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Fused Pentacyclic Imidazole Derivatives as Modulators of TNF Activity

20230250105 · 2023-08-10

    Inventors

    Cpc classification

    International classification

    Abstract

    A compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, being potent modulators of human TNFα activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

    Claims

    1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR00085## wherein X represents N or C-F; R.sup.1 represents hydrogen or methyl; R.sup.2 represents hydrogen, methyl or trifluoromethyl; and R.sup.3 represents hydrogen, cyano, hydroxy or hydroxymethyl.

    2. A compound as claimed in claim 1 represented by formula (IIA), or a pharmaceutically acceptable salt thereof: ##STR00086## wherein X, R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1.

    3. A compound as claimed in claim 1 represented by formula (IIB), or a pharmaceutically acceptable salt thereof: ##STR00087## wherein X, R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1.

    4. A compound as claimed in claim 1 selected from the following: cis-3-amino-3-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-1-methyl-cyclobutanecarbonitrile; cis-3-amino-3-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-1-methyl-cyclobutanecarbonitrile; cis-3-amino-3-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzim idazo[1,2-b][2,5]benzodiazocin-11-yl]-3-fluoropyridin-2-yl}-1-methylcyclobutanecarbonitrile; cis-3-amino-3-{5-[(7R,14R)-1 -(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]-3-fluoropyridin-2-yl}-1-methyl-cyclobutanecarbonitrile; (7R,14R)-11-{6-[(1S,2R)-1-amino-2-methylcyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one; (7R,14R)-11-{6-[(1R,2S)-1-amino-2-methylcyclobutyl]-5-fluoropyridin-3-yl}-1 -(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one; (7R,14R)-11-[6-(cis-1-amino-3-hydroxy-3-methylcyclobutyl)-5-fluoropyridin-3-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; (7R,14R)-11-[6-(cis-1-amino-3-hydroxy-3-methylcyclobutyl)-5-fluoropyridin-3-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one; (7R,14R)-11-{2-[cis-1-amino-3-(hydroxymethyl)-3-methylcyclobutyl]pyrimidin-5-yl}-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; (7R,14R)-11-{6-[cis-1-am ino-3-(hydroxymethyl)-3-methylcyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; (7R,14R)-11 -{6-[cis-1-am ino-3-hydroxy-3-(trifluoromethyl)cyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; (7R,14R)-11-{2-[cis-1-amino-3-hydroxy-3-(trifluoromethyl)cyclobutyl]pyrimidin-5-yl}-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; (7R,14R)-11 -{6-[cis-1-am ino-3-hydroxy-3-(trifluoromethyl)cyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; (7R,14R)-11-(2-{cis-1-amino-3-[hydroxy(dideutero)methyl]-3-methylcyclobutyl}-pyrimidin-5-yl)-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; (7R,14R)-11-{2-[cis-1-amino-3-(hydroxymethyl)-3-methylcyclobutyl]pyrimidin-5-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one; and (7R,14R)-11-(6-{cis-1-amino-3-[hydroxy(dideutero)methyl]-3-methylcyclobutyl}-5-fluoropyridin-3-yl)-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b]-[2,5]benzodiazocin-5(14H)-one.

    5. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in therapy.

    6. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of TNFα function is indicated.

    7. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.

    8. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

    9. A pharmaceutical composition as claimed in claim 8 further comprising an additional pharmaceutically active ingredient.

    10. (canceled)

    11. (canceled)

    12. A method for the treatment and/or prevention of disorders for which the administration of a modulator of TNFα function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof.

    13. A method for the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof.

    14. The method according to claim 13 wherein the inflammatory or autoimmune disorder is selected from the group consisting of psoriasis, ankylosing spondylitis, psoriatic arthropathy, rheumatoid arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, hidradenitis suppurativa, inflammatory bowel disease, Behçet’s disease, scleroderma, systemic sclerosis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, fibrosing disorders, and diabetic nephropathy; the neurological or neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, and spinal cord injury; the cardiovascular disorder is selected from the group consisting of cardiac hypertrophy and myocardial infarction; the metabolic disorder is selected from the group consisting of diabetes and metabolic syndrome; the ocular disorder is retinopathy; and the oncological disorder is selected from the group consisting of haematological malignancy and non-haematological malignancy (including solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma).

    15. The method according to claim 13 wherein the inflammatory bowel disease is selected from Crohn’s disease, ulcerative colitis, indeterminate colitis and pouchitis.

    16. The method according to claim 13 wherein the inflammatory or autoimmune disorder is a fibrosing disorder selected from hepatic and pulmonary fibrosis.

    17. The method according to claim 13 wherein the metabolic disorder is insulin-dependent diabetes mellitus or juvenile diabetes.

    18. The method according to claim 13 wherein the ocular disorder is selected from diabetic retinopathy, proliferative retinopathy, non-proliferative retinopathy and retinopathy of prematurity.

    19. The method according to claim 13 wherein the oncological disorder is a haematological malignancy selected from leukaemia and lymphoma, or a non-haematological malignancy selected from solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma.

    20. A process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR00088## wherein X represents N or C-F; R.sup.1 represents hydrogen or methyl; R.sup.2 represents hydrogen, methyl or trifluoromethyl; and R.sup.3 represents hydrogen, cyano, hydroxy or hydroxymethyl, comprising reacting a compound of formula (III) with a compound of formula (IV): ##STR00089## ##STR00090## wherein X, R.sup.1, R.sup.2 and R.sup.3 are as defined above, L.sup.1 represents a leaving group, M.sup.1 represents a boronic acid moiety —B(OH).sub.2 or a cyclic ester thereof formed with an organic diol, and R.sup.p represents an N-protecting group; in the presence of a transition metal catalyst; followed, as necessary, by removal of the N-protecting group R.sup.p.

    21. The process according to claim 20, wherein the leaving group L.sup.1 is a halogen atom.

    22. The process according to claim 20, wherein the leaving group L.sup.1 is bromo.

    23. The process according to claim 20, wherein the N-protecting group R.sup.p represents tert-butoxycarbonyl or tert-butylsulfinyl.

    24. The process according to claim 23, wherein the N-protecting group R.sup.p is removed by treatment with an acid.

    25. The process according to claim 20, wherein the transition metal catalyst is tris(dibenzylideneacetone)dipalladium(0), or [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), or chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II).

    26. The process according to claim 25, wherein the transition metal catalyst is utilised in conjunction with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl or tricyclohexylphosphonium tetrafluoroborate.

    27. The process according to claim 20, wherein the reaction between the compound of formula (III) and the compound of formula (IV) is performed in the presence of potassium phosphate or potassium carbonate.

    28. The process according to claim 20, wherein M.sup.1 represents a cyclic ester of moiety —B(OH).sub.2 formed with pinacol and the compound of formula (IV) is prepared by reacting bis-(pinacolato)diboron with a compound of formula (V): ##STR00091## wherein L.sup.2 represents a suitable leaving group; in the presence of a transition metal catalyst.

    29. A compound which is: ##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## .

    Description

    EXAMPLES

    [0084] TABLE-US-00001 Abbreviations DCM: dichloromethane EtOAc: ethyl acetate MeOH: methanol THF: tetrahydrofuran DMSO: dimethyl sulfoxide DMF: N,N-dimethylformamide TBAF: tetra-n-butylammonium fluoride LDA: lithium diisopropylamide Dess-Martin periodinane: 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one XPhos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl XPhos Pd G2: chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) r.t.: room temperature h: hour M: mass RT: retention time HPLC: High Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry ES+: Electrospray Positive Ionisation

    Analytical Conditions

    [0085] All NMR spectra were obtained at 250 MHz, 300 MHz, 400 MHz or 500 MHz.

    [0086] All reactions involving air-or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware.

    LCMS Data Determination

    [0087] TABLE-US-00002 Column: X-Bridge C18 Waters 2.1 × 20 mm, 2.5 .Math.m column Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: Flow rate pump 1: 1 mL/min; Flow rate pump 2: 0.5 mL/min Pump 1: Pump 2: Time A% B% Time A% B% 0.00 95.10 4.90 0.10 5.00 95.00 4.00 5.00 95.00 1.00 5.00 95.00 5.00 5.00 95.00 1.10 95.00 5.00 5.10 95.10 4.90

    TABLE-US-00003 Column: X-Bridge C18 Waters 2.1 × 20 mm, 2.5 .Math.m column Mobile Phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile Phase B: acetonitrile + 5% water + 0.1% formic acid Gradient program: Flow rate pump 1: 1 mL/min; Flow rate pump 2: 0.5 mL/min Pump 1: Pump 2: Time A% B% Time A% B% 0.00 95.00 5.00 0.10 5.00 95.00 4.00 5.00 95.00 1.00 5.00 95.00 5.00 5.00 95.00 1.10 95.00 5.00 5.10 95.00 5.00

    TABLE-US-00004 Column: X-Bridge C18 Waters 2.1 × 20 mm, 2.5 .Math.m column Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: Flow rate 1 mL/min Time A% B% 0.00 96.00 4.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 96.00 4.00

    TABLE-US-00005 Column: X-Bridge C18 Waters 2.1 × 20 mm, 2.5 .Math.m column Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: Flow rate 1 mL/min Time A% B% 0.00 96.00 4.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 96.00 4.00

    TABLE-US-00006 Column: X-Bridge C18 Waters 2.1 × 20 mm, 2.5 .Math.m column Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: Flow rate 1 mL/min Time A% B% 0.00 94.00 6.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 94.00 6.00

    TABLE-US-00007 Agilent Technologies 1260 Infinity Part Model LC/MSD G6130B Degasser G4225A BinPump G1312B HiP ALS (autosampler) G1367E Valve Drive G1170A TCC G1316A DAD VL G1315D Interface 5900E

    Apparatus

    [0088] Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom. DAD: Agilent G1315D, 220-320 nm. MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-800, ELSD Alltech 3300.

    [0089] Gas flow: 1.5 mL/minute; Gas temp.: 40° C.; Column: Waters XSelect™ C18, 30 × 2.1 mm, 3.5 .Math.m; Temperature: 35° C.; Flow: 1 mL/minute; Gradient: t.sub.0 = 5% A, t.sub.1.6 min = 98% A, t.sub.3.0 min = 98% A; Post-time: 1.3 minutes; Eluent A: 0.1% formic acid in acetonitrile; Eluent B: 0.1% formic acid in water.

    TABLE-US-00008 Agilent Technologies 1260 Infinity Part Model LC/MSD G6130B Degasser G4225A BinPump G1312B HiP ALS (autosampler) G1367E Valve Drive G1170A TCC G1316A DAD VL G1315D Interface 5900E

    Apparatus

    [0090] Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom. DAD: Agilent G1315D, 220-320 nm. MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-800, ELSD Alltech 3300.

    [0091] Gas flow 1.5 mL/minute; Gas temp.: 40° C.; Column: Waters XSelect™ C18, 50 × 2.1 mm, 3.5 .Math.m; Temperature: 35° C.; Flow: 0.8 mL/minute; Gradient: t.sub.0 = 5% A, t.sub.3.5 min = 98% A, t.sub.6.0 min = 98% A; Post-time: 2.0 minutes; Eluent A: 0.1% formic acid in acetonitrile; Eluent B: 0.1% formic acid in water.

    TABLE-US-00009 Column: Kinetex Core-Shell C18, 50 × 2.1 mm, 5 .Math.m column protected by Phenomenex ‘Security Guard’ column Mobile Phase A: 0.1% formic acid in water Mobile Phase B: 0.1% formic acid in acetonitrile Gradient program: Flow rate 1.2 mL/min Column temperature: 40° C. Time A% B% 0.00 95 5 1.20 0 100 1.30 0 100 1.31 95 5

    TABLE-US-00010 Column: Phenomenex Kinetex Core-Shell C8, 50 × 2.1 mm, 5 .Math.m column protected by Phenomenex ‘Security Guard’ column Mobile Phase A: 0.1% formic acid in water Mobile Phase B: 0.1% formic acid in acetonitrile Gradient program: Flow rate 1.2 mL/min Column temperature: 40° C. Time A% B% 0.00 95 5 1.83 0 100 2.25 0 100 2.26 95 5

    TABLE-US-00011 Column: Phenomenex Gemini C18, 2.0 mm × 50 mm, 3 .Math.m column Mobile Phase A: 2 mM ammonium bicarbonate, pH 10 Mobile Phase B: acetonitrile Gradient program: Flow rate 1.0 mL/minute Column temperature: 60° C. Time A% B% 0.00 99 1 1.80 0 100 2.10 0 100 2.30 99 1

    TABLE-US-00012 Column: Phenomenex Kinetex-XB C18, 2.1 mm × 100 mm, 1.7 .Math.m column Mobile Phase A: 0.1% formic acid in water Mobile Phase B: 0.1% formic acid in acetonitrile Gradient program: Flow rate 0.6 mL/min Column temperature: 40° C. Time A% B% 0.00 95 0 5.30 0 100 5.80 0 100 5.82 95 5

    GCMS Data Determination

    [0092] TABLE-US-00013 Agilent Technologies Part Model 5973 MSD G2577A autosampler G2614A 7683B injector G2913A 6890N GC system G1530N

    [0093] Instrument: GC: Agilent 6890N, FID: Detection temp.: 300° C. and MS: 5973 MSD, EI-positive, Detection temp.: 280° C.; Mass range: 50-550; Column: RXi-5MS 20 m, ID 180 .Math.m, df 0.18 .Math.m; Average velocity: 50 cm/s; Injection vol.: 1 .Math.L; Injector temp.: 250° C.; Split ratio: 20/1; Carrier gas: He; Initial temperature: 100° C.; Initial time: 1.5 minute; Solvent delay: 1.3 minute; Rate: 75° C./minute; Final temp.: 250° C.; Final time: 2.5 minutes.

    Intermediate 1

    [0094] ##STR00007##

    (R)-N-Cyano-3-Methylcyclobutylidene)-2-Methylpropane-2-Sulfinamide

    [0095] To 1-methyl-3-oxocyclobutanecarbonitrile (532 mg, 4.63 mmol) dissolved in THF (35 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (570 mg, 4.61 mmol), followed by titanium(IV) ethoxide (1.8 mL, 8.7 mmol). The reaction mixture was heated at 75° C. under nitrogen overnight with stirring, then cooled to r.t. Saturated aqueous sodium bicarbonate solution (50 mL) was added. The reaction mixture was filtered through celite, washing with EtOAc. The organic layer was separated and washed sequentially with water (50 mL), followed by brine (50 mL). The organic layer was separated and filtered through a phase separator, then the organic layer was concentrated in vacuo. The resulting orange oil was purified by flash column chromatography on silica (gradient elution with 100% isohexane to 100% EtOAc). The resulting straw-coloured oil solidified on standing to afford the title compound (863 mg, 88%) as an off-white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 3.95-3.59 (m, 2 H), 3.60-3.36 (m, 1 H), 3.25 (ddt, J 17.6, 9.8, 3.3 Hz, 1 H), 1.58 (d, J 1.4 Hz, 3 H), 1.16 (d, J 1.2 Hz, 9 H).

