Design, synthesis, and structure–activity relationship studies of N-arylsulfonyl morpholines as γ-secretase inhibitors (original) (raw)

Bioorganic Chemistry 79 (2018) 46–59 -5.pdf

A novel series of 4,6-disubstituted pyrazolo[3,4-]pyrimidines ( -) bearing various anilines at C-4 d 7 43 position and thiophenethyl or thiopentane moieties at C-6 position have been designed and synthesized by molecular hybridization approach. All the synthesized compounds were evaluated for in vitro CDK2/cyclin E and Abl kinase inhibitory activity as well as anti-proliferative activity against K-562 (chronic myelogeneous leukemia), and MCF-7 (breast adenocarcinoma) cell lines. The structure-activity relationship (SAR) studies revealed that compounds with thiophenethyl group at C-6 with monosubstituted anilines at C-4 exhibited better CDK2 inhibitory activity compared to alkyl group (thiopentane) at C-6 and di-substituted anilines at C-4 of the scaffold. In particular, compounds having 2-chloro, 3-nitro and 4-methylthio aniline groups at C-4 displayed significant enzymatic inhibitory activity against CDK2 with single digit micromolar IC 50 values. The molecular docking studies suggested in silico possible binding orientation and the binding energies were in agreement with the observed SAR as well as experimental results. In addition, some of the synthesized compounds showed anti-proliferative effects against K-562 and MCF-7 cancer cell lines with IC 50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization. H NMR (400 MHz, DMSO-d 6 ): 10.47 (s, 1H, NH), 7.98 (s, 1H, NH), 7.62-7.58 d (m, 2H, ArH), 7.41-7.08 (m, 8H, ArH), 3.20 (t, = 7.68 Hz, 2H, J CH 2 ), 2.83 (t, = 7.56 Hz, 2H, C J H 2 ) ppm; 13 C NMR (100 MHz, DMSO-d 6 ) : 166.95, 155.03, 140.21, 134.86, 130.46, 129.95, d 129.39, 128.49, 128.29, 127.81, 126.20, 98.12, 35.33 (CH 2 ), 31.37 (CH 2 ) ppm.

5-Pentyl-4-phenylsulfonyl-1H-pyrazol-3-ol Tara Shahani, Hoong-Kun Fun, R. Venkat Ragavan, V. Vijayakumar and S. Sarveswari, Acta Cryst. (2010). E66, o1482-1483

Metal-organic compounds Organic compounds Acta Crystallographica Section E: Structure Reports Online is the IUCr's highly popular open-access structural journal. It provides a simple and easily accessible publication mechanism for the growing number of inorganic, metal-organic and organic crystal structure determinations. The electronic submission, validation, refereeing and publication facilities of the journal ensure very rapid and high-quality publication, whilst key indicators and validation reports provide measures of structural reliability. In 2007, the journal published over 5000 structures. The average publication time is less than one month.

Synthesis of benzamide derivatives and their evaluation as antiprion agents

Bioorganic & Medicinal Chemistry, 2012

A new set of 5-(2-(pyrrolidin-1-yl)acetamido)-N-butyl-2-(substituted)benzamide and 5-(2-(piperidin-1yl)acetamido)-N-butyl-2-(substituted) benzamide derivatives were synthesized in which as structural features the 2-(1-pyrrolidinyl)-or 2-(1-piperidyl)acetylamino group or a diphenylether moiety are associated to a benzamide scaffold. Their binding affinity for human PrP C and inhibition of its conversion into PrP Sc were determined in vitro; moreover, the antiprion activity was assayed by inhibition of PrP Sc accumulation in scrapie-infected mouse neuroblastoma cells (ScN2a) and scrapie mouse brain (SMB) cells. The results clearly indicate the benzamide derivatives as attractive lead compounds for the development of potential therapeutic agents against prion disease. j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b m c J = 8.

