POLYCYCLIC COMPOUNDS AS SOLUBLE EPOXIDE HYDROLASE INHIBITORS

Abstract

The present invention relates to soluble epoxide hydrolase (sEH) inhibitors of formula (I) to processes for their obtention and to their therapeutic indications.

##STR00001##

Claims

1. A compound of formula (I) ##STR00031## or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: G.sup.1 represents an oxygen atom or a methylene group or a single bond; G.sup.2 represents an oxygen atom or a sulphur atom; G.sup.3 represents a radical selected from the group consisting of —NH—(CH.sub.2).sub.m—, —O—(CH.sub.2).sub.m— and —(CH.sub.2).sub.n—; m is an integer from 0 to 6; n is an integer from 1 to 7 R.sup.1 is a radical selected from the group consisting of: a) C.sub.6-C.sub.10 aryl which may be optionally substituted by 1 to 4 substituents selected from the group consisting of halogen atoms, C.sub.1-C.sub.6 acyl, nitro (NO.sub.2), cyano (C≡N), trifluoromethyl (CF.sub.3), trifluoromethoxy (OCF.sub.3), pentafluorosulfanyl (SF.sub.5), sulfonyl (SO.sub.3H), fluorosulfonyl (SO.sub.2F), carboxylic group (COOH), amino (NH.sub.2), mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonylmethyl and methylaminocarbonylpyridyloxy; b) heteroaryl having from 2 to 11 carbon atoms and 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S and which may be optionally substituted by 1 to 4 substituents selected from the group consisting of halogen atoms, C.sub.1-C.sub.6 acyl, nitro (NO.sub.2), cyano (C≡N), trifluoromethyl (CF.sub.3), trifluoromethoxy (OCF.sub.3), pentafluorosulfanyl (SF.sub.5), sulfonyl (SO.sub.3H), fluorosulfonyl (SO.sub.2F), carboxylic group (COOH), amino (NH.sub.2), mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxycarbonylmethyl; c) saturated or partially unsaturated, monocyclic or bicyclic heterocyclyl having from 5 to 11 carbon atoms and 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S and which may be optionally substituted by 1 to 4 substituents selected from the group consisting of halogen atoms, C.sub.1-C.sub.6 acyl, C.sub.3-C.sub.6 cycloalkyl-C(═O), nitro (NO.sub.2), cyano (C≡N), trifluoromethyl (CF.sub.3), trifluoromethylcarbonyl (CF.sub.3CO), pentafluorosulfanyl (SF.sub.5), sulfonyl (SO.sub.3H), carboxylic group (COOH), amino (NH.sub.2), mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonylmethyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.3-C.sub.6 cycloalkylsulfonyl, benzyl, heteroarylmethyl, pyridincarbonyl, phenylcarbonyl, tetrahydropyrancarbonyl, C.sub.6-C.sub.10 arylsulfonyl which may be optionally substituted by 1 to 2 substituents selected from the group consisting of halogen atoms, nitro (NO.sub.2), cyano (C≡N), trifluoromethyl (CF.sub.3), trifluoromethoxy (OCF.sub.3), pentafluorosulfanyl (SF.sub.5), sulfonyl (SO.sub.3H), carboxylic group (COOH), amino (NH.sub.2), mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonylmethyl and phenyl which may be optionally substituted by 1 to 4 substituents selected from the group consisting of halogen atoms, C.sub.1-C.sub.6 acyl, nitro (NO.sub.2), cyano (C≡N), trifluoromethyl (CF.sub.3), trifluoromethoxy (OCF.sub.3), pentafluorosulfanyl (SF.sub.5), sulfonyl (SO.sub.3H), fluorosulfonyl (SO.sub.2F), carboxylic group (COOH), amino (NH.sub.2), mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl and C.sub.1-C.sub.6 alkoxycarbonylmethyl; d) C.sub.6-C.sub.10 cycloalkyl which may be optionally substituted by 1 to 4 substituents selected from the group consisting of halogen atoms, C.sub.1-C.sub.6 acyl, nitro (NO.sub.2), cyano (C≡N), trifluoromethyl (CF.sub.3), trifluoromethoxy (OCF.sub.3), pentafluorosulfanyl (SF.sub.5), sulfonyl (SO.sub.3H), carboxylic group (COOH), amino (NH.sub.2), mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonylmethyl, pyridinyloxy which may be unsubstituted or substituted by a group selected from COOH and CONHCH.sub.3, and phenoxy which may be unsubstituted or substituted by COOH, COOR.sup.5, CONH.sub.2, CN or OH; R.sup.2 is a radical selected from the group consisting of hydrogen or deuterium atoms, halogen atoms, methyl, hydroxy and C.sub.1-C.sub.6 alkoxy; R.sup.3 and R.sup.4 are radicals which may be identical or different and which are independently selected from the group consisting of hydrogen atoms, halogen atoms, C.sub.1-C.sub.6 acyl, nitro (NO.sub.2), cyano (C≡N), carboxylic group (COOH), hydroxy (OH), trifluoromethyl (CF.sub.3), trifluoromethoxy (OCF.sub.3), pentafluorosulfanyl (SF.sub.5), sulfonyl (SO.sub.3H), fluorosulfonyl (SO.sub.2F), amino (NH.sub.2), mono-C.sub.1-C.sub.6 alkylamino, di-C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxycarbonylmethyl; or R.sup.3 and R.sup.4 may form together a radical —O—(CH.sub.2).sub.p—O—, wherein p is an integer from 1 to 3; R.sup.5 is a radical selected from C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.6 cycloalkyl.

2. A compound according to claim 1 wherein G.sup.1 represents a methylene group.

3. A compound according to claim 1 wherein G.sup.2 represents an oxygen atom.

4. A compound according to claim 1 wherein G.sup.3 represents a radical selected from the group consisting of —NH—(CH.sub.2).sub.m— and —(CH.sub.2).sub.n—, m is an integer from 0 to 6 and n is an integer from 1 to 7.

5. A compound according to claim 4 wherein G.sup.3 represents a radical-NH—(CH.sub.2).sub.m— and m is an integer from 0 to 6.

6. A compound according to claim 1 wherein, when G.sup.3 is selected from the group consisting of —NH—(CH.sub.2).sub.m— and —O—(CH.sub.2).sub.m—, m has a value of 0 and wherein G.sup.3 is —(CH.sub.2).sub.n— n has a value of 1.

7. A compound according to claim 1 wherein R.sup.1 is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl and substituted or unsubstituted piperidinyl.

8. A compound according to claim 1 wherein R.sup.2 is selected from the group consisting of hydrogen atoms, fluorine atoms, chlorine atoms, methyl, hydroxyl and C.sub.1-C.sub.3 alkoxy.

9. A compound according to claim 1 wherein R.sup.3 and R.sup.4 are radicals which may be identical or different and which are independently selected from the group consisting of hydrogen atoms, halogen atoms, C.sub.1-C.sub.6 acyl, trifluoromethyl (CF.sub.3), trifluoromethoxy (OCF.sub.3), nitro (NO.sub.2), amino (NH.sub.2) and C.sub.1-C.sub.6 alkoxy.

10. A compound according to claim 1 wherein R.sup.3 is hydrogen and R.sup.4 is a radical selected from the group consisting of hydrogen atoms, halogen atoms, C.sub.1-C.sub.6 acyl, trifluoromethyl (CF.sub.3), trifluoromethoxy (OCF.sub.3), nitro (NO.sub.2), amino (NH.sub.2) and C.sub.1-C.sub.6 alkoxy.

11. The compound according to claim 1, which is selected from the group consisting of: i. p-tolyl (9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)carbamate ii. 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(4-(trifluoromethyl)phenyl)thiourea iii. 1-(1-acetylpiperidin-4-yl)-3-(5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-yl)urea iv. 1-(1-acetylpiperidin-4-yl)-3-(1,5,6,7-tetrahydro-1, 5:3,7-dimethanobenzo[e]oxonin-3(2H)-yl)urea v. 1-(1-acetylpiperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea vi. 1-(1-acetylpiperidin-4-yl)-3-(9-hydroxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea vii. 1-(1-acetylpiperidin-4-yl)-3-(9-methoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea viii. 1-(1-acetylpiperidin-4-yl)-3-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea ix. 1-(1-acetylpiperidin-4-yl)-3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea x. 4-(((1r,4r)-4-(3-(5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-yl)ureido)cyclohexyl)oxy)benzoic acid xi. 4-(((1r,4r)-4-(3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)cyclohexyl)oxy)benzoic acid xii. 1-[1-(isopropylsulfonyl)piperidin-4-yl]-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xiii. 1-(1-benzylpiperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xiv. 1-(2-acetyl-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-acetylpiperidin-4-yl)urea xv. 1-(1-acetylpiperidin-4-yl)-3-(9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xvi. 1-(1-acetylpiperidin-4-yl)-3-(2-amino-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xvii. tert-butyl 4-(2-((9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)amino)-2-oxoethyl)piperidine-1-carboxylate xviii. N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-2-(piperidin-4-yl)acetamide xix. 2-[1-(isopropylsulfonyl)piperidin-4-yl]-N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide xx. 2-(1-acetylpiperidin-4-yl)-N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide xxi.1-(9-methyl-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(2,3,4-trifluorophenyl)urea xxii.1-(5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-yl)-3-(2,3,4-trifluorophenyl)urea xxiii. 2-(1-benzylpiperidin-4-yl)-N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide xxiv. 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-propionylpiperidin-4-yl)urea xxv. 1-(1-(4-acetylphenyl)piperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xxvi. 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea xxvii. 1-(1-(2-fluorobenzoyl)piperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xxviii. 1-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xxix. 1-(1-acetylpiperidin-4-yl)-3-(2-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xxx. 1-(1-acetylpiperidin-4-yl)-3-(2-methoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xxxi. 1-(1-acetylpiperidin-4-yl)-3-(1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xxxii. 1-(1-acetylpiperidin-4-yl)-3-(2,3-dimethoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xxxiii. 1-(1-acetylpiperidin-4-yl)-3-(5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulen-7(6H)-yl)urea xxxiv. 1-(benzo[d]thiazol-2-yl)-3-(9-methoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xxxv. 1-(1-acetylpiperidin-4-yl)-3-(1,9-difluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea xxxvi. 1-(1-acetylpiperidin-4-yl)-3-(1,5,6,7-tetrahydro-1,5:3,7-dimethano-benzo[e]oxonin-3(2H)-yl-5-d)urea

12. A pharmaceutical or veterinary composition comprising a therapeutically effective amount of a compound as defined in claim 1.

13. (canceled)

14. A method of treating or preventing a disease or disorder susceptible of improvement by inhibition of soluble epoxide hydrolase comprising administering to an animal in need thereof a compound as defined in claim 1.

15. The method according to claim 14, wherein the disease or disorder is selected from the group consisting of hypertension, atherosclerosis, pulmonary diseases such as chronic obstructive pulmonary disorder, asthma, sarcoidosis and cystic fibrosis, kidney diseases such as acute kidney injury, diabetic nephrology, chronic kidney diseases, hypertension-mediated kidney disorders and high fat diet-mediated renal injury, stroke, pain, neuropathic pain, inflammation, pancreatitis in particular acute pancreatitis, immunological disorders, neurodevelopmental disorders such as schizophrenia and autism spectrum disorder, eye diseases in particular diabetic keratopathy, wet age-related macular degeneration and retinopathy such as premature retinopathy and diabetic retinopathy, cancer, obesity, including obesity-induced colonic inflammation, diabetes, metabolic syndrome, preeclampsia, anorexia nervosa, depression, male sexual dysfunction such as erectile dysfunction, wound healing, NSAID-induced ulcers, emphysema, scrapie, Parkinson's disease, arthritis, arrhythmia, cardiac fibrosis, Alzheimer's disease, Raynaud's syndrome, Niemann-Pick-type C disease, cardiomyopathy, vascular cognitive impairment, mild cognitive impairment, inflammatory bowel diseases, cirrhosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, osteoporosis, chronic periodontitis, sepsis, seizure disorders such as epilepsy, dementia, edema such as cerebral edema, attention-deficit hyperactivity disorder, schizophrenia, drug dependency, social anxiety, colitis, amyotrophic lateral sclerosis, chemotherapy induced side effects, laminitis, inflammatory joint pain and synovitis, endothelial dysfunction, subarachnoid hemorrhage, including aneurysmal subarachnoid hemorrhage, traumatic brain injury, cerebral ischemia and diabetes-induced learning and memory impairment.