    Intermediate 2

    [0096] ##STR00008##

    (R)-N-(5-Bromopyrimidin-2-yl)-3-Cyano-3-Methylcyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0097] Two separate batches of 5-bromo-2-iodopyrimidine (1.6 g, 5.62 mmol) were dissolved in DCM (50 mL) and DCM (100 mL). The separate reaction mixtures were cooled to -78° C. under nitrogen, then 2.5 M n-butyllithium (2.26 mL, 5.65 mmol) was added to each reaction mixture dropwise over 5 minutes. The reaction mixtures were stirred at -78° C. under nitrogen for 2 minutes, prior to the slow addition of Intermediate 1 (1 g, 4.71 mmol) dissolved in DCM (5 mL) via syringe to each reaction mixture. The reaction mixtures were stirred at -78° C. for 2 h. The larger (100 mL) batch was stirred in an ice bath for 3 h, whilst the smaller (50 mL) batch was stirred in a cardice/acetone bath for 3 h. The reaction mixtures were combined and quenched with saturated aqueous ammonium chloride solution (50 mL), then the organic layer was separated, filtered through a phase separator and concentrated in vacuo. The resulting crude yellow oil was purified by flash column chromatography on silica (gradient elution with 100% isohexane to 100% EtOAc) to afford the title compound (530 mg, 14%) (60:40 mixture of trans:cis isomers) as a yellow gum. LCMS (ES+) [M+H].sup.+ 371.0, RT 1.66 and 1.69 minutes, purity 68.1% (Method 4).

    Intermediate 3

    [0098] ##STR00009##

    (7R,14R)-11-Chloro-1-(Difluoromethoxy)-6-Methyl-6,7-Dihydro-7,14-Methano-Benzimidazo[1,2-b][2,5]Benzodiazocin-5(14H)-One

    [0099] To a solution of (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (WO 2016/050975, Example 11) (10 g, 26.6 mmol) in dry THF (135 mL), cooled to -78° C. under nitrogen, was added potassium bis(trimethylsilyl)amide (1 M in THF, 30 mL, 30 mmol) dropwise over 15 minutes. The resulting mixture was stirred at -78° C. for 1 h prior to the addition of iodomethane (2.5 mL, 40 mmol) dropwise over 5 minutes. The reaction mixture was stirred at -78° C. for 1 h, then allowed to warm slowly to ambient temperature overnight. The reaction mixture was poured into saturated aqueous ammonium chloride solution (600 mL) and extracted with EtOAc (2 × 800 mL). The organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. Purification by flash chromatography on silica (elution with 5% MeOH/DCM) afforded the title compound (9.12 g, 88%) as a beige solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 8.33-8.21 (m, 1 H), 7.87-7.33 (m, 5 H), 7.22 (dd, J 8.7, 2.1 Hz, 1 H), 6.23 (d, J 7.1 Hz, 1 H), 5.22 (d, J 7.1 Hz, 1 H), 3.55-3.41 (m, 1 H), 3.33 (s, 3 H), 2.81 (d, J 13.8 Hz, 1 H). LCMS (ES+) [M+H].sup.+ 390.0, RT 1.10 minutes (Method 3).

    Intermediate 4

    [0100] ##STR00010##

    (7R,14R)-1-(Difluoromethoxy)-6-Methyl-11-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-Yl)-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-5(14H)-One

    [0101] Intermediate 3 (4 g, 10.3 mmol) in 1,4-dioxane (42 mL) was treated with bis-(pinacolato)diboron (3.9 g, 15 mmol) and potassium acetate (3 g, 30.6 mmol). The reaction mixture was degassed and flushed with nitrogen. Tris(dibenzylideneacetone)-dipalladium(0) (484 mg, 0.51 mmol) and tricyclohexylphosphonium tetrafluoroborate (390 mg, 1.03 mmol) were added, then the reaction mixture was degassed and flushed with nitrogen, before being heated overnight at 140° C. Further bis(pinacolato)diboron (2.6 g, 10.3 mmol) was added. The reaction mixture was heated at 140° C. for 24 h, then partitioned between EtOAc and brine. The organic phase was separated and concentrated in vacuo, then purified by flash column chromatography on silica (gradient elution with 0-10% EtOAc/MeOH), to afford the title compound (2.5 g, 50%) as a white solid. LCMS (ES+) [M+H].sup.+ 482.2, RT 2.40 minutes (Method 4).

    Intermediate 5

    [0102] ##STR00011##

    (R)-N-Cyano-1-{5-[(7R,14R)-1-(Difluoromethoxy)-6-Methyl-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-B][2,5]Benzodiazocin-11-Yl]Pyrimidin-2-yl}-3-Methylcyclobutyl)-2-Methylpropane-2-Sulfinamide

    [0103] To potassium phosphate tribasic (171 mg, 0.80 mmol), tricyclohexylphosphonium tetrafluoroborate (18.8 mg, 0.050 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.7 mg, 0.018 mmol) and Intermediate 4 (126 mg, 0.263 mmol) was added Intermediate 2 (83 mg, 0.225 mmol) dissolved in degassed 1,4-dioxane (1.5 mL). Degassed water (0.04 mL) was added and the reaction mixture was degassed under three cycles of vacuum and nitrogen, then transferred to a sealed tube and placed in a pre-heated block at 110° C. for 3 h. The reaction mixture was allowed to cool to ambient temperature, then diluted with EtOAc (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with additional EtOAc (20 mL). The organic layers were combined and washed with brine (20 mL), then dried (Na.sub.2SO.sub.4) and filtered. The solvent was removed in vacuo. The resulting brown oil was purified by flash column chromatography on silica (gradient elution with 100% isohexane to 100% EtOAc, followed by 100% DCM to 25% MeOH/DCM) to afford the title compound (178 mg, 92%) (mixture of trans and cis isomers) as a brown oil. LCMS (ES+) [M+H].sup.+ 646.2, RT 1.11 minutes (Method 3).

    Intermediate 6

    [0104] ##STR00012##

    (R)-N-Cyano-1-{5-[(7R,14R)-1-(Difluoromethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]Pyrimidin-2-Yl}-3-MethylCyclobutyl)-2-Methylpropane-2-Sulfinamide

    [0105] To a mixture of potassium phosphate tribasic (80 mg, 0.377 mmol), Intermediate 2 (50 mg, 0.121 mmol) and (7R,14R)-1-(difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (WO 2016/050975, Intermediate 171) (60 mg, 0.128 mmol) under nitrogen were added tricyclohexylphosphonium tetrafluoroborate (5 mg, 0.013 mmol) and tris-(dibenzylideneacetone)dipalladium(0) (6 mg, 0.0064 mmol). The reagents were dissolved in 1,4-dioxane (3 mL) and water (0.2 mL) was added, then the reaction mixture was degassed under vacuum and nitrogen, before being heated at reflux overnight. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extractedwith further EtOAc (20 mL). The organic layer was separated and filtered through a phase separator, then concentrated in vacuo. The resulting crude brown oil was purified by flash column chromatography on silica (gradient elution with 0-100% DCM/EtOAc, followed by 1-10% MeOH/EtOAc) to afford the title compound (51 mg, 57%) as a yellow solid. LCMS (ES+) [M+H].sup.+ 632.0, RT 1.85 minutes (Method 1). LCMS (ES+) [M+H].sup.+ 632.1, RT 1.81 minutes (Method 2).

    Intermediate 7

    [0106] ##STR00013##

    (R)-N-[Trans-1-(5-Bromo-3-Fluoropyridin-2-Yl)-3-Cyano-3-Methylcyclobutyl]-2-MethylPropane-2-Sulfinamide

    [0107] 2,5-Dibromo-3-fluoropyridine (536 mg, 2.11 mmol) was dissolved in DCM (100 mL) and cooled under nitrogen to -78° C. n-Butyllithium (2.5 M, 0.9 mL, 2 mmol) was added dropwise, and the reaction mixture was stirred at -78° C. under nitrogen for 5 minutes, prior to the slow addition of Intermediate 1 (390 mg, 1.84 mmol) dissolved in DCM (10 mL) via syringe. The reaction mixture was stirred at -78° C. for 1 h, then for 2 h in an ice bath. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL), then the organic layer was separated and washed with brine (50 mL). The organic layer was separated and filtered through a phase separator, then the solvent was removed in vacuo. The resulting crude dark red/brown oil was purified by flash column chromatography on silica (gradient elution with 100% isohexane to 100% EtOAc) to afford the title compound (220 mg, 28%). LCMS (ES+) [M+H].sup.+ 388.0/390.0, RT 0.961 minutes (Method 3).

    Intermediate 8

    [0108] ##STR00014##

    (R)-N-(cis-3-Cyano-1-{5-[(7R,14R)-1-(Difluoromethoxy)-6-Methyl-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]-3-Fluoropyridin-2-Yl}-3-Methylcyclobutyl)-2-Methylpropane-2-Sulfinamide

    [0109] To a mixture of Intermediate 4 (113 mg, 0.241 mmol) and potassium phosphate tribasic (167 mg, 0.773 mmol) was added a solution of Intermediate 7 (75 mg, 0.193 mmol) in 1,4-dioxane (3 mL). The reaction mixture was degassed and flushed with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (9.1 mg, 0.0097 mmol) and tricyclohexylphosphonium tetrafluoroborate (8.8 mg, 0.023 mmol) in 1,4-dioxane were added with several drops of water. The reaction mixture was heated under microwave irradiation for 4 h at 120° C., then separated between EtOAc and brine. The organic layer was filtered through a phase separator and the organic phase was concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 100% isohexane to 100% EtOAc, followed by 1-15% MeOH/DCM) to afford the title compound (102 mg, 81%) as an off-white solid. LCMS (ES+) [M+H].sup.+ 663, RT 1.32 minutes (Method 5).

    Intermediate 9

    [0110] ##STR00015##

    (R)-N-(Cis-3-Cyano-1-{5-[(7R,14R)-1-(Difluoromethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo [1,2-b][2,5]Benzodiazocin-11-Yl-3-Fluoropyridin-2-Yl}-3-MethylCyclobutyl)-2-Methylpropane-2-Sulfinamide

    [0111] (7R,14R)-1-(Difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (WO 2016/050975, Intermediate 171) (297 mg, 0.636 mmol) was treated with potassium phosphate tribasic (441 mg, 2.04 mmol), then Intermediate 7 (220 mg, 0.510 mmol) was added, followed by 1,4-dioxane (3 mL). The reaction mixture was degassed and flushed with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.025 mmol) and tricyclohexylphosphonium tetrafluoroborate (23 mg, 0.061 mmol) were added, together with several drops of water. The mixture was heated under microwave irradiation at 120° C. for 4 h. EtOAc and brine were added to the reaction mixture, which was stirred before filtration through a phase separator. The organic phase was concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution 100% isohexane to 100% EtOAc, followed by 1-15% MeOH in DCM) to afford the title compound (189 mg, 54%) as an off-white solid. LCMS (ES+) [M+H].sup.+ 649.2, RT 1.32 minutes (Method 5).

    Intermediate 10

    [0112] ##STR00016##

    (S)Methyl-N-(2-Methylcyclobutylidene)PropaneSulfinamide

    [0113] 2-Methylcyclobutan-1-one (1.00 g, 11.3 mmol) was dissolved in THF (30 mL) and (S)-2-methyl-2-propanesulfinamide (1.20 g, 9.60 mmol) was added, followed by titanium(IV) ethoxide (4.0 mL, 19 mmol). The reaction mixture was stirred at r.t. for 48 h. Water (5 mL) was added and the mixture was stirred, then EtOAc (100 mL) was added, followed by Na.sub.2SO.sub.4 (10 g). After 15 minutes the mixture was filtered, and the solids were washed with EtOAc (3 × 15 mL). The combined organic layers were concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 0-40% EtOAc in isohexane) to afford the title compound (1.55 g, 86%) as a colourless oil. LCMS (ES+) [M+H].sup.+ 188.2, RT 1.37 minutes and 1.41 minutes (Method 4).

    Intermediate 11

    [0114] ##STR00017##

    ##STR00018##

    N-[(1S,2R)-1-(5-Bromo-3-Fluoropyridin-2-Yl)-2-Methylcyclobutyl]-2-Methylpropane-2-Sulfinamide or N-[(1R,2S)-1-(5-Bromo-3-Fluoropyridin-2-Yl)-2-Methylcyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0115] 2,5-Dibromo-3-fluoropyridine (2.34 g, 8.81 mmol) was dissolved in DCM (30 mL) and cooled to -78° C. under nitrogen, then N-butyllithium (2.5 M, 3.5 mL, 8.8 mmol) was added. The reaction mixture was stirred for 10 minutes prior to the addition of a solution of Intermediate 10 (1.50 g, 8.01 mmol) in DCM (3 mL). The mixture was stirred at -78° C. for 2 h, then quenched with saturated aqueous ammonium chloride solution (30 mL) and stirred for 5 minutes. The organic layer was separated and dried (Na.sub.2SO.sub.4), then filtered and concentrated in vacuo. The resulting crude residue was purified by flash column chromatography on silica (gradient elution with 0-45% EtOAc in isohexanes) to afford the title compound (800 mg, 27%; cis-isomer), plus a 3:1 mixture of predominantly trans-isomer with the other cis-isomer (650 mg, 22%).

    [0116] Title compound: δ.sub.H (300 MHz, CDCl.sub.3) 8.49-8.39 (m, 1 H), 7.54 (dd, J 9.9, 1.9 Hz, 1 H), 3.87 (s, 1 H), 2.92 (dtt, J 12.3, 9.0, 1.6 Hz, 1 H), 2.71 (h, J 7.4 Hz, 1H), 2.45-2.32 (m, 1 H), 2.11-1.97 (m, 1 H), 1.86-1.69 (m, 1 H), 1.28-1.23 (m, 12 H). LCMS (ES+) [M+H].sup.+ 363.0 and 365.0, RT 2.28 minutes (Method 4).

