Design, synthesis, and biological evaluation of first-in-class dual acting

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1 Design, synthesis, and biological evaluation of first-in-class dual acting histone deacetylases (HDACs) and phosphodiesterase 5 (PDE5) inhibitors for the treatment of Alzheimer s disease Obdulia Rabal, 1,5 Juan A. Sánchez-Arias, 1,5 Mar Cuadrado-Tejedor, 2,3,5 Irene de Miguel, 1 Marta Pérez-González, 2 Carolina García-Barroso, 2 Ana Ugarte, 1 Ander Estella-Hermoso de Mendoza, 1 Elena Sáez, 1 Maria Espelosin, 2 Susana Ursua, 2 Tan Haizhong, 4 Wu Wei, 4 Xu Musheng, 4 Ana Garcia-Osta, 2,* and Julen Oyarzabal. 1,* SUPPORTING INFORMATION Table of Contents S1. Protocol for preparative HPLC purification methods.....s2 S2. Protocol for SFC purification method of 7a and 7b... S2 S3. Synthesis of intermediates 1 to S3 S4. HPLC purities and HRMS of final compounds S18 S5. HPLC traces for final compounds S21 S6. Figure S1..S45 S7. Table S1 S46 S1

2 S1. Protocol for preparative HPLC purification methods The HPLC measurement was performed using Gilson 281 or SHIMADZU preparative HPLC, an autosampler and a UV detector. The fractions were detected by LC-MS. The MS detector was configured with an electrospray ionization source. The source temperature was maintained at o C. Method 1 Reverse phase HPLC was carried out on luna C18 (100 x 30 mm; 4 µm). Solvent A: water with 0.075% trifluoroacetic acid; Solvent B: acetonitrile with 0.075% trifluoroacetic acid. Gradient: At room temperature, 20% of B to 40% of B within 6 minutes at 25 ml/min; then 40% B at 25 ml/min over 2 minutes. Method 2 Reversed phase HPLC was carried out on luna (100 x 30 mm; 5 µm). Solvent A: water; Solvent B: acetonitrile. Gradient: At room temperature, 45% of B to 75% of B within 9.5 minutes; then 75% B over 2 minutes, Flow rate: 20 ml/min. Method 3 Reversed phase HPLC was carried out on luna (100 x 30 mm; 5 µm). Solvent A: water with 0.075% trifluoroacetic acid; Solvent B: acetonitrile. Gradient: At room temperature, 25% of B to 55% of B within 11 minutes; then 55% B over 2 minutes. Flow rate: 25 ml/min. S2. Protocol for SFC purification method of 7a and 7b Preparative separation was performed using Thar SFC Pre-80 instrument with a Chiralcel OD-H column (5mm, 3.0 cm id x 25 cm L). Solvent A: CO 2 ; Solvent B: IPA (isopropylantipyrine). Mobile phase 65% of A and 35% of B at 70 g/min. Back pressure: 100 bar. S2

3 S3. Synthesis of intermediates 1 to 20 Synthesis of ethyl 2-piperazin-1-ylpyrimidine-5-carboxylate (Int.1) Pd(dppf)Cl 2 K 2 CO 3 CH 3 CN, 80 ºC SI-1 Et 3 N, CO EtOH, 100 ºC SI-2 HCl/CH 2 Cl 2 Int. 1 tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (SI-1) To a solution of 5-bromo-2-chloro-pyrimidine (9.75 g, 50 mmol) in CH 3 CN (100 ml) were added tert-butyl piperazine-1-carboxylate (9.25 g, 50 mmol) and K 2 CO 3 (13.8 g, 100 mmol) and the reaction mixture was stirred at 80 ºC overnight. Then the reaction mixture was concentrated under vacuum and extracted with EtOAc. The organic phase was washed with water, dried over anhydrous Na 2 SO 4, filtered and concentrated to give compound SI-1 (15 g 87%). ESI-MS m/z 343 [M+H] + calc. for C 13 H 19 BrN 4 O 2 ethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)pyrimidine-5-carboxylate (SI-2) To a solution of SI-1 (6.00 g, mmol) in EtOH (100 ml) were added Et 3 N (1.77 g, 2.43 ml) and Pd(dppf)Cl 2 (5 g, 6.83 mmol) and the reaction mixture was stirred at 100 ºC at 1.5 MPa under CO atmosphere overnight. The reaction mixture was filtrated and the filtrate was concentrated to give the desired product SI-2 (5 g, 85%). ESI-MS m/z 337 [M+H] + calc. for C 16 H 24 N 4 O 4 ethyl 2-piperazin-1-ylpyrimidine-5-carboxylate (Int. 1) A solution of SI-2 (2.50 g, 7.44 mmol) in HCl/CH 2 Cl 2 (4.0 M, 30 ml) was stirred at room temperature overnight. Then, the solution was concentrated to give the desired Int. 1 (1.7 g, 97%). 1 H NMR (MeOD, 400 MHz): δ 8.88 (s, 2H), 4.35 (q, 2H), 4.15 (m, 4H), 3.30 (m, 4H), 1.38 (t, 3H). ESI-MS m/z 237 [M+H] + calc. for C 11 H 16 N 4 O 2 S3

