.67 (s, 3 H, SO2CH3), 2.96 (dd, J = 7.6, 14.0 Hz, 1 H, CH2), 3.16 (dd, J = 4.5, 14.0 Hz, 1 H, CH2), 3.78 (s, 3 H, OCH3), 4.35 (m, 1 H, CH), 5.10 (br. s, 1 H, NH), 6.86 (d, J = 8.5 Hz, 2 H, aromatic H), 7.16 (d, J = 8.5 Hz, 2 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 38.07 (SO2CH3), 41.23 (CH2CH), 55.28 (OCH3), 57.48 (CH2CH), 114.18, 127.74, 130.66, 158.85 (Carom), 175.10 (C=O) ppm. – C11H15NO5S (273.31): calcd. C 48.34, H 5.53, N 5.12; found C 48.29, H 5.59, N 5.05.

4.10 2-(5-(3-((tert-Butoxycarbonyl)amino)propoxy)-1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)-1H-pyrazol-4-yl)ethyl acetate (36)

To a solution of 35 (2.00 g, 5.11 mmol) in DMF (20 mL) was sequentially added K2CO3 (0.92 g, 6.66 mmol) followed by tert-butyl-(3-bromoropropyl)carbamate (1.45 g, 6.12 mmol), and the mixture was further stirred for 8 h at room temperature. The reaction was diluted with H2O (15 mL) and extracted with EtOAc (50 mL). The organic layer was washed with H2O (10 mL), brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. Column chromatography of the dark orange oily material, eluting with EtOAc-hexane (3:1), yielded compound 36 as a light yellow oil (yield 59 %). – IR (neat): ν = 3361, 3040, 2973, 1740, 1710, 1675, 1592, 1481, 1386, 1234, 1029 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.44 (s, J = 6.4 Hz, 9 H, OC(CH3)3), 1.96 (s, 3 H, COCH3), 2.27 (pent, 2 H, CH2CH2CH2), 2.98 (t, J = 7.3 Hz, 2 H, ArCH2), 3.29 (m, 2 H, NCH2), 4.04 (t, J = 6.1 Hz, 2 H, OCH2), 4.22 (t, J = 7.0 Hz, 2 H, OCH2), 7.39 (dd, J = 4.85, 7.9 Hz, 1 H, aromatic H), 7.66 (dd, J = 2.4, 8.5 Hz, 1 H, aromatic H), 7.94 (d, J = 2.4 Hz, 1 H, aromatic H), 8.00–8.03 (m, 2 H, aromatic H), 8.64 (dd, J = 2.1, 6.5 Hz, 1 H, aromatic H), 8.93 (d, J =1.8 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 20.84 (COCH3), 21.25 (Ar-CH2), 28.38 (OC(CH3)3), 30.30 (CH2CH2CH2), 36.50 (NCH2), 65.39 (OCH2), 73.34 (OCH2), 79.44 (OC(CH3)3), 103.27, 120.47, 123.62, 123.70, 129.58, 130.86, 133.23, 135.12, 137.62, 148.19, 148.46, 149.10, 152.06 (all Carom), 155.97 (C=O), 170.97 (C=O) ppm. – C26H30Cl2N4O5 (549.45): calcd. C 56.84, H 5.50, N 10.20; found C 56.78, H 5.55, N 10.14.

4.11 tert-Butyl (3-((1-(3,4-dichlorophenyl)-4-(2-hydroxyethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-oxy)propyl)carbamate (37)

To a cold solution of compound 36 (0.83 g, 1.64 mmol) in a mixture of THF (10 mL) and MeOH (5 mL) at 0 °C was added a solution of KOH (0.34 g, 6.06 mmol) in H2O (5 mL). After being stirred for 15 min at 0 °C, the reaction was further stirred for 45 min at room temperature. Upon completion of the reaction (TLC), the mixture was concentrated under reduced pressure and diluted with EtOAc (30 mL) and successively washed with H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and evaporated to dryness under reduced pressure. Column chromatography of the light orange oil material, eluting with EtOAc-hexane (6:4), gave the title compound 37 as a light yellow gum (yield 85 %). – IR (neat): ν = 3345, 3055, 2974, 1691, 1593, 1482, 1366, 1169 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.44 (s, 9 H, OC(CH3)3), 1.91 (pent, 2 H, CH2CH2CH2), 2.86 (t, J = 6.7 Hz, 2 H, Ar-CH2), 3.36 (m, 2 H, NCH2), 3.77 (t, J = 5.8 Hz, 2 H, OCH2), 4.02 (t, J = 5.8 Hz, 2 H, OCH2), 4.81 (br. s, 1 H, NH/OH), 7.36 (dd, J = 4.8, 7.9 Hz, 1 H, aromatic H), 7.54 (d, J = 8.5 Hz, 1 H, aromatic H), 7.67 (dd, J = 2.4, 8.5 Hz, 1 H, aromatic H), 7.96 (d, J = 2.4 Hz, 1 H, aromatic H), 8.00 (dd, J = 5.8, 7.9 Hz, 1 H, aromatic H), 8.61 (dd, J = 1.5, 4.9 Hz, 1 H, aromatic H), 8.91 (d, J = 2.1 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 23.30 (Ar-CH2), 28.36 (OC(CH3)3), 30.28 (CH2CH2CH2), 37.25 (NCH2), 63.37 (OCH2), 73.30 (OCH2), 79.44 (OC(CH3)3), 102.68, 120.94, 123.54, 123.68, 129.46, 130.83, 133.21, 134.98, 137.58, 148.26, 148.59, 149.35, 152.26 (all Carom), 155.97 (C=O) ppm. – C24H28Cl2N4O4 (507.41): calcd. C 56.81, H 5.56, N 11.04; found C 56.76, H 5.50, N 11.97.