    Intermediate 12

    [0117] ##STR00019##

    ##STR00020##

    N-[(1S,2R)-1-{5-[(7R,14R)-1-(Difluoromethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-B][2,5]Benzodiazocin-11-Yl]-3-Fluoropyridin-2-Yl}-2-MethylCyclobutyl1-2-Methylpropane-2-Sulfinamide or N-[(1R,2S)-1-{5-[(7R,14R)-1-(Difluoromethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,51-Benzodiazocin-11-Yl]-3-Fluoropyridin-2-Yl}-2-Methylcyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0118] To Intermediate 11 (187 mg, 0.51 mmol), (7R,14R)-1-(difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (WO 2016/050975, Intermediate 171) (200 mg, 0.43 mmol), tricyclohexylphosphonium tetrafluoroborate (16 mg, 0.042 mmol) and tris-(dibenzylideneacetone)dipalladium(0) (20 mg, 0.021 mmol) in 1,4-dioxane (5 mL) under nitrogen was added potassium phosphate tribasic (278 mg, 1.28 mmol) in water (1 mL). The reaction mixture was degassed under nitrogen, then sealed in a pressure tube and heated at 105° C. for 3 h. The reaction mixture was cooled to r.t., then partitioned between DCM and water. The organic layer was separated and dried (Na.sub.2SO.sub.4), then filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution 0-10% MeOH in DCM) to afford the title compound (145 mg, 54%) as a yellow solid. LCMS (ES+) [M+H].sup.+ 624.2, RT 2.44 minutes (Method 4).

    Intermediate 13

    [0119] ##STR00021##

    N-(Cyclobutylidene)-2-Methylpropane-2-Sulfinamide

    [0120] A solution of cyclobutanone (100 g, 1.43 mol) in THF (722 mL) was cooled to 15-20° C. 2-Methyl-2-propanesulfinamide (144 g, 1.19 mol), cooled to 15-20° C., was added, followed by titanium(IV) isopropoxide (847 g, 2.98 mol). The reaction mixture was heated at 60° C. for 16 h, then concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution, 0-20% EtOAc/petroleum ether) to afford the title compound (combined yield from 19 batches: 2.14 kg, 55%) as a yellow oil. δ.sub.H (400 MHz, DMSO-d.sub.6) 3.37-3.17 (m, 1 H), 3.14-3.07 (m, 3 H), 2.06-1.99 (m, 2 H), 1.14 (s, 9 H).

    Intermediate 14

    [0121] ##STR00022##

    N-(5-Bromopyrimidin-2-Yl)Cyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0122] 5-Bromoiodopyrimidine (345 g, 1.21 mol) was cooled to 15-20° C. and dissolved in anhydrous DCM (6 L). The reaction mixture was cooled to between -60° C. and -70° C., whereupon 2.5 M n-butyllithium (450 mL, 1.13 mol) was added dropwise. The reaction mixture was stirred for 2 h at a temperature between -60° C. and -70° C., then a solution of Intermediate 13 (150 g, 866 mmol) in anhydrous DCM (150 mL) was added. The temperature was maintained between -60° C. and -70° C. for 2 h with stirring, before warming to 15-20° C. The reaction mixture was stirred for a further 12 h, then quenched with water (100 mL). Eleven batches were combined and extracted with DCM (2 × 3330 mL). The organic layer was washed with brine (1650 mL), separated and dried (Na.sub.2SO.sub.4), then filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 1:0:10 to 1:1:3 EtOAc/DCM/petroleum ether) to afford the title compound (combined yield from 11 batches: 1.38 kg, 44%) as a yellow solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 9.00 (s, 2 H), 2.65-2.45 (m, 2 H), 2.44-2.42 (m, 2 H), 1.99-1.94 (m, 1 H), 1.73-1.70 (m, 1 H), 1.07 (s, 9 H).

    Intermediate 15

    [0123] ##STR00023##

    1-Bromopyrimidin-2-Yl)Cyclobutanamine Hydrochloride

    [0124] In six separate batches Intermediate 14 (302 g, 909 mmol) was dissolved in MeOH (1.2 L) at 15-20° C. To the mixture was added MeOH/hydrochloric acid (600 mL), and the reaction mixture was stirred at 15-20° C. for 2 h. The six batches were combined and concentrated. To the crude residue were added isopropyl ether (9 L) and MeOH (1 L). The mixture was stirred for 1 h at 15-20° C. The solid was filtered, rinsed with DCM (3 L) and dried, to afford the title compound (1.21 kg, 84%) as a yellow solid. δ.sub.H (400 MHz, CD.sub.3OD) 9.02 (s, 2 H), 2.84-2.82 (m, 2 H), 2.81-2.78 (m, 2 H), 2.60-2.27 (m, 2 H).

    Intermediate 16

    [0125] ##STR00024##

    Tert-Butyl N-[1-(5-Bromopyrimidin-2-Yl)Cyclobutyl]Carbamate

    [0126] To a suspension of Intermediate 15 (202 g, 764 mmol) in THF (400 mL), cooled on an ice bath, were added di-tert-butyl dicarbonate (183 g, 832 mmol) and triethylamine (154 g, 212 mL, 1.51 mol). The mixture was stirred at 0-5° C. for 30 minutes, then the ice bath was removed and the reaction mixture was allowed to reach ambient temperature. The reaction mixture was partitioned between EtOAc (1000 mL) and water (600 mL). The aqueous phase was separated, then the organic phase was washed sequentially with water (600 mL) and brine (2 × 200 mL). The organic phase was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The resulting crude solid was dried overnight in vacuo at 50° C. to afford the title compound (254 g, quantitative) as an off-white solid. LCMS (ES+) [M+Na].sup.+ 350.0, RT 2.20 minutes (Method 4).

    Intermediate 17

    [0127] ##STR00025##

    Tert-Butyl (1-{5-[(7R,14R)-1-(Difluoromethoxy)-6-Methyl-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]Pyrimidin-2-Yl}Cyclobutyl)-Carbamate

    [0128] A flame-dried flask under nitrogen equipped with a reflux condenser was charged with Intermediate 3 (13.3 g, 34.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.61 g, 1.71 mmol), XPhos (1.63 g, 3.43 mmol), bis(pinacolato)diboron (9.85 g, 38.8 mmol) and potassium acetate (8.5 g, 87 mmol), then 1,4-dioxane (136 mL) was added. The resulting mixture was stirred at 100° C. for 22 h before Intermediate 16 (12.3 g, 37.4 mmol) and aqueous tribasic potassium phosphate solution (1.27 mol/L, 40 mL, 50.8 mmol) were added. The reaction mixture was heated under reflux for 3 h before being charged with additional tris(dibenzylideneacetone)dipalladium(0) (500 mg, 0.53 mmol), XPhos (510 mg, 1.07 mmol) and aqueous tribasic potassium phosphate solution (1.27 mol/L, 20 mL, 25.4 mmol). The mixture was stirred for 1 h, then cooled to room temperature, diluted with DCM (600 mL) and washed with brine (400 mL). The aqueous phase was extracted with DCM (500 mL), then the combined organic extracts were passed through a phase separator and concentrated in vacuo. Purification by flash chromatography on silica (elution with 0-5% MeOH/DCM) afforded the title compound (18.0 g, 88%) as an off-white solid. δ.sub.H (400 MHz, CDCl.sub.3) 8.93 (s, 2 H), 8.49 (dd, J 8.2, 1.3 Hz, 1 H), 7.84 (dd, J 8.5, 0.7 Hz, 1 H), 7.74-7.63 (m, 1 H), 7.48-7.38 (m, 2 H), 7.34-7.29 (m, 1 H), 6.84 (t, J 72.8 Hz, 1 H), 6.31 (d, J 7.2 Hz, 1 H), 5.92 (s, 1 H), 5.01 (d, J 7.1 Hz, 1 H), 3.53 (s, 3 H), 3.51-3.43 (m, 1 H), 2.90 (d, J 13.6 Hz, 1 H), 2.84-2.57 (m, 3 H), 2.22-2.07 (m, 3 H), 1.43 (s, 9 H). LCMS (ES+) [M+H].sup.+ 603.2, RT 1.25 minutes (Method 3).

    Intermediate 18

    [0129] ##STR00026##

    3-Benzyloxy-1-Methylcyclobutanol

    [0130] Methylmagnesium iodide was prepared by slow addition of iodomethane (42.6 mL, 681 mmol) to a mixture of magnesium (20.7 g, 851 mmol) in diethyl ether (500 mL). The mixture was heated on a warm water bath for 30 minutes. The solution of methylmagnesium iodide was cooled in a dry ice/acetone bath to an internal temperature of -25° C., then a solution of 3-benzyloxycyclobutan-1-one (94 mL, 567 mmol) in diethyl ether (100 mL) was added slowly, maintaining the internal temperature below -10° C. After the addition was complete, the mixture was stirred at -10° C., warming to 15° C. over 30 minutes. The reaction mixture was cooled to 0° C., then diluted with diethyl ether and quenched with saturated aqueous ammonium chloride solution. The organic layer was separated and the aqueous layer was extracted with diethyl ether (2 × 300 mL). The combined organic layers were filtered and washed with saturated aqueous ammonium chloride solution, then dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo, to afford the title compound (109 g, 100%) (~3:1 mixture of stereoisomers) as a yellow oil. GCMS: major isomer RT 3.664 (74.6%), [M-C.sub.7H.sub.7].sup.+ 101, [M-C.sub.5H.sub.9O.sub.2].sup.+ 91; minor isomer RT 3.630 (25.4%), [M-C.sub.7H.sub.7].sup.+ 101, [M-C.sub.5H.sub.9O.sub.2].sup.+ 91 (Method 12).

    Intermediate 19

    [0131] ##STR00027##

    Benzyloxy-1-Methylcyclobutoxy)-Tert-Butyl(Dimethyl)Silane

    [0132] Imidazole (190 g, 2.79 mol) was added to a solution of Intermediate 18 (107 g, 558 mmol) in DMF (1 L). tert-Butyl(chloro)dimethylsilane (252 g, 1.67 mmol) was added. The reaction mixture was stirred at r.t. overnight, then poured into ice-water. The aqueous phase was extracted with diethyl ether (3 × 500 mL). The organic layers were combined and washed with water, then dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The resulting crude yellow oil (291 g) was purified by flash column chromatography on silica (heptane, followed by 2% EtOAc in heptane) to afford the title compound (121 g, 46%) (~3:1 mixture of stereoisomers). Major isomer: δ.sub.H (400 MHz, CDCl.sub.3) 7.38-7.24 (m, 5 H), 4.40 (s, 2 H), 3.70-3.62 (m, 1 H), 2.41-2.33 (m, 2 H), 2.18-2.09 (m, 2 H), 1.28 (s, 3 H), 0.87 (s, 9 H), 0.07 (s, 6 H).

    Intermediate 20

    [0133] ##STR00028##

    3-[Tert-Butyl(Dimethyl)Silyl]Oxy-3-Methylcyclobutanol

    [0134] A mixture of Intermediate 19 (121 g, 257 mmol) in ethanol (500 mL) was treated with Norit (or activated charcoal) (13 g) and stirred for 1 h. The mixture was filtered over kieselguhr and rinsed with ethanol (500 mL). The filtrate was transferred to a 3-neck round-bottomed flask (4 L) and the mixture was evacuated and back-filled three times with argon. A slurry of palladium on activated carbon (10%, 6.1 g, 5.73 mmol) in water was added and the mixture was evacuated and back-filled with argon. The mixture was evacuated and back-filled three times with hydrogen, then stirred overnight at r.t. The mixture was filtered through kieselguhr under a nitrogen flow, then rinsed with ethanol. The filtrate was concentrated in vacuo. The crude residue (68 g) was combined with additional batches (62 g and 63 g), then purified by flash column chromatography on silica (gradient elution with 10-20% EtOAc in heptane), to afford the title compound (164 g, 85%) (~8:2 mixture of isomers) as a colourless oil. δ.sub.H (400 MHz, CDCl.sub.3) 4.52-4.43 (m, 0.2 H), 3.98-3.87 (m, 0.8 H), 2.50-2.40 (m, 2 H), 2.10-2.02 (m, 1.6 H), 1.98-1.91 (m, 0.4 H), 1.64-1.58 (m, 0.8 H), 1.58-1.52 (m, 0.2 H), 1.44 (s, 0.6 H), 1.28 (s, 2.4 H), 0.88 (s, 7 H), 0.87 (s, 2 H), 0.07 (s, 6 H).

    Intermediate 21

    [0135] ##STR00029##

    3-[tert-Butyl(dimethyl)silyl]oxy-3-methylcyclobutanone

    [0136] To a solution of Intermediate 20 (192 g, 887 mmol) in DCM (2 L) at 5° C. was added Dess-Martin periodinane (452 g, 1.07 mmol). The suspension was stirred at 10° C. for 1 h, then allowed to warm to r.t. over 1 h. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution (~1 L) and stirred until gas evolution had ceased. Aqueous sodium thiosulfate solution (10%) was added, and the mixture was stirred for 1 h. The layers were separated and the aqueous phase was extracted with DCM. The organic layers were combined and dried (Na.sub.2SO.sub.4), then filtered and concentrated in vacuo. The resulting crude yellow oil was purified by flash column chromatography on silica (gradient elution with 0-20% EtOAc in heptane) to afford the title compound (186 g, 98%) as a colourless oil. δ.sub.H (400 MHz, CDCl.sub.3) 3.25-3.13 (m, 2 H), 3.03-2.90 (m, 2 H), 1.59 (s, 3 H), 0.89 (s, 9 H), 0.11 (s, 6 H).

    Intermediate 22

    [0137] ##STR00030##

    (S)-N-{3-[Tert-Butyl(Dimethyl)Silyl]Oxy-3-Methylcyclobutylidene}-2-Methylpropane-2-Sulfinamide

    [0138] To a solution of Intermediate 21 (186 g, 0.87 mol) in THF (2 L) was added (S)-(-)-tert-butylsulfinamide (126 g, 1.04 mol), followed by titanium(IV) ethoxide (367 mL, 1.74 mol). The reaction mixture was stirred overnight at r.t., then concentrated in vacuo. The residue was diluted with acetonitrile. Water (47 mL) was added and the reaction mixture was stirred for 10 minutes, then filtered over kieselguhr and rinsed with acetonitrile. The filtrate was concentrated in vacuo. The resulting crude yellow oil (264 g) was purified by flash column chromatography on silica (10% EtOAc in heptane) to afford the title compound (223 g, 81%) (~1:1 mixture of isomers) as a colourless oil. δ.sub.H (400 MHz, CDCl.sub.3) 3.59-3.41 (m, 1 H), 3.34-3.11 (m, 2 H), 3.05-2.92 (m, 1 H), 1.52-1.41 (m, 3 H), 1.21 (s, 9 H), 0.85 (s, 9 H), 0.06 (s, 6 H). LCMS [M+H].sup.+ 318, RT 2.34 minutes (Method 6).