4 Synthesis of ethyl (E)-3-[4-(piperazin-1-ylmethyl)phenyl]prop-2-enoate (Int. 2) THF SI-3 AcOH, MeOH SI-4 Boc 2 O, Et 3 N CH 2 Cl 2 TFA CH 2 Cl 2 SI-5 Int. 2 ethyl (E)-3-(4-formylphenyl)prop-2-enoate (SI-3) To a solution of terephthalaldehyde (15 g, 0.11 mol) in anhydrous THF (100 ml) was added ethyl (triphenylphosphoranylidene)acetate (19.5 g, 56 mmol) and the reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated and purified by column chromatography to give the desired product SI-3 (5 g, 44%). 1 H NMR (CDCl 3, 400 MHz): δ (s, 1H), (d, J = 8 Hz, 2H), (m, 3H), (d, J = 16 Hz, 1H), 4.30 (q, 2H), 1.36 (t, 3H). ESI-MS m/z 205 [M+H] + calc. for C 12 H 12 O 3 ethyl (E)-3-[4-(piperazin-1-ylmethyl)phenyl]prop-2-enoate (SI-4) To a solution of compound SI-3 (0.204 g, 1 mmol) in MeOH (10 ml) was added AcOH (0.1 ml) and piperazine (0.164 g, 2 mmol) and the reaction mixture was stirred at room temperature overnight. Then, NaBH 3 CN (189 g, 3 mmol) was added into the reaction mixture and stirred at room temperature for 2 hours. Then the reaction mixture was concentrated to give the desired compound SI-4 (250 mg, 91%). ESI-MS m/z 275 [M+H] + calc. for C 16 H 22 N 2 O 2 tert-butyl 4-[[4-[(E)-3-ethoxy-3-oxo-prop-1-enyl]phenyl]methyl]piperazine-1-carboxylate (SI-5) To a solution of compound SI-4 (250 mg, 0.91 mmol) in CH 2 Cl 2 (12 ml) was added Et 3 N (152 mg, 1.50 mmol) and Boc 2 O (236 mg, 1.09 mmol). The reaction mixture was stirred at room temperature overnight, and then concentrated. The residue was purified by column S4

5 chromatography to give SI-5 (320 mg, 94%). ESI-MS m/z 375 [M+H] + calc. for C 21 H 30 N 2 O 4 ethyl (E)-3-[4-(piperazin-1-ylmethyl)phenyl]prop-2-enoate (Int. 2) To a solution of compound SI-5 (320 mg, 0.86 mmol) in CH 2 Cl 2 (10 ml) was added TFA (1 ml). The reaction mixture was stirred at room temperature for 5 hours, and then concentrated to give the desired compound Int. 2 (200 mg, 85%). ESI-MS m/z 275 [M+H] + calc. for C 16 H 22 N 2 O 2 Synthesis of methyl 3-(4-piperidyl)propanoate (Int.3) Pd/C, H 2 THF EtOH, 40 ºC SI-6 Int. 3 ethyl (E)-3-(4-pyridyl)prop-2-enoate (SI-6) To a solution of commercially available pyridine-4-carbaldehyde (5.16 g, mmol) in anhydrous THF (50 ml) was added ethyl (triphenylphosphoranylidene)acetate (20.13 g, mmol) and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture was concentrated and purified by column chromatography to give the desired compound SI-6 (3 g, 36%). 1 H NMR (CDCl 3, 400 MHz): δ (d, J = 6.4 Hz, 2H), (d, J = 16 Hz, 1H), (d, J = 6.4 Hz, 2H), (d, J = 16 Hz, 1H), 4.32 (q, 2H), 1.35 (t, 3H). ESI-MS m/z 178 [M+H] + calc. for C 10 H 11 NO 2 methyl 3-(4-piperidyl)propanoate (Int.3) A mixture of SI-6 (3 g, mmol) and Pd/C (0.5 g) in EtOH (30 ml) was stirred at 40 o C under H 2 atmosphere (40 Psi) overnight. The mixture was filtrated and washed with MeOH. Then, the filtrate was concentrated under vacuum to give the desired compound Int. 3 (3 g, 99 crude%). 1 H NMR (MeOD, 400 MHz): δ 3.67 (s, 3H), 3.04 (m, 2H), 2.65 (t, 2H), 2.35 (t, 2H), 1.75 (m, 2H), 1.65 (m, 2H), 4.32 (q, 2H), 1.41 (m, 1H), 1.25 (m, 2H). ESI-MS m/z 172 [M+H] + calc. for C 9 H 17 NO 2. (The methyl ester is formed when washing with MeOH). S5