4.12 2-(5-(3-((tert-Butoxycarbonyl)amino)propoxy)-1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)-1H-pyrazol-4-yl)ethyl methanesulfonate (38)

To an ice-cold solution of compound 37 (0.41 g, 0.81 mmol) in anhydrous CH2Cl2 (10 mL) was added Et3N (0.34 mL, 2.44 mmol), and after being stirred for 15 min, methanesulfonyl chloride (0.094 mL, 1.212 mmol) was added to the mixture. The stirring was continued for 1 h at 0 °C, and the mixture then diluted with H2O (5 mL) followed by the addition of 1 m aq. HCl (5 mL). The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain the target compound 38 as a crystalline white solid (yield 98 %). M.p. 94–95 °C. – IR (neat): ν = 3356, 3038, 3015, 2986, 1682, 1590, 1483, 1384, 1172 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.44 (s, 9 H, OC(CH3)3), 1.93 (pent, 2 H, CH2CH2CH2), 3.00 (s, 3 H, SO2CH3), 3.14 (t, J = 6.4 Hz, 2 H, Ar-CH2), 3.29 (m, 2 H, NCH2), 4.02 (t, J = 6.1 Hz, 2 H, OCH2), 4.37 (t, J = 6.7 Hz, 2 H, OCH2), 4.72 (br. s, 1 H, NH), 7.59 (d, J = 8.5 Hz, 1 H, aromatic H), 7.65 (dd, J = 2.4, 8.8 Hz, 1 H, aromatic H), 7.86 (m, 1 H, aromatic H), 7.92 (d, J = 2.4 Hz 1 H, aromatic H), 8.63 (m, 1 H, aromatic H), 8.70 (d, J = 5.2 Hz, 1 H, aromatic H), 9.09 (d, J = 1.2 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 23.32 (Ar-CH2), 28.38 (OC(CH3)3), 30.46 (CH2CH2CH2), 37.70 (SCH3), 38.35 (NCH2), 68.43 (OCH2), 73.78 (OCH2), 79.59 (OC(CH3)3), 102.56, 121.15, 123.91, 126.23, 131.10, 131.89, 132.99, 133.52, 137.00, 141.11, 141.26, 141.55, 144.57, 152.92 (all Carom), 156.03 (C=O) ppm.

4.13 tert-Butyl (3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)carbamate (39)

To a solution of compound 38 (1.25 g, 2.14 mmol) in DMF (15 mL) at 0 °C was added NaSCH3 (0.6 g, 8.57 mmol), and the mixture was stirred for 2 h at room temperature. The reaction was diluted with EtOAc (30 mL) and washed with H2O (10 mL) and brine (10 mL × 2). The light yellow residue was resolved over column chromatography, eluting with EtOAc-hexane (6:4), to produce the title compound 39 as a light brown gum (yield 78 %). – IR (neat): ν = 3402, 3092, 2975, 1696, 1590, 1483, 1386, 1171 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.43 (s, 9 H, OC(CH3)3), 1.95 (pent, 2 H, CH2CH2CH2), 2.10 (s, 3 H, SCH3), 2.71 (t, J = 7.3 Hz, 2 H, SCH2), 2.95 (t, J = 7.3 Hz, 2 H, Ar-CH2), 3.28 (m, 2 H, NCH2), 4.04 (t, J = 6.1 Hz, 2 H, OCH2), 7.59 (d, J = 8.8 Hz, 1 H, aromatic H), 7.65 (dd, J = 2.4, 8.8 Hz, 1 H, aromatic H), 7.89 (m, 1 H, aromatic H), 7.93 (d, J = 2.4 Hz, 1 H, aromatic H), 8.65 (d, J = 7.9 Hz, 1 H, aromatic H), 8.71 (d, J = 4.6 Hz, 1 H, aromatic H), 9.12 (d, J = 2.4 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.90 (SCH3), 23.21 (Ar-CH2), 28.44 (OC(CH3)3), 30.96 (CH2CH2CH2), 34.15 (SCH2), 36.97 ((CH2CH)), 38.49 (NCH2), 73.54 (OCH2), 79.33 (OC(CH3)3), 104.85, 120.89, 123.67, 125.66, 131.06, 131.61, 133.50, 137.17, 139.68, 142.50, 143.50, 144.82, 152.60 (all Carom), 156.20 (C=O) ppm. – C25H30Cl2N4O3S (537.50): calcd. C 55.86, H 5.63, N 10.42; found C 55.80, H 5.68, N 10.36.

4.14 3-((1-(3,4-Dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)-propan-1-amine hydrochloride (40)

To a solution of compound 39 (0.37 g, 0.69 mmol) in anhydrous CH3OH (10 mL) at 0 °C was added acetyl chloride (1 mL), and the reaction mixture was stirred overnight at room temperature. The volatiles were evaporated under reduced pressure and then triturated with diethyl ether to get a compound 40 as a hygroscopic light yellow solid (yield 98 %). – IR (neat): ν = 3419, 2962, 1624, 1586, 1481, 1140 cm−1. – 1H NMR (500 MHz, CD3OD): δ = 1.98 (s, 3 H, SCH3), 2.00 (m, 2 H, CH2CH2CH2), 2.64 (t, J = 7.3 Hz 2 H, SCH2), 2.95–3.00 (m, 4H, Ar-CH2, NCH2), 4.09 (t, J = 6.15 Hz, 2 H, OCH2), 7.65 (m, 2 H, aromatic H), 7.90 (d, J = 2.2 Hz, 1 H, aromatic H), 8.07 (m, 1 H, aromatic H), 8.77 (d, J = 5.8 Hz, 1 H, aromatic H), 8.85 (d, J = 8.2 Hz, 1 H, aromatic H), 9.12 (d, J = 2.4 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CD3OD): δ = 15.66 (SCH3), 23.65 (Ar-CH2), 29.02 (CH2CH2CH2), 35.05 (SCH2), 38.01 (NCH2), 74.02 (OCH2), 108.02, 123.38, 125.60, 128.63, 131.18, 132.50, 132.78, 137.10, 141.73, 142.43, 145.02, 153.56, 156.13 (Carom) ppm. – C20H23Cl3N4OS (473.85): calcd. C 50.69, H 4.89, N 11.82; found C 50.63, H 4.95, N 11.74.

