Selective IKur Inhibitors for the Potential Treatment of Atrial Fibrillation

Apr 18, 2017 - Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical ... Atrial fibrillation (AF) is a condition defined by ...
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Selective IKur Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5‑[5-Phenyl-4-(pyridin-2ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide Prashantha Gunaga,*,∥ John Lloyd,† Somanadham Mummadi,∥ Abhisek Banerjee,∥ Naveen Kumar Dhondi,∥ James Hennan,‡ Veena Subray,∥ Ramya Jayaram,∥ Nagendra Rajugowda,∥ Kommuri Umamaheshwar Reddy,∥ Duraimurugan Kumaraguru,∥ Umasankar Mandal,∥ Dasthagiri Beldona,∥ Ashok Kumar Adisechen,∥ Navnath Yadav,∥ Jayakumar Warrier,∥ James A. Johnson,† Harinath Sale,∥ Siva Prasad Putlur,# Ajay Saxena,@ Anjaneya Chimalakonda,§ Sandhya Mandlekar,∇ MaryLee Conder,‡ Dezhi Xing,‡ Arun Kumar Gupta,∥ Anuradha Gupta,∥ Richard Rampulla,† Arvind Mathur,† Paul Levesque,‡ Ruth R. Wexler,† and Heather J. Finlay*,† †

Department of Discovery Chemistry, ‡Department of Biology, and §Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States ∥ Department of Discovery Chemistry, Department of Biology, @Department of Biopharmaceutics, #Department of Pharmaceutical Candidate Optimization, and ∇Biocon BMS R&D Center, Syngene International Limited, BMS India Pvt. Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India S Supporting Information *

ABSTRACT: We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2′ position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.

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example, amiodarone and dronedarone.5 Prolonging the ventricular effective refractory period can lead to the potentially fatal ventricular arrhythmia, torsade de pointes. Therefore, targeting inhibition of atrial specific ion channels may provide a potentially safer treatment for maintenance of NSR. IKur is the ultrarapid delayed rectifier potassium current encoded by the KCNA5 (KV1.5) gene in humans and is functionally expressed in human atrium and not in the ventricle.6 Selective inhibition of IKur is expected to prolong the atrial action potential duration (APD) without prolonging QT as the ventricular effective refractory period remains unchanged.7 Thus, compounds that selectively inhibit IKur are expected to

INTRODUCTION Atrial fibrillation (AF) is a condition defined by abnormal sinus rhythm resulting from irregular electrical activity in the atrium. AF has an associated higher risk of stroke because of thromboembolism, and patients have a reduced quality of life.1,2 Electrical cardioversion is the standard of care for conversion to normal sinus rhythm (NSR), and pharmacologic intervention and ablation are the current standards of care for maintenance of normal sinus rhythm. Antiarrhythmic therapy is recommended for patients with symptomatic paroxysmal AF.3,4 Antiarrhythmic agents maintain normal sinus rhythm or control the heart rate (HR) and are targeted for combination with anticoagulation therapy indicated for AF. Currently available antiarrhythmic drugs for the treatment of AF inhibit multiple cardiac ion channels that are expressed in both atria and ventricles, in addition to having antiadrenergic properties, for © 2017 American Chemical Society

Received: December 29, 2016 Published: April 18, 2017 3795

DOI: 10.1021/acs.jmedchem.6b01889 J. Med. Chem. 2017, 60, 3795−3803

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routinely used for SAR development or assessment of P-gp efflux. To reduce the extent of brain penetration observed in this series further, we targeted analogues with (1) an increased number of hydrogen bond donors, (2) an increased number of rotatable bonds, (3) increased polarity, and (4) increased polar surface area.14,15 We first focused on introducing polar groups and hydrogen bond donors at the C2, C4, and C5 positions to target B/P values of ≤0.1 in a molecule with acceptable potency and selectivity.

have a low potential for ventricular proarrhythmia along with an improved safety profile.8−11 Our recent disclosure12 in the phenylquinazoline series details the discovery of 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin5-yl)quinazolin-4-amine (1) as a potent (KV1.5; IC50 = 90 nM) and selective IKur inhibitor that demonstrated robust effects in both rat and rabbit pharmacodynamic models (Figure 1).