16. (canceled)

17. (canceled)

18. (canceled)

19. A method for the treatment or prevention of a disease or disorder susceptible of improvement by inhibition of soluble epoxide hydrolase comprising administering to an animal in need thereof an effective amount of a composition according to claim 12.

20. The method for the treatment according to claim 19, wherein the disease or disorder susceptible of improvement by inhibition of soluble epoxide hydrolase is selected from the group consisting of hypertension, atherosclerosis, pulmonary diseases such as chronic obstructive pulmonary disorder, asthma, sarcoidosis and cystic fibrosis, kidney diseases such as acute kidney injury, diabetic nephrology, chronic kidney diseases, hypertension-mediated kidney disorders and high fat diet-mediated renal injury, stroke, pain, neuropathic pain, inflammation, pancreatitis in particular acute pancreatitis, immunological disorders, neurodevelopmental disorders such as schizophrenia and autism spectrum disorder, eye diseases in particular diabetic keratopathy, wet age-related macular degeneration and retinopathy such as premature retinopathy and diabetic retinopathy, cancer, obesity, including obesity-induced colonic inflammation, diabetes, metabolic syndrome, preeclampsia, anorexia nervosa, depression, male sexual dysfunction such as erectile dysfunction, wound healing, NSAID-induced ulcers, emphysema, scrapie, Parkinson's disease, arthritis, arrhythmia, cardiac fibrosis, Alzheimer's disease, Raynaud's syndrome, Niemann-Pick-type C disease, cardiomyopathy, vascular cognitive impairment, mild cognitive impairment, inflammatory bowel diseases, cirrhosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, osteoporosis, chronic periodontitis, sepsis, seizure disorders such as epilepsy, dementia, edema such as cerebral edema, attention-deficit hyperactivity disorder, schizophrenia, drug dependency, social anxiety, colitis, amyotrophic lateral sclerosis, chemotherapy induced side effects, laminitis, inflammatory joint pain and synovitis, endothelial dysfunction, subarachnoid hemorrhage, including aneurysmal subarachnoid hemorrhage, traumatic brain injury, cerebral ischemia and diabetes-induced learning and memory impairment.

21. The method of claim 14, wherein the animal is a human.

22. The method of claim 19, wherein the animal is a human.

Description

EXAMPLES

[0182] Analytical methods [0183] Melting points were determined in open capillary tubes with a MFB 595010 M Gallenkamp melting point apparatus. [0184] Infrared (IR) spectra were run either on a Perkin-Elmer Spectrum RX I spectrophotometer (using the attenuated total reflectance technique) or on a spectrophotometer Nicolet Avatar 320 FT-IR. Absorption values are expressed as wavenumbers (cm.sup.−1); only significant absorption bands are given. [0185] Elemental analyses were carried out at the Microanalysis Service of the IIQAB (CSIC, Barcelona, Spain) with a Carlo Erba model 1106 analyzer. [0186] Preparative normal phase chromatography was performed on a CombiFlash Rf 150 (Teledyne Isco) with pre-packed RediSep Rf silica gel cartridges. Thin-layer chromatography was performed with aluminum-backed sheets with silica gel 60 F254 (Merck, ref 1.05554 or Sigma-Aldrich, ref 60805), and spots were visualized with UV light, 1% aqueous solution of KMnO.sub.4 and/or iodine. [0187] High-resolution mass spectrometry (HRMS) analyses were performed with an LC/MSD TOF Agilent Technologies spectrometer. [0188] Analytical grade solvents were used for crystallization, while pure for synthesis solvents were used in the reactions, extractions and column chromatography. [0189] The analytical samples of all of the new compounds which were subjected to pharmacological evaluation possess a purity ≥95% as evidenced by their elemental analysis.

Reference Example 1: 2-fluoro-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione

[0190] In a round-bottomed flask equipped with a condenser and magnetic stirring a solution of 4-fluorophthalaldehyde (3.08 g, 20 mmol) and dimethyl 3-oxopentanedioate (6.98 g, 40 mmol) in MeOH (60 mL) was prepared. Four drops of diethylamine were added and the reaction was heated at reflux for 1.5 h, the reaction was cooled down and 7 drops more of diethylamine were added and the reaction was stored at 4° C. overnight. The precipitate was filtered off under vacuum and was washed with cold MeOH (4 mL), obtaining tetramethyl 2-fluoro-7,11-dioxo-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene-6,8,10,12-tetracarboxylate as white needles (3.05 g). A solution of this solid in glacial acetic acid (18 mL) and conc. HCl (5 mL) was heated at reflux for 12 h. The solvent was removed under vacuum to give a solid. A solution of this solid in toluene (50 mL) was heated a reflux for 16 h in a Dean-Stark apparatus. The toluene was removed under vacuum to give pure 2-fluoro-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione (1.53 g, 33% overall yield) as a light brown solid. mp 105-107° C. IR (NaCl disk): 2923, 2848, 1710, 1607, 1593, 1490, 1428, 1380, 1346, 1253, 1208, 1119, 1074, 985, 944, 865, 806 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.14H.sub.13FO.sub.2+H].sup.+: 233.0972, found: 233.0967.

Reference Example 2: 2-methoxy-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione

[0191] From 4-methoxyphthalaldehyde (10.2 g, 61.9 mmol), dimethyl 3-oxopentanedioate (21.5 g, 124 mmol) and diethylamine (28 drops) in MeOH (380 mL) and following the procedure described in reference example 1, tetramethyl 2-methoxy-7,11-dioxo-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene-6,8,10,12-tetracarboxylate was obtained (19.4 g, 66% yield). From the aforementioned tetracarboxylate (250 mg, 0.5 mmol), conc. HCl (0.4 mL) and glacial acetic acid (1.4 mL) and following the procedure described in reference example 1, 2-methoxy-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione (125 mg, 98% yield) was obtained.

[0192] mp 157-158° C. IR (NaCl disk): 2941, 2910, 2837, 1701, 1610, 1585, 1504, 1431, 1414, 1370, 1321, 1300, 1266, 1166, 1094, 1033, 989 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.15H.sub.16O.sub.3+H].sup.+: 245.1172, found: 245.1180.

Reference Example 3: 2,3-dimethoxy-5,6,8,9-tetrahydro-7H-5,9-propanobenzo [7]annulene-7,11-dione

[0193] From 4,5-dimethoxyphthalaldehyde (6.54 g, 33.7 mmol), dimethyl 3-oxopentanedioate (11.7 g, 67.4 mmol) and diethylamine (19 drops) in MeOH (130 mL) and following the procedure described in reference example 1, tetramethyl 2,3-dimethoxy-7,11-dioxo-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene-6,8,10,12-tetracarboxylate was obtained (6.84 g, 40% yield). From the aforementioned tetracarboxylate (6.84 g, 13.5 mmol), conc. HCl (10 mL) and glacial acetic acid (35 mL), and following the procedure described in reference example 1, 2,3-dimethoxy-5,6,8,9-tetrahydro-7H-5,9-propanobenzo [7]annulene-7,11-dione (2.8 g, 76% yield) was obtained.

[0194] mp 236-237° C. IR (NaCl disk): 2952, 2840, 1698, 1605, 1516, 1467, 1451, 1416, 1355, 1336, 1254, 1221, 1192, 1162, 1025, 1002, 880, 811 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.16H.sub.18O.sub.4+H].sup.+: 275.1278, found: 275.1279.

Reference Example 4: 1-fluoro-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione

[0195] From 3-fluorophthalaldehyde (11.2 g, 73.6 mmol), dimethyl 3-oxopentanedioate (25.6 g, 147 mmol) and diethylamine (33 drops) in MeOH (220 mL) and following the procedure described in reference example 1, tetramethyl 1-fluoro-7,11-dioxo-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene-6,8,10,12-tetracarboxylate was obtained (18.5 g, 54% yield). The aforementioned tetracarboxylate (18.5 g, 39.9 mmol), conc. HCl (31 mL) and glacial acetic acid (103 mL), and following the procedure described in reference example 1, 1-fluoro-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione was obtained (8.73 g, 94% yield).

[0196] mp>150° C. (dec.). IR (NaCl disk): 2940, 2908, 1701, 1619, 1585, 1468, 1421, 1370, 1303, 1245, 1222, 1203, 1072, 1052, 988, 931, 897, 789, 746 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.14H.sub.13FO.sub.2+H].sup.+: 233.0972, found: 233.0976.

Reference Example 5: 2-fluoro-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene

[0197] In a 3-necked round-bottomed flask equipped with magnetic stirring and argon atmosphere, a suspension of NaH (1.08 g, 60% purity, 27.0 mmol) in anhydrous DMSO (13.3 mL) was heated at 75° C. over 45 min. The green suspension was cooled down to room temperature and methyltriphenylphosphonium iodide (10.92 g, 27.0 mmol) diluted in anhydrous DMSO (22 mL) and 2-fluoro-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione (1.53 g, 6.59 mmol) diluted in anhydrous DMSO (50 mL) were sequentially added. The resulting mixture was heated at 90° C. overnight. The reaction was cooled down and poured into water (80 mL). The aqueous layer was extracted with hexane (4×80 mL). The combined organic extracts were dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum. Column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures) gave 2-fluoro-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene as a colorless wax (1.09, 73% yield).

[0198] mp 108-109° C. IR (NaCl disk): 3072, 2985, 2921, 2844, 1639, 1612, 1592, 1494, 1451, 1444, 1363, 1246, 1162, 1135, 1095, 1048, 974, 951, 930, 887, 820, 716, 658, 638, 598, 528 cm.sup.−1.

Reference Example 6: 2-methoxy-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene

[0199] From 2-methoxy-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione (4 g, 16.4 mmol) and following the procedure described in reference example 5, 2-methoxy-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene was obtained (1.5 g, 38% yield).

[0200] mp 68-69° C. IR (NaCl disk): 3068, 2979, 2911, 2833, 1639, 1609, 1580, 1501, 1464, 1449, 1431, 1363, 1313, 1260, 1203, 1172, 1152, 1109, 1034, 955, 929, 889, 851, 809, 661, 613 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.17H.sub.20O+H].sup.+: 241.1587, found: 241.1588.

Reference Example 7: 2,3-dimethoxy-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene

[0201] From 2,3-dimethoxy-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione (2.8 g, 10.2 mmol) and following the procedure described in reference example 5, 2,3-dimethoxy-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene was obtained (633 mg, 23% yield).

[0202] mp 74-75° C. IR (NaCl disk): 3068, 2977, 2913, 2832, 1639, 1606, 1515, 1464, 1450, 1429, 1414, 1358, 1342, 1293, 1261, 1240, 1225, 1191, 1173, 1103, 1023, 956, 931, 889, 804, 634 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.18H.sub.22O.sub.2+H].sup.+: 271.1693, found: 271.1688.

Reference Example 8: 1-fluoro-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene

[0203] From 1-fluoro-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione (4 g, 17.2 mmol) and following the procedure described in reference example 5, 1-fluoro-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene was obtained as a colourless oil (2.69 g, 69% yield).

[0204] IR (NaCl disk): 3071, 2981, 2921, 2838, 1639, 1614, 1583, 1464, 1446, 1429, 1365, 1248, 1046, 991, 935, 919, 895 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.16H.sub.17F+H].sup.+: 229.1387, found: 229.1392.

Reference Example 9: 1-fluoro-7-methylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulen-11-one

[0205] In a 3-necked round-bottomed flask equipped with magnetic stirring and argon atmosphere, a suspension of NaH (1.01 g, 60% purity, 25.2 mmol) in anhydrous DMSO (50 mL) was heated at 75° C. over 45 min. The green suspension was cooled down to room temperature and methyltriphenylphosphonium iodide (10.61 g, 25.33 mmol) diluted in anhydrous DMSO (58 mL) and 1-fluoro-5,6,8,9-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione (4.72 g, 20.3 mmol, from reference example 4) diluted in anhydrous DMSO (50 mL) were sequentially added. The resulting mixture was heated at 90° C. overnight. The reaction was cooled down and poured into water (80 mL). The aqueous layer was extracted with hexane (5×80 mL). The combined organic extracts were dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum. Column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures) afforded 1-fluoro-7-methylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulen-11-one (2.16, 55% yield).

[0206] mp 96° C. IR (ATR): 2927, 2913, 2895, 1688, 1613, 1583, 1432, 1406, 1366, 1247, 1196, 1104, 1049, 1034, 1002, 970, 921, 911, 883, 819, 789, 749, 715, 657 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.15H.sub.15FO+H].sup.+: 231.1180, found: 231.1180.