6 Synthesis of ethyl 2-(4-amino-1-piperidyl)pyrimidine-5-carboxylate (Int. 4) Pd(dppf) 2 Cl 2 K 2 CO 3 CH 3 CN, 80 ºC SI-7 Et 3 N, CO EtOH, 100 ºC SI-8 HCl/CH 2 Cl 2 Int. 4 tert-butyl N-[1-(5-bromopyrimidin-2-yl)-4-piperidyl]carbamate (SI-7) To a solution of 5-bromo-2-chloro-pyrimidine (9.75 g, 50 mmol) in CH 3 CN (100 ml) were added tert-butyl piperidin-4-ylcarbamate (9.95 g, 50 mmol) and K 2 CO 3 (13.8 g, 100 mmol) and the reaction mixture was stirred 80 o C overnight. Then, the reaction mixture was concentrated and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous Na 2 SO 4, filtered and concentrated under vacuum to give the crude product which was purified through column chromatography to give SI-7 (15 g, 84%). ESI-MS m/z 357 [M+H] + calc. for C 14 H 21 BrN 4 O 2 ethyl 2-[4-(tert-butoxycarbonylamino)-1-piperidyl]pyrimidine-5-carboxylate (SI-8) To a solution of SI-7 (5.00 g, mmol) in EtOH (100 ml) were added Et 3 N (1.77 g, 2.43 ml) and Pd(dppf)Cl 2 (512 mg, 0.7 mmol) and the reaction mixture was stirred at 100 o C at 1.5 MPa under CO atmosphere overnight. The reaction mixture was filtrated and the filtrate was concentrated to give the crude product which was purified through column chromatography to give desired SI-8 (3 g, 61%). ESI-MS (M+1): calc. for C 17 H 26 N 4 O 4 ethyl 2-(4-amino-1-piperidyl)pyrimidine-5-carboxylate (Int. 4) A solution of SI-8 (3 g, 8.57 mmol) in HCl/CH 2 Cl 2 (4.0 M, 30 ml) was stirred at room temperature overnight. Then, the solution was concentrated to give the desired Int. 4 (2 g, 93%). 1 H NMR (CDCl 3, 400 MHz): δ 8.88 (s, 2H), 4.88 (m, 2H), 4.35 (q, 2H), 3.51 (m, 1H), 3.25 (m, 2H), 2.15 (m, 2H), 1.65 (m, 2H), 1.38 (t, 3H). ESI-MS m/z 251 [M+H] + calc. for C 12 H 18 N 4 O 2 S6

7 Synthesis of ethyl (E)-3-(4-aminophenyl)prop-2-enoate (Int. 5) Fe THF AcOH SI-9 Int. 5 ethyl (E)-3-(4-nitrophenyl)prop-2-enoate (SI-9) To a solution of 4-nitrobenzaldehyde (10 g, mmol) in anhydrous THF (100 ml) was added ethyl (triphenylphosphoranylidene)acetate (34 g, mmol) and the reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated and purified by column chromatography to give the desired compound SI-9 (10 g, 68%). 1 H NMR (CDCl 3, 400 MHz): δ (d, J = 8.8 Hz, 2H), (m, 3H), (d, J = 16 Hz, 1H), 4.32 (q, 2H), 1.38 (t, 3H). ESI-MS (M+1): calc. for C 11 H 11 NO 4 ethyl (E)-3-(4-aminophenyl)prop-2-enoate (Int. 5) To a solution of SI-9 (2.07 g, 10 mmol) in AcOH (30 ml) was added Fe (1112 mg, 20 mmol) and the reaction mixture was stirred at room temperature overnight. Then, the mixture was filtrated and the residue was concentrated to give the Int. 5 (1.5 g, 78%). 1 H NMR (CDCl 3, 400 MHz): δ (d, J = 15.6 Hz, 1H), (d, J = 8.4 Hz, 2H), (d, J = 8.4 Hz, 2H), (d, J = 15.6 Hz, 1H) 4.32 (q, 2H), 1.38 (t, 3H). ESI-MS (M+1): calc. for C 11 H 13 NO 2 Synthesis of methyl 4-(4-oxo-1-piperidyl)benzoate (Int. 6) Cu(OAc) 2, Et 3 N CH 2 Cl 2 HCl/EtOAc 70 ºC SI-10 Int. 6 methyl 4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate (SI-10) To a solution of compound 1,4-dioxa-8-azaspiro[4.5]decane (1.43 g, 10 mmol) in CH 2 Cl 2 (20 ml) were added (4-methoxycarbonylphenyl)boronic acid (3.6 g, 20 mmol), Cu(OAc) 2 (1.82 g, 10 mmol) and Et 3 N (2 g, 20 mmol) and the mixture was stirred overnight. Then, S7