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RESULTS AND DISCUSSION All compounds described were assayed for block of IKur current in patch-clamped mammalian L-929 cells that were transfected with human KV1.5 and stably expressed IKur protein.16 Inhibition data for compounds 3−28 are listed in Tables 1−4. Compounds that were potent for KV1.5 were also evaluated for selectivity versus the hERG channel in an in vitro electrophysiology assay.17−19 Phenylquinazoline analogues 3−28 were obtained utilizing the general sequence described previously12 (Scheme 1). Dichloroquinazoline 2 was a versatile intermediate for exploring the SAR at the C2 and C4 positions. To further explore diversity at the C4 position, a library approach was used to incorporate polar groups and functional groups with hydrogen bond donors (Table 1). Intermediate 2 underwent selective C4 chloro displacement to yield the corresponding C4 amines, and the respective amines were subsequently converted to C2 heteroaryl analogues via transition metal cross coupling (Scheme 1). Utilizing compounds 3 and 4, corresponding analogues 5 and 6 were prepared, and utilizing amino-methyl-2-pyridine for the displacement at C4, corresponding analogues 7−28 were prepared. We were encouraged to find that sulfonamide 3 retained KV1.5 potency and selectivity versus hERG and was the first compound in the series to demonstrate a B/P of 10

1 40 >200 >200 >200

Table 6. PK Parameters for Compound 25a mouse iv (2 mg/kg), po (5 mg/kg) Cl (mL min−1 kg−1) Vss (L/kg) T1/2 (h) Cmax (μM) Tmax (h) AUC (μM h) %F

rat iv (2 mg/kg), po (5 mg/kg)

cynomolgus monkey iv (1 mg/kg), po (1 mg/kg)

dog iv (0.1 mg/kg), po (1 mg/kg)

10.6

3.3

3.2

0.05

1.8 2 4 0.5 21 100

0.9 3.2 7.9 2.6 49 100 (35)b

1.2 4.6 0.9 4.9 11 100 (54)b

0.2 51 7.8 590 64

Figure 3. Compound 25 in DMF (0.17 mg/mL). Data are means ± the standard error. AERP data were normalized with DMF. The time was counted from infusion of 0.17 mg/kg (maintenance dose). Tissues were collected after 30 min; n = 3 rabbits.

a

Vehicle, 1:4:5 EtOH/PG/PEG400. bPercent F with a micronized crystalline suspension.

Compound 25 was also progressed into the simultaneous atrio-ventricular pacing dog model, a clinically relevant pharmacodynamic model for atrial arrhythmia,23 to measure AF inducibility (0.1 or 0.3 mg/kg, dosed orally in a 10% EtOH/ 40% propylene glycol/50% PEG 400 PO vehicle). Compound 25 reduced the mean number of AF inductions and total AF duration in the absence of any effect on QTc interval at doses of 0.1 mg/kg (plasma concentration of 0.47 μM) and 0.3 mg/kg (plasma concentration of 1.84 μM) (Figure 4). The target efficacious human exposure at Ctrough was calculated to be between 150 and 400 nM based on the rabbit and dog pharmacodynamic studies, respectively. The human PK parameters were projected on the basis of allometric scaling of PK in preclinical species, except dog. The projected human dose of 25 was 30−80 mg, BID. Compound 25 was negative in the AMES and micronucleus assay, suggesting a low potential for mutagenicity. On the basis of further in vivo toxicological studies and the overall profile, compound 25 was selected as the clinical candidate. Compound 25 demonstrated pH-dependent solubility (Figure 5), and further evaluation of the pharmacokinetic profile in the monkey famotidine model showed that 25 demonstrated pH-dependent absorption at 10 mg/kg. On the basis of these observations, compound 25 had the potential to demonstrate pH-dependent

Figure 2. At 1 mg/kg IV, AERP was prolonged 10.6 and 10.7% at the 20 and 30 min time points, respectively. Changes in AERP were positively and significantly correlated to the compound 25 plasma concentration, which was 1.1 and 1.3 μM at the 20 and 30 min time points, respectively. At 3 mg/kg iv, AERP was prolonged by 10.8, 16.2, and 21.6% at the 10, 20, and 30 min time points, respectively, which correlated with plasma concentrations of 2.3, 3.6, and 3.3 μM, respectively.