    Intermediate 23

    [0139] ##STR00031##

    (S)-N-{Cis-1-(5-Bromo-3-Fluoropyridin-2-Yl)-3-[Tert-Butyl(Dimethyl)Silyl]Oxy-3-Methylcyclobutyl}-2-Methylpropane-2-Sulfinamide

    [0140] A three-necked round-bottomed flask (2 L) was charged with 2,5-dibromo-3-fluoropyridine (26.9 g, 106 mmol) and DCM (750 mL). The resulting solution was cooled with dry ice/isopropanol to -70° C., then n-butyllithium (2.5 M in hexanes; 46 mL, 115 mmol) was added dropwise, to afford a dark solution at -50° C. The temperature was lowered to -66° C. and a solution of Intermediate 22 (30.5 g, 96 mmol) in DCM (150 mL) was added dropwise. After addition, the mixture was stirred for 1.5 h, by which time the temperature had risen to -30° C. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, and water was added to dissolve the precipitated salts. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine and dried (Na.sub.2SO.sub.4), then filtered and concentrated in vacuo. The resulting crude dark brown oil (49.7 g) was purified by flash column chromatography on silica (gradient elution with 10-60% EtOAc in heptane) to afford the title compound (9.71 g, 21%). δ.sub.H (400 MHz, CDCl.sub.3) 8.47-8.41 (m, 1 H), 7.56 (dd, J 9.9, 1.9 Hz, 1 H), 3.91 (s, 1 H), 3.35 (dd, J 12.6, 3.6 Hz, 1 H), 2.97-2.87 (m, 1 H), 2.73 (d, J 12.6 Hz, 1 H), 2.54 (d, J 12.6 Hz, 1 H), 1.15 (s, 9 H), 1.11 (s, 3 H), 0.90 (s, 9 H), 0.10 (s, 6 H). LCMS [M+H].sup.+ 493/495 (Br-pattern), RT 2.50 minutes (Method 6).

    Intermediate 24

    [0141] ##STR00032##

    (S)-N-(Cis-3-[Tert-Butyl(Dimethyl)Silyl]Oxy-1-{5-[(7R,14R)-1-(Difluoromethoxy)-6-Methyl-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]-3-Fluoropyridin-2-Yl}-3-Methylcyclobutyl)-2-Methylpropane-2-Sulfinamide

    [0142] A three-necked round-bottomed flask (2 L) was charged with Intermediate 3 (25.6 g, 65.7 mmol), potassium acetate (16.1 g, 164 mmol), bis(pinacolato)diboron (20.0 g, 79 mmol) and anhydrous 1,4-dioxane (400 mL). The reaction mixture was evacuated and back-filled three times with argon. Tris(dibenzylideneacetone)dipalladium(0) (5 mol %, 3.01 g, 3.28 mmol) and XPhos (10 mol %, 3.13 g, 6.57 mmol) were added. The apparatus was evacuated and back-filled twice with argon, then placed in a preheated oil bath at 110° C. for 2.5 h. The reaction mixture was cooled to r.t. and Intermediate 23 (32.4 g, 65.7 mmol), dissolved in 1,4-dioxane (400 mL), was added. Tripotassium phosphate (20.9 g, 99 mmol) and water (200 mL) were added, followed by [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (5 mol %, 2.40 g, 3.28 mmol). The reaction mixture was evacuated and back-filled twice with argon, then placed in a preheated oil bath at 115° C. for 1 h. The reaction mixture was cooled to r.t., then trithiocyanuric acid (5.24 g, 29.6 mmol) and activated charcoal (12 g) were added. The mixture was stirred overnight, then filtered through a pad of kieselguhr. The filter pad was rinsed with EtOAc and MeOH. The filtrate was diluted with water (600 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 400 mL). The combined organic layers were washed with brine and dried (Na.sub.2SO.sub.4), then filtered and concentrated in vacuo. The resulting crude dark thick semi-solid (~130 g) was purified by flash column chromatography on silica (gradient elution with 0-20% MeOH in EtOAc), followed by repurification by flash column chromatography on silica (0-10% MeOH in EtOAc), to afford the title compound (44.6 g, 88%). δ.sub.H (400 MHz, CDCl.sub.3) 8.63 (t, J 1.5 Hz, 1 H), 8.52-8.48 (m, 1 H), 7.79 (d, J 8.5 Hz, 1 H), 7.69 (d, J 1.3 Hz, 1 H), 7.56 (dd, J 11.9, 1.7 Hz, 1 H), 7.46 (dd, J 8.5, 1.7 Hz, 1 H), 7.43 (t, J 8.2 Hz, 1 H), 7.35 (d, J 8.1 Hz, 1 H), 6.88 (t, J 72.7 Hz, 1 H), 6.28 (d, J 7.2 Hz, 1 H), 4.98 (d, J 7.1 Hz, 1 H), 4.00 (s, 1 H), 3.52 (s, 3 H), 3.51-3.40 (m, 1 H), 3.07-2.99 (m, 1 H), 2.89 (d, J 13.6 Hz, 1 H), 2.78 (d, J 12.5 Hz, 1 H), 2.62 (d, J 12.6 Hz, 1 H), 1.63 (s, 1 H), 1.17 (s, 9 H), 1.16 (s, 3 H), 0.92 (s, 9 H), 0.12 (s, 6 H). LCMS [M+H].sup.+ 768, RT 2.44 minutes (Method 6).

    Intermediate 25

    [0143] ##STR00033##

    (S)-N-(Cis-3-[Tert-Butyl(Dimethyl)Silyl]Oxy-1-{5-[(7r,14r)-1-(Difluoromethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-B][2,5]Benzodiazocin-11-yl]-3-Fluoropyridin-2-Yl}-3-Methylcyclobutyl)-2-Methylpropane-2-Sulfinamide

    [0144] (7R,14R)-1-(Difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (WO 2016/050975, Intermediate 171) (1.3 g, 2.78 mmol), Intermediate 23 (900 mg, 1.82 mmol) and potassium phosphate tribasic (1.58 g, 7.29 mmol) were suspended in a mixture of 1,4-dioxane (22 mL) and water (2 mL). The reaction mixture was degassed three times with nitrogen, then tris(dibenzylideneacetone)dipalladium(0) (90 mg, 0.095 mmol) was added. The reaction mixture was further degassed with nitrogen and heated at 120° C. for 2.5 h. The mixture was diluted with water and extracted twice with EtOAc. The organic phases were combined and dried (sodium sulphate), then filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc/hexane, followed by 0-10% MeOH/DCM) to afford the title compound (930 mg, 65%). LCMS (ES+) [M+H].sup.+ 754.2, RT 3.26 minutes (Method 4).

    Intermediate 26

    [0145] ##STR00034##

    Methyl 3,3-Dimethoxycyclobutanecarboxylate

    [0146] Methyl 3-oxocyclobutanecarboxylate (45 g, 394 mmol), trimethyl orthoformate (259 mL, 2.37 mol) and p-toluenesulfonic acid monohydrate (7.50 g, 39.4 mmol) were combined in MeOH (500 mL). The solution was stirred at reflux for 2 h, then cooled to r.t. and concentrated in vacuo. The residue was dissolved in diethyl ether (500 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (500 mL). The aqueous phase was extracted with diethyl ether (500 mL). The combined organic layers were washed with brine and dried (Na.sub.2SO.sub.4), then filtered and concentrated in vacuo, to afford the title compound (74.4 g). δ.sub.H (400 MHz, CDCl.sub.3) 3.70 (s, 3 H), 3.17 (s, 3 H), 3.15 (s, 3 H), 2.94-2.83 (m, 1 H), 2.48-2.34 (m, 4 H).

    Intermediate 27

    [0147] ##STR00035##

    Methyl 3,3-Dimethoxy-1-Methylcyclobutanecarboxylate

    [0148] n-Butyllithium in hexanes (2.5 M, 133 mL, 332 mmol) was added to a cooled solution of diisopropylamine (56 mL, 398 mmol) in THF (1 L) at -78° C. The mixture was stirred for 15 minutes prior to the dropwise addition of Intermediate 26 (68 g, 332 mmol) in THF (50 mL). The reaction mixture was stirred for 30 minutes prior to the dropwise addition of iodomethane (41 mL, 664 mmol), which caused the internal temperature to increase to -60° C. The reaction mixture was stirred at -78° C. for 30 minutes, then warmed to ambient temperature. The reaction mixture was poured into saturated aqueous ammonium chloride solution (1 L) and was extracted with diethyl ether (2 × 500 mL). The combined organic layers were washed with brine and dried (Na.sub.2SO.sub.4), then filtered and concentrated in vacuo. The crude residue (64.7 g) was purified by flash column chromatography on silica (gradient elution with 10-40% EtOAc in heptane) to afford the title compound (52.5 g). δ.sub.H (400 MHz, CDCl.sub.3) 3.71 (s, 3 H), 3.16 (s, 3 H), 3.13 (s, 3 H), 2.67-2.58 (m, 2 H), 2.10-2.01 (m, 2 H), 1.44 (s, 3 H).

    Intermediate 28

    [0149] ##STR00036##

    (3,3-Dimethoxy-1-Methylcyclobutyl)Methanol

    [0150] To a solution of Intermediate 27 (42 g, 224 mmol) in THF (800 mL), cooled in an ice bath, was added 2.4 M lithium aluminium hydride solution in THF (94 mL, 235 mmol). The reaction mixture was stirred at r.t. for 60 minutes. Water (8 mL) was added dropwise, followed by 10% aqueous sodium hydroxide solution (8 mL). To the suspension was added water (24 mL) and the mixture was stirred. Sodium sulphate was added and the granular suspension was filtered. The filtrate was rinsed with diethyl ether, and the combined filtrate was concentrated in vacuo, to afford the title compound (38 g, 15%) as a light oil. δ.sub.H (400 MHz, CDCl.sub.3) 3.50 (d, J 5.6 Hz, 2 H), 3.15 (s, 3 H), 3.14 (s, 3 H), 2.11 (d, J 13.2 Hz, 2 H), 1.94-1.82 (m, 2 H), 1.19 (s, 3 H). GCMS [M-CH.sub.3O].sup.+ 129, RT 2.325 (90.2%) (Method 12).

    Intermediate 29

    [0151] ##STR00037##

    3-(Hydroxymethyl)-3-Methylcyclobutanone

    [0152] To a stirred solution of Intermediate 28 (44.8 g, 280 mmol) in acetone (600 mL) and water (200 mL) was added p-toluenesulfonic acid monohydrate (53.2 g, 280 mmol). The reaction mixture was heated at 65° C. for 1 h, then cooled to r.t. The acetone was removed by concentration in vacuo. The resulting mixture was diluted with DCM and washed with aqueous sodium hydrogen carbonate solution. The aqueous layer was back-extracted three times with DCM. The combined organic layers were dried (MgSO.sub.4), then filtered and concentrated in vacuo, to afford the title compound (30.8 g, 78%). δ.sub.H (400 MHz, CDCl.sub.3) 3.69 (d, J 5.1 Hz, 2 H), 3.09-2.97 (m, 2 H), 2.76-2.64 (m, 2 H), 1.36 (s, 3 H).

    Intermediate 30

    [0153] ##STR00038##

    3-({[Tert-Butyl(Dimethyl)Silyl]Oxy}Methyl)-3-Methylcyclobutanone

    [0154] Imidazole (0.63 g, 9.29 mmol) was added to a solution of Intermediate 29 (10.6 g, 55.0 mmol) in DMF (150 mL), then tert-butyl(chloro)dimethylsilane (24.9 g, 165 mmol) was added. The reaction mixture was stirred at r.t. overnight. Diethyl ether was added, followed by brine. The organic layer was separated and washed three times with brine.

    [0155] The organic layers were dried and concentrated in vacuo. The crude residue (62 g) was purified by flash column chromatography on silica (gradient elution with 0-10% EtOAc in heptane) to afford the title compound (59.5 g) as a yellow oil. δ.sub.H (400 MHz, CDCl.sub.3) 3.59 (s, 2 H), 3.08-2.98 (m, 2 H), 2.66-2.56 (m, 2 H), 1.30 (s, 3 H), 0.89 (s, 9 H), 0.06 (s, 6 H).

    Intermediate 31

    [0156] ##STR00039##

    (S)-N-({[Tert-Butyl(Dimethyl)Silyl]Oxy}Methyl)-3-Methylcyclobutylidene]-2-MethylPropane-2-Sulfinamide

    [0157] To a solution of Intermediate 30 (54.5 g, 205 mmol) in THF (500 mL) were added (S)-2-methylpropane-2-sulfinamide (29.8 g, 246 mmol) and titanium(IV) ethoxide (87 mL, 410 mmol). The reaction mixture was stirred overnight at r.t., then concentrated in vacuo. The residue was diluted with acetonitrile, then water (47 mL) was added. The mixture was stirred for 10 minutes, then filtered over kieselguhr and rinsed with acetonitrile. The filtrate was concentrated in vacuo. The resulting crude yellow oil (71.5 g) was purified by flash column chromatography on silica (gradient elution with 0-20% EtOAc in heptane) to afford the title compound (66.9 g, 98%) as a yellow oil (~1:1 mixture of isomers). δ.sub.H (400 MHz, CDCl.sub.3) 3.50 (d, J 1.6 Hz, 2 H), 3.46-3.38 (m, 0.5 H), 3.24-3.00 (m, 2 H), 2.92-2.82 (m, 0.5 H), 2.71-2.55 (m, 1 H), 1.29-1.19 (m, 12 H), 0.90-0.88 (m, 9 H), 0.05 (s, 6 H).