ChemInform Abstract: Synthesis and Inhibitory Activity Against Human Monoamine Oxidase of N1-Thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole Derivatives

ChemInform, 2010

A series of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives has been synthesized and assayed for their ability to inhibit the activity of the A and B isoforms of human monoamine oxidase (hMAO). Some of these compounds were endowed with a selective inhibitory activity against hMAO-B in the micromolar range. The most active of the series is the compound 13, N1thiocarbamoyl-3-(fur-2 0 -yl)-5-(4 0 -fluoro-phenyl)-4,5-dihydro-(1H)-pyrazole, with IC 50 2.75 AE 0.81 mM value and selectivity ratio of 25, which is the best candidate for further investigations. European Journal of Medicinal Chemistry 45 (2010) 800-804 thiophene), 7.26-7.28 (m, 1H, thiophene), 7.34-7.36 (m, 2H, Ar), 7.78-7.80 (m, 2H, Ar), 8.03 (s, 2H, NH 2 , D 2 O exch.). 7 a 3.34-3.39 (dd, J ab ¼ 17.48 Hz, J ac ¼ 3.08 Hz, 1H, H a ), 3.76-3.83 (dd, J ab ¼ 17.48 Hz, J bc ¼ 11.12 Hz, 1H, H b ), 6.36-6.39 (dd, J ac ¼ 3.09 Hz, J bc ¼ 11.12 Hz, 1H, H c ), 6.94-6.98 (m, 2H, thiophene), 7.05-7.06 (m, 1H, thiophene), 7.12-7.20 (m, 4H, Ar), 7.75 (s, 2H, NH 2 , D 2 O exch.). 9 b 3.18-3.20 (dd, J ab ¼ 17.52 Hz, J ac ¼ 3.02 Hz, 1H, H a ), 3.81-3.84 (dd, J ab ¼ 17.52 Hz, J bc ¼ 11.16 Hz, 1H, H b ), 6.02-6.04 (dd, J ac ¼ 3.04 Hz, J bc ¼ 11.16 Hz, 1H, H c ), 7.02-7.04 (m, 3H, Ar), 7.23-7.24 (m, 1H, Ar), 7.41-7.43 (m, 2H, Ar), 7.64-7.66 (m, 2H, Ar), 8.09 (s, 2H, NH 2 , D 2 O exch.). 11 b 3.38-3.40 (dd, J ab ¼ 17.48 Hz, J ac ¼ 3.13 Hz, 1H, H a ), 3.69-3.74 (dd, J ab ¼ 17.48 Hz, J bc ¼ 11.18 Hz, 1H, H b ), 5.88-5.90 (dd, J ac ¼ 3.13 Hz, J bc ¼ 11.19 Hz, 1H, H c ), 6.54-6.57 (m, 1H, pyrrole), 7.53-7.55 (m, 2H, pyrrole), 7.86-7.94 (m, 4H, Ar), 7.99 (s, 2H, NH 2 , D 2 O exch.), 10.64 (bs, 1H, NH, D 2 O exch.). 12 b 2.24 (s, 3H, ArCH 3 ), 2.94-2.98 (dd, J ab ¼ 17.44 Hz, J ac ¼ 3.10 Hz, 1H, H a ), 3.82-3.86 (dd, J ab ¼ 17.44 Hz, J bc ¼ 11.12 Hz, 1H, H b ), 5.85-5.88 (dd, J ac ¼ 3.09 Hz, J bc ¼ 11.12 Hz, 1H, H c ), 6.65-6.67 (m, 1H, furan), 6.97-7.11 (m, 5H, Ar and furan), 7.87-7.89 (m, 1H, Ar), 7.90 (s, 2H, NH 2 , D 2 O exch.). 13 b 3.00-3.02 (dd, J ab ¼ 17.40 Hz, J ac ¼ 3.00 Hz, 1H, H a ), 3.84-3.89 (dd, J ab ¼ 17.40 Hz, J bc ¼ 11.19 Hz, 1H, H b ), 5.89-5.93 (dd, J ac ¼ 3.00 Hz, J bc ¼ 11.19 Hz, 1H, H c ), 6.66-6.67 (m, 1H, furyl), 7.03-7.15 (m, 5H, Ar and furan), 7.91 (s, 1H, Ar), 8.01 (s, 2H, NH 2 , D 2 O exch.). 