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DOI: 10.1021/acs.jmedchem.6b01889 J. Med. Chem. 2017, 60, 3795−3803

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CONCLUSIONS We have further optimized the phenylquinazoline series of selective IKur inhibitors to reduce the level of brain penetration and have identified 25 as the lead compound in this series. Compound 25 had an acceptable in vitro selectivity and liability profile and a good pharmacokinetic profile across species. Compound 25 was advanced to rabbit and dog pharmacodynamic models of arrhythmia and demonstrated robust and dosedependent effects in these models. An acceptable human projected dose and in vivo safety profile in toxicology studies led to selection of compound 25 as our clinical candidate. The physicochemical properties of 25 were further improved by preparation of phosphoramide prodrug 29 as a backup candidate if needed. Clinical data for compound 25 will be disclosed in due course.

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EXPERIMENTAL SECTION

All reactions were performed under a static atmosphere of argon or nitrogen and mixtures stirred magnetically unless otherwise stated. All reagents used were of commercial quality. 1H NMR spectra were recorded with Bruker or JEOL FOURIER transform spectrometers operating at the following frequencies: 1H NMR, 400 MHz (Bruker or JEOL) or 500 MHz (JEOL); 13C NMR, 100 MHz (Bruker or JEOL). Spectral data are reported as chemical shift (multiplicity, coupling constants, number of hydrogens). Chemical shifts are specified in parts per million downfield of a tetramethylsilane internal standard (δ units; tetramethylsilane, 0 ppm) and/or referenced to solvent peaks, which in 1 H NMR spectra appear at 2.49 ppm for CD2HSOCD3, 3.30 ppm for CD2HOD, and 7.24 ppm for CHCl3 and in 13C NMR spectra appear at 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD, and 77.0 ppm for CDCl3. All 13C NMR spectra were proton-decoupled. 15N chemical shifts are referenced to (aqueous) 15NH4Cl at 27.3 ppm. Reverse phase analytical HPLC/MS was performed on an Agilent 1200 Series, Single Quadrapole instrument. A Waters Aquity system was coupled with a Waters Micromass SQ Mass Spectrometer. Chiral analytical LC was performed on a Waters SFC instrument. Methods used for the experiments are listed below (methods 1−9). Method 1: linear gradient from 0 to 100% B over 2 min; UV visualization at 220 nm; column, PHENOMENEX Luna C18 4.6 mm × 30 mm; flow rate, 5 mL/min; solvent A, 10 mM ammonium acetate, 90% water, and 10% methanol; solvent B, 10 mM ammonium acetate, 90% methanol, and 10% water. Method 2: linear gradient from 0 to 100% B over 2 min; UV visualization at 220 nm; column, CHROMOLITH SpeedROD C18 4.6 mm × 30 mm; flow rate, 5 mL/min; solvent A, 0.1% TFA, 90% water, and 10% methanol; solvent B, 0.1% TFA, 90% methanol, and 10% water. Method 3: linear gradient, 0/10, 12/100, 15/100, 18/10, 23/10 (T/% B); UV visualization at 220 and 254 nm; column, Waters Sun fire C18 (4.6 mm × 150 mm, 3.5 μm); flow rate, 1 mL/min; buffer, 0.05% TFA in water pH adjusted to 2.5 with dilute ammonia; mobile phase A, 95:5 buffer:acetonitrile; mobile phase B, 5:95 buffer:acetonitrile. Method 4: linear gradient, 0/10, 12/100, 15/100, 18/10, 23/10 (T/% B); UV visualization at 220 and 254 nm; column, Waters XBridge Phenyl (4.6 mm × 150 mm, 3.5 μm); flow rate, 1 mL/min; buffer, 0.05% TFA in water pH adjusted to 2.5 with dilute ammonia; mobile phase A, 95:5 buffer:acetonitrile; mobile phase B, 5:95 buffer:acetonitrile. Method 5: linear gradient from 10 to 100% B over 15 min, with a 12 min hold at 100% B; UV visualization at 220 nm; column, XBridge