Reference Example 10: 2-chloro-N-(2-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0207] A suspension of 2-fluoro-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene (1.09 g, 4.77 mmol), chloroacetonitrile (1.2 mL, 19.1 mmol) and acetic acid (3.5 mL) was cooled to 0° C. and concentrated H.sub.2SO.sub.4 (1.53 mL, 28.6 mmol) was added dropwise (T<10° C.). The mixture was allowed to reach room temperature and was stirred overnight. The suspension was added to ice (20 g) and after 10 min stirring, the suspension was extracted with DCM (3×15 mL). The combined organic layers were washed with NaOH 10 N (1×25 mL) and dried with anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain 2-chloro-N-(2-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide as a white solid (1.2 g, 78% yield).

[0208] mp 141-144° C. IR (NaCl disk): 3399, 3313, 3067, 2944, 2920, 2851, 1657, 1607, 1591, 1518, 1498, 1451, 1361, 1345, 1252, 1179, 1145, 966, 963, 863, 820 cm.sup.−1.

[0209] HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.18H.sub.21ClFNO+H].sup.+: 322.1368, found: 322.1370.

Reference Example 11: 2-chloro-N-(2-methoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0210] From 2-methoxy-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene (1.5 g, 6.24 mmol), and following the procedure described in reference example 10, 2-chloro-N-(2-methoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide was obtained (1.18 g, 57% yield).

[0211] mp 144-145° C. IR (NaCl disk): 3403, 3304, 3062, 2997, 2945, 2905, 2860, 2838, 1662, 1609, 1582, 1528, 1499, 1454, 1382, 1361, 1311, 1267, 1242, 1198, 1180, 1154, 1043, 1013, 955, 873 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.19H.sub.24ClNO.sub.2+H].sup.+: 334.1568, found: 334.1569.

Reference Example 12: 2-chloro-N-(2,3-dimethoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0212] From 2,3-dimethoxy-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene (498 mg, 1.84 mmol), and following the procedure described in reference example 10, 2-chloro-N-(2,3-dimethoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide was obtained (501 mg, 75% yield).

[0213] mp 204-205° C. IR (NaCl disk): 3306, 2941, 2907, 2861, 2838, 1666, 1605, 1516, 1467, 1452, 1415, 1381, 1361, 1345, 1293, 1252, 1231, 1191, 1168, 1092, 1021, 948, 861, 802 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.20H.sub.26ClNO.sub.3+H].sup.+: 364.1674, found: 364.1674.

Reference Example 13: 2-chloro-N-(1-fluoro-9-hydroxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0214] A solution of 1-fluoro-7-methylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulen-11-one (2.06 g, 8.94 mmol), chloroacetonitrile (0.6 mL, 9.83 mmol) in DCM (21 mL) was cooled to 0° C. and concentrated H.sub.2SO.sub.4 (0.75 mL) was added dropwise (T<10° C.). The mixture was allowed to reach room temperature and was stirred overnight. The suspension was added to ice (20 g) and after 10 min stirring, the suspension was extracted with DCM (3×15 mL). The combined organic layers were washed with NaOH 10 N (1×25 mL) and dried with anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum. Column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures) gave 2-chloro-N-(1-fluoro-9-hydroxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide as a white solid (921 mg, 32% yield).

[0215] mp 150° C. IR (ATR): 3406, 3272, 3075, 2926, 2905, 2850, 1661, 1561, 1466, 1443, 1409, 1362, 1341, 1311, 1298, 1243, 1218, 1158, 1105, 1037, 991, 974, 891, 884, 791, 734, 679, 625 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.17H.sub.19ClFNO.sub.2+H].sup.+: 324.1161, found: 324.1162.

Reference Example 14: 2-chloro-N-(1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0216] From 1-fluoro-7,11-dimethylene-6,7,8,9-tetrahydro-5H-5,9-propanobenzo[7]annulene (2.36 g, 10.36 mmol), and following the procedure described in reference example 10, 2-chloro-N-(1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide was obtained (2.28 g, 68% yield). The analytical sample was obtained by crystallization from DCM.

[0217] mp 154-155° C. IR (NaCl disk): 3402, 3308, 3073, 2947, 2911, 2863, 2840, 1660, 1613, 1583, 1529, 1463, 1363, 1348, 1312, 1242, 1186, 1155, 979, 798, 748 cm.sup.−1.

[0218] HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.18H.sub.21ClFNO+H].sup.+: 322.1368, found: 322.1374.

Reference Example 15: 2-chloro-N-(1,9-difluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0219] A solution of 2-chloro-N-(1-fluoro-9-hydroxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (611 mg, 1.89 mmol) in DCM (10 mL) was cooled to −30° C. with a dry ice in an acetone bath. Then DAST (2.8 mL, 1 M in DCM, 2.8 mmol) was added and the reaction mixture was stirred with the dry ice in an acetone bath overnight. To the resulting solution water (10 mL) was added and the pH adjusted to ˜12 with NaOH 1 N. The two layers were separated, the aqueous phase was extracted further with DCM (2×8 mL), and the combined organic phases were dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum. Crystallization from DCM/Pentane afforded 2-chloro-N-(1,9-difluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (420 mg, 68% yield).

[0220] mp 180° C. IR (ATR): 3276, 3075, 2964, 2940, 2901, 2858, 1671, 1650, 1552, 1463, 1442, 1360, 1317, 1282, 1242, 1175, 1143, 1104, 1066, 1018, 1004, 979, 929, 901, 887, 865, 799, 746, 737, 696, 662 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.17H.sub.18ClF.sub.2NO+H].sup.+: 326.1118, found: 326.1116.

Reference Example 16: 2-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride

[0221] Thiourea (25 mg, 0.32 mmol) and glacial acetic acid (200 μL) were added to a solution of 2-chloro-N-(2-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo [9]annulen-7-yl)acetamide (87 mg, 0.27 mmol) in absolute ethanol (5 mL) and the mixture was heated at reflux overnight. The resulting suspension was then tempered to room temperature, water (5 mL) was added and the pH adjusted to 12 with 5 N NaOH solution. EtOAc (5 mL) was added, the phases were separated and the aqueous phase was extracted with further EtOAc (2×5 mL). The combined organic layers were dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give a light brown oil. Its hydrochloride was obtained by adding an excess of Et.sub.2O/HCl to a solution of the amine in ethyl acetate, followed by filtration of the resulting beige precipitate affording 2-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11 dimethanobenzo[9]annulen-7-amine hydrochloride (18 mg, 24% yield).

[0222] mp>300° C. (dec.). IR (KBr disk): 3200-2500 (2983, 2945, 2917, 2867), 2059, 1612, 1595, 1501, 1456, 1444, 1431, 1379, 1364, 1302, 1283, 1256, 1246, 1186, 1157, 1143, 1132, 1030, 1004, 962, 863, 814 cm.sup.−1. Anal. Calcd for C.sub.16H.sub.20FN. 2.6 HCl: C 56.50, H 6.70, N 4.12. Found: C 56.18, H 6.40, N 4.01.

Reference Example 17: 2-methoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride

[0223] From 2-chloro-N-(2-methoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (1.10 g, 3.95 mmol), and following the procedure described in reference example 16, 2-methoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride was obtained. The analytical sample was obtained by crystallization from DCM/Pentane (779 mg, 81% yield).

[0224] mp>250° C. (dec.). IR (KBr disk): 3200-2500 (2985, 2942, 2908), 2056, 1735, 1609, 1582, 1499, 1449, 1379, 1364, 1334, 1305, 1268, 1252, 1205, 1170, 1132, 1103, 1040, 1001, 954, 869, 849, 815, 756, 692 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.17H.sub.23NO+H].sup.+: 258.1852, found: 258.1862.

Reference Example 18: 2,3-dimethoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride

[0225] From 2-chloro-N-(2,3-dimethoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (436 mg, 1.2 mmol), and following the procedure described in reference example 16, 2,3-dimethoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride was obtained (285 mg, 73% yield).

[0226] mp>200° C. (dec.). IR (KBr disk): 3200-2500 (2993, 2918, 2831), 2047, 1701, 1606, 1517, 1451, 1416, 1386, 1365, 1327, 1310, 1291, 1252, 1237, 1192, 1174, 1131, 1098, 1031, 973, 950, 863, 798, 586, 543 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.18H.sub.25NO.sub.2+H].sup.+: 288.1958, found: 288.1954.

Reference Example 19: 1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride

[0227] From 2-chloro-N-(1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (1 g, 3.11 mmol), and following the procedure described in reference example 16, 1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride was obtained. The analytical sample was obtained by crystallization from Methanol (521 mg, 59% yield).

[0228] mp>200° C. (dec.). IR (KBr disk): 3200-2500 (2945, 2717), 2060, 1677, 1608, 1584, 1511, 1464, 1390, 1380, 1366, 1317, 1303, 1248, 1214, 1199, 1165, 1132, 1071, 1052, 1032, 1000, 977, 946, 885, 877, 854, 798, 747, 623 cm.sup.−1. HRMS-ESI+m/z [M+H]+ calcd for [C.sub.16H.sub.20FN+H].sup.+: 246.1653, found: 246.1649.

Reference Example 20: 2-chloro-N-(9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0229] To a cold (0° C.) solution of known 2-chloro-N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (Bioorg Med Chem. 2012, 20, 942) (3 g, 9.87 mmol) in acetic anhydride (10.5 mL) were carefully added glacial acetic acid (1.6 mL) and fuming nitric acid (1.85 mL). The mixture was allowed to reach room temperature and left stirring overnight. The obtained yellow solution was then poured to ice-water (20 mL), and extracted with DCM (3×40 mL). The combined organic extracts were washed with aqueous 2 N NaOH (1×40 mL), water (1×40 mL) and brine (1×40 mL). The organic layer was dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give a yellow residue. Purification by column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures) gave 2-chloro-N-(9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (2.92 g, 85% yield) as a white solid.

[0230] mp 174° C. IR (KBr disk): 3403, 3288, 3077, 2946, 2922, 2847, 1667, 1607, 1588, 1520, 1456, 1409, 1348, 1229, 1166, 1136, 1082, 1051, 1009, 972, 945, 896, 865, 841, 797, 740, 764, 704, 666 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.18H.sub.21ClN.sub.2O.sub.3+H].sup.+: 349.1313, found: 349.1313.

Reference Example 21: 9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride

[0231] From 2-chloro-N-(9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (677 mg, 1.94 mmol) and following the procedure described in reference example 16, 9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride was obtained (443 mg, 74% yield).

[0232] mp>225° C. (dec.). IR (KBr disk): 3200-2500 (2928, 2641, 2603, 2535), 2066, 1648, 1612, 1591, 1522, 1487, 1458, 1352, 1304, 1286, 1256, 1221, 1181, 1134, 1088, 1031, 955, 946, 895, 884, 865, 836, 799, 766 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.16H.sub.20N.sub.2O.sub.2+H].sup.+: 273.1598, found: 273.1604.

Reference Example 22: 1,9-difluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride

[0233] From 2-chloro-N-(1,9-difluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (382 mg, 1.17 mmol), and following the procedure described in reference example 16, 1,9-difluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride was obtained (218 mg, 65% yield). The analytical sample was obtained by crystallization from methanol. mp>200° C. (dec.). IR (ATR): 2980-2831 (2950, 2911, 2867), 2703, 2676, 2559, 2063, 1611, 1588, 1509, 1465, 1445, 1363, 1321, 1246, 1194, 1105, 1095, 1008, 1002, 988, 967, 903, 888, 860, 801, 743, 673 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.15H.sub.17F.sub.2N+H].sup.+: 250.1402, found: 250.1401.

Reference Example 23: 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulene-2,7-diamine dihydrochloride

[0234] To a solution of amine 9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine (201 mg, 0.738 mmol) in methanol (25 mL), Pd on charcoal (68.6 mg, cat. 10% Pd) was added and the resulting suspension was hydrogenated at 1 atm of H.sub.2 at room temperature for 48 h. The black suspension was filtered and the solvent removed by concentration under vacuum to give 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulene-2,7-diamine as a brown solid (130 mg, 89% yield). Its dihydrochloride was obtained by addition of an excess of Et.sub.2O/HCl to a solution of the diamine in methanol followed by filtration of the resulting brown precipitate.