8 the mixture was quenched with water and extracted with CH 2 Cl 2, the organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give the crude product which was purified by column chromatography to give compound SI-10 (1.2 g, 44%) as a pale yellow solid. ESI-MS m/z 278 [M+H] + calc. for C 15 H 19 NO 4 methyl 4-(4-oxo-1-piperidyl)benzoate (Int. 6) A solution of compound SI-10 (0.8 g, 2.9 mmol) in HCl/EtOAc (2.0 M, 10 ml) was stirred at 70 o C overnight, then concentrated to give the crude product which was purified by column chromatography to obtained pure Int. 6 (0.3 g, 44%) as white solid. ESI-MS m/z [M+H] + calc. for C 13 H 15 NO 3 Synthesis of methyl 2-azaspiro[5.5]undecane-9-carboxylate (Int. 7) HCl/EtOAc Int. 7 A solution of O2-tert-butyl O9-methyl 2-azaspiro[5.5]undecane-2,9-dicarboxylate (200 mg, 0.64 mmol) in HCl/EtOAc (1.0 N, 15 ml) was stirred at room temperature for 1 hour, then concentrated to give the desired Int. 7 (120 mg, 89%) as yellow solid. ESI-MS m/z [M+H] + calc. for C 12 H 21 NO 2 Synthesis of ethyl 4-hydroxycyclohexanecarboxylate (Int. 8) NaBH 4 MeOH, 0 ºC then rt Int. 8 To a solution of ethyl 4-oxocyclohexanecarboxylate (5.0 g, 29 mmol) in MeOH (50 ml) was added NaBH 4 (2.24 g, 59 mmol) at 0 o C in portions, then the mixture was stirred at room temperature for 1 hour. Then, the reaction was quenched with water and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous S8

9 Na 2 SO 4, filtered and concentrated to give Int. 8 (4.95 g, 99%) as a pale yellow oil. ESI-MS m/z 173 [M+H] + calc. for C 9 H 16 O 3 Synthesis of tert-butyl 4-hydroxypiperidine-1-carboxylate (Int. 9) Boc 2 O, Et 3 N CH 2 Cl 2 Int.9 To a solution of piperidin-4-ol (10.1 g, 0.1 mol) in anhydrous CH 2 Cl 2 (100 ml) were added Et 3 N (20.2 g, 0.2 mol) and di-tert-butyl dicarbonate (21.6 g, 0.1 mmol) and the reaction mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was washed with water and extracted with CH 2 Cl 2. The organic layer was dried over anhydrous Na 2 SO 4, filtered and concentrated under vacuum to give Int. 9 (20 g, 99%). ESI-MS m/z 202 [M+H] + calc. for C 10 H 19 NO 3 Synthesis of bromo-(2-ethoxy-2-oxo-ethyl)zinc (Int. 10) Zn, TMSCl THF, rt then 40 ºC Int. 10 Zn powder (5.2 g, 80 mmol) was put into a 250 ml of three-neck flask under N 2 protection, and then TMSCl (0.5 ml, 3.96 mmol) dissolved in dry THF (20 ml) was injected into the flask. The suspension mixture was stirred at room temperature for 20 minutes, then ethyl 2- bromoacetate (6.5 ml, mmol) dissolved in dry THF (50 ml) was dropped into the flask for about 30 minutes at room temperature. After the addition was complete, the reaction mixture was stirred at 40 o C for another 30 minutes and then was used for the next step directly. Synthesis of tert-butyl 4-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)piperidine-1-carboxylate (Int. 11) CH 3 P(C 6 H 5 ) 3 Br nbuli, THF SI-11 9-BBN-H THF, reflux Int. 11 S9

10 tert-butyl 4-methylenepiperidine-1-carboxylate (SI-11) To a solution of methyl triphenyl phosphonium bromide (59.03 g, mol) in THF (300 ml) was added n-buli (66 ml, 2.5 M in THF, 166 mmol) at -78 ºC and the mixture was stirred for 1 hour. Then, tert-butyl 4-oxopiperidine-1-carboxylate (30 g, mol) was added dropwise in THF (30 ml) at -78 ºC. After addition, the mixture was stirred at room temperature overnight. Then, the reaction was quenched with aqueous NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give the crude compound which was purified by column chromatography to obtain pure compound SI-11 (18 g, 61%) as a pale yellow oil. ESI-MS m/z 198 [M+H] + calc. for C 11 H 19 NO 2. tert-butyl 4-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)piperidine-1-carboxylate (Int. 11) Compound SI-11 (6 g, 31 mmol) was treated with a solution of 9-BBN-H (0.5 M in THF, 62 ml) and the mixture was heated at reflux for 4 hours. The resulting Int. 11 was immediately used for the synthesis of compound 43d. Synthesis of tert-butyl 4-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)piperidine-1-carboxylate (Int. 12) 9-BBN-H n-buli THF, - 78 ºC to rt THF, reflux SI-12 Int. 12 tert-butyl 4-methylenepiperidine-1-carboxylate (SI-12) To a solution of methyltriphenylphosphonium bromide (59.03 g, mol) in THF (300 ml) was added n-buli (66 ml, 2.5 M, mol) at -78 o C and the mixture was stirred at - 78 o C for 1 hour. Then, tert-butyl 4-oxopiperidine-1-carboxylate (30 g, mol) in THF (30 ml) was added dropwise at -78 o C and the mixture was stirred at room temperature overnight. Then, the reaction was quenched with aqueous NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give the crude compound which was purified by column S10