Figure 4. Effect of 25 on AF duration and total AF burden in a canine pharmacodynamic model (n = 7 control dogs; n = 5 dogs at 0.1 mg/kg; and n = 6 dogs at 0.3 mg/kg).

Figure 5. pH-dependent solubility of 25 and corresponding prodrug 29.

absorption in humans and an increased probability of food effects and drug−drug interactions with co-administration of compounds that affect the stomach or intestinal pH. A prodrug strategy was employed to improve the solubility profile and mitigate the potential issues associated with pH-dependent absorption. Several prodrugs attached through the sulfonamide group were evaluated in vivo for (i) cleavage to compound 25, (ii) the concentration of the circulating prodrug, and (iii) the absorption profile. The prodrug with the best overall profile was phosphoramide 29. Compound 29 had an improved solubility profile (Figure 5) and mitigated pH-dependent absorption in the monkey famotidine model likely because of efficient hydrolysis at the intestinal brush border followed by rapid absorption of compound 25. No circulating prodrug was observed in vivo. 3801

DOI: 10.1021/acs.jmedchem.6b01889 J. Med. Chem. 2017, 60, 3795−3803

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phenyl (4.6 mm × 150 mm, 3.5 μm SC/1072); flow rate, 1 mL/min; buffer, 0.05% TFA in water at pH 2.5; mobile phase A, 95:5 buffer:acetonitrile; mobile phase B, 95:5 acetonitrile:buffer. Method 6: linear gradient, 0/0, 12/100, 15/100 [T (minutes)/% B]; column, Xbridge Phenyl [3.5 μm × 150 mm (length) × 4.6 mm]; flow rate, 1.0 mL/min; mobile phase A, 0.05% TFA in water pH adjusted to 2.5 using a dilute NH3/ACN mixture (95:5); mobile phase B, 0.05% TFA in water pH adjusted to 2.5 using a dilute NH3/ACN mixture (5:95). Method 7: linear gradient, 0/20, 4/100, 4.6/100, 4.7/20 [T (minutes)/% B]; column, Kinetex XB-C18 (75 mm × 3 mm, 2.6 μm); flow rate, 1.0 mL/min; mobile phase A, 10 mM ammonium formate in a water/ACN mixture (98:02); mobile phase B, 10 mM ammonium formate in a water/ACN mixture (02:98). Method 8: linear gradient, 0/0, 15/50, 18/100, 23/100 [T (minutes)/% B]; column, Xbridge Phenyl [3.5 μm × 150 mm (length) × 4.6 mm]; flow rate, 1.0 mL/min; mobile phase A, 0.05% TFA in water pH adjusted to 2.5 using a dilute NH3/ACN mixture (95:5); mobile phase B, 0.05% TFA in water pH adjusted to 2.5 using a dilute NH3/ ACN mixture (5:95). Method 9: linear gradient, 0/0, 15/50, 18/100, 23/100 (T/% B); UV visualization at 220 and 254 nm; column, Waters Sunfire C18 (4.6 mm × 150 mm, 3.5 μm); flow rate, 1 mL/min; buffer, 0.05% TFA in water pH adjusted to 2.5 with dilute ammonia; mobile phase A, 95:5 buffer:acetonitrile; mobile phase B, 5:95 buffer:acetonitrile. The purity for compounds was measured by HPLC analysis using the conditions listed for the methods described above and determined to be ≥95%. 