    Intermediate 32

    [0158] ##STR00040##

    (S)-N-[cis-1-(5-Bromopyrimidin-2-yl)-3-({[Tert-Butyl(Dimethyl)Silyl]Oxy}Methyl)-3-Methylcyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0159] A solution of 5-bromo-2-iodopyrimidine (58.6 g, 206 mmol) in DCM (500 mL) was cooled to -78° C. n-Butyllithium (2.5 M in hexanes, 90 mL, 226 mmol) was added dropwise over 10 minutes, resulting in a thick suspension. The mixture was stirred for 40 minutes at -78° C. A solution of Intermediate 31 (56.8 g, 171 mmol) in DCM (500 mL) was added dropwise. The reaction mixture was stirred for 2.5 h at -78° C., then allowed to warm to r.t. and stirred for 1 h. The mixture was poured into saturated aqueous ammonium chloride solution and was stirred for 5 minutes. After dilution with water, the layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were combined, washed with brine and dried (Na.sub.2SO.sub.4), then filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 1:1 to 0:1 heptane:EtOAc), followed by additional purification by flash column chromatography on silica (gradient elution with 20-80% EtOAc in heptane), to furnish the title compound (16 g, 17%). δ.sub.H (400 MHz, CDCl.sub.3) 8.76 (s, 2 H), 4.40 (s, 1 H), 3.58 (d, J 9.6 Hz, 1 H), 3.52 (d, J 9.5 Hz, 1 H), 2.84 (d, J 12.7 Hz, 1 H), 2.54-2.38 (m, 2 H), 2.30 (d, J 12.3 Hz, 1 H), 1.20 (s, 9 H), 1.04 (s, 3 H), 0.91 (s, 9 H), 0.07 (s, 6 H). LCMS [M+H].sup.+ 490/492 (Br-pattern), RT 2.49 minutes (Method 6).

    Intermediate 33

    [0160] ##STR00041##

    (S)-N-[cis-3-({[Tert-Butyl(Dimethyl)Silvl]Oxy}Methyl)-1-{5-[(7R,14R)-1-(DifluoroMethoxy)-6-Methyl-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]-Benzodiazocin-11-Yl]Pyrimidin-2-Yl}-3-Methylcyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0161] A round-bottom flask (2 L) was charged with Intermediate 3 (11.1 g, 28.4 mmol), potassium acetate (6.97 g, 71.0 mmol), bis(pinacolato)diboron (8.65 g, 34.1 mmol) and 1,4-dioxane (170 mL). The apparatus was flushed three times with argon, then tris-(dibenzylideneacetone)dipalladium(0) (1.30 g, 1.42 mmol) and XPhos (1.35 g, 2.84 mmol) were added. The apparatus was evacuated and back-filled twice with argon, then heated at 115° C. for 3 h. The reaction mixture was cooled to r.t. Intermediate 32 (16.2 g, 28.4 mmol) dissolved in 1,4-dioxane (170 mL) was added, followed by water (70 mL) and anhydrous potassium phosphate tribasic (9.04 g, 42.6 mmol). The apparatus was again degassed twice with argon, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.04 g, 1.42 mmol) was added. The reaction mixture was heated at 115° C. for 5 h, then stirred at r.t. overnight. Trithiocyanuric acid (2.27 g, 12.78 mmol) and activated charcoal (5.19 g) were added. The mixture was stirred at r.t. overnight, then diluted with water and EtOAc and filtered, washing the solids with EtOAc. The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were combined and washed with brine, then dried (Na.sub.2SO.sub.4), filtered and stirred overnight. The organic layers were concentrated in vacuo, and the residue was purified by flash column chromatography on silica (gradient elution with 0-10% MeOH in EtOAc) to afford the title compound (17.5 g, 81%). LCMS [M+H].sup.+ 765, RT 2.46 minutes (Method 6).

    Intermediate 34

    [0162] ##STR00042##

    (S)-N-[Cis-1-(5-Bromo-3-Fluoropyridin-2-Yl)-3-({[Tert-Butyl(Dimethyl)Silyl]Oxy}Methyl)-3-Methylcyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0163] 2,5-Dibromo-3-fluoropyridine (2.4 g, 9.23 mmol) was dissolved in DCM (120 mL) and the reaction mixture was cooled to -65° C. in an acetone-dry ice bath. n-Butyllithium (2.5 M in hexanes, 3.8 mL, 9.5 mmol) was added dropwise and the mixture was stirred at -65° C. for 15 minutes. Intermediate 31 (2.4 g, 7.2 mmol) in DCM (20 mL) was added. The reaction mixture was stirred at -65° C. for 1 h, then warmed to r.t. and stirred for 2 h. The reaction mixture was quenched with aqueous ammonium chloride solution at 0° C. and was extracted twice with DCM. The organic phases were combined and concentrated in vacuo, then purified by flash column chromatography on silica (gradient elution with 0-50% EtOAc/hexane) to afford the title compound (1.15 g, 31%). δ.sub.H (300 MHz, CDCl.sub.3) 8.47 (dd, J 1.9, 1.2 Hz, 1 H), 7.56 (dd, J 9.9, 1.9 Hz, 1 H), 3.85 (s, 1 H), 3.60-3.46 (m, 2 H), 2.87-2.73 (m, 1 H), 2.54-2.47 (m, 2 H), 2.47-2.38 (m, 1 H), 1.16 (s, 9 H), 0.96 (s, 3 H), 0.94 (s, 9 H), 0.09 (s, 6 H).

    Intermediate 35

    [0164] ##STR00043##

    (S)-N-[Cis-3-({[Tert-Butyl(Dimethyl)Silyl]Oxy}Methyl)-1-{5-[(7R,14R)-1-(DifluoroMethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]-Benzodiazocin-11-Yl]-3-Fluoropyridin-2-Yl}-3-Methylcyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0165] (7R,14R)-1-(Difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (WO 2016/050975, Intermediate 171) (405 mg, 0.87 mmol), Intermediate 34 (400 mg, 0.79 mmol), potassium phosphate tribasic (734 mg, 3.39 mmol) and tricyclohexylphosphonium tetrafluoroborate (40 mg, 0.11 mmol) were suspended in a mixture of 1,4-dioxane (10 mL) and water (1 mL). The mixture was degassed three times with nitrogen prior to the addition of tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.042 mmol). The mixture was further degassed with nitrogen and heated at 110° C. for 2.5 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc/hexane, followed by 0-10% MeOH/DCM) to afford the title compound (280 mg, 46%). LCMS (ES+) [M+H].sup.+ 768.2, RT 3.42 minutes (Method 4).

    Intermediate 36

    [0166] ##STR00044##

    3-(Benzyloxy)-1-(Trifluoromethyl)Cyclobutan-1-Ol

    [0167] TBAF in THF (1 M, 2.84 mL) was added dropwise to a stirred solution of 3-(benzyloxy)cyclobutan-1-one (5 g, 28.4 mmol) and trimethyl(trifluoromethyl)silane (5.03 mL, 34.1 mmol) in THF (50 mL) at 0° C. (external temperature). The resulting mixture was stirred at 0° C. for 2 h, then overnight at r.t. Further TBAF in THF (25.5 mL) was added and the mixture was stirred at r.t. for 2 h. Water (50 mL) was added and the mixture was poured onto brine (50 mL). The residue was extracted with EtOAc (3 × 75 mL). The combined organic phases were washed with brine (25 mL) and dried (MgSO.sub.4), then filtered and concentrated in vacuo. The resulting crude orange oil was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc in heptanes) to afford the title compound (6.5 g, 92%) as a pale orange oil. δ.sub.H (250 MHz, CDCl.sub.3) 7.42-7.27 (m, 5 H), 4.44 (s, 2 H), 3.88 (p, J 6.7 Hz, 1 H), 2.91-2.74 (m, 2 H), 2.56 (s, 1 H), 2.32-2.15 (m, 2 H).

    Intermediate 37

    [0168] ##STR00045##

    (Benzyloxy)-1-(Trifluoromethyl)Cyclobutoxy](Tert-Butyl)Dimethylsilane

    [0169] tert-Butyldimethylsilyl trifluoromethanesulfonate (6.16 mL, 30 mmol) was added dropwise to a stirred solution of Intermediate 36 (6 g, 24.4 mmol) and 2,6-dimethylpyridine (8.16 mL, 70 mmol) in DCM (60 mL) at -78° C. The mixture was stirred at -78° C. for 30 minutes, then allowed to warm slowly to r.t. overnight. The mixture was treated with saturated aqueous sodium hydrogen carbonate solution (60 mL) and the layers were separated. The aqueous phase was further extracted with DCM (60 mL). The combined organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc in heptanes) to afford the title compound (8.14 g, 93%) as a pale yellow oil. δ.sub.H (250 MHz, CDCl.sub.3) 7.45-7.27 (m, 5 H), 4.43 (s, 2 H), 3.82 (p, J 6.8 Hz, 1 H), 2.92-2.74 (m, 2 H), 2.35-2.17 (m, 2 H), 0.90 (s, 9 H), 0.14 (s, 6 H).

    Intermediate 38

    [0170] ##STR00046##

    3-{[Tert-Butyl(Dimethyl)Silyl1]Oxy}-3-(Trifluoromethyl)Cyclobutan-1-Ol

    [0171] A stirred mixture of Intermediate 37 (8.14 g, 22.6 mmol) and 10% palladium on carbon (50% in water, 2.41 g, 11.3 mmol) in ethanol (163 mL) was placed under an atmosphere of hydrogen gas. The reaction mixture was stirred at r.t. for 24 h, then filtered through celite. The filter cake was washed with MeOH (3 × 50 mL). The filtrate was concentrated in vacuo. The resulting dark residue was filtered over celite and the filter cake was washed with MeOH (3 × 50 mL). The filtrate was concentrated in vacuo to afford the title compound (6.2 g, 98%) as an opaque light yellow wax. δ.sub.H (250 MHz, CDCl.sub.3) 4.21-4.01 (m, 1 H), 2.99-2.84 (m, 2 H), 2.34-2.14 (m, 2 H), 1.89 (s, 1 H), 0.90 (s, 9 H), 0.14 (s, 6 H).

    Intermediate 39

    [0172] ##STR00047##

    3-{[Tert-Butyl(Dimethyl)Silyl]Oxy}-3-(Trifluoromethyl)Cyclobutan-1-One

    [0173] Dess-Martin periodinane (11.3 g, 26.9 mmol) was added to a stirred solution of Intermediate 38 (6.2 g, 22.2 mmol) in DCM (175 mL) at r.t. The mixture was stirred at r.t. overnight, then diluted with DCM (50 mL) and filtered over a pad of celite. The filter cake was washed with further DCM (25 mL), and the filtrate was poured onto saturated aqueous sodium hydrogen carbonate solution (100 mL). The layers were separated, and the aqueous phase was further extracted with DCM (50 mL). The combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The resulting waxy crystalline solid was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc in heptanes) to afford the title compound (5.71 g, 86%) as a pale yellow oil. δ.sub.H (250 MHz, CDCl.sub.3) 3.61-3.40 (m, 2 H), 3.31-3.15 (m, 2 H), 0.91 (s, 9 H), 0.20-0.13 (m, 6 H).

    Intermediate 40

    [0174] ##STR00048##

    (R)-N-{[Tert-Butyl(Dimethyl)Silyl]Oxy}-3-(Trifluoromethyl)Cyclobutylidene)-2-MethylPropane-2-Sulfinamide

    [0175] Titanium(IV) ethoxide (24.4 mL, 38.1 mmol) was added to a stirred solution of Intermediate 39 (5 g, 18.6 mmol) in THF (100 mL) at r.t. under nitrogen. The mixture was stirred for 10 minutes, then (R)-2-methylpropane-2-sulfinamide (4.52 g, 37.3 mmol) was added. The mixture was heated at 65° C. for 1.5 h, then cooled to r.t. The mixture was diluted with brine (70 mL), EtOAc (200 mL) and water (35 mL), then stirred vigorously for 15 minutes. The organic layer was decanted and the remaining emulsion was filtered over filter paper. The filtrate was further extracted with EtOAc (100 mL). The combined organic phases were washed with brine (50 mL) and dried (MgSO.sub.4), then filtered and concentrated in vacuo. The resulting crude yellow syrup was purified by flash column chromatography on silica (gradient elution with 0-50% EtOAc in heptanes) to afford the title compound (5.5 g, 80%) as a light yellow oil. δ.sub.H (250 MHz, CDCl.sub.3) 4.18-3.11 (m, 4 H), 1.29-1.20 (m, 9 H), 0.90 (s, 9 H), 0.15 (s, 6 H). LCMS (ESI) [M+H].sup.+ 372.15, RT 1.52 minutes (Method 8).

    Intermediate 41

    [0176] ##STR00049##

    (R)-N-(5-Bromo-3-Fluoropyridin-2-Yl)-3-{[Tert-Butyl(Dimethyl)Silyl]Oxy}-3-(TrifluoroMethyl)Cyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0177] n-Butyllithium in hexanes (2.5 M, 3.47 mL, 8.66 mmol) was added dropwise to a stirred solution of 2,5-dibromo-3-fluoropyridine (2.17 g, 8.51 mmol) in DCM (140 mL) at -70° C. (internal temperature). After stirring for 15 minutes, a solution of Intermediate 40 (2.75 g, 7.4 mmol) in DCM (14 mL) was added dropwise. Stirring was maintained at -70° C. for 2 h. The mixture was slowly warmed to r.t. over approximately 1.5 h, then recooled to 0° C. Saturated aqueous ammonium chloride solution (100 mL) was added and the mixture was stirred vigorously for 10 minutes. The layers were separated and the aqueous phase was further extracted with DCM (2 × 100 mL). The combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 0-50% EtOAc in heptanes) to afford the title compound (1.68 g, 42%) as a pale orange gum. δ.sub.H (250 MHz, CDCl.sub.3) 8.46 (d, J 6.7 Hz, 1 H), 7.65-7.50 (m, 1 H), 3.86 (s, 1 H), 3.50-3.33 (m, 1 H), 3.13-2.89 (m, 2 H), 2.88-2.59 (m, 1 H), 1.19-1.11 (m, 9 H), 0.95-0.69 (m, 9 H), 0.24 to -0.07 (m, 6 H). LCMS (ESI) [M+H].sup.+ 547.2, RT 1.91 minutes (Method 9).