[0235] mp 294-295° C. IR (KBr disk): 3200-2500 (3024, 2912, 2847, 2588), 1994, 1598, 1502, 1454, 1381, 1365, 1303, 1261, 1173, 1131, 1021, 957, 877, 827, 576, 473 cm.sup.−1. Anal. Calcd. for C.sub.16H.sub.22N.sub.2.3.4 HCl: C 52.46, H 6.99, N 7.65. Found C 52.64, H 7.18, N 7.43.

Reference Example 24: 2-chloro-N-(2-hydroxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0236] To a solution of N-(2-amino-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-2-chloroacetamide (999 mg, 3.10 mmol) in H.sub.2O (5 mL) and conc. HCl (5 mL), at 0° C., was added dropwise a solution of sodium nitrite (427 mg, 6.21 mmol) in H.sub.2O (2 mL). To the resulting solution was added CuCl (652 mg, 6.56 mmol) in conc. HCl (3 mL) and over 10 min gas evolution was observed. The resulting solution was warmed to 60° C. for 90 minutes, then was cooled to room temperature, diluted in H.sub.2O (60 mL) and extracted with DCM (4×90 mL). The combined organic extracts were washed with sat. NaHCO.sub.3 and brine, were dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give a dark green solid. Purification by column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixture) gave the 2-chloro-N-(2-hydroxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (78 mg, 9% yield) as a white solid. mp 98-100° C. IR (NaCl disk): 3300-2700 (3266, 3186, 3118, 2966, 2942, 2916, 2861), 2175, 1590, 1568, 1504, 1451, 1426, 1376, 1356, 1309, 1267, 1161, 1130, 1081, 1058, 827, 804 cm.sup.−1. HRMS-ESI-m/z [M−H].sup.− calcd for [C.sub.18H.sub.22ClNO.sub.2—H].sup.−: 318.1266, found: 318.1272.

Reference Example 25: 2-hydroxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride

[0237] From 2-chloro-N-(2-hydroxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (72 mg, 0.23 mmol), and following the procedure described in reference example 16, 2-hydroxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride was obtained (42 mg, 67% yield). The analytical sample was obtained by crystallization from Methanol/Diethyl ether.

[0238] mp 183-185° C. Anal. Calcd for C.sub.16H.sub.21NO. 1.7HCl.1H.sub.2O: C 59.43, H 7.70, N 4.33. Found C 59.63, H 7.44, N 4.77.

Reference Example 26: N-(9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0239] To a cold (0° C.) solution of known (Tetrahedron Lett. 1987, 28, 1585-1588) N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (2.68 g, 9.93 mmol) in acetic anhydride (10.6 mL) were carefully added glacial acetic acid (1.6 mL) and fuming nitric acid (1.86 mL). The mixture was allowed to reach room temperature and left stirring overnight. The obtained yellow solution was then poured to ice-water (20 mL), and extracted with DCM (3×40 mL). The combined organic extracts were washed with aqueous 2 N NaOH (1×40 mL), water (1×40 mL) and brine (1×40 mL). The organic layer was dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give a yellow residue. Purification by column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures) gave N-(9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (1.88 g, 60% yield) as a white solid.

[0240] mp 174-176° C. IR (NaCl disk): 3398, 3301, 3201, 3063, 2943, 2917, 2863, 1653, 1588, 1523, 1455, 1346, 1322, 1304, 1268, 1245, 1217, 1166, 1141, 1124, 1081, 1037, 1010, 945, 893, 865, 838, 798, 763, 740, 701 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.18H.sub.22N.sub.2O.sub.3+H].sup.+: 315.1703, found: 315.1714.

Reference Example 27: N-(2-amino-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0241] From N-(9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (2.64 g, 8.41 mmol), PtO.sub.2 (258 mg) in absolute EtOH and following the procedure described in the reference example 23, N-(2-amino-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (1.9 g, 80% yield) was obtained after purification by column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures).

[0242] mp 112-113° C. IR (NaCl disk): 3432, 3324, 3224, 3056, 3004, 2938, 2903, 2856, 2835, 1651, 1618, 1546, 1507, 1447, 1362, 1344, 1300, 1262, 1194, 1164, 1136, 1065, 862, 735, 701 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.18H.sub.24N.sub.2O+H].sup.+: 285.1961, found: 285.1972.

Reference Example 28: N-(2-chloro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0243] From N-(2-amino-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide hydrochloride (1.04 g, 3.25 mmol) in H.sub.2O (6 mL) and conc. HCl (6 mL), sodium nitrite (448 mg, 6.5 mmol) in H.sub.2O (2 mL), CuCl (691 mg, 6.99 mmol) dissolved in conc. HCl solution (3 mL), and following the procedure described in reference example 24, N-(2-chloro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide was obtained (210 mg, 21% yield). mp 190-191° C. IR (NaCl disk): 3301, 3196, 3071, 2921, 2855, 1651, 1594, 1549, 1487, 1454, 1414, 1364, 1343, 1308, 1281, 1263, 1211, 1139, 1109, 1012, 950, 875, 820 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.18H.sub.22ClNO+H].sup.+: 304.1463, found: 304.1460.

Reference Example 29: 2-chloro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride

[0244] A mixture of N-(2-chloro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (190 mg, 0.63 mmol), conc. HCl (4 mL), H.sub.2O (8 mL) and isopropanol (6 mL) was stirred under reflux for 4 days. The solution was cooled down and isopropanol was concentrated under vacuum. The aqueous phase was extracted with EtOAc (3×8 mL) and then was basified with a solution of 5 N NaOH. The base aqueous solution was extracted with further EtOAc (3×10 mL), dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give a yellow oil. Purification by column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures) gave 2-chloro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine. Its hydrochloride was obtained by adding an excess of Et.sub.2O/HCl to a solution of the amine in EtOAc (10 mg, 5.5% yield). mp>250° C. IR (KBr disk): 3200-2500 (2990, 2950, 2916, 2861), 2058, 1597, 1570, 1509, 1488, 1454, 1416, 1380, 1365, 1302, 1217, 1155, 1133, 1093, 1032, 1000, 948, 875, 820, 771, 673 cm.sup.−1. Anal. Calcd for C.sub.16H.sub.20ClN.1.35 HCl: C 61.79, H 6.95, N 4.50. Found C 61.70, H 6.78, N 4.93.

Reference Example 30: 5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulen-7(6H)-yl methanesulfonate

[0245] To a solution of 5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulen-7(6H)-ol (1.19 g, 5.97 mmol) in pyridine (9 mL), (prepared as reported in Liebigs Ann Chem. 1973; 1839-1850), mesyl chloride (2.32 mL, 29.28 mmol) was added slowly with stirring at room temperature. The mixture was then heated at 120° C. for 5 h. After cooling, crushed ice (100 g) was added and the mixture was extracted with DCM (5×40 mL). The combined organic phase was washed with 2 N HCl (2×40 mL), H.sub.2O (2×40 mL), saturated aqueous NaHCO.sub.3 (2×40 mL), and dried over anh. Na.sub.2SO.sub.4. After filtration and removal of the solvent under reduced pressure, 5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulen-7(6H)-yl methanesulfonate (1.32 g, 80% yield) was isolated as a dark oil that was used in the next step without further purification.

[0246] IR (NaCl disk): 3060, 3010, 2934, 2857, 1488, 1451, 1341, 1232, 1175, 1145, 1102, 1046, 1012, 992, 966, 923, 853, 800, 753 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.15H.sub.18O.sub.3S+NH.sub.4].sup.+: 296.1315, found: 296.1318.

Reference Example 31: 7-iodo-5,6,7,8,9,10-hexahydro-5,8:7,10-dimethanobenzo[8]annulene

[0247] A mixture of H.sub.3PO.sub.4 (99%, 135 g), 5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulen-7(6H)-yl methanesulfonate (1.32 g, 4.75 mmol) and NaI (63 g, 420 mmol) were stirred at 150° C. for 6 h. After cooling, H.sub.2O (150 mL) was added slowly to the mixture. The resulting purple solution was extracted with DCM (4×80 mL) and the combined organic phase was washed with 10% aqueous sodium thiosulfate (1×100 mL), dried over anh. Na.sub.2SO.sub.4 and the solvent was removed under vacuum to obtain 7-iodo-5,6,7,8,9,10-hexahydro-5,8:7,10-dimethanobenzo[8]annulene as a white solid (1.39 g, 95%).

[0248] mp 132-133° C. IR (NaCl disk) 3052, 3013, 2950, 2892, 2852, 1490, 1447, 1304, 1278, 1232, 1215, 1095, 1046, 1032, 967, 830, 778, 755 cm.sup.−1. GC-MS (EI): 310 [(M).sup.−+, 2], 183 [(M-I).sup.+, 100], 141 (73), 129 (23), 128 (15).

Reference Example 32: 5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulene-7(6H)-carboxylic acid

[0249] To a solution of 7-iodo-5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulene (2.03 g, 6.5 mmol) in dry and degassed toluene (20 mL) was added methyl oxalyl chloride (2.39 g, 19.5 mmol) and bis(tributyltin) (4.5 g, 7.8 mmol). The mixture was irradiated in a quartz reactor under argon atmosphere with a 125 W Hg lamp for 20 h. Then, DCM (15 mL), methanol (0.6 mL) and triethylamine (1.2 mL) were successively added to the reaction mixture at 0° C. and was concentrated under vacuum to give a dark oil (3.99 g). A solution of this oil in a 40% methanol solution of KOH (50 mL) was heated to reflux for 2 h. Water (50 mL) was added and the reaction was refluxed for 3 h. The reaction mixture was allowed to cool down to room temperature and the methanol was removed under vacuum. Water (40 mL) was added to the residue and the aqueous layer was washed with DCM (4×50 mL). After that, the aqueous phase was acidified with conc. HCl until pH=1 and extracted with DCM (4×50 mL). The organic extracts were dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulene-7(6H)-carboxylic acid as a brown solid (555 mg, 37% overall yield). An analytical sample of the acid was obtained by crystallization from DCM/Pentane.

[0250] mp 188-189° C. IR (NaCl disk): 3300-2800 (3065, 3011, 2946, 2858), 1690, 1488, 1450, 1410, 1318, 1290, 1231, 1218, 1092, 1052, 1038, 941 cm.sup.−1. HRMS-ESI-m/z [M−H].sup.− calcd for [C.sub.15H.sub.16O.sub.2—H].sup.−: 227.1078, found: 227.1078.

Reference Example 33: 5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulen-7(6H)-amine hydrochloride

[0251] To a solution of 5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulene-7(6H)-carboxylic acid (90 mg, 0.39 mmol) in toluene (1.2 mL), Et.sub.3N (73 μL, 0.53 mmol) and diphenylphosphoryl azide (159 mg, 0.58 mmol) were added and heated at reflux for 3 h. The mixture was cooled down and washed with 1 N HCl (10×2 mL). Thereafter, to the organic layer was added 6 N HCl (1.6 mL) and the suspension was heated at reflux for 24 h. The reaction mixture was then cooled to room temperature and the two phases were separated. The aqueous phase was extracted with ethyl acetate (3×3 mL). The combined organic phases were washed with 5 N NaOH (3×10 mL), dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give 5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulen-7(6H)-amine. Its hydrochloride was obtained by adding an excess of HCl in methanol to a solution of the amine in methanol. The methanol was removed under reduced pressure to give 5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulen-7(6H)-amine hydrochloride as a brown solid (35 mg, 45% yield). An analytical sample was obtained by crystallization from Methanol/Diethyl ether.

[0252] mp>250° C. (dec). IR (KBr disk): 3100-2500 (2943, 2881), 2043, 1622, 1598, 1501, 1448, 1336, 1246, 1089, 1057, 1028, 952, 769, 749, 614 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.14H.sub.17N+H].sup.+: 200.1434, found: 200.1432.

Example 34: p-tolyl (9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)carbamate

[0253] To a solution of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (250 mg, 0.95 mmol) in DCM (2 mL), p-tolyl chloroformate (194 mg, 1.14 mmol) and Et.sub.3N (287 mg, 2.84 mmol) were added. The reaction mixture was stirred at room temperature overnight and then the solvent was evaporated under vacuum. The residue was dissolved in EtOAc (30 mL) and water (20 mL) and phases were separated. The aqueous phase was extracted with further EtOAc (2×30 mL). The combined organic phases were dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain 300 mg of a yellow gum. Column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures) gave p-tolyl (9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)carbamate (46 mg, 14% yield) as a white solid.