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25). A mixture of pyridine-3-sulfonic acid (10.30 g, 64.80 mmol), phosphorus pentachloride (20.82 g, 100.0 mmol), and phosphorus oxychloride (10 mL, 110 mmol) was heated at 120 °C for 4 h. The reaction mixture was allowed to cool to room temperature and evaporated to dryness under reduced pressure to yield a residue. The residue was treated with bromine (6.00 mL, 116 mmol) and heated to reflux at 80 °C for 14 h. The reaction mixture was cooled to 0 °C, and a saturated solution of NH4OH in H2O (40 mL) was slowly added. The resulting reaction mixture was allowed to warm to room temperature while being stirred and filtered, and the filter cake was washed with hexane to afford 5-bromopyridine-3-sulfonamide (6.0 g, 58%) as an off-white solid. The compound was used without further purification. LC/MS method 1: retention time, 0.75 min; [M + 1] 237.0. HPLC method 8: purity, 94.8%; retention time, 8.93 min. HPLC method 9: purity, 94.6%; retention time, 5.49 min. 1H NMR (400 MHz, DMSO-d6): δ 7.73 (s, 2H), 8.39 (t, J = 2.4 Hz, 1H), 8.95 (dd, J = 2.4, 6.4 Hz, 2H). 13C NMR (126 MHz, DMSO-d6): δ 120.14, 135.84, 141.28, 144.69, 153.31. Pyridine-3-sulfonamide-5-ylboronic Acid Pinacol Ester. A solution of 5-bromopyridine-3-sulfonamide (1.50 g, 6.33 mmol), bis(pinacolato)diboron (2.41 g, 9.50 mmol), and potassium acetate (1.86 g, 19.0 mmol) in 1,4-dioxane (15 mL) was degassed with nitrogen for 15 min, and then the [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (0.232 g, 0.317 mmol) was added and the resulting mixture degassed further with nitrogen for 10 min. The reaction mixture was heated in a microwave reactor at 120 °C for 45 min, allowed to cool, and filtered through Celite, and the filtrate was concentrated under reduced pressure to provide pyridine-3-sulfonamide-5-ylboronic acid pinacol ester (0.740 g, 41.3%) as a brown solid. The compound was used without further purification. LC/MS method 7: retention time, 0.36 min; [M + 1] 285.2. 1H NMR (400 MHz, DMSO-d6): δ 8.83 (s, 1H), 8.80 (s, 1H), 8.26 (s, 1H), 7.56− 7.74 (bs, 2H), 1.17 (s, 12H). HRMS: [M + 1] observed 285.1071, calcd 285.1075. 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25). To a solution of 2-chloro-5-phenyl-N(pyridin-2-ylmethyl)quinazolin-4-amine (0.150 g, 0.430 mmol) in 1,4dioxane (6 mL) and H2O (1 mL) under nitrogen were added pyridine-3sulfonamide-5-ylboronic acid pinacol ester (0.185 g, 0.650 mmol) and potassium carbonate (0.119 g, 0.860 mmol). The reaction mixture was degassed with nitrogen for 15 min, and the [1,1′-bis-