    Intermediate 42

    [0178] ##STR00050##

    (R)-N-{[tert-Butyl(dimethyl)silyl[oxy}-1-{5-[(7R,14R)-1-(difluoromethoxy)-6-Methyl-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]-3-Fluoropyridin-2-Yl}-3-(Trifluoromethyl)Cyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0179] Intermediate 4 (886 mg, 1.84 mmol) was added to a stirred solution of Intermediate 41 (840 mg, 1.53 mmol) in 1,4-dioxane (10 mL) at r.t. in a sealable pressure vessel. The mixture was treated with 2 M aqueous potassium carbonate solution (2.3 mL) and purged with nitrogen for 15 minutes. XPhos (73 mg, 0.15 mmol) and XPhos Pd G2 (121 mg, 0.15 mmol) were added and the vessel was sealed. The mixture was stirred at 100° C. for 4 h, then cooled to r.t. The dark mixture was diluted with EtOAc (30 mL) and poured onto brine (50 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 × 25 mL). The combined organic phase was washed with brine (25 mL) and dried (MgSO.sub.4), then filtered and concentrated in vacuo. The resulting dark residue was purified by flash column chromatography on silica (gradient elution with 0-10% MeOH in DCM). The resulting crude pale brown foam was purified by further flash column chromatography on silica (gradient elution with 0-100% EtOAc in heptanes) to afford the title compound (1.00 g, 76%) as an off-white foam. δ.sub.H (250 MHz, CDCl.sub.3) 8.64 (dd, J 3.4, 1.7 Hz, 1 H), 8.49 (d, J 8.1 Hz, 1 H), 7.82-7.30 (m, 6 H), 7.19-6.53 (m, 1 H), 6.35-6.21 (m, 1 H), 5.04-4.94 (m, 1 H), 3.94 (s, 1 H), 3.53 (s, 3 H), 3.49-3.39 (m, 1 H), 3.17-2.67 (m, 4 H), 1.30-1.22 (m, 1 H), 1.22-1.12 (m, 9 H), 1.00-0.63 (m, 9 H), 0.25 to -0.05 (m, 6 H). LCMS (ESI) [M+H].sup.+ 822.4, RT 2.22/2.26 minutes (Method 10).

    Intermediate 43

    [0180] ##STR00051##

    (R)-N-{5-[(7R,14R)-1-(Difluoromethoxy)-6-Methyl-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazol[1,2-b][2,5]Benzodiazocin-11-Yl]-3-Fluoropyridin-2-Yl}-3-Hydroxy-3-(Trifluoromethyl)Cyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0181] TBAF in THF (1 M, 2.33 mL, 2.32 mmol) was added to a stirred solution of Intermediate 42 (1 g, 1.16 mmol) in THF (15 mL) at r.t. The mixture was warmed and stirred at 35° C. for 2 h. After cooling to r.t., the mixture was poured onto water (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic phase was washed with brine (30 mL) and dried (MgSO.sub.4), then filtered and concentrated in vacuo. The resulting off-white solid (0.9 g) was suspended in DMSO-MeOH (1:1; 6 mL). The resulting thick paste was concentrated in vacuo to afford crude title compound (0.82 g) as an off-white solid, which was utilised without further purification. LCMS (ESI) [M+H].sup.+ 708.4, RT 3.11 minutes (Method 11).

    Intermediate 44

    [0182] ##STR00052##

    (R)-N-(5-Bromopyrimidin-2-Yl)-3-{[Tert-Butyl(Dimethyl)Silyl]Oxy}-3-(TrifluoroMethyl)Cyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0183] n-Butyllithium in hexanes (2.5 M, 5.09 mL, 12.7 mmol) was added dropwise to a stirred solution of 5-bromo-2-iodopyrimidine (3.56 g, 12.51 mmol) in DCM (230 mL) at -70° C. (internal temperature). After stirring for 15 minutes, a solution of Intermediate 40 (4.04 g, 10.9 mmol) in DCM (20 mL) was added dropwise. Stirring was maintained at -70° C. for 2 h. Whilst at this temperature, the mixture was quenched with saturated aqueous ammonium chloride solution (150 mL) and the resulting slurry was warmed slowly to r.t. The layers were separated and the aqueous phase was further extracted with DCM (100 mL). The combined organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The resulting dark brown oil/solid was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc in heptanes). Further purification of the resulting partially purified yellow oil by flash column chromatography on reverse phase silica (gradient elution with 10-100% acetonitrile in water spiked with 0.1% formic acid) afforded the title compound (0.51 g, 9%) as a pale orange oil. δ.sub.H (250 MHz, CDCl.sub.3) 8.81-8.74 (m, 2 H), 4.48 (d, J 33.1 Hz, 1 H), 3.90-2.64 (m, 4 H), 1.23-1.15 (m, 9 H), 0.97-0.70 (m, 9 H), 0.22 to -0.05 (m, 6 H). LCMS (ESI) [M+H].sup.+ 530/532, RT 1.53 minutes (Method 8).

    Intermediate 45

    [0184] ##STR00053##

    (R)-N-{[Tert-Butyl(Dimethyl)Silyl]Oxy}-1-{5-[(7R,14R)-1-(Difluoromethoxy)-6-Methyl-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]-Pyrimidin-2-Yl}-3-(Trifluoromethyl)Cyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0185] Intermediate 4 (552 mg, 1.15 mmol) was added to a stirred solution of Intermediate 44 (507 mg, 0.96 mmol) in 1,4-dioxane (7 mL) at r.t. in a sealable pressure vessel. The mixture was treated with 2 M aqueous potassium carbonate solution (1.44 mL) and the mixture was purged with nitrogen for 15 minutes. XPhos (46 mg, 0.1 mmol) and XPhos Pd G2 (75 mg, 0.1 mmol) were added and the vessel was sealed. The mixture was stirred at 100° C. for 4 h, then cooled to r.t. The dark mixture was diluted with EtOAc (30 mL) and poured onto brine (50 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 × 25 mL). The combined organic phases were washed with brine (25 mL) and dried (MgSO.sub.4), then filtered and concentrated in vacuo. The resulting dark residue (1.18 g) was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc in heptanes). The resulting crude pale orange foam was further purified by column chromatography on reverse phase silica (gradient elution with 10-100% acetonitrile in water spiked with 0.1% formic acid) to afford the title compound (0.61 g, 79%) as an off-white glass. δ.sub.H (250 MHz, CDCl.sub.3) 9.04-8.87 (m, 2 H), 8.50 (d, J 8.1 Hz, 1 H), 7.92-7.79 (m, 1 H), 7.71 (s, 1 H), 7.56-7.31 (m, 3 H), 6.89 (t, J 72.7 Hz, 1 H), 6.31 (d, J 7.2 Hz, 1 H), 5.04 (d, J 7.2 Hz, 1 H), 4.66-4.40 (m, 1 H), 3.64 (d, J 14.8 Hz, 1 H), 3.52 (s, 3 H), 3.20-2.70 (m, 5 H), 1.36-1.14 (m, 9 H), 1.02-0.66 (m, 9 H), 0.26 to -0.11 (m, 6 H). LCMS (ESI) [M+H].sup.+ 805.4, RT 1.54 minutes (Method 8).

    Intermediate 46

    [0186] ##STR00054##

    (R)-N-{5-[(7R,14R)-1-(Difluoromethoxy)-6-Methyl-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]Pyrimidin-2-Yl}-3-Hydroxy-3-(Trifluoromethyl)Cyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0187] TBAF in THF (1 M, 1.52 mL) was added to a stirred solution of Intermediate 45 (0.61 g, 0.76 mmol) in THF (10 mL) at r.t. The mixture was stirred at r.t. overnight, then poured onto water (35 mL). The residue was extracted with EtOAc (3 × 35 mL). The combined organic phases were washed with water (30 mL) and brine (30 mL), then dried (MgSO.sub.4), filtered and concentrated in vacuo, to give the title compound (0.474 g, 90%) as an off-white solid. δ.sub.H (250 MHz, CD.sub.3OD) 9.14-9.04 (m, 2 H), 8.47-8.35 (m, 1 H), 7.96-7.89 (m, 1 H), 7.82 (d, J 8.5 Hz, 1 H), 7.65 (dd, J 8.6, 1.7 Hz, 1 H), 7.63-7.03 (m, 3 H), 6.49 (d, J 7.1 Hz, 1 H), 5.26 (d, J 7.1 Hz, 1 H), 4.59 (s, 1 H), 3.73-3.57 (m, 1 H), 3.52 (s, 3 H), 3.43-3.36 (m, 1 H), 3.10-2.87 (m, 3H), 2.75 (d, J 14.4 Hz, 1 H), 1.33-1.19 (m, 9 H). LCMS (ESI) [M+H].sup.+ 691.25, RT 1.10 & 1.13 minutes (Method 8).

    Intermediate 47

    [0188] ##STR00055##

    (R)-N-{[Tert-Butyl(Dimethyl)Silyl]Oxy}-1-{5-[(7R,14R)-1-(Difluoromethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]-3-FluoroPylidin-2-Yl}-3-(Trifluoromethyl)Cyclobutyll-2-Methylpropane-2-Sulfinamide

    [0189] To a stirred solution of Intermediate 41 (400 mg, 0.73 mmol) and (7R,14R)-1-(difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b] [2,5]benzodiazocin-5(14H)-one (WO 2016/050975, Intermediate 171) (383 mg, 0.8 mmol) in 1,4-dioxane (10 mL) was added 2 M aqueous potassium carbonate solution (1.1 mL). The reaction mixture was degassed with nitrogen, then XPhos (35 mg, 0.07 mmol) and XPhos Pd G2 (57 mg, 0.07 mmol) were added. The reaction mixture was heated in a sealed tube at 100° C. for 2.5 h. The reaction mixture was allowed to cool, then diluted with EtOAc (50 mL) and washed with brine (2 × 25 mL). The organic layer was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc/heptanes followed by 0-20% MeOH/EtOAc), then by column chromatography on reverse phase silica (gradient elution with 10-100% acetonitrile/water + 0.1% formic acid), to afford the title compound (469 mg, 72%) (4:5 mixture of cis/trans isomers) as a white solid. δ.sub.H (500 MHz, CDCl.sub.3) 8.62 (dd, J 7.2, 1.6 Hz, 1 H), 8.42 (dt, J 7.9, 1.8 Hz, 1 H), 7.79 (dd, J 8.3, 6.6 Hz, 1 H), 7.66 (dd, J 5.3, 1.4 Hz, 1 H), 7.61-7.52 (m, 1 H), 7.49-7.36 (m, 3 H), 7.09 (t, J 5.9 Hz, 1 H), 6.87 (t, J 72.6 Hz, 1 H), 6.37 (dd, J 7.2, 4.2 Hz, 1 H), 4.99-4.87 (m, 1 H), 3.94 (s, 1 H), 3.91-3.83 (m, 0.56 H, major), 3.55-3.48 (m, 2 H), 3.14-3.05 (m, 1 H), 3.03-2.99 (m, 0.44 H, minor), 2.90-2.86 (m, 1 H), 2.86-2.69 (m, 1 H), 1.18 (s, 4 H, minor), 1.17 (s, 5 H, major), 0.94 (s, 4 H, minor), 0.70 (s, 5 H, major), 0.19 (d, J 11.3 Hz, 2.67 H, minor), -0.01 (d, J 11.3 Hz, 3.33 H, major).

    Intermediate 48

    [0190] ##STR00056##

    (R)-N-{5-[(7R,14R)-1-(Difluoromethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-MethanoBenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]-3-Fluoropyridin-2-Yl}-3-Hydroxy-3-(Trifluoromethyl)Cyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0191] To a solution of Intermediate 47 (469 mg, 0.56 mmol) in THF (6 mL) was added TBAF in THF (1 M, 1.11 mL). The reaction mixture was stirred at 35° C. for 2 h, then cooled, diluted with brine (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried (Na.sub.2SO.sub.4), then filtered and concentrated in vacuo, to afford crude title compound (440 mg, quantitative) as an off-white powder, which was utilised without further purification. δ.sub.H (500 MHz, CDCl.sub.3) 8.49 (d, J 23.5 Hz, 1 H), 8.41-8.28 (m, 1 H), 7.67 (dd, J 31.2, 8.5 Hz, 1 H), 7.57 (dd, J 13.3, 1.4 Hz, 1 H), 7.47 (ddd, J 12.0, 6.2, 1.8 Hz, 1 H), 7.39-7.26 (m, 3 H), 7.10-7.00 (m, 1 H), 6.78 (td, J 72.7, 4.2 Hz, 1 H), 6.28 (d, J 7.2 Hz, 1 H), 4.86 (t, J 6.5 Hz, 1 H), 4.43-4.04 (m, 1 H), 3.52-3.33 (m, 3 H), 3.06-2.55 (m, 4 H), 1.11 (d, J 4.1 Hz, 9 H). LCMS (ESI) [M+H].sup.+ 694.3, RT 1.35 and 1.40 minutes (Method 9).

    Intermediate 49

    [0192] ##STR00057##

    Methyl 3,3-Dimethoxycyclobutanecarboxylate

    [0193] Ethyl 3-oxocyclobutanecarboxylate (53 g, 372.8 mmol), trimethyl orthoformate (200 mL, 1830 mmol) and 4-methylbenzenesulfonic acid hydrate (1:1) (7.09 g, 37.3 mmol) were combined in methanol (500 mL) and heated under reflux, with stirring, for 1 h. The reaction mixture was cooled to r.t. and concentrated under reduced pressure. The residue was dissolved in diethyl ether (500 mL) and washed with saturated aqueous NaHCO.sub.3 solution (400 mL). The aqueous phase was extracted with diethyl ether (500 mL). The combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was azeotroped with heptane, to remove the remaining trimethyl orthoformate, to afford the title compound (71.5 g, 99%) as light beige oil. δ.sub.H (500 MHz, CDCl.sub.3) 3.69 (s, 3 H), 3.17 (s, 3 H), 3.15 (s, 3 H), 2.88 (m, 1 H), 2.48-2.32 (m, 4 H).

    Intermediate 50

    [0194] ##STR00058##

    Methyl 3,3-Dimethoxy-1-Methylcyclobutanecarboxylate

    [0195] Under a nitrogen atmosphere, 2 M LDA solution (108.5 mL, 217 mmol in THF) was added to THF (300 mL) at -78° C. A solution of Intermediate 49 (90%, 35 g, 180.8 mmol) in THF (50 mL) was added dropwise over 25 minutes, maintaining the internal temperature at -78° C. After complete addition, the mixture was stirred for 30 minutes, then iodomethane (15 mL, 241 mmol) was added dropwise. The mixture was stirred at -78° C. for 30 minutes, then allowed to warm to r.t. over 1 h. The mixture was poured into saturated aqueous NH.sub.4Cl solution (300 mL) and extracted with diethyl ether (2 × 500 mL). The combined organic phases were washed with brine and dried (Na.sub.2SO.sub.4), then filtered and evaporated to dryness. The residue was purified by flash column chromatography (40% EtOAc in heptane) to afford the title compound (23 g, 57%) as a light yellow oil. δ.sub.H (250 MHz, CDCl.sub.3) 3.70 (s, 3 H), 3.16 (s, 3 H), 3.13 (s, 3 H), 2.68-2.55 (m, 2 H), 2.13-1.99 (m, 2 H), 1.43 (s, 3 H).