11 chromatography to give pure compound SI-12 (18 g, 61%) as a pale yellow oil. ESI-MS m/z 198 [M+H] + calc. for C 11 H 19 O 2 tert-butyl 4-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)piperidine-1-carboxylate (Int. 12) Compound SI-12 (6 g, 31 mmol) was treated with a solution of 9-BBN-H in THF (0.5 M, 62 ml) and the mixture was heated at reflux for 4 hours. The resulting Int. 11 was immediately used for the synthesis of compound 43g. Synthesis of ethyl 2-[4-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)cyclohexyl]acetate (Int. 13) Pd/C NaH MeOH, H 2 THF, 0 ºC to rt SI-13 SI-14 HCl/EtOAc 70 ºC 9-BBN-H n-buli THF, reflux SI-15 THF, -70 ºC to rt SI-16 Int. 13 ethyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate (SI-13) To a solution of ethyl 2-diethoxyphosphorylacetate (9.5 g, 42.3 mmol) in THF (20 ml) was added NaH (1.7 g 60% in mineral oil, 42.3 mmol) at 0 o C and the mixture was stirred at 0 o C for 1 hour. Then, a solution of 1,4-dioxaspiro[4.5]decan-8-one (6 g, 38.5 mmol) in THF (5 ml) was added at 0 o C and the solution was stirred at room temperature overnight. The mixture was quenched with aqueous NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give the crude product which was purified by the column chromatography to give compound SI-13 (6.6 g, 76%) as a white solid. 1 H NMR (CDCl 3, 400 MHz): δ 5.64 (s, 1H), (m, 2H), (m, 4H), (m, 2H), (m, 2H), (m, 4H), (m, 3H). ESI-MS m/z [M+H] + calc. for C 12 H 18 O 4 S11

12 ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate (SI-14) To a solution of compound SI-13 (6 g, 26.5 mmol) in MeOH (40 ml) was added Pd/C (3 g). The solution was stirred at room temperature for 3 hours under H 2 atmosphere (1 atm). The solution was filtered and the filtrate was concentrated to give compound SI-14 (5 g, 83%) as a white solid. ESI-MS m/z [M+H] + calc. for C 12 H 20 O 4 ethyl 2-(4-oxocyclohexyl)acetate (SI-15) A solution of compound SI-14 (5 g, 21.9 mmol) in HCl/EtOAc (2.0 M, 10 ml) was stirred at 70 o C overnight. Then, the solution was concentrated to give the crude product which was purified by column chromatography to obtain pure compound SI-15 (3 g, 74%) as white solid. 1 H NMR (CDCl 3, 400 MHz): δ (m, 2H), (m, 4H), (m, 3H), (m, 2H), (m, 2H), (m, 3H). ESI-MS m/z [M+H] + calc. for C 10 H 16 O 3 ethyl 2-(4-methylenecyclohexyl)acetate (SI-16) To a solution of methyltriphenylphosphonium bromide (2.94 g, 8.2 mmol) in THF was added n-buli (3.4 ml, 2.5 M, 8.2 mmol) at -70 o C and the mixture was stirred at 0 o C for 2 hours. Then a solution of SI-15 (1 g, 5.43 mmol) in THF was added at -70 o C and the mixture was stirred at room temperature overnight. Then, the reaction was quenched with aqueous NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give the crude product which was purified by the column chromatography to give compound SI-16 (0.5 g, 50%) as a white solid. 1 H NMR (CDCl 3, 400 MHz): δ (m, 2 H) 4.61 (s, 2H), (m, 2H), (m, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 3H), (m, 2H). ESI-MS m/z [M+H] + calc. for C 11 H 18 O 2 ethyl 2-[4-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)cyclohexyl]acetate (Int. 13) Compound SI-16 (500 mg, 2.74 mmol) was treated with a solution of 9-BBN-H in THF (0.5 M, 10 ml) and the mixture was heated at reflux for 4 hours. The resulting Int. 13 was immediately used for the synthesis of compound 43h. S12

13 Synthesis of ethyl 4-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)cyclohexanecarboxylate (Int. 14) 9-BBN-H n-buli THF, -70 ºC to rt THF, reflux SI-17 Int. 14 ethyl 4-methylenecyclohexanecarboxylate (SI-17) To a solution of methyltriphenylphosphonium bromide (5.3 g, 15 mmol) in THF was added n-buli (6 ml, 2.5 M, 15 mmol) at -70 o C and the mixture was stirred at 0 o C for 2 hours. Then, a solution of ethyl 4-oxocyclohexanecarboxylate (1.7 g, 10 mmol) in THF was added to the solution at -70 o C and the mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give the crude product which was purified by the column chromatography to give compound SI-17 (1.02 g, 60%) as a white solid. ESI-MS m/z [M+H] + calc. for C 10 H 16 O 2 ethyl 4-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)cyclohexanecarboxylate (Int. 14) Compound SI-17 (500 mg, 3 mmol) was treated with a solution of 9-BBN-H in THF (0.5 M, 10 ml), and the mixture was heated at reflux for 4 hours. The resulting Int. 14 was immediately used for the synthesis of compound 43i. Synthesis of methyl 3-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)cyclopentanecarboxylate (Int. 15) 9-BBN-H n-buli THF, -70 ºC to rt THF, reflux SI-18 Int. 15 Synthesis of methyl 3-methylenecyclopentanecarboxylate (SI-18) To a solution of methyltriphenylphosphonium bromide (10.7 g, 30 mmol) in THF was added n-buli (12 ml, 2.5 M, 30 mmol) at -70 o C. The mixture was stirred at 0 o C for 2 S13