14 b 3.28-3.30 (dd, J ab ¼ 17.38 Hz, J ac ¼ 3.03 Hz, 1H, H a ), 4.01-4.03 (dd, J ab ¼ 17.38 Hz, J bc ¼ 11.29 Hz, 1H, H b ), 5.49-5.52 (dd, J ac ¼ 3.03 Hz, J bc ¼ 11.29 Hz, 1H, H c ), 6.12-6.17 (m, 2H, furan), 6.53-7.55 (m, 1H, furan), 6.97-6.99 (m, 3H, thiophene), 7.70 (s, 2H, NH 2 , D 2 O exch.). 15 b 3.39-3.43 (dd, J ab ¼ 17.45 Hz, J ac ¼ 3.06 Hz, 1H, H a ), 3.75-3.81 (dd, J ab ¼ 17.44 Hz, J bc ¼ 11.10 Hz, 1H, H b ), 6.06-6.09 (dd, J ac ¼ 3.06 Hz, J bc ¼ 11.10 Hz, 1H, H c ), 6.66 (s, 1H, thiophene), 7.16-7.19 (m, 2H, thiophene), 7.58-7.59 (m, 2H, pyrrole), 7.76-7.78 (m, 1H, pyrrole), 8.00 (bs, 2H, NH 2 , D 2 O exch.), 10.74 (bs, 1H, NH, D 2 O exch.). 16 b 3.06-3.11 (dd, J ab ¼ 17.42 Hz, J ac ¼ 3.10 Hz, 1H, H a ), 4.38-4.39 (dd, J ab ¼ 17.40 Hz, J bc ¼ 11.14 Hz, 1H, H b ), 6.11-6.13 (dd, J ac ¼ 3.10 Hz, J bc ¼ 11.15 Hz, 1H, H c ), 6.89-7.02 (m, 2H, pyrrole), 7.19-7.27 (m, 4H, Ar and pyrrole), 7.39-7.43 (m, 2H, Ar), 7.75 (bs, 2H, NH 2 , D 2 O exch.), 11.85 (bs, 1H, NH, D 2 O exch.). 17 b 3.08-3.11 (dd, J ab ¼ 17.45 Hz, J ac ¼ 3.02 Hz, 1H, H a ), 4.25-4.29 (dd, J ab ¼ 17.45 Hz, J bc ¼ 11.10 Hz, 1H, H b ), 6.09-6.12 (dd, J ac ¼ 3.02 Hz, J bc ¼ 11.10 Hz, 1H, H c ), 6.92-7.03 (m, 4H, pyrrole and Ar), 7.40-7.50 (m, 3H, Ar), 7.70 (s, 2H, NH 2 , D 2 O exch.), 11.69 (bs, 1H, NH, D 2 O exch.). 18 b 3.18-3.20 (dd, J ab ¼ 17.48 Hz, J ac ¼ 3.11 Hz, 1H, H a ), 4.20-4.24 (dd, J ab ¼ 17.48 Hz, J bc ¼ 11.13 Hz, 1H, H b ), 6.07-6.10 (dd, J ac ¼ 3.12 Hz, J bc ¼ 11.14 Hz, 1H, H c ), 6.94-7.00 (m, 2H, pyrrole), 7.30-7.32 (m, 2H, Ar and pyrrole), 7.40-7.44 (m, 3H, Ar), 7.79 (s, 2H, NH 2 , D 2 O exch.), 11.70 (bs, 1H, NH, D 2 O exch.). 19 b 3.08-3.11 (dd, J ab ¼ 17.45 Hz, J ac ¼ 3.02 Hz, 1H, H a ), 4.25-4.29 (dd, J ab ¼ 17.45 Hz, J bc ¼ 11.10 Hz, 1H, H b ), 6.09-6.12 (dd, J ac ¼ 3.02 Hz, J bc ¼ 11.10 Hz, 1H, H c ), 6.92-7.03 (m, 4H, pyrrole and Ar), 7.40-7.50 (m, 3H, Ar), 7.70 (s, 2H, NH 2 , D 2 O exch.), 11.69 (bs, 1H, NH, D 2 O exch.). 20 b 3.08-3.11 (dd, J ab ¼ 17.45 Hz, J ac ¼ 3.02 Hz, 1H, H a ), 4.25-4.29 (dd, J ab ¼ 17.45 Hz, J bc ¼ 11.10 Hz, 1H, H b ), 6.09-6.12 (dd, J ac ¼ 3.02 Hz, J bc ¼ 11.10 Hz, 1H, H c ), 6.92-7.03 (m, 4H, pyrrole and Ar), 7.40-7.50 (m, 3H, Ar), 7.70 (s, 2H, NH 2 , D 2 O exch.), 11.69 (bs, 1H, NH, D 2 O exch.). a CDCl 3 . b DMSO-d 6 .