    Intermediate 51

    [0196] ##STR00059##

    Dideuterio(3,3-dimethoxy-1-methylcyclobutyl)methanol

    [0197] Under a nitrogen atmosphere, to a suspension of LiAlD.sub.4 (5 g, 119 mmol) in THF (400 mL) at 0° C. (ice bath) was added dropwise a solution of Intermediate 50 (27.2 g, 118.5 mmol) in THF (100 mL). When the addition was complete, the reaction mixture was stirred at r.t. overnight, then cooled in an ice bath. Water (5 mL) was added dropwise with stirring. The suspension which formed was diluted with THF (150 mL), followed by the addition of 15% aqueous NaOH solution (5 mL) and water (15 mL). To the resulting suspension was added Na.sub.2SO.sub.4 (40 g), and the mixture was stirred for 30 minutes. The granular suspension was filtered and rinsed with diethyl ether, then the combined filtrates were concentrated under reduced pressure, to give the title compound (23.8 g, 99%) as a light yellow oil. δ.sub.H (250 MHz, CDCl.sub.3) 3.22-3.07 (m, 6 H), 2.17-2.03 (m, 2 H), 1.93-1.78 (m, 2 H), 1.18 (s, 3 H).

    Intermediate 52

    [0198] ##STR00060##

    3-[Dideuterio(Hydroxy)Methyl]-3-Methylcyclobutanone

    [0199] To a stirred solution of Intermediate 51 (23.8 g, 117.3 mmol) in acetone (240 mL) and water (80 mL) was added 4-methylbenzenesulfonic acid hydrate (1:1) (5 g, 26.3 mmol). The reaction mixture was heated at 65° C. for 2 h, then allowed to stand at r.t. overnight. The acetone was removed under reduced pressure. The resulting mixture was basified with solid NaHCO3 to pH 8 and extracted with DCM (5 × 130 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and filtered through a fritted funnel, then concentrated under reduced pressure, to afford the title compound (16 g, 94%) as a light brown oil. δ.sub.H (250 MHz, CDCl.sub.3) 3.12-2.92 (m, 2 H), 2.79-2.57 (m, 2 H), 1.69 (s, 1 H), 1.36 (s, 3 H).

    Intermediate 53

    [0200] ##STR00061##

    3-{[Tert-Butyl(Dimethyl)Silyl]Oxy(Dideuterio)Methyl}-3-Methylcyclobutanone

    [0201] To a solution of Intermediate 52 (16 g, 110 mmol) in DMF (100 mL) were added 1H-imidazole (15 g, 220 mmol) and tert-butyl(chloro)dimethylsilane (22 g, 146 mmol). The mixture was stirred at r.t. overnight, then diluted with diethyl ether (250 mL) and water (200 mL). The layers were separated, then the aqueous layer was extracted with diethyl ether (250 mL). The combined organic phases were washed with brine (3 × 80 mL) and dried over MgSO.sub.4, then filtered and concentrated in vacuo, to afford the title compound (30 g, 97%) as a light brown oil. δ.sub.H (250 MHz, CDCl.sub.3) 3.13-2.94 (m, 2 H), 2.70-2.51 (m, 2 H), 1.29 (s, 3 H), 0.89 (s, 9 H), 0.06 (s, 6 H).

    Intermediate 54

    [0202] ##STR00062##

    N-{[Tert-Butyl(dimethyl)Silylloxy(Dideuterio)Methyl}-3-Methylcyclobutylidene)-2-Methylpropane-2-Sulfinamide

    [0203] To a solution of Intermediate 53 (30 g, 107 mmol) in anhydrous THF (250 mL) under a nitrogen atmosphere was added (R)-2-methylpropane-2-sulfinamide (15.53 g, 128.1 mmol), followed by titanium(IV) ethoxide (50 mL, 202.7 mmol). The mixture was stirred at r.t. for 24 h. Further portions of (R)-2-methylpropane-2-sulfinamide (2.8 g, 23.1 mmol) and titanium(IV) ethoxide (5 mL, 20.27 mmol) were added to the reaction mixture, which was then stirred at 65° C. for 4 h. The reaction mixture was cooled to r.t. and water (13 mL) was added, followed by EtOAc (200 mL). The reaction mixture was filtered over celite and the solid was washed extensively with EtOAc. The filtrate was dried over Na.sub.2SO.sub.4, then filtered and evaporated in vacuo. The crude residue was purified by column chromatography (5-20% EtOAc in heptane) to afford the title compound (31.5 g, 84%) as a yellow oil. δ.sub.H (500 MHz, CDCl.sub.3) 3.47-3.16 (m, 1 H), 3.13-2.83 (m, 2 H), 2.71-2.55 (m, 1 H), 1.25-1.21 (m, 12 H), 0.91-0.87 (m, 9 H), 0.05 (s, 6 H) (1:1 mixture of E/Z isomers).

    Intermediate 55

    [0204] ##STR00063##

    N-(5-Bromopyrimidin-2–Yl)-3-{[Tert-Butyl(Dimethyl)Silylloxyfdideuterio)Methyl]-3-Methylcyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0205] Under a nitrogen atmosphere, a solution of 5-bromo-2-iodopyrimidine (71.2 g, 250 mmol) in anhydrous DCM (1.25 L) was cooled to -78° C. To the solution was added 2.5 M butyllithium solution (100 mL, 250 mmol in hexane) via cannula, maintaining the internal temperature below -68° C. The thick suspension was stirred for 20 minutes at -78° C. A solution of Intermediate 54 (24 g, 68.3 mmol) in anhydrous DCM (100 mL) was added, maintaining the internal temperature below -68° C. After addition, the mixture was stirred for 10 minutes, then saturated aqueous NH.sub.4Cl solution (400 mL) and water (100 mL) were added. The mixture was allowed to warm to room temperature, then the organic phase was separated and the aqueous phase was extracted with DCM (2 × 300 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, then filtered and evaporated in vacuo. The crude residue was purified by flash column chromatography (20-100% EtOAc in heptane), then recrystallized from heptane. The residue was further purified by flash column chromatography (20-35% EtOAc in heptane) to afford the title compound (0.93 g) as a white solid. δ.sub.H (500 MHz, CDCl.sub.3) 8.70 (s, 2 H), 4.34 (s, 1 H), 2.80-2.74 (m, 1 H), 2.44-2.35 (m, 2 H), 2.26-2.20 (m, 1 H), 1.13 (s, 9 H), 0.97 (s, 3 H), 0.86-0.83 (m, 9 H), 0.00 (s, 6 H).

    Intermediate 56

    [0206] ##STR00064##

    N-(Cis{[Tert-Butyl(Dimethyl)Silylloxy(Dideutero)Methyl}-1-{5-[(7R,14R)-1-(DifluoroMethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazol[1,2-b][2,5]-Benzodiazocin-11-Yl]Pyrimidin-2-Yl}Methylcyclobutyl)-2-Methylpropane-2-Sulfinamide

    [0207] A solution of Intermediate 55 (1.36 g, 2.51 mmol), (7R,14R)-1-(difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (WO 2016/050975, Intermediate 171) (1.32 g, 2.51 mmol) and potassium phosphate tribasic (2.13 g, 10 mmol) in 1,4 dioxane (5 mL) and water (1.5 mL) was degassed with nitrogen, then tris(dibenzylideneacetone)-dipalladium(0) (0.12 g, 0.13 mmol) and tricyclohexylphosphonium tetrafluoroborate (0.11 g, 0.3 mmol) were added. The reaction mixture was heated at 100° C. for 16 h, then diluted with water (5 mL) and extracted with EtOAc (3 × 15 mL). The organic phases were combined, washed with saturated brine (10 mL) and dried over Na.sub.2SO.sub.4, then filtered and evaporated in vacuo. The resulting brown oil was purified by column chromatography using a 55 g KP-NH column (50-100% EtOAc in heptane, followed by 0-15% MeOH in EtOAc) to give the title compound (1.68 g, 94%) as a yellow powder. δ.sub.H (500 MHz, DMSO-d.sub.6) 9.15 (d, J 6.8 Hz, 1 H), 9.08 (s, 2 H), 8.23 (dd, J 7.7, 1.6 Hz, 1 H), 7.84-7.67 (m, 3 H), 7.64 (dd, J 8.6, 1.7 Hz, 1 H), 7.55-7.47 (m, 2 H), 6.37 (d, J 7.1 Hz, 1 H), 5.64 (s, 1 H), 4.90 (t, J 6.8 Hz, 1 H), 3.54-3.45 (m, 1 H), 2.75 (d, J 13.3 Hz, 1 H), 2.70 (d, J 12.3 Hz, 1 H), 2.46-2.40 (m, 3 H), 1.07 (s, 9 H), 0.94 (s, 3 H), 0.89 (s, 9 H), 0.07 (d, J 0.8 Hz, 6 H). LCMS (ESI+) [M+H].sup.+ 753.4, RT 1.87 minutes (Method 1).

    Intermediate 57

    [0208] ##STR00065##

    N-[cis({[Tert-Butyl(Dimethyl)Silyl]Oxy}Methyl)-1-{5-([7R,14R)-1-(Difluoromethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b]2,5]Benzodiazocin-11-Yl]-Pyrimidin-2-Yl}Methylcyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0209] Prepared from Intermediate 32 and (7R,14R)-1-(difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one (WO 2016/050975, Intermediate 171) following the experimental procedure described for Intermediate 56. LCMS (ESI+) [M+H].sup.+ 751.2, RT 3.20 minutes (Method 1).

    Intermediate 58

    [0210] ##STR00066##

    N-(5-Bromo-3-Fluoropyrdin-2-Yl)-3-{[Tert-Butyl(Dimethyl)Silylloxy(Dideuterio)-Methyl}-3-Methylcyclobutyl]-2-Methylpropane-2-Sulfinamide

    [0211] Prepared from Intermediate 54 and 2,5-dibromo-3-fluoropyridine following the experimental procedure described for Intermediate 55. δ.sub.H (500 MHz, CDCl.sub.3) 8.41-8.35 (m, 1 H), 7.47 (dd, J 9.9, 1.9 Hz, 1 H), 3.76 (s, 1 H), 2.70 (d, J 12.9 Hz, 1 H), 2.48-2.38 (m, 2 H), 2.37-2.30 (m, 1 H), 1.07 (s, 9 H), 0.87 (s, 3 H), 0.85 (s, 9 H), 0.00 (s, 6 H). LCMS (ESI+) [M+H].sup.+ 509.05, RT 1.67 minutes (Method 1).

    Intermediate 59

    [0212] ##STR00067##

    N-(Cis{[Tert-Butyl(Dimethyl)Silyl]Oxy(Dideutero)Methyl}-1-{5-[(7R,14R)-1-(DifluoroMethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]-Benzodiazocin-11-Yl]Fluororpyridin-2-Yl}Methylcyclobutyl)-2-Methylpropane-2-Sulfinamide

    [0213] Prepared from Intermediate 58 and (7R,14R)-1-(difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one (WO 2016/050975, Intermediate 171) following the experimental procedure described for Intermediate 56. δ.sub.H (500 MHz, DMSO-d.sub.6) 9.14 (d, J 6.8 Hz, 1 H), 8.73-8.62 (m, 1 H), 8.23 (dd, J 7.8, 1.5 Hz, 1 H), 7.89 (dd, J 12.2, 1.8 Hz, 1 H), 7.86-7.54 (m, 4 H), 7.54-7.47 (m, 2 H), 6.36 (d, J 7.1 Hz, 1 H), 5.46 (s, 1 H), 4.89 (t, J 6.8 Hz, 1 H), 3.49 (dt, J 13.4, 6.9 Hz, 1 H), 2.74 (d, J 13.3 Hz, 1 H), 2.68-2.57 (m, 2 H), 2.48-2.41 (m, 2 H), 1.04 (s, 9 H), 0.90 (s, 9 H), 0.87 (s, 3 H), 0.07 (d, J 1.2 Hz, 6 H). LCMS (ESI+) [M+H].sup.+ 770.3, RT 1.60 minutes (Method 1).

    Example 1

    [0214] ##STR00068##

    CisAmino{5-[(7R,14R)-1-(Difluoromethoxy)-6-Methyl-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]Pyrimidin-2-Yl}-1-MethylCyclobutanecarbonitrile

    [0215] To Intermediate 5 (178 mg, 0.24 mmol) dissolved in MeOH (5 mL) was added 4 M hydrochloric acid in 1,4-dioxane (0.31 mL). The reaction mixture was stirred at r.t. for 90 minutes, then the solvent was removed in vacuo. The resulting brown glass was purified by flash column chromatography on silica (gradient elution with 100% DCM to 25% MeOH/DCM). The resulting mixture of cis and trans isomers was purified by preparative HPLC to afford the title compound (9 mg, 7%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 9.07 (s, 2 H), 8.32-8.20 (m, 1 H), 7.96-7.40 (m, 6 H), 6.31 (d, J 7.1 Hz, 1 H), 5.26 (d, J 7.1 Hz, 1 H), 3.52 (dt, J 14.1, 7.4 Hz, 1 H), 3.36 (s, 3 H), 2.88-2.75 (m, 3 H), 2.64-2.57 (m, 2 H), 1.46 (s, 3 H). LCMS (ES+) [M+H].sup.+ 542.0, RT 1.766 minutes (Method 1). LCMS (ES+) [M+H].sup.+ 542.2, RT 1.43 minutes (Method 2).

    Example 2

    [0216] ##STR00069##

    CisAmino{5-[(7R,14R)-1-(Difluoromethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]Pyrimidin-2-yl}-1-MethylCyclobutanecarbonitrile

    [0217] To Intermediate 6 (50 mg, 0.079 mmol) dissolved in 1,4-dioxane (5 mL) was added 4 M hydrochloric acid in 1,4-dioxane (5 mL). The reaction mixture was stirred at r.t. for 1 h, then separated between EtOAc (10 mL) and 0.5 M aqueous hydrochloric acid solution (10 mL). The aqueous layer was washed with DCM (2 × 10 mL), then basified with aqueous sodium carbonate solution and extracted into DCM. The organic layer was concentrated in vacuo. The resulting crude white solid (mixture of cis and trans isomers) was purified by preparative HPLC to afford the title compound (12 mg, 29%). δ.sub.H (300 MHz, DMSO-d.sub.6) 9.15 (d, J 6.8 Hz, 1 H), 9.07 (s, 2 H), 8.23 (dd, J 5.7, 3.7 Hz, 1 H), 7.97-7.43 (m, 6 H), 6.36 (d, J 6.9 Hz, 1 H), 4.90 (t, J 6.8 Hz, 1 H), 3.59-3.39 (m, 1 H), 2.85-2.68 (m, 3 H), 2.65-2.57 (m, 2 H), 1.46 (s, 3 H). LCMS (ES+) [M+H].sup.+ 528.0, RT 1.69 minutes (Method 1).