14 hours. Then, a solution of methyl 3-oxocyclopentanecarboxylate (3 g, 21 mmol) in THF was added at -70 o C and the mixture was stirred at room temperature overnight. Then the mixture was quenched with aqueous NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give the crude product which was purified by column chromatography to give compound SI-18 (0.7 g, 24%) as a white solid. ESI-MS m/z [M+H] + calc. for C 8 H 12 O 2 methyl 3-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)cyclopentanecarboxylate (Int. 15) Compound SI-18 (700 mg, 5 mmol) was treated with a solution of 9-BBN-H in THF (0.5 M, 10 ml), and the mixture was heated at reflux for 4 hours. The resulting Int. 15 was immediately used for the synthesis of compound 43j. Synthesis of tert-butyl 3-oxocyclobutanecarboxylate (Int. 16) DCC, CH 2 Cl 2 Int. 16 To a solution of 3-oxocyclobutanecarboxylic acid (11.4 g, 100 mmol) in anhydrous CH 2 Cl 2 (100 ml) were added DCC (31 g, 150 mmol) and 2-methylpropan-2-ol (8.9 g, 120 mmol) and the mixture was stirred at room temperature overnight. Then, the mixture was quenched with water and extracted with CH 2 Cl 2. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuum. The residue was purified by column chromatography to give pure Int. 16 (15.1 g, 89%). 1 H NMR (CDCl MHz): δ (m, 2H), (m, 2H), (m, 1H), 1.44 (s, 9H). Synthesis of ethyl 3-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)cyclobutanecarboxylate (Int. 17) KOH EtOH, 100 ºC SI-19 CH 3 CH 2 I K 2 CO 3 DMF 9-BBN-H THF, reflux SI-20 Int. 17 S14

15 3-methylenecyclobutanecarboxylic acid (SI-19) To a mixture of 3-methylenecyclobutanecarbonitrile (15 g, 161 mmol) in EtOH (500 ml) was added KOH (30.70 g, 540 mmol) in one portion under N 2 and the mixture was stirred at 100 C for 12 hours. Then, the mixture was cooled to 25 C and the residue was poured into water. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with saturated brine, dried with anhydrous Na 2 SO 4, filtered and concentrated in vacuum to afford compound SI-19 (12.00 g, 67%) as yellow oil. ESI-MS m/z [M+H] + calc. for C 6 H 8 O 2 ethyl 3-methylenecyclobutanecarboxylate (SI-20) To a solution of compound SI-19 (12 g, 107 mmol) in DMF (250 ml) was added K 2 CO 3 (29.6 g, 214 mmol), then CH 3 CH 2 I (20 g, 128 mmol) was added slowly. The reaction mixture was stirred at 25 C for 12 hours. Then, the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give the crude compound which was purified by column chromatography to give pure compound SI-20 (9.5 g, 63%) as a pale yellow oil. 1 H NMR (CDCl 3 400MHz): δ 4.79 (s, 2H), (m, 2H), (m, 5H), (m, 3H). ESI-MS m/z [M+H] + calc. for C 8 H 12 O 2 ethyl 3-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)cyclobutanecarboxylate (Int. 17) Compound SI-20 (3 g, 21.4 mmol) was treated with a solution of 9-BBN-H (0.5 M in THF, 40 ml) and the mixture was heated at reflux for 4 hours. The resulting Int. 17 was immediately used for the synthesis of compound 43p. S15

16 Synthesis of ethyl 3-[4-(bromomethyl)phenyl]propanoate (Int. 18) NaBH 4 POT, n-bu 3 N, Pd(OAc) 2 DMF, 90 ºC SI-21 THF/MeOH, 0 ºC NBS, PPh 3 CH 2 Cl 2, 0 ºC to rt SI-22 Int. 18 ethyl 3-(4-formylphenyl)propanoate (SI-21) To a solution of 4-bromobenzaldehyde (6.0 g, 32 mmol) in DMF (30 ml) were added 3,3- diethoxyprop-1-ene (12.65 g, 96 mmol), tri-o-tolylphosphine (1.2 g, 3.84 mmol), n-bu 3 N (11.84 g, 64 mmol) and Pd(OAc) 2 (215 mg, 0.96 mmol) and the reaction mixture was stirred at 90 o C for 1 hour. Then, the mixture was diluted with 2 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give the crude compound which was purified by column chromatography to give pure compound SI-21 (3.78 g, 57%) as a yellow oil. ESI-MS m/z 207 [M+H] + calc. for C 12 H 14 O 3 ethyl 3-[4-(hydroxymethyl)phenyl]propanoate (SI-22) To a solution of compound SI-21 (2.2 g, mmol) in THF/MeOH (3:1, 40 ml) was added NaBH 4 (619 mg, mmol) in portions at 0 o C and the reaction mixture was stirred at 0 o C for 1 hour. Then, the mixture was extracted with CH 2 Cl 2. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give the desired compound SI-22 (1.93 g, 86%) as a pale yellow oil. ESI-MS m/z 209 [M+H] + calc. for C 12 H 16 O 3 ethyl 3-[4-(bromomethyl)phenyl]propanoate (Int. 18) To a solution of compound SI-22 (1.93 g, 9.28 mmol) in anhydrous CH 2 Cl 2 (30 ml) was added PPh 3 (0.97 g, 3.71 mmol) and the mixture was cooled to 0 o C. Then, NBS (1.96 g, mmol) was added and the mixture was stirred at room temperature overnight. After LC-MS showed the starting material was consumed completely, the mixture was extracted S16