Synthesis and biological evaluation of imidazo[1,2- a]pyridine derivatives as novel PI3 kinase p110α inhibitors

Bioorganic & Medicinal Chemistry, 2007

Cyclin-dependent kinase RNA polymerase II Anti-tumour activity Induction of apoptosis Mcl-1 anti-apoptotic protein Drug discovery Cancer therapy a b s t r a c t A series of N-phenyl-imidazo [4,5-b]pyridin-2-amines, 4-indazolyl-N-phenylpyrimidin-2-amines and N-phenyl-4-pyrazolo[3,4-b]pyridin-pyrimidin-2-amines have been synthesized. Their anti-proliferative activities were tested in HCT-116 human colon carcinoma and MCF-7 breast carcinoma cell lines. Many exhibited potent anti-proliferative and CDK9 inhibitory activities. A lead compound 18b demonstrated the ability to reduce the level of Mcl-1 anti-apoptotic protein, to activate caspase 3/7 and induce cancer cell apoptosis. Propyl-1H-indazol-3-yl)ethanone (12, R 1 ¼ n-Pr) As bright yellow crystalline solid (4.72 g, 75%); 1 H NMR (DMSOd 6 ) d 0.85 (3H, t, CH 3 , J ¼ 7.2 Hz), 1.89 (2H, q, CH 2 , J ¼ 7.2 Hz), 2.61 (3H, s, CH 3 ), 4.46 (2H, t, CH 2 , J ¼ 7.2 Hz), 7.32 (1H, t, IndeH, J ¼ 7.6 Hz), 7.46 (1H, t, IndeH, J ¼ 7.6 Hz), 7.79 (1H, d, IndeH, J ¼ 8.4 Hz), 8.18 (1H, d, IndeH, J ¼ 8.0 Hz); HR-MS (m/z): calcd for C 12 H 14 N 2 O requires 202.1106; found 203.1392 [M þ 1] þ . 5.1.15. 1-(1-(Pyridin-3-ylmethyl)-1H-indazol-3-yl)ethanone (12, R 1 ¼ 3-methylpyridine) As a bright yellow crystalline solid (1.01 g, 64%); 1 H NMR (DMSOd 6 ) d 2.63 (3H, s, CH 3 ), 5.86 (2H, s, CH 2 ), 7.34 (1H, d, PyreH, J ¼ 6.4 Hz), 7.35 (1H, d, IndeH, J ¼ 7.6 Hz), 7.48 (1H, t, IndeH, J ¼ 8.0 Hz), 7.68 (1H, dt, PyreH, J ¼ 7.6, 1.6 Hz), 7.89 (1H, d, IndeH, J ¼ 8.4 Hz), 8.20 (1H, d, IndeH, J ¼ 8.4 Hz), 8.49 (1H, dd, PyreH, J ¼ 4.8, 1.6 Hz), 8.64 (1H, d, PyreH, J ¼ 2.0 Hz); HR-MS (m/z): calcd for C 15 H 13 N 3 O 251.1059; found 252.0645 [M þ 1] þ .