[0254] mp 114-115° C. IR (NaCl disk): 3330, 3018, 2944, 2919, 2854, 1744, 1591, 1531, 1502, 1452,1379, 1362,1345,1255, 1214,1198, 1167, 1137,1069,1042, 1014, 987, 948, 900, 825, 757 cm.sup.−1. Anal. Calcd for C.sub.24H.sub.27NO.sub.2.0.3C.sub.5H.sub.12.0.05 CH.sub.2Cl.sub.2: C 79.22, H 7.99, N 3.62. Found: C 79.23, H 7.88, N 3.45.

Example 35: 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(4-(trifluoromethyl)phenyl)thiourea

[0255] To a solution of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (250 mg, 0.95 mmol) in DCM (2 mL), 1-isothiocyanato-4-(trifluoromethyl)benzene (193 mg, 0.95 mmol) and Et.sub.3N (287 mg, 2.84 mmol) were added. The reaction mixture was stirred at room temperature overnight and then the solvent was evaporated under vacuum. The residue was dissolved in EtOAc (30 mL) and water (20 mL) and phases were separated. The aqueous phase was extracted with further EtOAc (2×30 mL). The combined organic phases were dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain 369 mg of a yellow solid. The product was washed with Et.sub.2O to obtain 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (188 mg, 46% yield) as a white solid. mp 158-159° C. IR (NaCl disk): 3283, 2911, 2834, 1615, 1532, 1493, 1454, 1422, 1324, 120, 1166, 1124, 1067, 1015, 948, 909, 837, 759, 732, 697, 665 cm.sup.−1. Anal. Calcd for C.sub.24H.sub.25F.sub.3N.sub.2S: C 66.96, H 5.85, N 6.51. Found: C 66.79, H 5.95, N 6.37.

Example 36: 1-(1-acetylpiperidin-4-yl)-3-(5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-yl)urea

[0256] To a solution of 5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-amine hydrochloride (180 mg, 0.69 mmol) in DCM (3 mL) and saturated aqueous NaHCO.sub.3 solution (2 mL), triphosgene (102 mg, 0.34 mmol) was added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic one was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of isocyanate in DCM. To this solution were added 1-(4-aminopiperidin-1-yl)ethan-1-one hydrochloride (122 mg, 0.68 mmol) and Et.sub.3N (139 mg, 1.37 mmol). The mixture was stirred overnight at room temperature, diluted with further DCM (10 mL) and washed with 2N NaOH solution (2×10 mL). The organic layer was dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain a yellow residue (206 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-yl)urea as a white solid (135 mg, 49% yield). The analytical sample was obtained by crystallization from hot EtOAc (112 mg).

[0257] mp 208-209° C. IR (NaCl disk): 3357, 3054, 3012, 2969, 2926, 2853, 1646, 1611, 1546, 1492, 1450, 1358, 1324, 1268, 1222, 1156, 1101, 1088, 1035, 1212, 991, 947, 918, 900, 866, 829, 760, 733, 699 cm.sup.−1. Anal. Calcd for C.sub.23H.sub.31N.sub.3O.sub.3: C 69.49, H 7.86, N 10.57. Found: C 69.47, H 7.92, N 10.38.

Example 37: 1-(1-acetylpiperidin-4-yl)-3-(1,5,6,7-tetrahydro-1,5:3,7-dimethano-benzo[e]oxonin-3(2H)-yl)urea

[0258] To a solution of 1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-amine hydrochloride (300 mg, 1.19 mmol) in DCM (7 mL) and saturated aqueous NaHCO.sub.3 solution (7 mL), triphosgene (130 mg, 0.44 mmol) was added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic one was washed with brine (10 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of isocyanate in DCM. To this solution were added 1-(4-aminopiperidin-1-yl)ethan-1-one hydrochloride (203 mg, 1.43 mmol) and Et.sub.3N (292 mg, 2.88 mmol). The mixture was stirred overnight at room temperature, diluted with further DCM (10 mL) and washed with 2N NaOH solution (2×10 mL). The organic layer was dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain a yellow residue (400 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-yl)urea as a white solid (50 mg, 49% yield).

[0259] mp 200-202° C. IR (NaCl disk): 3347, 3065, 3016, 2922, 1645, 1624, 1548, 1492, 1451, 1436, 1362, 1323, 1268, 1230, 1211, 1196, 1109, 1073, 1022, 980, 967 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.22H.sub.29N.sub.3O.sub.3+H].sup.+: 384.2282, found: 384.2285.

Example 38: 1-(1-acetylpiperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0260] To a solution of 5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-amine hydrochloride (180 mg, 0.69 mmol) in DCM (3 mL) and saturated aqueous NaHCO.sub.3 solution (2 mL), triphosgene (102 mg, 0.34 mmol) was added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution were added 1-(4-aminopiperidin-1-yl)ethan-1-one hydrochloride (122 mg, 0.68 mmol) and Et.sub.3N (138 mg, 1.36 mmol). The mixture was stirred overnight at room temperature, diluted with further DCM (10 mL) and washed with 2N NaOH solution (2×10 mL). Organics were dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain a yellow oil (232 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(9-methyl-5,6,8,9, 10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea as a white solid (143 mg, 53% yield). The analytical sample was obtained by crystallization from hot EtOAc (113 mg).

[0261] mp 206-207° C. IR (NaCl disk): 3359, 3065, 3016, 2938, 2906, 2860, 1644, 1620, 1555, 1493, 1452, 1360, 1344, 1319, 1267, 1228, 1212, 1136, 1090, 1049 cm.sup.−1. Anal. Calcd for C.sub.24H.sub.33N.sub.3O.sub.2.0.21 Ethyl Acetate: C 71.91, H 8.45, N 10.06. Found: C 71.73, H 8.43, N 10.27.

Example 39: 1-(1-acetylpiperidin-4-yl)-3-(9-hydroxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0262] To a solution of 1-(4-aminopiperidin-1-yl)ethan-1-one (192 mg, 1.35 mmol) in DCM (4 mL) and saturated aqueous NaHCO.sub.3 solution (3 mL) triphosgene (200 mg, 0.68 mmol) was added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic one was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 9-amino-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-ol hydrochloride (300 mg, 1.14 mmol) followed by Et.sub.3N (228 mg, 2.25 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum. Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-(isopropylsulfonyl)piperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (19 mg, 4.2% yield) as a grey solid.

[0263] mp 222-223° C. IR (NaCl disk): 3313, 2921, 2852, 1733, 1716, 1646, 1621, 1557, 1542, 1506,1490, 1472,1455, 1358,1336, 1318, 1300,1265,1231,1204, 1134, 1104, 1053 cm.sup.−1. Anal. Calcd for C.sub.23H.sub.31N.sub.3O.sub.3.0.2C.sub.5H.sub.12. 0.9H.sub.2O: C 67.33, H 8.29, N 9.81. Found: C 67.25, H 8.15, N 9.72

Example 40: 1-(1-acetylpiperidin-4-yl)-3-(9-methoxy-5,6,8,9,10,11-hexahydro-7H-5.9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0264] To a solution of 9-methoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethano-benzo[9]annulen-7-amine (300 mg, 1.23 mmol) in DCM (4.5 mL) and saturated aqueous NaHCO.sub.3 solution (3 mL) triphosgene (183 mg, 0.61 mmol) was added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and organics were washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (210 mg, 1.47 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a white gum (521 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(9-methoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (148 mg, 30% yield) as a white solid. The analytical sample was obtained by crystallization from hot EtOAc (119 mg).

[0265] mp 212-213° C. IR (NaCl disk): 3358, 2930, 2847, 1646, 1617, 1555, 1495, 1451, 1356, 1319, 1266, 1228, 1094, 1075, 972, 849, 755, 735 cm.sup.−1. Anal. Calcd for C.sub.24H.sub.33N.sub.3O.sub.3.0.15 EtOAc: C 69.56, H 8.12, N 9.89. Found: C 69.63, H 8.28, N 8.86

Example 41: 1-(1-acetylpiperidin-4-yl)-3-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0266] To a solution of 9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine (143 mg, 0.53 mmol) in DCM (4 mL) and saturated aqueous NaHCO.sub.3 solution (2 mL) was added triphosgene (78 mg, 0.26 mmol). The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (90 mg, 0.63 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a yellow gum (259 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(9-fluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (180 mg, 85% yield). The analytical sample was obtained by crystallization from hot DCM (57 mg).

[0267] mp 228-229° C. IR (NaCl disk): 3357, 2927, 2856, 1643, 1618, 1553, 1494, 1451, 1358, 1340, 1316, 1267, 1227, 1207, 1134, 1097, 1042, 1004 cm.sup.−1. Anal. Calcd for C.sub.23H.sub.30FN.sub.3O.sub.2.0.15C.sub.5H.sub.12.0.62H.sub.2O: C 67.59, H 7.91, N 9.96. Found: C 67.61, H 7.93, N 8.94.

Example 42: 1-(1-acetylpiperidin-4-yl)-3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0268] To a solution of 9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (150 mg, 0.53 mmol) in DCM (3 mL) saturated aqueous NaHCO.sub.3 solution (3 mL) and triphosgene (58 mg, 0.20 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (3 mL), dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (90 mg, 0.63 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a white solid (204 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(9-chloro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (115 mg, 55% yield) as a white solid. mp 209-210° C. IR (NaCl disk): 3358, 3019, 2926, 2855, 1644, 1619, 1556, 1494, 1452,1358,1319,1301, 1268,1228, 1206,1135, 1090,1050, 991, 969, 947, 802, 761, 735 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.23H.sub.30ClN.sub.3O.sub.2+H].sup.+: 416.2099, found: 416.2100.

Example 43: 4-(((1r,4r)-4-(3-(5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo [e]oxonin-3(2H)-yl)ureido)cyclohexyl)oxy)benzoic acid

[0269] To a solution of 5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-amine hydrochloride (200 mg, 0.76 mmol) in DCM (3.5 mL) and saturated aqueous NaHCO.sub.3 solution (2.2 mL) was added triphosgene (113 mg, 0.38 mmol). The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of isocyanate in DCM. To this solution were added 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoic acid hydrochloride (206 mg, 0.76 mmol) and Et.sub.3N (153 mg, 1.52 mmol). The mixture was stirred overnight at room temperature. The resulting suspension was evaporated to obtain a white solid, which was suspended in DCM (20 mL) and washed with 2N HCl solution (2×10 mL). The resulting organic suspension was filtered to afford a white solid (200 mg, 54% yield).

[0270] mp: 220-222° C. IR (NaCl disk): 3352, 2626, 1678, 1601, 1558, 1506, 1454, 1373, 1343, 1312, 1288, 1247, 1221, 1161, 1104, 1029, 997, 953, 776 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.29H.sub.34N.sub.2O.sub.5+H]: 491.254, found: 491.254.

Example 44: 4-(((1r,4r)-4-(3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)cyclohexyl)oxy)benzoic acid

[0271] To a solution of 5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-amine hydrochloride (180 mg, 0.69 mmol) in DCM (3 mL) and saturated aqueous NaHCO.sub.3 solution (2 mL) was added triphosgene (102 mg, 0.34 mmol). The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of isocyanate in DCM. To this solution were added 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoic acid hydrochloride (206 mg, 0.76 mmol) and Et.sub.3N (153 mg, 1.52 mmol). The mixture was stirred overnight at room temperature. The resulting suspension was evaporated and the residue was suspended in DCM (20 mL) and washed with 2N HCl solution (2×10 mL). The resulting organic suspension was filtered and the filtrate was dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give a white gum. Crystallization from hot EtOAc provided 4-(((1r,4r)-4-(3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)ureido)cyclohexyl)oxy)benzoic acid as a white solid (55 mg, 16% yield). mp 182-183° C. IR (NaCl disk): 3335, 2921, 2855, 1692, 1681, 1642, 1632, 1602, 1564, 1537, 1504, 1494, 1469, 1453, 1419, 1360, 1307, 1248, 1163, 1122,1096, 1969 cm.sup.−1. Anal. Calcd for C.sub.30H.sub.36N.sub.2O.sub.4.1,5 H.sub.2O: C 69.88, H 7.62, N 5.43. Found: C 69.53, H 7.37, N 5.10.