4.15 (S)-2-acetamido-N-(3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-3-phenylpropanamide (2)

To a solution of mixture of compounds 40 (0.15 g, 0.32 mmol) and 13 (0.068 g, 0.33 mmol) in CH2Cl2 (10 mL) was sequentially added hydroxybenzotriazole (0.050 g, 0.33 mmol), N-(3-dimethylaminopropyl)- N′-ethylcarbodiimide hydrochloride (0.084 g, 0.44 mmol) and Et3N (0.15 mL, 1.1 mmol), and the mixture was stirred overnight at room temperature. The reaction was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. Column chromatography purifications of light yellow oily material, eluting with EtOAc-hexane (8:2), gave the product as a light green solid (yield 69 %). M.p. 125–126 °C. – [α]D20 = –3.1 (c = 0.005, EtOH). – IR (neat): ν = 3255, 3072, 2952, 1670, 1639, 1592, 1563, 1480.7, 1368, 1139, 1082 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.83 (pent, 2 H, CH2CH2CH2), 1.97 (s, 3 H, COCH3), 2.08 (s, 3 H, SCH3), 2.67 (t, J = 7.1 Hz, 2 H, SCH2), 2.91 (t, J = 7.9 Hz, 2 H, ArCH2), 3.10 (dd, J = 8.2, 13.7 Hz, 1 H, CH2CH), 3.11 (dd, J = 5.8, 13.7 Hz, 1 H, CH2CH), 3.31 (m, 2 H, NCH2), 3.87 (t, J = 6.2 Hz, 2 H, OCH2), 4.58 (m, 1 H, CH2CH), 6.23–6.29 (br. s, 2 H, 2NH), 7.18–7.22 (m, 2 H, aromatic H), 7.25–7.29 (m, 3 H, aromatic H), 7.57 (d, J = 8.8 Hz, 1 H, aromatic H), 7.63 (dd, J = 2.4, 8.8 Hz, 1 H, aromatic H), 7.76 (m, 1 H, aromatic H), 7.90 (d, J = 2.4 Hz, 1 H, aromatic H), 8.49 (d, J = 8.0 Hz, 1 H, aromatic H), 8.73 (d, J = 6.5 Hz, 1 H, aromatic H), 9.10 (s, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.89 (SCH3), 23.05 (COCH3), 23.21 (Ar-CH2), 30.93 (CH2CH2CH2), 34.19 (SCH2), 36.15 (CH2CH), 38.38 (NCH2), 54.46 (CH2CH), 73.21 (OCH2), 106.19, 121.06, 123.72, 127.06, 128.68, 129.21, 129.42, 131.00, 131.33, 133.32, 136.62, 137.31, 152.12 (all Carom), 170.10 (C=O), 171.10 (C=O) ppm. – C31H33Cl2N5O3S (626.60): calcd. C 59.42, H 5.31, N 11.18; found C 59.36, H 5.37, N 11.10.

4.16 (S)-N-(3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-2-(methylsulfonamido)-3-phenylpropanamide (3)

Following the procedure adopted for the synthesis of 2, the reaction of 40 with 14 gave the title compound 3 as a colorless solid (yield 57 %). M.p. 130–131 °C. – [α]D20 = –38.4 (c = 0.003, EtOH). – IR (neat): ν = 3376, 3280, 3062, 2920, 1664. 1592, 1566, 1482, 1457, 1317, 1149 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.95 (pent, 2 H, CH2CH2CH2), 2.08 (s, 3 H, SCH3), 2.54 (s, 3 H, SO2CH3), 2.70 (t, J = 6.7 Hz, 2 H, SCH2), 2.89 (dd, J = 7.2, 13.7 Hz, 1 H, CH2CH), 2.97 (t, J = 7.6 Hz, 2 H, ArCH2), 3.31 (m, 2 H, NCH2), 3.41 (dd, J = 5.6, 13.7 Hz, 1 H, CH2CH), 4.03 (t, J = 6.4 Hz, 2 H, OCH2), 4.08 (m, 1 H, CH2CH), 5.73 (br. s, 1 H, NH), 7.20–7.24 (m, 2 H, aromatic H), 7.25–7.30 (m, 3 H, aromatic H), 7.57 (d, J = 8.8 Hz, 1 H, aromatic H), 7.66 (dd, J = 2.4, 8.8 Hz, 1 H, aromatic H), 7.90 (m, 1 H, aromatic H), 7.95 (m, 1 H, aromatic H), 8.49 (d, J = 7.6 Hz, 1 H, aromatic H), 8.76 (d, J = 6.5 Hz, 1 H, aromatic H), 9.10 (s, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.66 (SCH3), 23.17 (Ar-CH2), 29.54 (CH2CH2CH2), 33.98 (SCH2), 36.45 (CH2CH), 38.66 (NCH2), 40.03 (SO2CH3), 59.12 (CH2CH), 72.97 (OCH2), 106.76, 121.03, 123.57, 123.69, 127.63, 129.13, 129.39, 129.62, 130.74, 130.89, 133.14, 134.92, 136.38, 137.66, 147.88, 148.52, 149.34, 151.73 (all Carom), 170.46 (C=O) ppm. – C30H33Cl2N5O4S2 (662.65): calcd. C 54.38, H 5.02, N 10.57; found C 54.33, H 5.07, N 10.50.