Synthesis and biological evaluation of imidazol-2-one and 2-cyanoiminoimidazole derivatives: novel series of PDE4 inhibitors

Bioorganic & medicinal chemistry letters, 2002

Cyclin-dependent kinase RNA polymerase II Anti-tumour activity Induction of apoptosis Mcl-1 anti-apoptotic protein Drug discovery Cancer therapy a b s t r a c t A series of N-phenyl-imidazo [4,5-b]pyridin-2-amines, 4-indazolyl-N-phenylpyrimidin-2-amines and N-phenyl-4-pyrazolo[3,4-b]pyridin-pyrimidin-2-amines have been synthesized. Their anti-proliferative activities were tested in HCT-116 human colon carcinoma and MCF-7 breast carcinoma cell lines. Many exhibited potent anti-proliferative and CDK9 inhibitory activities. A lead compound 18b demonstrated the ability to reduce the level of Mcl-1 anti-apoptotic protein, to activate caspase 3/7 and induce cancer cell apoptosis. Propyl-1H-indazol-3-yl)ethanone (12, R 1 ¼ n-Pr) As bright yellow crystalline solid (4.72 g, 75%); 1 H NMR (DMSOd 6 ) d 0.85 (3H, t, CH 3 , J ¼ 7.2 Hz), 1.89 (2H, q, CH 2 , J ¼ 7.2 Hz), 2.61 (3H, s, CH 3 ), 4.46 (2H, t, CH 2 , J ¼ 7.2 Hz), 7.32 (1H, t, IndeH, J ¼ 7.6 Hz), 7.46 (1H, t, IndeH, J ¼ 7.6 Hz), 7.79 (1H, d, IndeH, J ¼ 8.4 Hz), 8.18 (1H, d, IndeH, J ¼ 8.0 Hz); HR-MS (m/z): calcd for C 12 H 14 N 2 O requires 202.1106; found 203.1392 [M þ 1] þ . 5.1.15. 1-(1-(Pyridin-3-ylmethyl)-1H-indazol-3-yl)ethanone (12, R 1 ¼ 3-methylpyridine) As a bright yellow crystalline solid (1.01 g, 64%); 1 H NMR (DMSOd 6 ) d 2.63 (3H, s, CH 3 ), 5.86 (2H, s, CH 2 ), 7.34 (1H, d, PyreH, J ¼ 6.4 Hz), 7.35 (1H, d, IndeH, J ¼ 7.6 Hz), 7.48 (1H, t, IndeH, J ¼ 8.0 Hz), 7.68 (1H, dt, PyreH, J ¼ 7.6, 1.6 Hz), 7.89 (1H, d, IndeH, J ¼ 8.4 Hz), 8.20 (1H, d, IndeH, J ¼ 8.4 Hz), 8.49 (1H, dd, PyreH, J ¼ 4.8, 1.6 Hz), 8.64 (1H, d, PyreH, J ¼ 2.0 Hz); HR-MS (m/z): calcd for C 15 H 13 N 3 O 251.1059; found 252.0645 [M þ 1] þ .

Synthesis and inhibitory activity against human monoamine oxidase of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives

European Journal of Medicinal Chemistry, 2010

A series of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives has been synthesized and assayed for their ability to inhibit the activity of the A and B isoforms of human monoamine oxidase (hMAO). Some of these compounds were endowed with a selective inhibitory activity against hMAO-B in the micromolar range. The most active of the series is the compound 13, N1thiocarbamoyl-3-(fur-2 0 -yl)-5-(4 0 -fluoro-phenyl)-4,5-dihydro-(1H)-pyrazole, with IC 50 2.75 AE 0.81 mM value and selectivity ratio of 25, which is the best candidate for further investigations. European Journal of Medicinal Chemistry 45 (2010) 800-804 thiophene), 7.26-7.28 (m, 1H, thiophene), 7.34-7.36 (m, 2H, Ar), 7.78-7.80 (m, 2H, Ar), 8.03 (s, 2H, NH 2 , D 2 O exch.). 7 a 3.34-3.39 (dd, J ab ¼ 17.48 Hz, J ac ¼ 3.08 Hz, 1H, H a ), 3.76-3.83 (dd, J ab ¼ 17.48 Hz, J bc ¼ 11.12 Hz, 1H, H b ), 6.36-6.39 (dd, J ac ¼ 3.09 Hz, J bc ¼ 11.12 Hz, 1H, H c ), 6.94-6.98 (m, 2H, thiophene), 7.05-7.06 (m, 1H, thiophene), 7.12-7.20 (m, 4H, Ar), 7.75 (s, 2H, NH 2 , D 2 O exch.). 9 b 3.18-3.20 (dd, J ab ¼ 17.52 Hz, J ac ¼ 3.02 Hz, 1H, H a ), 3.81-3.84 (dd, J ab ¼ 17.52 Hz, J bc ¼ 11.16 Hz, 1H, H b ), 6.02-6.04 (dd, J ac ¼ 3.04 Hz, J bc ¼ 11.16 Hz, 1H, H c ), 7.02-7.04 (m, 3H, Ar), 7.23-7.24 (m, 1H, Ar), 7.41-7.43 (m, 2H, Ar), 7.64-7.66 (m, 2H, Ar), 8.09 (s, 2H, NH 2 , D 2 O exch.). 11 b 3.38-3.40 (dd, J ab ¼ 17.48 Hz, J ac ¼ 3.13 Hz, 1H, H a ), 3.69-3.74 (dd, J ab ¼ 17.48 Hz, J bc ¼ 11.18 Hz, 1H, H b ), 5.88-5.90 (dd, J ac ¼ 3.13 Hz, J bc ¼ 11.19 Hz, 1H, H c ), 6.54-6.57 (m, 1H, pyrrole), 7.53-7.55 (m, 2H, pyrrole), 7.86-7.94 (m, 4H, Ar), 7.99 (s, 2H, NH 2 , D 2 O exch.), 10.64 (bs, 1H, NH, D 2 O exch.). 12 b 2.24 (s, 3H, ArCH 3 ), 2.94-2.98 (dd, J ab ¼ 17.44 Hz, J ac ¼ 3.10 Hz, 1H, H a ), 3.82-3.86 (dd, J ab ¼ 17.44 Hz, J bc ¼ 11.12 Hz, 1H, H b ), 5.85-5.88 (dd, J ac ¼ 3.09 Hz, J bc ¼ 11.12 Hz, 1H, H c ), 6.65-6.67 (m, 1H, furan), 6.97-7.11 (m, 5H, Ar and furan), 7.87-7.89 (m, 1H, Ar), 7.90 (s, 2H, NH 2 , D 2 O exch.). 13 b 3.00-3.02 (dd, J ab ¼ 17.40 Hz, J ac ¼ 3.00 Hz, 1H, H a ), 3.84-3.89 (dd, J ab ¼ 17.40 Hz, J bc ¼ 11.19 Hz, 1H, H b ), 5.89-5.93 (dd, J ac ¼ 3.00 Hz, J bc ¼ 11.19 Hz, 1H, H c ), 6.66-6.67 (m, 1H, furyl), 7.03-7.15 (m, 5H, Ar and furan), 7.91 (s, 1H, Ar), 8.01 (s, 2H, NH 2 , D 2 O exch.). 