(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (0.0031 g, 0.043 mmol) was added. The resulting mixture was degassed with nitrogen for 10 min and heated to 90 °C for 16 h. The reaction mixture was allowed to cool to room temperature, the reaction quenched by the addition of water, and then the mixture transferred to a separation funnel. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by preparative TLC using 5% methanol in dichloromethane to afford compound 25 (0.050 g, 20%) as a brown solid. LC/MS method 2: retention time, 1.49 min; [M + 1] 469.0. HPLC method 3: purity, 96.5%; retention time, 9.19 min. HPLC method 4: purity, 96.6%; retention time, 8.89 min. 1H NMR (400 MHz, DMSO-d6): δ 9.81 (d, J = 1.93 Hz, 1H), 9.18 (t, J = 2.20 Hz, 1H), 9.10 (d, J = 2.20 Hz, 1H), 8.24 (d, J = 4.95 Hz, 1H), 7.93 (d, J = 8.25 Hz, 1H), 7.86 (m, 1H), 7.77 (br s, 2H), 7.73 (t, J = 7.70 Hz, 1H), 7.55 (m, 2H), 7.55 (m, 2H), 7.55 (m, 1H), 7.33 (d, J = 7.29 Hz, 1H), 7.33 (d, J = 7.29 Hz, 1H), 7.24 (t, J = 6.05 Hz, 1H), 6.95 (t, J = 3.85 Hz, 1H), 4.76 (d, J = 3.30 Hz, 2H). 13C NMR (126 MHz, DMSO-d6): δ 46.04, 111.66, 121.60, 122.14, 127.87, 128.41, 129.06, 129.08, 129.43, 132.20, 132.29, 133.68, 136.69, 138.94, 139.72, 140.17, 147.48, 148.18, 150.76, 151.81, 155.26, 156.06, 158.97. 15N NMR (400 Hz, DMSO-d6): δ 96.1, 100.2, 224.1, 243.5, 305.0, 317.9. Elemental analysis, MF C25H20N6O2S. Calcd: C, 64.09; H, 4.30; N, 17.94; O, 6.83; S, 6.84. Found: C, 63.34; H, 4.24; N, 17.29; S, ND; H2O, ND. IR peak assignments (KBr film): 3361, 3341 cm−1 (N−H stretches); 1356, 1162 cm−1 (sulfur dioxide stretches). HRMS: [M + 1] observed 469.1432, calcd 469.1441. 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-ylsulfonylphosphoramidic Acid (29). To a solution of 5{5-phenyl-4-[(pyridin-2-ylmethyl)amino]quinazolin-2-yl}pyridine-3sulfonamide (25) (3.0 g, 6.4 mmol) in DCM (50 mL) was added DIPEA (2.237 mL, 12.81 mmol). The reaction mixture was stirred for 20 min and cooled to 0 °C, and POCl3 (2.39 mL, 25.6 mmol) was added and the reaction mixture stirred for 4 h. DCM and excess POCl3 were removed under reduced pressure, and the residue was dissolved in 100 mL of water and stirred for 1 h. The resulting solid was filtered and the solid washed with excess water and then dried under reduced pressure to yield 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridin-3-ylsulfonylphosphoramidic acid (30) (2.50 g, 71.0%) as an off-white solid. To a solution of amorphous [(5-{5-phenyl-4-[(pyridin-2-ylmethyl)amino]quinazolin-2-yl}pyridin-3-yl)sulfonyl]phosphoramidic acid (30) (6.00 g, 10.9 mmol) (HPLC purity, 97%) in DMSO (100 mL) was added water (40 mL), and the suspension was stirred for 1 h. The resulting solid was filtered, washed with water (10 mL), and dried under reduced pressure to yield crystalline [(5-{5-phenyl-4-[(pyridin-2ylmethyl)amino]quinazolin-2-yl}pyridin-3-yl)sulfonyl]phosphoramidic acid (29) (4.60 g, 77.1%). LC/MS method 6: retention time, 6.19 min; [M + 1] 549.1. HPLC method 5: purity, 99.3%; retention time, 6.30 min. 1H NMR (400 MHz, DMSO-d6): δ 4.78 (d, J = 4 Hz, 2H), 6.91 (t, J = 4 Hz, 1H), 7.30−7.36 (m, 2H), 7.40 (d, J = 8 Hz, 1H), 7.53−7.58 (m, 5H), 7.81 (ddd, J = 13.6, 7.6, 1.6 Hz, 1H), 7.86 (t, J = 8.4 Hz, 1H), 7.94 (dd, J = 8.4, 1.2 Hz, 1H), 8.35 (d, J = 4.4 Hz, 1H), 9.09 (d, J = 2.4 Hz, 1H), 9.28 (t, J = 2 Hz, 1H), 9.75 (d, J = 2 Hz, 1H). 13C NMR (400 MHz, DMSO-d6): δ 159.429, 156.404, 155.804, 152.351, 151.061, 148.554, 147.659, 140.087, 139.540, 139.394, 138.517, 134.042, 133.818, 132.799, 130.009, 129.630, 129.548, 128.977, 128.171, 123.061, 122.610, 111.997, 46.022. Elemental analysis, MF C25H21N6O5PS·4H2O. Calcd: C, 48.57; H, 4.69; N, 13.53; S, 5.46; H2O, 11.53. Found: C, 48.26; H, 4.80; N, 13.19; S, 5.53; H2O, 12.42.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b01889. Experimental details for synthesis and analysis of compounds 6−24 and 26−29 (PDF) 3802