4.17 (S)-2-acetamido-N-(3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-3-(4-fluorophenyl)propanamide (4)

Following the procedure adopted for the synthesis of 2, the reaction of 40 with 21 gave the title compound 4 as a colorless solid (yield 67 %). M.p. 117–118 °C. – [α]D20 = –5.6 (c = 0.005, EtOH). – IR (neat): ν = 3505, 3272, 3066, 2921, 1892, 1654, 1593.3, 1509, 1482, 1368, 1220, 1132 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 2.06 (s, 3 H, SCH3), 2.08 (s, 3 H, COCH3), 2.17 (pent, 2 H, CH2CH2CH2), 2.70 (t, J = 7.2 Hz, 2 H, SCH2), 2.89–2.95 (m, 4 H, ArCH2, CH2CH), 3.32 (t, J = 6.2 Hz, 2 H, NCH2), 3.96 (t, J = 7.1 Hz, 2 H, OCH2), 4.70 (m, 1 H, CH2CH), 6.94 (m, 2 H, aromatic H), 7.20 (m, 2 H, aromatic H), 7.58 (d, J = 8.2 Hz, 1 H, aromatic H), 7.64 (d, J = 8.2 Hz, 1 H, aromatic H), 7.90 (m, 1 H, aromatic H), 7.99 (d, J = 2.6 Hz, 1 H, aromatic H), 8.74–8.79 (m, 2 H, aromatic H), 89.24 (d, J = 2.1 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.69 (SCH3), 23.17 (COCH3, Ar-CH2), 29.67 (CH2CH2CH2), 34.04 (SCH2), 36.31 (CH2CH), 37.57 (NCH2), 54.79 (CH2CH), 72.98 (OCH2) 105.72, 115.51 (d, J = 20.8 Hz), 120.98, 123.63, 129.63, 130.76, 130.89, 132.24, 133.17, 135.00, 137.63, 147.89, 148.45, 149.31, 151.73, 161.91 (d, J = 245.9 Hz) (all Carom), 170.08 (C=O), 170.92 (C=O) ppm. – C31H32Cl2FN5O3S (644.59): calcd. C 57.76, H 5.00, N 10.86; found C 57.70, H 5.06, N 10.80.

4.18 (S)-N-(3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-3-(4-fluorophenyl)-2-(methylsulfonamido)propanamide (5)

Following the procedure adopted for the synthesis of 2, the reaction of 40 with 22 gave the title compound 5 as a white crystaline solid (yield 60 %). M.p. 126–127 °C. – [α]D20 = –18.0 (c = 0.005, EtOH). – IR (neat): ν = 3663, 3282, 3066, 2921, 1664, 1593, 1511, 1482, 1319, 1223, 1150 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.92 (pent, 2 H, CH2CH2CH2), 2.08 (s, 3 H, SCH3), 2.54 (s, 3 H, SO2CH3), 2.64 (t, J = 7.3 Hz, 2 H, SCH2), 2.89–2.93 (m, 3 H, ArCH2, CH2CH), 3.20 (dd, J = 5.1, 12.2 Hz, 1 H, -CH2CH-), 3.44 (t, J = 6.4 Hz, 2 H, NCH2), 3.96–3.99 (m, 3 H, OCH2, CH2CH), 4.93 (d, J = 5.6 Hz, 1 H, NH), 6.42 (br. s, 1 H, NH), 7.03 (m, 2 H, aromatic H), 7.19 (m, 2 H, aromatic H), 7.38 (dd, J = 2.7, 8.5 Hz, 1 H, aromatic H), 7.55 (d, J = 8.5 Hz, 1 H, aromatic H), 7.65 (dd, J = 2.4, 8.5 Hz, 1 H, aromatic H), 7.93 (d, J = 2.4 Hz, 1 H, aromatic H), 8.00 (m, 1 H, aromatic H), 8.63 (dd, J = 2.1, 7.6 Hz, 1 H, aromatic H), 8.90 (d, J = 2.1, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.69 (SCH3), 23.22 (Ar-CH2), 29.57 (CH2CH2CH2), 34.03 (SCH2), 36.56 (CH2CH), 37.97 (NCH2), 40.50 (SO2CH3), 58.94 (CH2CH), 72.97 (OCH2), 105.78, 116.00 (d, J = 20.8 Hz), 121.09, 123.58, 123.72, 129.63, 130.81, 130.93, 131.03, 133.17, 134.94, 137.69, 148.56, 149.41, 161.72 (d, J = 247.3 Hz) (all Carom), 170.34 (C=O) ppm. – C30H32Cl2FN5O4S2 (680.64): calcd. C 52.94, H 4.74, N 10.29; found C 52.88, H 4.80, N 10.21.