17 with CH 2 Cl 2 and the organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give the crude compound which was purified by column chromatography to give pure Int. 18 (680 mg, 27%) as a pale yellow oil. ESI-MS m/z 271 [M+H] + calc. for C 12 H 15 BrO 2 Synthesis of ethyl 2-[4-(trifluoromethylsulfonyloxy)cyclohex-3-en-1-yl]acetate (Int. 19) PhN(SO 2 CF 3 ) 2 LiHMDS THF, -78 ºC to rt Int. 19 To a solution of ethyl 2-(4-oxocyclohexyl)acetate (1.0 g, 5.43 mmol) in anhydrous THF (30 ml) was added LiHMDS (5.7 ml, 1.0 M in THF, 5.70 mmol) at -78 o C and the mixture was stirred at the same temperature for 1 hour. Then, PhN(SO 2 CF 3 ) 2 (2.04 g, 5.70 mmol) in THF (20 ml) was added under N 2 protection. After addition, the mixture was stirred at room temperature overnight. Then, the reaction was quenched with aqueous KHSO 4, extracted with methyl tert-butyl ether and the organic layer was washed with 1.0 M aqueous NaOH, aqueous NH 4 Cl and brine. The organic phase was dried over anhydrous Na 2 SO 4, filtered and concentrated to give Int. 19 (1.50 g, 87%) as a yellow oil. 1 H NMR (CDCl MHz): δ 5.66 (s, 1H), (m, 2H), (m, 5H), (m, 1H), (m, 2H), (m, 1H), (m, 3H). ESI-MS m/z 317 [M+H] + calc. for C 11 H 15 F 3 O 5 S Synthesis of methyl 5-bromofuran-2-carboxylate (Int. 20) MeI, K 2 CO 3 DMF Int. 20 To a solution of 5-bromofuran-2-carboxylic acid (4 g, 21 mmol) in DMF (50 ml) was added K 2 CO 3 (5.8 g, 42 mmol) and then MeI (4.44 g, 31.5 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 5 hours. Then the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered and concentrated to give Int. 20 (3.5 g, 81%) as a pale yellow oil. ESI-MS m/z 205 [M+H] + calc. for C 6 H 5 BrO 3 S17

18 S4. LC purities and HRMS of final compounds HPLC-analysis was performed using a Shimadzu LC-20AB or LC-20AD with a Luna- C18(2), 5µm, 2.0*50mm column at 40 ºC and UV detection at 215, 220 or 254 nm. Three different methods were used (Methods 1, 2 and 3). UHPLC analysis was performed using an Acquity UPLC system (Waters Corp., Milford, MA, USA) with thermostatized autosampler. Separation was carried out on an Acquity UPLC TM BEH C18 column (50 mm 2.1 mm, 1.7 mm) at 40 ºC and UV detection at 215, 220 or 254 nm. One method was used (Method 4). High Resolution Mass Spectrometry (HRMS) of final compounds High resolution mass spectrometry, m/z determination, was performed by a nanolc Ultra HPLC system (Eksigent, Sciex, Ontario, Canada) coupled to a TripleTOF system (Sciex, Ontario, Canada). Separation was carried out on an Acclaim PepMap TM 100 column (100 µm 2 cm, 5µm, 100Å, nanoviper, ThermoScientific) at 25 ºC. One method was used (Method 4) Method 1 Solvent A: water with 0.056% trifluoroacetic acid; Solvent B: acetonitrile with 0.056% trifluoroacetic acid. Gradient: After 0.1 minutes at the initial condition of 90% A and 10% B, solvent B was increased to 80% over 4 minutes, maintained at 80% for 0.9 minutes, then a linear gradient to initial conditions was applied for 0.02 minutes and maintained for 0.58 minutes to re-equilibrate the column, giving a cycle time of 5.50 minutes. Flow rate was 0.8 ml/min from 0.01 to 4.90 minutes, increased to 1.2 ml/min in 0.03 minutes and maintained until the end of the run. Method 2 Solvent A: water with 0.056% trifluoroacetic acid; Solvent B: acetonitrile with 0.056% trifluoroacetic acid. Gradient: After 0.4 minutes at the initial condition of 100% A, solvent B was increased to 60% over 4 minutes, maintained at 60% for 0.8 minutes, then a linear gradient to initial conditions was applied for 0.02 minutes and maintained for 0.68 minutes S18