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(11) Ravens, U.; Wettwer, E. Ultra-rapid delayed rectifier channels: molecular basis and therapeutic implications. Cardiovasc. Res. 2011, 89, 776−785. (12) Finlay, H. J.; Johnson, J. A.; Lloyd, J. L.; Jiang, J.; Neels, J.; Gunaga, P.; Banerjee, A.; Dhondi, N.; Chimalakonda, A.; Mandlekar, S.; Conder, M. L.; Sale, H.; Xing, D.; Levesque, P.; Wexler, R. R. Discovery of 5phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a potent IKur inhibitor. ACS Med. Chem. Lett. 2016, 7, 831−834. (13) Hitchcock, S. A.; Pennington, L. D. Structure-brain exposure relationships. J. Med. Chem. 2006, 49, 7559−7583. (14) Cho, S. J.; Sun, X.; Harte, W. ADAAPT: Amgen’s data access, analysis, and prediction tools. J. Comput.-Aided Mol. Des. 2006, 20, 249− 261. (15) Tamayo, N.; Liao, H.; Stec, M. M.; Wang, X.; Chakrabarti, P.; Retz, D.; Doherty, E. M.; Surapaneni, S.; Tamir, R.; Bannon, A. W.; Gavva, N. R.; Norman, M. H. Design and synthesis of peripherally restricted transient receptor potential vanilloid 1(TRPV1) antagonists. J. Med. Chem. 2008, 51, 2744−2757. (16) Snyders, D. J.; Tamakun, M. N.; Bennett, P. B. A rapidly activating and slowly inactivating potassium channel cloned from human heart: functional analysis after stable mammalian cell culture expression. J. Gen. Physiol. 1993, 101, 513−543. (17) Zhou, Z.; Vorperian, V. R.; Gong, Q.; Zhang, S.; January, C. T. January, C.T. Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. Journal of Cardiovascular Electrophysiology 1999, 10, 836−843. (18) De Bruin, M. L.; Hoes, A. W.; Leufkens, H. G. QTc-Prolonging drugs and hospitalizations for cardiac arrhythmias. Am. J. Cardiol. 2003, 91, 59−62. (19) Yap, Y. G.; Camm, A. J. Drug induced QT prolongation and torsades de pointes. Br. Heart J. 2003, 89, 1363−1372. (20) Thanga Mariappan, T.; Mandlekar, S.; Marathe, P. Insight into tissue unbound concentration: utility in drug discovery and development. Curr. Drug Metab. 2013, 14, 324−340. (21) Johnson, J. A.; Lloyd, J.; Finlay, H.; Jiang, J.; Neels, J.; Dhondi, N. K.; Gunaga, P.; Banerjee, A.; Adisechan, A. Preparation of 5phenylquinazoline derivatives as potassium ion channel inhibitors. WO 2011028741, 2011. (22) Carlsson, L. The anaesthetised methoxamine-sensitised rabbit model of torsades de pointes. Pharmacol. Ther. 2008, 119, 160−167. (23) Laurent, G.; Moe, G. W.; Hu, X.; Pui-Sze So, P.; Ramadeen, A.; Leong-Poi, H.; Doumanovskaia, L.; Konig, A.; Trogadis, J.; Courtman, D.; Strauss, B. H.; Dorian, P. Simultaneous right atrioventricular pacing: a novel model to study atrial remodeling and fibrillation in the setting of heart failure. J. Card. Failure 2008, 14, 254−262.