4.19 (S)-2-acetamido-N-(3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-3-(4-methoxyphenyl)propanamide (6)

Following the procedure adopted for the synthesis of 2, the reaction of 40 with 28 gave the title compound 6 as a colorless solid (yield 61 %). M.p. 131–132 °C. – [α]D20 = –19.1 (c = 0.003, EtOH). – IR (neat): ν = 3275, 3039, 2917, 1652, 1591, 1483, 1368, 1284, 1030 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.82 (pent, 2 H, CH2CH2CH2), 1.97 (s, 3 H, COCH3), 2.07 (s, 3 H, SCH3), 2.62 (t, J = 7.1 Hz, 2 H, SCH2), 2.84–2.93 (m, 3 H, ArCH2, CH2CH), 3.01 (dd, J = 5.5, 12.2 Hz, 1 H, CH2CH), 3.32 (m, 2 H, NCH2), 3.74 (s, 3 H, OCH3), 3.88 (t, J = 6.2 Hz, 2 H, OCH2), 4.49 (m, 1 H, CH2CH), 6.05 (br. s, 1 H, NH), 6.18 (d, J = 6.7 Hz, 1 H, NH), 6.80 (d, J = 8.5 Hz, 2 H, aromatic H), 7.10 (d, J = 8.5 Hz, 2 H, aromatic H), 7.39 (m, 1 H, aromatic H), 7.54 (d, J = 8.8 Hz, 1 H, aromatic H), 7.65 (dd, J = 2.4, 8.8 Hz, 1 H, aromatic H), 7.91 (d, J = 2.4 Hz, 1 H, aromatic H), 8.00 (d, J = 7.9 Hz, 1 H, aromatic H), 8.63 (d, J = 4.9 Hz, 1 H, aromatic H), 8.90 (s, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.71 (SCH3), 23.12 (COCH3), 23.19 (Ar-CH2), 32.75 (CH2CH2CH2), 34.07 (SCH2), 36.24 (CH2CH), 37.57 (NCH2), 54.97 (OCH3), 55.22 (CH2CH), 73.05 (OCH2), 105.82, 114.07, 120.95, 123.63, 123.92, 128.48, 130.22, 130.90, 133.20, 135.80, 137.58, 147.37, 147.46, 148.20, 151.83, 158.65 (all Carom), 170.00 (C=O), 171.17 (C=O) ppm. – C32H35Cl2N5O4S (656.62): calcd. C 58.53, H 5.37, N 10.67; found C 58.47, H 5.43, N 10.60.

4.20 (S)-N-(3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-3-(4-methoxyphenyl)-2-(methylsulfonamido)propanamide (7)

Following the procedure adopted for the synthesis of 2, the reaction of 40 with 32 gave the title compound 7 as a yellow thick gum (yield 64 %). – [α]D20= –13.9 (c = 0.005, EtOH). – IR (neat): ν = 3403, 3066, 2925, 2835, 1667, 1592, 1514, 1482, 1321, 1248, 1150 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.92 (pent, 2 H, CH2CH2CH2), 2.07 (s, 3 H, SCH3), 2.50 (s, 3 H, SO2CH3), 2.64 (t, J = 7.3 Hz, 2 H, SCH2), 2.82–2.90 (m, 3 H, ArCH2, CH2CH), 3.19 (dd, J = 6.4, 14.0 Hz, 1 H, CH2CH), 3.40 (m, 2 H, NCH2), 3.77 (s, 3 H, OCH3), 3.96 (t, J = 6.4 Hz, 2 H, OCH2), 4.48 (m, 1 H, CH2CH), 5.04 (br. s, 1 H, NH), 6.22 (br. s, 1 H, NH), 6.86 (d, J = 8.5 Hz, 2 H, aromatic H), 7.14 (d, J = 8.5 Hz, 2 H, aromatic H), 7.38 (m, 1 H, aromatic H), 7.55 (d, J = 8.8 Hz, 1 H, aromatic H), 7.66 (dd, J = 2.4, 8.8 Hz, 1 H, aromatic-H), 7.92 (d, J = 2.45 Hz, 1 H, aromatic H), 8.00 (d, J = 7.9 Hz, 1 H, aromatic H), 8.63 (m, 1 H, aromatic H), 8.90 (d, J = 2.1 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.67 (SCH3), 23.19 (Ar-CH2), 29.61 (CH2CH2CH2), 34.02 (SCH2), 36.48 (CH2CH), 37.87 (NCH2), 40.19 (SO2CH3), 55.33 (OCH3), 59.18 (CH2CH), 73.02 (OCH2), 114.04, 114.48, 121.06, 123.58, 123.72, 128.10, 129.66, 130.44, 130.75, 130.91, 133.16, 134.96, 137.69, 147.92, 148.54, 149.34, 151.77, 159.09 (all Carom), 170.65 (C=O) ppm. – C31H35Cl2N5O5S2 (692.68): calcd. C 53.75, H 5.09, N 10.11; found C 53.70, H 5.15, N 10.03.

4.21 (S)-tert-butyl (1-((3-((1-(3,4-dichloro phenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (8)

Following the procedure adopted for the synthesis of 2, the reaction of 40 with 29 yielded compound 8 as a colorless crystalline solid (yield 55 %). M.p. 123–124 °C. – [α]D20= –8.9 (c = 0.003, EtOH). – IR (neat): ν = 3427, 3314, 3042, 2974, 2922, 1714, 1592, 1513, 1366, 1247, 1166 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.39 (s, 9 H, OC(CH3)3, 1.84 (pent, 2 H, CH2CH2CH2), 2.06 (s, 3 H, SCH3), 2.62 (t, J = 7.5 Hz, 2 H, SCH2), 2.86 (t, J = 8.8 Hz, 2 H, ArCH2), 2.93–3.02 (m, 2 H, CH2CH), 3.34 (m, 2 H, NCH2), 3.75 (s, 3 H, OCH3), 3.91 (t, J = 6.4 Hz, 2 H, OCH2), 4.42 (m, 1 H, CH2CH), 5.04 (br. s, 1 H, NH), 6.01 (br. s, 1 H, NH), 6.80 (d, J = 8.5 Hz, 2 H, aromatic H), 7.10 (d, J =8.5 Hz, 2 H, aromatic H), 7.39 (m, 1 H, aromatic H), 7.55 (d, J = 8.5 Hz, 1 H, aromatic H), 7.65 (dd, J = 2.4, 8.5 Hz, 1 H, aromatic H), 7.91 (d, J = 2.4 Hz, aromatic H), 8.00 (dd, J = 2.1, 7.6 Hz, 1 H, aromatic H), 8.63 (d, J = 7.9 Hz, 1 H, aromatic H), 8.90 (d, J = 2.1, 7.6 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.66 (SCH3), 23.12 (Ar-CH2), 28.26 (OC(CH3)3), 29.70 (CH2CH2CH2), 34.00 (SCH2), 36.28 (CH2CH), 37.59 (NCH2), 55.20 (OCH3), 55.24 (CH2CH), 73.12 (OCH2), 79. 92 (OC(CH3)3), 105.74, 114.06, 120.95, 123.58, 123.63, 129.60, 130.29, 130.76, 130.88, 133.17, 134.92, 137.62, 147.91, 148.52, 149.37, 151.76 (all Carom), 158.60 (C=O), 171.54 (C=O) ppm. – C35H41Cl2N5O5S (387.52): calcd. C 58.82, H 5.78, N 9.80; found C 58.77, H 5.82, N 9.74.