19 to re-equilibrate the column, giving a cycle time of 5.90 minutes. Flow rate was 0.8 ml/min from 0.01 to 5.21 minutes, increased to 1.2 ml/min in 0.02 minutes and maintained until the end of the run. Method 3 Solvent A: water with 0.056% trifluoroacetic acid; Solvent B: acetonitrile with 0.019% trifluoroacetic acid. Gradient: After 0.1 minutes at the initial condition of 90% A and 10% B, solvent B was increased to 80% over 4 minutes, maintained at 80% for 2 minutes, then a linear gradient to initial conditions was applied for 0.01 minutes and maintained for 0.68 minutes to re-equilibrate the column, giving a cycle time of 7.80 minutes. Flow rate was 3 ml/ min. Method 4 Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile. Gradient: After 0.1 minutes at the initial condition of 90% A and 10% B solvent B was increased from 5 to 100% over 8 minutes, maintained at 100% for 2 minutes, then a linear gradient to initial conditions was applied for 0.5 minutes and maintained for 1.5 minutes to re-equilibrate the column (A: 95%, B: 5%), giving a cycle time of 12 minutes. Flow rate was 0.6 ml/min (Acquity UHPLC system) and 0.6µL/min (nanolc Ultra HPLC system) during the complete run. LC purities and HRMS of final compounds Compound Method Rt m/z by HRMS Purity a b a b c d e f g S19

20 21a b c d e f a b c d e f g a b c d e f g h i i j k l m n o a b c d e f S20

21 LC traces for final compounds Compound Compound 7a S21

22 Compound 7b λ: 220 nm, 1.2 nm Compound 13a S22

23 Compound 13b Compound 13c λ: 254 nm, 1.2 nm S23

24 Compound 13d Compound 13e λ: 254 nm, 8 nm S24

25 Compound 13f λ: 254 nm, 1.2 nm Compound 13g S25

26 Compound 21a Compound 21b S26

27 Compound 21c Compound 21d S27

28 Compound 21e Compound 21f S28

29 Compound 30a Compound 30b S29

30 Compound 30c λ: 254 nm, 1.2 nm Compound 30d S30

31 Compound 30e λ: 215 nm, 8 nm Compound 30f S31

32 Compound 30g Compound 37 λ: 254 nm, 1.2 nm S32

33 Compound 42 λ: 254 nm, 1.2 nm Compound 48a λ: 215 nm, 8 nm S33

34 Compound 48b Compound 48c S34

35 Compound 48d λ: 254 nm, 1.2 nm Compound 48e S35

36 Compound 48f Compound 48g S36

37 Compound 48h Compound 48i1 λ: 254 nm, 1.2 nm S37

38 Compound 48i2 λ: 254 nm, 1.2 nm Compound 48j λ: 254 nm, 1.2 nm S38

39 Compound 48k Compound 48l S39

40 Compound 48m λ: 215 nm, 8 nm Compound 48n S40

41 Compound 48o Compound 52a λ: 254 nm, 1.2 nm S41

42 Compound 52b λ: 254 nm, 1.2 nm Compound 52c λ: 220 nm, 1.2 nm S42

43 Compound 52d λ: 254 nm, 1.2 nm Compound 52e λ: 254 nm, 1.2 nm S43

44 Compound 52f λ: 254 nm, 1.2 nm S44

45 S6. Figure S1. Superposition of sildenafil and vardenafil in the different crystal complexes with PDE5: 1TBF (sildenafil, orange) 1, 2H42 (sildenafil, pink) 2, 1UDT (sildenafil, blue) 3 and 3B2R (vardenafil, green) 4. S45

46 S7. Table S1. PDE5A and HDACs biochemical activities as pic 50. Cpd PDE5A HDAC1 HDAC2 HDAC3- HDAC6 pic 50 pic 50 pic 50 NCOR2 pic 50 pic 50 13a < b c * d e f * g a < b < c d e f a < b c < d < e S46

47 30f g <4.70 < a 7.72 <4.70 <4.70 < b < a < b < c d e f 6.92 <4.70 <4.70 < g 7.24 <4.70 <4.70 < h < i < i < j a b k l < m 6.52 <4.70 <4.70 <5.00 S47

48 48n o < c < d e < f 8.30 <4.70 < * HDAC3_NCOR2 values obtained at BPS ( BIBLIOGRAPHY (1) Bischoff, E. Int. J. Impot. Res. 2004, 16 Suppl 1, S11 S14. (2) Wang, H.; Liu, Y.; Huai, Q.; Cai, J.; Zoraghi, R.; Francis, S.H.; Corbin, J.D.; Robinson, H.; Xin, Z.; Lin, G.; Ke, H. J. Biol. Chem. 2006, 281, (3) Sung, B.-J.; Hwang, K. Y.; Jeon, Y. H.; Lee, J. I.; Heo, Y.-S.; Kim, J. H.; Moon, J.; Yoon, J. M.; Hyun, Y.-L.; Kim, E.; Eum, S. J.; Park, S.-Y.; Lee, J.-O.; Lee, T. G.; Ro, S.; Cho, J. M. Nature 2003, 425 (6953), (4) Wang, H.; Ye, M.; Robinson, H.; Francis, S. H.; Ke, H. Mol. Pharmacol. 2008, 73 (1), S48

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