Reference Example 45: tert-butyl [1-(isopropylsulfonyl)piperidin-4-yl]carbamate

[0272] To a solution of tert-butyl (piperidin-4-yl)carbamate (850 mg, 4.24 mmol) in DCM (7 mL) was added Et.sub.3N (858 mg, 8.48 mmol). The mixture was cooled down to 0° C. with an ice bath and then propane-2-sulfonyl chloride (725 mg, 5.09 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The suspension was washed with 2N NaOH solution (2×5 mL) and the organic phase was dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain tert-butyl [1-(isopropylsulfonyl)piperidin-4-yl] carbamate (1.15 g, 89% yield).

Reference Example 46: 1-(isopropylsulfonyl)piperidin-4-amine

[0273] To a solution of tert-butyl (1-(isopropylsulfonyl)piperidin-4-yl)carbamate (1.15 g, 3.75 mmol) in dissolved in DCM (5 mL) and 4 M HCl in 1,4-dioxane (2 mL) was added. The mixture was stirred at room temperature for 2 days and the solvents were evaporated under vacuum. The residue was then dissolved in DCM (5 mL) and washed with 5N NaOH solution (5 mL). The organic layer was dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give 1-(isopropylsulfonyl)piperidin-4-amine (704 mg, 91% yield) as a yellow oil.

Example 47: 1-[1-(isopropylsulfonyl)piperidin-4-yl]-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0274] To a solution of 5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-amine hydrochloride (300 mg, 1.13 mmol) in DCM (6 mL) and saturated aqueous NaHCO.sub.3 solution (4 mL) was added triphosgene (169 mg, 0.57 mmol). The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM.

[0275] To a solution of 1-(isopropylsulfonyl)piperidin-4-amine (233 mg, 1.13 mmol) in anh. THE (5 mL) under argon atmosphere at −78° C., was added dropwise a solution of n-butyllithium (2.5 M in hexanes, 0.59 mL, 1.47 mmol) during 20 minutes. After the addition, the mixture was tempered to 0° C. using an ice bath. This solution was added carefully to the solution of the isocyanate from the previous step cooled to 0° C., under argon atmosphere. The reaction mixture was stirred at room temperature overnight. Methanol (2 mL) was then added to quench any unreacted n-butyllithium. The solvents were evaporated under vacuum to give an orange gum (506 mg). This residue was dissolved in EtOAc (10 mL) and washed with 2N HCl solution (2×5 mL) and the organic layer was dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain a white gum (241 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave a white solid. Crystallization from hot DCM/Pentane provided pure 1-(1-(isopropylsulfonyl)piperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (66 mg, 13% yield) as a white solid. mp 218-219° C. IR (NaCl disk): 3364, 3061, 3012, 2945, 2919, 2853, 1709, 1638, 1553, 1493, 1453, 1360, 1319, 1305, 1265, 1248, 1232, 1133, 1091, 1045, 943, 880, 841, 759, 732, 665, 592, 555 cm.sup.−1. Anal. Calcd for C.sub.25H.sub.37N.sub.3O.sub.3S: C 65.33, H 8.11, N 9.14. Found: C 65.41, H 8.31, N 8.93

Example 48: 1-(1-benzylpiperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0276] To a solution of 5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-amine hydrochloride (250 mg, 0.95 mmol) in DCM (4.5 mL) and saturated aqueous NaHCO.sub.3 solution (3 mL) was added triphosgene (140 mg, 0.47 mmol). The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (216 mg, 1.13 mmol). The reaction mixture was stirred at room temperature for 24 h and the solvent was evaporated under vacuum to obtain a yellow gum. Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave the title compound as a white solid (159 mg, 36% yield).

[0277] mp 106-107° C. IR (NaCl disk): 3318, 3058, 3025, 2945, 2918, 2838, 2792, 2761, 1632, 1559, 1493, 1453, 1361, 1343, 1321, 1302, 1281, 1234, 1209, 1136, 1120, 1066, 1028, 909, 757, 733, 698 cm.sup.−1. Anal. Calcd for C.sub.29H.sub.37N.sub.3O.0.5 Methanol: C 77.09, H 8.55, N 9.14. Found: C 77.19, H 8.36, N 8.98.

Reference Example 49: N-(2-acetyl-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-2-chloroacetamide

[0278] To a solution of 2-chloro-N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide (2.0 g, 6.58 mmol) in DCM (50 mL) was added acetyl chloride (5.16 g, 65.8 mmol). Then, the mixture was treated with AlCl.sub.3 (4.38 g, 32.9 mmol) and the resulting orange mixture was stirred for 1 h at room temperature. The solution was poured over ice (50 g) and saturated aqueous NaHCO.sub.3 solution (40 mL) was added. After stirring 20 min, the mixture was extracted with DCM (3×50 mL) and the combined organic phases were dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain a green gum (1.85 g). Column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures) gave N-(2-acetyl-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-2-chloroacetamide (1.27 g, 56% yield) as a yellowish solid.

Reference Example 50: 1-(7-amino-9-methyl-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethanobenzo[9]annulen-2-yl)ethan-1-one hydrochloride

[0279] A mixture of N-(2-acetyl-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-2-chloroacetamide (1.18 g, 3.43 mmol), thiourea (313 mg, 4.12 mmol), acetic acid (1.3 mL) and ethanol (6 mL) was stirred at reflux overnight. The mixture was tempered to room temperature and water (40 mL) and 10N NaOH solution (14 mL) were added. The mixture was extracted with EtOAc (3×50 mL) and the combined organic extracts were dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain a yellow residue (980 mg) which was dissolved in EtOAc (5 mL) and an excess of HCl/Et.sub.2O was added. The resulting suspension was filtrated obtaining a beige solid. This product was dissolved in DCM (50 mL) and washed with 5N NaOH solution (40 mL). The organic layer was dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to obtain a yellow residue which was dissolved in EtOAc (5 mL) and an excess of HCl/Et.sub.2O was added. The resulting suspension was filtered obtaining 1-(7-amino-9-methyl-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethanobenzo[9]annulen-2-yl)ethan-1-one as its hydrochloride (758 mg, 73% yield) as a beige solid.

Example 51: 1-(2-acetyl-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethano-benzo[9]annulen-7-yl)-3-(1-acetylpiperidin-4-yl)urea

[0280] To a solution of 1-(7-amino-9-methyl-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethanobenzo[9]annulen-2-yl)ethan-1-one hydrochloride (300 mg, 0.98 mmol) in DCM (5 mL) and saturated aqueous NaHCO.sub.3 solution (3.52 mL) was added triphosgene (145 mg, 0.49 mmol). The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (167 mg, 1.17 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a yellow gum (483 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(2-acetyl-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-acetylpiperidin-4-yl)urea (324 mg, 76% yield).

[0281] mp 144-145° C. IR (NaCl disk): 3363, 3005, 2918, 2861, 2239, 1679, 1619, 1552, 1453, 1426, 1361, 1320, 1272, 1229, 1203, 1137, 1106, 1057, 973, 950, 917, 830, 731, 645 cm.sup.−1. Anal. Calcd for C.sub.26H.sub.35N.sub.3O.sub.3.0.15C.sub.5H.sub.12.0.6C.sub.3H.sub.6O: C 70.96, H 8.43, N 8.70. Found: C 70.83, H 8.60, N 8.88

Example 52: 1-(1-acetylpiperidin-4-yl)-3-(9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0282] To a solution of 9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethano-benzo[9]annulen-7-amine hydrochloride (600 mg, 1.94 mmol) in DCM (10 mL) saturated aqueous NaHCO.sub.3 solution (10 mL) and triphosgene (213 mg, 0.718 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (331 mg, 2.33 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a brown solid (840 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (640 mg, 75% yield) as a yellowish solid. mp 155-156° C. IR (NaCl disk): 3360, 2918, 2237, 1619, 1552, 1522, 1454, 1345, 1322, 1266, 1230, 1164, 1137, 1081, 974, 949, 911, 865, 838, 798, 761, 731, 644 cm.sup.−1. Anal. Calcd for C.sub.24H.sub.32N.sub.4O.sub.4: C 65.43, H 7.32, N 12.72. Found: C 65.22, H 7.45, N 12.56.

Example 53: 1-(1-acetylpiperidin-4-yl)-3-(2-amino-9-methyl-5,6,8,9,10,11-hexa-hydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0283] To a solution of 1-(1-acetylpiperidin-4-yl)-3-(9-methyl-2-nitro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (260 mg, 0.59 mmol) in EtOH (17 ml) was added PtO.sub.2 (20 mg). The mixture was hydrogenated at room temperature and atmospheric pressure for 8 days. The resulting suspension was filtered and the filtrate was evaporated under vacuum to obtain a dark brown solid (223 mg), which was dissolved in DCM (10 mL). To this solution, Et.sub.2O was added and a white solid precipitated (140 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave a white solid (82 mg, 34% yield).

[0284] mp 150-151° C. IR (NaCl disk): 3344, 3006, 2905, 2853, 1614, 1556, 1505, 1454, 1360, 1344, 1320, 1303, 1266, 1229, 1194, 1162, 1136, 1060, 974, 868, 820, 734 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.24H.sub.34N.sub.4O.sub.2+H].sup.+: 411.2755, found: 411.2756.

Example 54: tert-butyl 4-(2-((9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)amino)-2-oxoethyl)piperidine-1-carboxylate

[0285] To a suspension of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethano-benzo[9]annulen-7-amine hydrochloride (500 mg, 1.89 mmol) in EtOAc (5 mL), 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (461 mg, 1.89 mmol), HOBt (384 mg, 2.84 mmol), EDC-HCl (440 mg, 2.84 mmol) and Et.sub.3N (767 mg, 7.58 mmol) were added. The mixture was stirred at room temperature for 24 h. Water (10 mL) and DCM (20 mL) were added to the resulting suspension and the 2 phases were separated. The organic phase was washed with saturated aqueous NaHCO.sub.3 solution (1×10 mL), brine (1×10 ml), 2N HCl solution (1×10 mL) and 2N NaOH (1×10 mL), dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give a yellow solid (515 mg, 60% yield).

[0286] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 0.92 (s, 3H), 1.11 (dq, J=4.4 Hz, J′=11.6 Hz, 2H), 1.4 (s, 9H), 1.54 (d, J=13.6 Hz, 2H), 1.63-1.68 (complex signal, 4H), 1.84 (s, 2H), 1.91 (m, 1H), 1.97 (s, 2H), 2.0 (d, J=12.8 Hz, 2H), 2.14-2.18 (complex signal, 2H), 2.69 (t, J=13.2 Hz, 2H), 3.06 (t, J=6 Hz, 2H), 4.06 (broad signal, 2H), 5.14 (s, 1H), 7.02-7.08 (complex signal, 4H).

Example 55: N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo [9]annulen-7-yl)-2-(piperidin-4-yl)acetamide

[0287] To a solution of tert-butyl 4-(2-((9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)amino)-2-oxoethyl)piperidine-1-carboxylate (250 mg, 0.55 mmol) in DCM (4 mL) was added 4M HCl in 1,4-dioxane (0.5 ml). The reaction mixture was stirred at room temperature for 3 days. Then, the solvent was evaporated under vacuum and the residue was dissolved in DCM (10 mL) and washed with 5N NaOH solution, dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give a yellow solid (189 mg, 97% yield).

[0288] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 0.91 (s, 3H), 1.12 (dq, J=4 Hz, J′=12.0 Hz, 2H), 1.53 (d, J=13.2 Hz, 2H), 1.62-1.71 (complex signal, 4H), 1.84 (s, 2H), 1.88 (m, 1H), 1.95-2.01 (complex signal, 4H), 2.14-2.19 (complex signal, 2H), 2.6 (dt, J=2.8 Hz, J′=12.0 Hz, 2H), 3.00-3.07 (complex signal, 4H), 5.15 (s, 1H), 7.02-7.09 (complex signal, 4H).

Example 56: 2-[1-(isopropylsulfonyl)piperidin-4-yl]-N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0289] To a solution of N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-2-(piperidin-4-yl)acetamide (185 mg, 0.52 mmol) in DCM (5 mL) was added Et.sub.3N (63 mg, 0.63 mmol). The mixture was cooled down to 0° C. and propane-2-sulfonyl chloride (74 mg, 0.52 mmol) was added dropwise. Then, the reaction mixture was stirred at room temperature overnight and quenched by addition of 2N HCl solution (3 mL). The two phases were separated and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with 5N NaOH solution, dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give a yellow solid. Column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures) gave a white solid (145 mg, 60% yield). The analytical sample was obtained by crystallization from hot EtOAc (76 mg).