4.22 (S)-2-acetamido-N-(3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-3-(pyridin-3-yl)propanamide (9)

Following the procedure adopted for the synthesis of 2, the reaction of 40 with 23 yielded compound 9 as a light brown gum (yield 58 %). – [α]D20 = –17.5 (c = 0.004, EtOH). – IR (neat): ν = 3442, 3060, 2923, 1653, 1592, 1482, 1369, 1133 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.85 (pent, 2 H, CH2CH2CH2), 1.96 (s, 3 H, COCH3), 2.07 (s, 3 H, SCH3), 2.62 (t, J = 7.0 Hz, 2 H, SCH2), 2.87 (t, J = 7.3 Hz, 2 H, ArCH2), 3.01 (dd, J = 5.5, 12.7 Hz, 1 H, CH2CH), 3.09 (dd, J = 7.3, 12.7 Hz, 1 H, CH2CH), 3.35 (m, 2 H, NCH2), 3.93 (t, J = 7.0 Hz, 2 H, OCH2), 4.61 (m, 1 H, CH2CH), 6.45 (br. s, 1 H, NH), 6.76 (br. s, 1 H, NH), 7.20 (m, 1 H, aromatic H), 7.38 (m, 1 H, aromatic H), 7.54 (d, J = 8.8 Hz, 1 H, aromatic H), 7.60 (m, 1 H, aromatic H), 7.64 (dd, J = 2.4, 8.8 Hz, 1 H, aromatic H), 7.91 (d, J = 2.5 Hz, 1 H, aromatic H), 8.00 (m, 1 H, aromatic H), 8.40 (d, J = 2.1 Hz, 1 H, aromatic H), 8.45 (dd, J = 2.1, 8.0 Hz, 1 H, aromatic H), 8.63 (dd, J = 2.1, 8.0 Hz, 1 H, aromatic H), 8.89 (d, J = 2.1 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.68 (SCH3), 23.11 (COCH3), 23.18 (Ar-CH2), 29.70 (CH2CH2CH2), 34.04 (SCH2), 35.58 (CH2CH), 36.35 (NCH2), 54.23 (CH2CH), 73.06 (OCH2), 105.72, 120.98, 123.48, 123.58, 129.59, 130.88, 132.31, 133.15, 134.92, 136.80, 137.66, 147.92, 148.36, 148.52, 149.73, 150.44, 151.75 (all Carom), 170.18 (C=O), 170.69 (C=O) ppm. – C30H32Cl2N6O3S (627.58): calcd. C 57.41, H 5.14, N 13.39; found C 57.36, H 5.19, N 13.34.

4.23 (S)-N-(3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-2-(methylsulfonamido)-3-(pyridin-3-yl)propanamide (10)

Following the procedure adopted for the synthesis of 2, the reaction of 40 with 24 yielded compound 10 as a colorless gum (yield 65 %). – [α]D20 = –28.3 (c = 0.004, EtOH). – IR (neat): ν = 3546, 3386, 3060, 2979, 1674, 1592, 1483, 1318, 1150 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.93 (pent, 2 H, CH2CH2CH2), 2.08 (s, 3 H, SCH3), 2.59 (s, 3 H, SO2CH3), 2.64 (t, J = 7.6 Hz, 2 H, SCH2), 2.88 (t, J = 6.7 Hz, 2 H, ArCH2), 2.97 (dd, J = 5.8, 14.0 Hz, 1 H, CH2CH), 3.20 (dd, J= 6.1, 14.0 Hz, 1 H, CH2CH), 3.45 (m, 2 H, NCH2), 3.97 (t, J = 5.8 Hz, 2 H, OCH2), 4.05 (m, 1 H, CH2CH), 5.36 (d, J = 5.8 Hz, 1 H, NH), 6.60 (br. s, 1 H, NH), 7.29 (dd, J = 4.9, 7.9 Hz, 1 H, aromatic H), 7.38 (dd, J = 4.9, 7.8 Hz, 1 H, aromatic H), 7.55 (d, J = 7.9 Hz, 1 H, aromatic H), 7.61 (m, 1 H, aromatic H), 7.65 (dd, J = 2.4, 8.8 Hz, 1 H, aromatic H), 7.92 (d, J = 2.4 Hz, 1 H aromatic H), 8.00 (m, 1 H, aromatic H), 8.49 (d, J = 2.1 Hz, 1 H, aromatic H), 8.52 (dd, J = 2.1, 8.1 Hz, 1 H, aromatic H), 8.63 (dd, J = 2.1, 8.0 Hz, 1 H, aromatic H), 8.90 (d, J = 2.1 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.69 (SCH3), 23.20 (Ar-CH2), 29.54 (CH2CH2CH2), 34.02 (SCH2), 36.06 (CH2CH), 36.62 (NCH2), 40.95 (SO2CH3), 58.45 (CH2CH), 72.96 (OCH2), 121.07, 123.60, 123.68, 123.75, 129.61, 130.78, 130.92, 132.15, 133.15, 134.94, 137.19, 137.66, 148.49, 148.77, 149.37, 150.57, 151.71 (all Carom), 170.21 (C=O) ppm. – C29H32Cl2N6O4S2 (663.64): calcd. C 52.48, H 4.86, N 12.66; found C 52.42, H 4.90, N 12.60.