14 b 3.28-3.30 (dd, J ab ¼ 17.38 Hz, J ac ¼ 3.03 Hz, 1H, H a ), 4.01-4.03 (dd, J ab ¼ 17.38 Hz, J bc ¼ 11.29 Hz, 1H, H b ), 5.49-5.52 (dd, J ac ¼ 3.03 Hz, J bc ¼ 11.29 Hz, 1H, H c ), 6.12-6.17 (m, 2H, furan), 6.53-7.55 (m, 1H, furan), 6.97-6.99 (m, 3H, thiophene), 7.70 (s, 2H, NH 2 , D 2 O exch.). 15 b 3.39-3.43 (dd, J ab ¼ 17.45 Hz, J ac ¼ 3.06 Hz, 1H, H a ), 3.75-3.81 (dd, J ab ¼ 17.44 Hz, J bc ¼ 11.10 Hz, 1H, H b ), 6.06-6.09 (dd, J ac ¼ 3.06 Hz, J bc ¼ 11.10 Hz, 1H, H c ), 6.66 (s, 1H, thiophene), 7.16-7.19 (m, 2H, thiophene), 7.58-7.59 (m, 2H, pyrrole), 7.76-7.78 (m, 1H, pyrrole), 8.00 (bs, 2H, NH 2 , D 2 O exch.), 10.74 (bs, 1H, NH, D 2 O exch.). 16 b 3.06-3.11 (dd, J ab ¼ 17.42 Hz, J ac ¼ 3.10 Hz, 1H, H a ), 4.38-4.39 (dd, J ab ¼ 17.40 Hz, J bc ¼ 11.14 Hz, 1H, H b ), 6.11-6.13 (dd, J ac ¼ 3.10 Hz, J bc ¼ 11.15 Hz, 1H, H c ), 6.89-7.02 (m, 2H, pyrrole), 7.19-7.27 (m, 4H, Ar and pyrrole), 7.39-7.43 (m, 2H, Ar), 7.75 (bs, 2H, NH 2 , D 2 O exch.), 11.85 (bs, 1H, NH, D 2 O exch.). 17 b 3.08-3.11 (dd, J ab ¼ 17.45 Hz, J ac ¼ 3.02 Hz, 1H, H a ), 4.25-4.29 (dd, J ab ¼ 17.45 Hz, J bc ¼ 11.10 Hz, 1H, H b ), 6.09-6.12 (dd, J ac ¼ 3.02 Hz, J bc ¼ 11.10 Hz, 1H, H c ), 6.92-7.03 (m, 4H, pyrrole and Ar), 7.40-7.50 (m, 3H, Ar), 7.70 (s, 2H, NH 2 , D 2 O exch.), 11.69 (bs, 1H, NH, D 2 O exch.). 18 b 3.18-3.20 (dd, J ab ¼ 17.48 Hz, J ac ¼ 3.11 Hz, 1H, H a ), 4.20-4.24 (dd, J ab ¼ 17.48 Hz, J bc ¼ 11.13 Hz, 1H, H b ), 6.07-6.10 (dd, J ac ¼ 3.12 Hz, J bc ¼ 11.14 Hz, 1H, H c ), 6.94-7.00 (m, 2H, pyrrole), 7.30-7.32 (m, 2H, Ar and pyrrole), 7.40-7.44 (m, 3H, Ar), 7.79 (s, 2H, NH 2 , D 2 O exch.), 11.70 (bs, 1H, NH, D 2 O exch.). 19 b 3.08-3.11 (dd, J ab ¼ 17.45 Hz, J ac ¼ 3.02 Hz, 1H, H a ), 4.25-4.29 (dd, J ab ¼ 17.45 Hz, J bc ¼ 11.10 Hz, 1H, H b ), 6.09-6.12 (dd, J ac ¼ 3.02 Hz, J bc ¼ 11.10 Hz, 1H, H c ), 6.92-7.03 (m, 4H, pyrrole and Ar), 7.40-7.50 (m, 3H, Ar), 7.70 (s, 2H, NH 2 , D 2 O exch.), 11.69 (bs, 1H, NH, D 2 O exch.). 20 b 3.08-3.11 (dd, J ab ¼ 17.45 Hz, J ac ¼ 3.02 Hz, 1H, H a ), 4.25-4.29 (dd, J ab ¼ 17.45 Hz, J bc ¼ 11.10 Hz, 1H, H b ), 6.09-6.12 (dd, J ac ¼ 3.02 Hz, J bc ¼ 11.10 Hz, 1H, H c ), 6.92-7.03 (m, 4H, pyrrole and Ar), 7.40-7.50 (m, 3H, Ar), 7.70 (s, 2H, NH 2 , D 2 O exch.), 11.69 (bs, 1H, NH, D 2 O exch.). a CDCl 3 . b DMSO-d 6 .