[0290] mp 172 -173° C. IR (NaCl disk): 3365, 3319, 3058, 3017, 2916, 2852, 1648, 1536, 1493, 1451,1361,1322, 1308,1264, 1167,1137, 1044,1011, 993, 944, 904,880, 800, 758, 731, 701, 665 cm.sup.−1. Anal. Calcd for C.sub.26H.sub.38N.sub.2O.sub.3S.0.25 Methanol: C 67.56, H 8.42, N 6.00. Found: C 67.75H 8.62, N 5.74.

Example 57: 2-(1-acetylpiperidin-4-yl)-N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5.9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0291] To a solution of N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethano-benzo[9]annulen-7-yl)-2-(piperidin-4-yl)acetamide (200 mg, 0.57 mmol) in anh. DCM (5 mL) under argon atmosphere was added anh. Et.sub.3N (69 mg, 0.68 mmol). The mixture was cooled down to 0° C. and acetyl chloride (45 mg, 0.57 mmol) was added dropwise. Then, the reaction mixture was stirred at room temperature overnight and quenched by addition of 2N HCl solution (3 mL). The two phases were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed with 2N NaOH solution, dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum. Column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures) gave a white solid (134 mg, 48% yield).

[0292] mp 85-86° C. IR (NaCl disk): 3314, 3060, 3016, 2915, 2859, 2239, 1630, 1544, 1492, 1450, 1361, 1303, 1273, 1196, 1164, 1137, 1096, 1048 cm.sup.−1. Anal. Calcd for C.sub.25H.sub.34N.sub.2O.sub.2.0.15 DCM: C 74.17, H 8.49, N 6.88. Found: C 74.31, H 8.73, N 6.72.

Example 58: 1-(9-methyl-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(2,3,4-trifluorophenyl)urea

[0293] To a solution of 5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-amine (273 mg, 1.2 mmol) in anhydrous DCM (10 mL), 2,3,4-trifluorophenylisocyanate (147 mg, 1.0 mmol) and triethylamine (0.55 mg, 4 mmol) were added. The reaction mixture was stirred at room temperature overnight. Then the solvent was removed under vacuum. Column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixture) of the crude and concentration under vacuum of the appropriate fractions gave the urea (38 mg, 13% yield) as a white solid.

[0294] mp 206-207° C. IR (ATR): 3331, 2903, 2839, 1654, 1556, 1510, 1473, 1361, 1344, 1290, 1237, 1174, 1101, 1038, 1019, 1004, 800, 756, 690, 669, 625 cm.sup.−1. Anal. Calcd for C.sub.23H.sub.23F.sub.3N.sub.2O: C 68.99, H 5.79, N 7.00. Found: C 68.94, H 5.92, N 6.71.

Example 59: 1-(5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-yl)-3-(2,3,4-trifluorophenyl)urea

[0295] To a solution of 5-methyl-1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-amine (275 mg, 1.2 mmol) in anhydrous DCM (10 mL), 2,3,4-trifluorophenylisocyanate (147 mg, 1.0 mmol) and and triethylamine (0.55 mg, 4 mmol) were added. The reaction mixture was stirred at room temperature overnight. Then the solvent was removed under vacuum. The desired urea was obtained as a white solid (205 mg, 54% yield).

[0296] mp 257-259° C. IR (ATR): 3295, 3241, 3118, 2916, 2173, 1693, 1620, 1564, 1510, 1493, 1468, 1462, 1356, 1345, 1320, 1302, 1286, 1273, 1254, 1229,1210, 1181,1167, 1111, 1091, 1074, 1049, 1035, 1008, 999, 958, 906, 820, 812, 763, 646 cm.sup.−1. Anal. Calcd for C.sub.22H.sub.21F.sub.3N.sub.2O.sub.2.0.1H.sub.2O: C 65.37, H 5.29, N 6.93. Found: C 65.18, H 5.31, N 6.73. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.22H.sub.21F.sub.3N.sub.2O.sub.2+H].sup.+: 403.1633, found: 403.1631.

Example 60: 2-(1-benzylpiperidin-4-yl)-N-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)acetamide

[0297] To a suspension of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (250 mg, 0.95 mmol) in EtOAc (5 mL), 2-(1-benzylpiperidin-4-yl)acetic acid hydrochloride (255 mg, 0.95 mmol), HOBt (192 mg, 1.42 mmol), EDC-HCl (220 mg, 1.42 mmol) and Et.sub.3N (480 mg, 4.74 mmol) were added. The mixture was stirred at room temperature for 24 h. Water (10 mL) and DCM (10 mL) were added to the resulting suspension and the 2 phases were separated. The organic phase was washed with saturated aqueous NaHCO.sub.3 solution (1×10 mL), brine (1×10 ml), dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give a yellow gum (479 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave a white solid (280 mg, 67% yield). The analytical sample was obtained by crystallization from hot EtOAc and Et.sub.2O (124 mg).

[0298] mp 145-146° C. IR (NaCl disk): 3302, 3060, 3024, 2917, 2841, 2798, 2755, 1641, 1544, 1493, 1452, 1361, 1342, 1309, 1279, 1211, 1184, 1143, 1077, 1008, 974, 943, 916, 794, 756, 737, 697 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.30H.sub.33N.sub.2O+H].sup.+: 443.3057, found: 443.3061.

Reference Example 61: tert-butyl (1-propionylpiperidin-4-yl)carbamate

[0299] To a solution of tert-butyl piperidin-4-ylcarbamate (500 mg, 2.49 mmol) in anh. THE (5 mL) was added Et.sub.3N (252 mg, 2.49 mmol). The mixture was cooled down to 0° C. with an ice bath and then propionyl chloride (230 mg, 2.49 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. The suspension was filtrated and the filtered was evaporated to obtain the carbamate as a yellowish solid (661 mg, quantitative yield).

Reference Example 62: 1-(4-aminopiperidin-1-yl)propan-1-one

[0300] To a solution of tert-butyl (1-propionylpiperidin-4-yl)carbamate (660 g, 2.57 mmol) in DCM (3 mL) 4 M HCl in 1,4-dioxane (2 mL) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated under vacuum. The residue was then dissolved in DCM (5 mL) and washed with 5N NaOH solution (5 mL). The organic layer was dried over anh. Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give 1-(4-aminopiperidin-1-yl)propan-1-one (335 mg, 83% yield) as a yellow oil.

Example 63: 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-propionylpiperidin-4-yl)urea

[0301] To a solution of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (464 mg, 1.76 mmol) in DCM (10 mL) saturated aqueous NaHCO.sub.3 solution (10 mL) and triphosgene (193 mg, 0.65 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)propan-1-one (350 mg, 2.11 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a white solid (741 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-propionylpiperidin-4-yl)urea (597 mg, 83% yield) as a white solid. The analytical sample was obtained by crystallization from hot EtOAc and DCM (300 mg). mp 207-208° C. IR (NaCl disk): 3357, 2917, 2858, 1644, 1620, 1555, 1493, 1449, 1360, 1344, 1318, 1263, 1221, 1131, 1067, 1023, 971, 948, 758 cm.sup.−1. Anal. Calcd for C.sub.25H.sub.35N.sub.3O.sub.2. 0.15 EtOAc: C 72.73, H 8.63, N 9.94. Found: C 72.65, H 8.49, N 9.82.

Example 64: 1-(1-(4-acetylphenyl)piperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0302] To a solution of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (241 mg, 0.95 mmol) in DCM (5 mL) saturated aqueous NaHCO.sub.3 solution (5 mL) and triphosgene (104 mg, 0.35 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (5 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-(4-aminopiperidin-1-yl)phenyl)ethan-1-one (250 mg, 1.15 mmol, prepared following the procedure reported in WO2007016496). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain an orange solid (475 mg). Column chromatography (SiO.sub.2, Hexane/Ethyl Acetate mixtures) gave 1-(1-(4-acetylphenyl)piperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (120 mg, 27% yield) as a yellowish solid. mp 211-212° C. IR (NaCl disk): 3357, 2919, 2844, 1666, 1633, 1596, 1552, 1518, 1493, 1452, 1427, 1389, 1359, 1306, 1281, 1224, 1193, 1128, 1068, 956, 915, 825, 758 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.30H.sub.37N.sub.3O.sub.2+H].sup.+: 472.2959, found: 472.2962.

Example 65: 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea

[0303] To a solution of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (258 mg, 0.98 mmol) in DCM (4 mL) saturated aqueous NaHCO.sub.3 solution (4 mL) and triphosgene (107 mg, 0.36 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (2 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (215 mg, 1.10 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a yellow residue (534 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-3-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)urea (207 mg, 45% yield) as a white solid.

[0304] mp 224-225° C. IR (NaCl disk): 3356, 3064, 2945, 2919, 2850, 1639, 1613, 1552, 1493, 1446, 1360, 1344, 1320, 1278, 1261, 1238, 1211, 1126, 1089, 1068, 1018, 983, 941, 874, 818, 758, 733 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.23H.sub.39N.sub.3O.sub.3+H].sup.+: 466.3064, found: 466.3065.

Example 66: 1-(1-(2-fluorobenzoyl)piperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexa-hydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0305] To a solution of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (247 mg, 0.93 mmol) in DCM (4 mL) saturated aqueous NaHCO.sub.3 solution (4 mL) and triphosgene (103 mg, 0.36 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (3 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl)(2-fluorophenyl)methanone (250 mg, 1.12 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a white solid (486 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-(2-fluorobenzoyl)piperidin-4-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (285 mg, 45% yield) as a white solid. mp 265-266° C. IR (NaCl disk): 3368, 2920, 2854, 1614, 1549, 1492, 1452, 1364, 1318, 1282, 1222, 1122, 1089, 1029, 974, 948, 817, 755 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.29H.sub.34FN.sub.3O.sub.2+H].sup.+: 476.2708, found: 476.2711.

Example 67: 1-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-(9-methyl-5,6, 8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0306] To a solution of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (253 mg, 0.96 mmol) in DCM (4 mL) saturated aqueous NaHCO.sub.3 solution (4 mL) and triphosgene (105 mg, 0.35 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (3 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added (1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-amine (250 mg, 1.15 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a yellow gum (498 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-(9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (293 mg, 65% yield) as a white solid. The analytical sample was obtained by crystallization from hot mixture EtOAc:Et.sub.2O (187 mg).

[0307] mp 100-101° C. IR (NaCl disk): 3319, 3022, 2944, 2919, 2843, 1632, 1557, 1493, 1452, 1344, 1321, 1304, 1279, 1263, 1235, 1164, 1122, 1056, 1027, 756, 729, 696 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.31H.sub.39N.sub.3O+H].sup.+: 470.3166, found: 470.3168.

Example 68: 1-(1-acetylpiperidin-4-yl)-3-(2-fluoro-9-methyl-5,6,8,9,10,11-hexahy-dro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0308] To a solution of 2-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethano-benzo[9]annulen-7-amine hydrochloride (150 mg, 0.53 mmol) in DCM (3 mL) saturated aqueous NaHCO.sub.3 solution (3 mL) and triphosgene (59 mg, 0.20 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (3 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (91 mg, 0.64 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a yellowish oil (165 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(2-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (103 mg, 49% yield) as a white solid. mp 269-270° C. IR (NaCl disk): 3357, 2919, 2856, 1644, 1620, 1555, 1499, 1453, 1361, 1342, 1320, 1228, 1153, 1138, 1064, 967, 863, 818 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.24H.sub.32FN.sub.3O.sub.2+H].sup.+: 414.2551, found: 414.2553.

Example 69: 1-(1-acetylpiperidin-4-yl)-3-(2-methoxy-9-methyl-5,6,8,9,10,11-hexa-hydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0309] To a solution of 2-methoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethano-benzo[9]annulen-7-aminehydrochloride (150 mg, 0.51 mmol) in DCM (3 mL) saturated aqueous NaHCO.sub.3 solution (3 mL) and triphosgene (56 mg, 0.19 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (3 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (87 mg, 0.61 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a brown oil (256 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(2-methoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (121 mg, 56% yield) as a white solid. mp 116-117° C. IR (NaCl disk): 3359, 2905, 2861, 1644, 1619, 1551, 1501, 1452, 1360, 1343, 1319, 1267, 1227, 1153, 1136, 1042, 973, 807, 736 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.25H.sub.35N.sub.3O.sub.3+H].sup.+: 426.2571, found: 4426.2760.