4.24 (S)-2-acetamido-N-(3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-3-(pyridin-4-yl)propanamide (11)

Following the procedure adopted for the synthesis of 2, the reaction of 40 with 25 yielded compound 11 as a light brown gum (yield 59 %). – [α]D20 = –14.6 (c = 0.003, EtOH). – IR (neat): ν = 3478, 3289, 3060, 2919, 1659, 1592, 1482, 1367, 1133 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.85 (pent, 2 H, CH2CH2CH2), 1.96 (s, 3 H, COCH3), 2.08 (s, 3 H, SCH3), 2.63 (t, J = 7.0 Hz, 2 H, SCH2), 2.86 (t, J = 7.3 Hz, 2 H, ArCH2), 3.02 (dd, J = 6.4, 12.7 Hz, 1 H, CH2CH), 3.06 (dd, J = 5.3, 12.7 Hz, 1 H, CH2CH), 3.36 (m, 2 H, NCH2), 3.90 (t, J = 7.0 Hz, 2 H, OCH2), 4.60 (m, 1 H, CH2CH), 6.06 (br. s, 1 H, NH), 6.15 (br. s, 1 H, NH), 7.14 (d, J = 6.1 Hz, 1 H, aromatic H), 7.39 (d, J = 6.6 Hz, 2 H, aromatic H), 7.54 (d, J = 8.8 Hz, 1 H, aromatic H), 7.64 (dd, J = 2.4, 8.8 Hz, 1 H, aromatic H), 7.92 (d, J = 2.4 Hz, 1 H, aromatic H), 8.00 (m, 1 H, aromatic H), 8.51 (d, J = 6.6 Hz, 2 H, aromatic H), 8.62 (m, 1 H, aromatic H), 8.89 (d, J = 2.1 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.69 (SCH3), 23.14 (COCH3), 23.20 (Ar-CH2), 29.54 (CH2CH2CH2), 34.02 (SCH2), 36.40 (CH2CH), 37.38 (NCH2), 53.82 (CH2CH), 72.96 (OCH2), 121.07, 123.60, 123.68, 123.75, 129.61, 130.78, 130.92, 132.15, 133.15, 134.94, 137.19, 137.66, 148.49, 148.77, 149.37, 150.57, 151.71 (all Carom), 170.21 (C=O), 170.71 (C=O) ppm. – C30H32Cl2N6O3S (627.58): calcd. C 57.41, H 5.14, N 13.39; found C 57.35, H 5.19, N 13.32.

4.25 (S)-N-(3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-2-(methylsulfonamido)-3-(pyridin-4-yl)propanamide (12)

Following the procedure adopted for the synthesis of 2, the reaction of 40 with 26 yielded compound 12 as a colorless crystalline solid (yield 62 %). M.p. 136–137 °C. – [α]D20 = –20.0 (c = 0.003, EtOH). – IR (neat): ν = 3373, 3281, 3062, 2919, 1675, 1592, 1482, 1415, 1319, 1183, 1150 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.92 (pent, 2 H, CH2CH2CH2), 2.08 (s, 3 H, SCH3), 2.59 (s, 3 H, SO2CH3), 2.65 (t, J = 7.7 Hz, 2 H, SCH2), 2.88 (t, J = 6.7 Hz, 2 H, ArCH2), 2.97 (dd, J = 5.2, 13.7 Hz, 1 H, CH2CH), 3.20 (dd, J = 6.2, 13.7 Hz, 1 H, CH2CH), 3.47 (m, 2 H, NCH2), 3.97 (t, J = 5.9 Hz, 2 H, OCH2), 4.08 (m, 1 H, CH2CH), 5.11 (m, 1 H, NH), 6.44 (br. s, 1 H, NH), 7.19 (d, J = 5.8 Hz, 1 H, aromatic H), 7.38 (d, J = 6.8 Hz, 2 H, aromatic H), 7.56 (d, J = 8.2 Hz, 1 H, aromatic H), 7.64 (dd, J = 2.4, 8.2 Hz, 1 H, aromatic H), 7.92 (d, J = 2.4 Hz, 1 H, aromatic H), 8.00 (m, 1 H, aromatic H), 8.56 (d, J = 6.8 Hz, 2 H, aromatic H), 8.62 (m, 1 H, aromatic H), 8.90 (d, J = 1.5 Hz, 1 H, aromatic H) ppm. – 13C NMR (125.7 MHz, CDCl3): δ = 15.71 (SCH3), 23.23 (Ar-CH2), 29.71 (CH2CH2CH2), 34.02 (SCH2), 36.65 (CH2CH), 38.16 (NCH2), 40.95 (SO2CH3), 58.02 (CH2CH), 72.91 (OCH2), 105.77, 121.10, 123.60, 123.70, 124.68, 130.94, 133.17, 134.92, 137.66, 145.44, 148.52, 149.42, 150.35, 151.68 (all Carom), 169.98 (C=O) ppm. – C29H32Cl2N6O4S2 (663.64): calcd. C 52.48, H 4.86, N 12.66; found C 52.44, H 4.92, N 12.60.