AUTHOR INFORMATION

Corresponding Authors

*Phone: 609-466-5038. Fax: 609-818-3550. E-mail: heather. fi[email protected]. *Phone: +91 9900150718. E-mail: prashantha.gunaga@ syngeneintl.com. ORCID

Heather J. Finlay: 0000-0003-2309-0136 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the following collaborators: Kavitha Govindrajulu and Shreelalitha Badagi for the synthesis of closely related analogues in this series, Amrita Roy at BBRC for library synthesis of the C4 analogues, and Lokesh Babu, Nanjundaswamy K C, Thirupala Reddy, Indasi Gopi Kumar, and Sridharan Ramalingamfor their contributions to scale-up of intermediate 2.

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ABBREVIATIONS USED AERP, atrial effective refractory period; VERP, ventricular effective refractory period; AF, atrial fibrillation

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REFERENCES

(1) Lip, G. Y. H.; Tse, H.-F. Management of atrial fibrillation. Lancet 2007, 370, 604−618. (2) Wilke, T.; Groth, A.; Mueller, S.; Pfannkuche, M.; Verheyen, F.; Linder, R.; Maywald, U.; Bauersachs, R.; Breithardt, G. Incidence and prevalence of atrial fibrillation: an analysis based on 8.3 million patients. Eurospace 2013, 15, 486−493. (3) Skanes, A. C.; Healey, J. S.; Cairns, J. A.; Dorian, P.; Gillis, A. M.; McMurtry, S. M.; Mitchell, B. L.; Verma, A.; Nattel, S. Canadian Cardiovascular Society Atrial Fibrillation Guidelines Committee. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/ rhythm control. Can. J. Cardiol. 2012, 28, 125−136. (4) Calkins, H.; Brugada, J.; Packer, D. L.; Cappato, R.; Chen, S.-A.; Crijns, H. J. G.; Damiano, R. J., Jr; Davies, D. W.; Haines, D. E.; Haissaguerre, M.; Iesaka, Y.; Jackman, W.; Jais, P.; Kottkamp, H.; Kuck, K. H.; Lindsay, B. D.; Marchlinski, F. E.; McCarthy, P. M.; Mont, J. L.; Morady, F.; Nademanee, K.; Natale, A.; Pappone, C.; Prystowsky, E.; Raviele, A.; Ruskin, J. N.; Shemin, R. J.; et al. HRS/EHRA/ECAS Expert Consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for personnel, policy, procedures and follow-up. Eurospace 2007, 9, 335−379. (5) Kathofer, S.; Thomas, D.; Karle, C. A. The novel antiarrhythmic drug dronedarone: comparison with amiodarone. Cardiovasc. Drug Rev. 2005, 23, 217−230. (6) Amos, G. J.; Wettwer, E.; Metzger, F.; Li, Q.; Himmel, H. M.; Ravens, U. Differences between outward currents of human atrial and subepicardial ventricular myocytes. J. Physiol. 1996, 491, 31−50. (7) Li, G. R.; Feng, J.; Yue, L.; Carrier, M.; Nattel, S. Evidence for two components of delayed rectifier K+ current in human ventricular myocytes. Circ. Res. 1996, 78, 689−696. (8) Ford, J. W.; Milnes, J. T. New drugs targeting the cardiac ultra-rapid delayed-rectifier current (IKur): Rationale, pharmacology and evidence for potential therapeutic value. J. Cardiovasc. Pharmacol. 2008, 52, 105− 120. (9) Li, D.; Sun, H.; Levesque, P. Antiarrhythmic drug therapy for atrial fibrillation: Focus on atrial selectivity and safety. Cardiovasc. Hematol. Agents Med. Chem. 2009, 7, 64−75. (10) Tamargo, J.; Caballero, R.; Gomez, R.; Delpon, E. IKur/ KV1.5 channel blockers for the treatment of atrial fibrillation. Expert Opin. Invest. Drugs 2009, 18, 399−416. 3803

DOI: 10.1021/acs.jmedchem.6b01889 J. Med. Chem. 2017, 60, 3795−3803