Example 70: 1-(1-acetylpiperidin-4-yl)-3-(1-fluoro-9-methyl-5,6,8,9,10,11-hexahy-dro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0310] To a solution of 1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethano-benzo[9]annulen-7-amine hydrochloride (150 mg, 0.53 mmol) in DCM (3 mL) saturated aqueous NaHCO.sub.3 solution (3 mL) and triphosgene (58 mg, 0.20 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (3 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (91 mg, 0.64 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a yellow oil (320 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(1-fluoro-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (160 mg, 73% yield) as a white solid. mp 122-123° C. IR (NaCl disk): 3351, 2944, 2918, 2861, 1642, 1618, 1555, 1462, 1362, 1321, 1238, 1137, 1066, 976, 885, 798, 749 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.24H.sub.32FN.sub.3O.sub.2+H].sup.+: 414.2551, found: 414.2554.

Example 71: 1-(1-acetylpiperidin-4-yl)-3-(2,3-dimethoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0311] To a solution of 2,3-dimethoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (150 mg, 0.46 mmol) in DCM (3 mL) saturated aqueous NaHCO.sub.3 solution (3 mL) and triphosgene (51 mg, 0.17 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (3 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (79 mg, 0.55 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a yellow oil (334 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(2,3-dimethoxy-9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (168 mg, 80% yield) as a white solid. mp 127-128° C. IR (NaCl disk): 3365, 3052, 2913, 2862, 2834, 1643, 1616, 1553, 1516, 1452, 1360, 1343, 1320, 1293, 1252, 1232, 1168, 1137, 1092, 1019, 974, 863, 801, 734 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.26H.sub.37N.sub.3O.sub.4+H].sup.+: 456.2857, found: 456.2859.

Example 72: 1-(1-acetylpiperidin-4-yl)-3-(5,8,9,10-tetrahydro-5,8:7,10-dimethano-benzo[8]annulen-7(6H)-yl)urea

[0312] To a solution of 5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulen-7(6H)-amine hydrochloride (57 mg, 0.24 mmol) in DCM (1 mL) saturated aqueous NaHCO.sub.3 solution (1 mL) and triphosgene (27 mg, 0.09 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (1 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (41 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to obtain a brown gum (93 mg). Column chromatography (SiO.sub.2, DCM/Methanol mixtures) gave 1-(1-acetylpiperidin-4-yl)-3-(5,8,9,10-tetrahydro-5,8:7,10-dimethanobenzo[8]annulen-7(6H)-yl)urea (47 mg, 53% yield) as a white solid. mp 98-99° C. IR (NaCl disk): 3359, 3013, 2927, 2856, 2239, 1621, 1556, 1449, 1372, 1334, 1318, 1268, 1238, 1225, 1192, 1153, 1107, 1081, 1048, 1041, 972, 920, 756, 730 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.22H.sub.29N.sub.3O.sub.2+H].sup.+: 4368.2333, found: 368.2331.

Example 73: 1-(benzo[d]thiazol-2-yl)-3-(9-methoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0313] To a solution of 9-methoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine (250 mg, 1.03 mmol) in DCM (3 mL) saturated aqueous NaHCO.sub.3 solution (3 mL) and triphosgene (113 mg, 0.38 mmol) were added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic layer was washed with brine (3 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of the isocyanate in DCM.

[0314] To a solution of benzo[d]thiazol-2-amine (141 mg, 0.94 mmol) in anh. THE (8 mL) under argon atmosphere at −78° C., was added dropwise a solution of n-butyllithium (2.5 M in hexanes, 0.38 mL, 0.94 mmol) during 20 minutes. After the addition, the mixture was tempered to 0° C. using an ice bath. This solution was added carefully to the solution of the isocyanate from the previous step cooled to 0° C., under argon atmosphere. The reaction mixture was stirred at room temperature overnight. Methanol (3 mL) was then added to quench any unreacted n-butyllithium. The solvents were evaporated under vacuum to give a yellow solid (531 mg). Column chromatography (SiO2, Hexane/Ethyl Acetate mixtures) gave a 1-(benzo[d]thiazol-2-yl)-3-(9-methoxy-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea (65 mg, 15% yield) as a white solid.

[0315] mp 247-248° C. IR (NaCl disk): 2926, 2851, 1712, 1675, 1593, 1537, 1445, 1358, 1268, 1217, 1556, 1116, 1080, 1044, 1015, 910, 845 cm.sup.−1 HRMS-ESI+m/z [M+H]+ calcd for [C.sub.24H.sub.25N.sub.3O.sub.2S+H].sup.+: 420.1740, found: 368.2331.

Example 74: 1-(1-acetylpiperidin-4-yl)-3-(1,9-difluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-yl)urea

[0316] To a solution of 1,9-difluoro-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo[9]annulen-7-amine hydrochloride (120 mg, 0.42 mmol) in DCM (3 mL) and saturated aqueous NaHCO.sub.3 solution (3 mL), triphosgene (46 mg, 0.16 mmol) was added. The biphasic mixture was stirred at room temperature for 30 minutes and then the two phases were separated and the organic one was washed with brine (3 mL), dried over anh. Na.sub.2SO.sub.4, filtered and evaporated under vacuum to obtain 1-2 mL of a solution of isocyanate in DCM. To this solution was added 1-(4-aminopiperidin-1-yl)ethan-1-one (72 mg, 0.51 mmol). The mixture was stirred overnight at room temperature and the solvent was then evaporated. Column chromatography (SiO.sub.2, DCM/Methanol mixtures) afforded the urea (84 mg, 48% yield) as a yellowish solid.

[0317] The analytical sample was obtained by crystallization from hot EtOAc/Pentane. mp 248-249° C. IR (ATR): 3382, 3266, 2923, 2164, 1645, 1622, 1562, 1503, 1464, 1454,1425,1362,1341, 1325,1318, 1304,1244, 1232,1185, 1135, 1099, 1059, 1036, 1015, 995, 978, 952, 929, 891, 868, 795, 746, 717, 695, 645, 625, 605, 590 cm.sup.−1.

[0318] HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.23H.sub.29F.sub.2N.sub.3O.sub.2+H].sup.+: 418.2301; Found: 418.2300.

Reference Example 75: 1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-5-d-3(2H)-ol

[0319] To a solution of 5,6,7,8-tetrahydro-7H-5,9-propanobenzo[7]annulene-7,11-dione (3.13 g, 14.6 mmol) in MeOH (88 mL), NaBD.sub.4 (1 g, 23.9 mmol) was added portion-wise and the suspension was stirred under reflux for 6 h. The solution was cooled down and the solvent was removed under vacuum. To the obtained white solid, NaOH 2 N (100 mL) was added and the suspension was refluxed for 30 min. After that, the suspension was filtered and washed with H.sub.2O (50 mL) to afford the 1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-5-d-3(2H)-ol (2.88 g, 91% yield) as a white solid. mp 200° C. IR (ATR): 3304, 2957, 2941, 2927, 2913, 1492, 1461, 1451, 1431, 1383, 1356, 1339, 1328, 1278, 1253, 1234, 1219, 1189, 1157, 1141, 1127,1082, 1047,1017, 1002, 958, 935, 863, 844, 773, 755, 718, 673 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.14H.sub.15DO.sub.2+H].sup.+: 218.1286, found: 218.1297.

Reference Example 76: (1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-yl-5-d)hydrazine hydrochloride

[0320] A solution of 1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-5-d-3(2H)-ol (1.2 g, 5.52 mmol) in hydrazine hydrate (9 mL, aq. sol. 64%, 183.98 mmol) and HCl conc. (0.2 mL) was heated at reflux overnight. The solution was cooled down and the suspension was filtered. The obtained solid was dissolved in methanol and HCl/MeOH was added to afford (1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-yl-5-d)hydrazine hydrochloride (1.26 g, 85% yield).

[0321] mp 232-235° C. IR (ATR): 3303, 3226, 2911, 2845, 2650, 1589, 1525, 1490, 1451, 1435, 1356, 1328, 1278, 1253, 1219, 1157, 1145, 1129, 1084, 1050, 1024, 1002, 958, 936, 892, 865, 830, 812, 771, 750, 721 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.14H.sub.17DN.sub.2O+H].sup.+: 232.1555, found: 232.1554.

Reference Example 77: 1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-5-d-3(2H)-amine hydrochloride

[0322] A solution of 1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-3(2H)-yl-5-d)hydrazine hydrochloride (1 g, 3.7 mmol) and PtO.sub.2 (100 mg) in ethanol (100 mL) was hydrogenated at room temperature, at a pressure of 1 atm for 5 days. The resulting suspension was filtered and the residue washed with methanol. The solvent was removed under vacuum affording a white solid. The solid was dissolved in MeOH and an excess of HCl/MeOH was added. The solvent was evaporated to afford 1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-5-d-3(2H)-amine hydrochloride (791 mg, 85% yield) as a white solid. The analytical sample was obtained by crystallization from Methanol/Et.sub.2O.

[0323] mp 195° C. IR (ATR): 3304, 3010, 2940, 2913, 2847, 1510, 1490, 1451, 1435, 1379, 1356, 1328, 1280, 1251, 1235, 1221, 1157, 1126, 1082, 1041, 1000, 957, 937, 866, 844, 773, 762, 755, 720, 670 cm.sup.−1. HRMS-ESI+m/z [M+H].sup.+ calcd for [C.sub.14H.sub.16DNO+H].sup.+: 217.1446, found: 217.1449.

Example 78: 1-(1-acetylpiperidin-4-yl)-3-(1,5,6,7-tetrahydro-1,5:3,7-dimethano-benzo[e]oxonin-3(2H)-yl-5-d)urea

[0324] From 1,5,6,7-tetrahydro-1,5:3,7-dimethanobenzo[e]oxonin-5-d-3(2H)-amine hydrochloride and following the procedure of example 37, 1-(1-acetylpiperidin-4-yl)-3-(1,5,6,7-tetrahydro-1,5:3,7-dimethano-benzo[e]oxonin-3(2H)-yl-5-d)urea was obtained

Example 79: In Vitro Determination of sEH Inhibition Activity

[0325] The following fluorescent assay was used for determination of the sEH inhibition activity (IC.sub.50), with the substrate and comparative control compound (TPPU) indicated below.

[0326] Substrate: cyano(6-methoxynaphthalen-2-yl)methyl 2-(3-phenyloxiran-2-yl)acetate (PHOME; from Cayman Chemical, item number 10009134; CAS 1028430-42-3); cf. N. M. Wolf et al., Anal. Biochem. 2006, vol. 355, pp. 71-80.

[0327] TPPU: N-[1-(1-Oxopropyl)-4-piperidinyl]-N′-[4-(trifluoromethoxy)phenyl]urea.

[0328] Solutions: [0329] Assay buffer: Bis/Tris HCl 25 mM pH 7.0 containing 0.1 mg/mL of bovine serum albumin (BSA). [0330] PHOME at 200 μM in DMSO. [0331] Solution of recombinant human sEH (hsEH) (Cayman Chemical, item number 10011669), diluted with assay buffer. [0332] Inhibitors dissolved in DMSO at appropriated concentrations.

[0333] Protocol: In a black 96-well plate (Greiner Bio-One, item number 655900), fill the background wells with 90 μL and the positive control and inhibitor wells with 85 μL of assay buffer. Add 5 μL of DMSO to background and positive control wells, and then add 5 μL of inhibitor solution in inhibitor wells. Add 5 μL of the solution of hsEH to the positive control and inhibitor wells and stir the mixture. Prepare a 1/21 dilution of the solution of PHOME with assay buffer according to final volume required, and then add 105 μL of each well. Shake carefully the plate for 10 seconds and incubate for 5 minutes at room temperature. Read the appearance of fluorescence with excitation wavelength: 337 nm, and emission wavelength: 460 nm (FLUOStar OPTIMA microplate reader, BMG). The intensity of fluorescence was used to analyze and calculate the IC.sub.50 values. Results were obtained by regression analysis from at least three data points in a linear region of the curve. IC.sub.50 values are average of minimum three independent replicates.

TABLE-US-00001 TABLE 1 and 2 human sEH inhibition activity (IC.sub.50, nM) of selected compounds (I).sup.a Ex. TTPU 35 36 38 39 40 41 42 43 44 47 48 51 52 53 56 IC.sub.50 A D D A D B A A B A A A A A B B Ex. 57 58 59 60 63 64 65 66 67 68 69 70 71 72 73 74 IC.sub.50 D A B D A A A A A A A A A B D A .sup.aA means that IC.sub.50 is lower than 10 nM, B means that IC.sub.50 is at least 10 nM but less than 50 nM, C means that IC.sub.50 is at least 50 nM but less than 100 nM and D means that IC.sub.50 is at least 100 nM but less than 1000 nM.

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