Acknowledgments

The financial support from National Plan for Science, Technology, and Innovation (project 11-BIO2138-04) and facilities provided by King Fahd University of Petroleum and Minerals are gratefully acknowledged.

References

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If the inline PDF is not rendering correctly, you can download the PDF file here.

  • [1]

    J. A. Glomset, M. H. Gelb, C. C. Farnsworth, Trends Biochem. Sci. 1990, 15, 139.

  • [2]

    F. L. Zhang, P. J. Casey, Annu. Rev. Biochem. 1996, 65, 241.

  • [3]

    P. J. Casey, M. C. Seabra, J. Biol. Chem. 1996, 271, 5289.

  • [4]

    M. H. Gelb, L. Brunsveld, C. A. Hrycyna, S. Michaelis, F. Tamanoi, W. C. Van Voorhis, H. Waldmann, Nat. Chem. Biol. 2006, 2, 518.

  • [5]

    S. Maurer-Stroh, M. Koranda, W. Benetka, G. Schneider, F. L. Sirota, F. Eisenhaber, PLoS Comput. Biol. 2007, 3, e66.

  • [6]

    M. N. Ashby, Curr. Opin. Lipidol. 1998, 9, 99.

  • [7]

    A. M. Winter-Vann, P. J. Casey, Nat. Rev. Cancer 2005, 5, 405.

  • [8]

    N. Berndt, A. D. Hamilton, S. M. Sebti, Nat. Rev. Cancer 2011, 11, 775.

  • [9]

    R. J. Doll, P. Kirschmeier, W. R. Bishop, Curr. Opin. Drug Discov. Devel. 2004, 7, 478.

  • [10]

    C. A. Omer, Z. Chen, R. E. Diehl, M. W. Conner, H. Y. Chen, M. E. Trumbauer, S. Gopal-Truter, G. Seeburger, H. Bhimnathwala, M. T. Abrams, J. P. Davide, M. S. Ellis, J. B. Gibbs, I. Greenberg, K. S. Koblan, A. M. Kral, D. Liu, R. B. Lobell, P. J. Miller, S. D. Mosser, T. J. O’Neill, E. Rands, M. D. Schaber, E. T. Senderak, A. Oliff, N. E. Kohl, Cancer Res. 2000, 60, 2680.

    • PubMed
    • Export Citation
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    A. D. Basso, P. Kirschmeier, W. R. Bishop, J. Lipid Res. 2006, 47, 15.

  • [12]

    D. B. Whyte, P. Kirschmeier, T. N. Hockenberry, I. Nunez-Oliva, L. James, J. J. Catino, W. R. Bishop, J. K. Pai, J. Biol. Chem. 1997, 272, 14459.

  • [13]

    J. Sun, Y. Qian, A. D. Hamilton, S. M. Sebti, Oncogene 1998, 16, 1467.

    • Crossref
    • Export Citation
  • [14]

    J. Sun, M. A. Blaskovich, D. Knowles, Y. Qian, J. Ohkanda, R. D. Bailey, A. D. Hamilton, S. M. Sebti, Cancer Res. 1999, 59, 4919.

  • [15]

    S. M. Sebti, A. D. Hamilton, Oncogene 2000, 19, 6584.

  • [16]

    K. M. Sane, M. Mynderse, D. T. LaLonde, I. S. Dean, J. W. Wojtkowiak, F. Fouad, R. F. Borch, J. J. Reiners, Jr., R. A. Gibbs, R. R. Mattingly, J. Pharmacol. Exp. Ther. 2010, 333, 23.

  • [17]

    J. Lu, K. Yoshimura, K. Goto, C. Lee, K. Hamura, O. Kwon, F. Tamanoi, PLoS One 2015, 10, e0137595.

    • Crossref
    • Export Citation
  • [18]

    A. K. Sjogren, K. M. Andersson, M. Liu, B. A. Cutts, C. Karlsson, A. M. Wahlstrom, M. Dalin, C. Weinbaum, P. J. Casey, A. Tarkowski, B. Swolin, S. G. Young, M. O. Bergo, J. Clin. Invest. 2007, 117, 1294.

  • [19]

    N. Ullah. Z. Naturforsch. 2012, 67b, 75.

  • [20]

    N. Ullah, A. A. Q. Al-Shaheri, Z. Naturforsch. 2012 , 67b, 253.

  • [21]

    N. Ullah, J. Enzyme Inhib. Med. Chem. 2014, 29, 281.

  • [22]

    N. Ullah, Med. Chem. 2014, 10, 484.

  • [23]

    Y. K. Peterson, P. Kelly, C. A. Weinbaum, P. J. Casey, J. Biol. Chem. 2006, 281, 12445.

  • [24]

    G. Naturale, M. Lamblin, C. Commandeur, F.-X. Felpin, J. Dessolin, Eur. J. Org. Chem. 2012, 29, 5774.

  • [25]

    T. Polonski, Tetrahedron 1985, 41, 603.

  • [26]

    K. Guzow, R. Ganzynkowicz, A. Rzeska, J. Mrozek, M. Szabelski, J. Karolczak, A. Liwo, W. Wiczk, J. Phys. Chem. B. 2004, 108, 3879.

  • [27]

    N.-N. Liu, S.-M. Zhao, J.-F. Zhao, G.-Z. Zeng, N.-H. Tan, J.-P. Liu, Tetrahedron 2014, 70, 6630.

    • Crossref
    • Export Citation
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Zeitschrift für Naturforschung B is an international scientific journal which publishes original papers, microreviews, and letters from all areas of inorganic chemistry, solid state chemistry, coordination chemistry, molecular chemistry, and organic chemistry.

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