    Example 3

    [0218] ##STR00070##

    CisAmino{5-[(7R,14R)-1-(Difluoromethoxy)-6-Methyl-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]Fluoropyridin-2-Yl}-1-Methylcyclobutanecarbonitrile

    [0219] Intermediate 8 (120 mg, 0.181 mmol) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (5 mL). The reaction mixture was stirred for 1 h. Diethyl ether was added, and the precipitate was filtered, to afford the title compound (82 mg, 81%) as a white solid (containing 7% of the trans isomer). δ.sub.H (300 MHz, DMSO-d.sub.6) 8.99 (s, 3 H), 8.84 (t, J 1.8 Hz, 1 H), 8.28 (p, J 4.3 Hz, 1 H), 8.20 (dd, J 12.3, 1.8 Hz, 1 H), 7.95-7.43 (m, 6 H), 6.31 (d, J 7.1 Hz, 1 H), 5.28 (d, J 7.0 Hz, 1 H), 3.61-3.49 (m, 1 H), 3.36 (s, 3 H), 3.33-3.13 (m, 4 H), 2.86 (d, J 13.8 Hz, 1 H), 1.29 (s, 3 H). LCMS (ES+) [M+H].sup.+ 559.0, RT 1.93 minutes (Method 1). LCMS (ES+) [M+H].sup.+ 559.0, 1.71 minutes (Method 2).

    Example 4

    [0220] ##STR00071##

    CisAmino{5-[(7R,14R)-1-(Difluoromethoxy)-5-Oxo-5,6,7,14-Tetrahydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-11-Yl]Fluoropyridin-2-Yl}-1-Methyl-Cyclobutanecarbonitrile

    [0221] Intermediate 9 (102 mg, 0.157 mmol) was dissolved in 1,4-dioxane (5 mL) and treated with 4 M hydrochloric acid in 1,4-dioxane (5 mL). The reaction mixture was stirred for 1 h. Diethyl ether was added, and the precipitate which formed was filtered. The crude residue (mixture of cis and trans isomers, 81 mg) was purified by preparative HPLC to afford the title compound (11 mg, 13%). δ.sub.H (300 MHz, DMSO-d.sub.6) 9.15 (d, J 6.9 Hz, 1 H), 8.62 (t, J 1.8 Hz, 1 H), 8.23 (dd, J 6.4, 3.0 Hz, 1 H), 7.99-7.44 (m, 7 H), 6.35 (d, J 7.1 Hz, 1 H), 4.89 (t, J 6.7 Hz, 1 H), 3.49 (dt, J 13.4, 7.2 Hz, 1 H), 2.85-2.71 (m, 3 H), 2.68-2.59 (m, 2 H), 2.38 (s, 2 H), 1.35 (s, 3 H). LCMS (ES+) [M+H].sup.+ 545.0, RT 1.79 minutes (Method 1). LCMS (ES+) [M+H].sup.+ 545.2, RT 1.38 minutes (Method 2).

    Example 5

    [0222] ##STR00072##

    ##STR00073##

    (7R,14R)-11-{6-[(1S,2R)-1-Amino-2-Methylcyclobutyl]-5-Fluoropyridin-3-Yl}-1-(Difluoromethoxy)-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-5(14H)-One or (7r,14r)-11-{6-[R,2,S)-1-Amino-2-Methylcyclobutyl]-5-Fluoropyridin-3-Yl}-1-(Difluoromethoxy)-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b][2,5]-Benzodiazocin-5(14H)-One

    [0223] To Intermediate 12 (135 mg, 0.22 mmol) dissolved in acetonitrile (10 mL) was added 2 M aqueous hydrochloric acid solution (10 mL). The reaction mixture was concentrated in vacuo and was treated with 2 M aqueous sodium hydroxide solution (30 mL). The mixture was extracted with DCM (3 × 20 mL). The organic layers were combined and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 0-20% MeOH in DCM) to afford the title compound (112 mg, 100%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 9.15 (d, J 6.8 Hz, 1 H), 8.60 (t, J 1.9 Hz, 1 H), 8.23 (dd, J 6.5, 3.0 Hz, 1 H), 7.95-7.42 (m, 7 H), 6.36 (d, J 7.1 Hz, 1 H), 4.89 (t, J 6.8 Hz, 1 H), 3.48 (dq, J 13.9, 7.0 Hz, 1 H), 2.83-2.67 (m, 2 H), 2.61-2.52 (m, 1 H), 2.01-1.82 (m, 4 H), 1.80-1.63 (m, 1 H), 1.14 (d, J 6.8 Hz, 3 H). LCMS (ES+) [M+H].sup.+ 520.0, RT 1.68 minutes (Method 1). LCMS (ES+) [M+H].sup.+ 520.2, RT 1.45 minutes (Method 2).

    Example 6

    [0224] ##STR00074##

    (7R,14R)-11-[2-(1-Aminocyclobutyl)Pyrimidin-5-Yl]-1-(Difluoromethoxy)-6-Methyl-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-5(14H)-One

    [0225] To a solution of Intermediate 17 (18.0 g, 29.9 mmol) in 1,4-dioxane (25 mL) was added 4 M hydrochloric acid in 1,4-dioxane (40 mL). The resulting mixture was stirred at room temperature for 1 h, then concentrated in vacuo. The residue was dissolved in water (500 mL) and washed with EtOAc (2 × 300 mL). The aqueous layer was basified to pH 9 with 2N aqueous sodium hydroxide solution, which resulted in precipitation of a solid. EtOAc (500 mL) was added and the mixture was stirred until all solids had dissolved. The residue was partitioned, then the aqueous layer was further extracted with EtOAc (500 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and filtered, then concentrated in vacuo and dried overnight under high vacuum. The foamy residue was suspended in a mixture of diethyl ether and hexane (150 mL), then stirred and shaken vigorously, before being concentrated in vacuo, to afford the title compound (12.4 g, 83%) as a white amorphous solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 9.05 (s, 2 H), 8.32-8.22 (m, 1 H), 7.91-7.66 (m, 3 H), 7.62 (dd, J 8.5, 1.8 Hz, 1 H), 7.53-7.46 (m, 2 H), 6.31 (d, J 7.1 Hz, 1 H), 5.26 (d, J 7.2 Hz, 1 H), 3.52 (dt, J 14.2, 7.3 Hz, 1 H), 3.36 (s, 3 H), 2.84 (d, J 13.8 Hz, 1 H), 2.63 (dtd, J 11.5, 5.6, 2.5 Hz, 2 H), 2.38 (s, 2 H), 2.16-2.05 (m, 2 H), 2.04-1.91 (m, 1 H), 1.87-1.73 (m, 1 H). LCMS (ES+APCI) [M-NH.sub.2].sup.- 486.0, RT 1.66 minutes (Method 2). LCMS (ES+) [M+H].sup.+ 503.0, RT 1.71 minutes (Method 1).

    Example 7

    [0226] ##STR00075##

    (7R,14R)-11-[6-(Cis-1-Amino-3-Hydroxy-3-Methylcyclobutyl)-5-Fluoropyidin-3-Yl]-1-(Difluoromethoxy)-6-Methyl-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b[2,5]-Benzodiazocin-5(14H)-One

    [0227] Hydrochloric acid in 1,4-dioxane (4.0 M, 100 mL, 400 mmol) was added to a stirred solution of Intermediate 24 (44.6 g, 58.1 mmol) in MeOH (290 mL). The reaction mixture was stirred at r.t. for 3 h, then diluted with DCM (400 mL). Water (400 mL) was added, then the layers were separated. The organic layer was extracted with 2N aqueous hydrochloric acid solution (2 × 200 mL). The combined aqueous extracts were washed twice with DCM. The aqueous layer was rendered alkaline with solid potassium carbonate, and extra water was added. The aqueous suspension was extracted three times with DCM/MeOH mixture (~1:1). The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude residue was triturated with diethyl ether and the mixture was stirred for 60 h. The beige solids were collected by filtration, then washed with diethyl ether and dried over a stream of air, to afford the title compound (26.5 g, 83%). δ.sub.H (400 MHz, DMSO-d.sub.6) 8.62 (s, 1 H), 8.31-8.23 (m, 1 H), 7.92-7.86 (m, 1 H), 7.77-7.72 (m, 2 H), 7.70 (t, J 71.9 Hz, 1 H), 7.60 (d, J 9.3 Hz, 1 H), 7.52-7.48 (m, 2 H), 6.30 (d, J 7.1 Hz, 1 H), 5.25 (d, J 7.1 Hz, 1 H), 5.01 (s, 1 H), 3.56-3.47 (m, 1 H), 3.36 (s, 3 H), 2.86 (t, J 13.3 Hz, 3 H), 2.26-2.18 (m, 4 H), 1.00 (s, 3 H). LCMS [M+H].sup.+ 550, RT 2.37 minutes (Method 7).

    Example 8

    [0228] ##STR00076##

    (7R,14R)-11-[6-(Cis-1-Amino-3-Hydroxy-3-Methylcyclobutyl)-5-Fluoropyidin-3-Yl]-1-(Difluoromethoxy)-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-5(14H)-One

    [0229] Intermediate 25 (930 mg, 1.23 mmol) was dissolved in ethanol (20 mL) and 4 M hydrochloric acid in 1,4-dioxane (5 mL) was added at 0° C. The reaction mixture was warmed to r.t. and stirred overnight, then concentrated in vacuo. The residue was re-dissolved in aqueous 1 M hydrochloric acid and washed twice with DCM. The aqueous layer was basified to pH 10 with 2 M aqueous sodium hydroxide solution and extracted with three portions of DCM. The organic phases were combined and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc/hexane, followed by 0-20% MeOH/[10% 7N ammonia in MeOH/DCM]) to afford the title compound (580 mg, 88%). δ.sub.H (300 MHz, DMSO-d.sub.6) 9.15 (d, J 6.8 Hz, 1 H), 8.62 (d, J 2.3 Hz, 1 H), 8.23 (dd, J 6.7, 2.8 Hz, 1 H), 7.98-7.80 (m, 1 H), 7.79-7.65 (m, 3 H), 7.64-7.38 (m, 3 H), 6.36 (d, J 7.0 Hz, 1 H), 5.00 (s, 1 H), 4.89 (t, J 6.7 Hz, 1 H), 3.49 (dt, J 13.4, 7.1 Hz, 1 H), 2.87 (d, J 11.7 Hz, 2 H), 2.75 (d, J 13.3 Hz, 1 H), 2.22 (t, J 6.0 Hz, 4 H), 1.00 (s, 3 H). LCMS (ES+) [M+H].sup.+ 536.0, RT 1.52 minutes (Method 1). LCMS (ES+) [M+H].sup.+ 536.2, RT 1.26 minutes (Method 2).

    Example 9

    [0230] ##STR00077##

    (7R,14R)-11-{2-[Cis-1-Amino-3-(Hydroxymethyl)-3-Methylcyclobutyl]Pyrimidin-5-Yl}-1-(Difluoromethoxy)-6-Methyl-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b][2,5]-Benzodiazocin-5(14H)-One

    [0231] Hydrochloric acid in 1,4-dioxane (4.0 M, 34.3 mL, 137 mmol) was added to a stirred solution of Intermediate 33 (17.5 g, 22.9 mmol) in MeOH (114 mL). The reaction mixture was stirred at r.t. for 2 h, then DCM (200 mL) and water (200 mL) were added. The layers were separated and the organic layer was extracted with aqueous 2N hydrochloric acid solution (2 × 100 mL). The combined aqueous phases were washed with DCM (2 × 100 mL), then rendered alkaline with solid potassium carbonate. The aqueous suspension was extracted with DCM/MeOH mixture (∼1:1; 4 × 150 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude residue was triturated with diethyl ether and stirred overnight. The suspension was filtered and air dried to afford the title compound (11.3 g, 90%) as a pale beige solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 9.06 (s, 2 H), 8.30-8.25 (m, 1 H), 7.78 (d, J 8.5 Hz, 1 H), 7.75 (s, 1 H), 7.69 (t, J 73.3 Hz, 1 H), 7.63 (d, J 8.5 Hz, 1 H), 7.50 (d, J 5.7 Hz, 2 H), 6.31 (d, J 7.1 Hz, 1 H), 5.26 (d, J 7.1 Hz, 1 H), 3.57-3.48 (m, 1 H), 3.45 (s, 2 H), 3.36 (s, 3 H), 2.84 (d, J 13.8 Hz, 1 H), 2.46 (d, J 12.6 Hz, 2 H), 2.09 (d, J 12.8 Hz, 2 H), 1.07 (s, 3 H). LCMS [M+H].sup.+ 547, RT 2.45 minutes (Method 7).

    Example 10

    [0232] ##STR00078##

    (7R,14R)-11-{6-[Cis-1-Amino-3-(Hydroxymethyl)-3-Methylcyclobutyl]-5-Fluoropyridin-3-Yl}-1-(Difluoromethoxy)-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b][2,5]-Benzodiazocin-5(14H)-One

    [0233] Intermediate 35 (347 mg, 0.45 mmol) was dissolved in ethanol (10 mL) and 4 M hydrochloric acid in 1,4-dioxane (2.5 mL) was added at 0° C. The reaction mixture was warmed to r.t. and stirred overnight. The reaction mixture was concentrated in vacuo, re-dissolved in 1 M aqueous hydrochloric acid and washed twice with DCM. The aqueous layer was basified to pH 10 with 2 M aqueous sodium hydroxide solution and extracted with three portions of DCM. The organic phases were combined and concentrated in vacuo. The crude residue was purified on silica (gradient elution with 0-100% EtOAc/ hexane, then 0-50% DCM/[10% 7N ammonia in MeOH]) to afford the title compound (194 mg, 78%). δ.sub.H (300 MHz, DMSO-d.sub.6) 9.15 (d, J 6.8 Hz, 1 H), 8.62 (t, J 1.8 Hz, 1 H), 8.23 (dd, J 6.5, 2.8 Hz, 1 H), 7.96-7.39 (m, 7 H), 6.36 (d, J 7.1 Hz, 1 H), 4.89 (t, J 6.8 Hz, 1 H), 3.57-3.45 (m, 1 H), 3.43 (s, 2 H), 2.75 (d, J 13.2 Hz, 1 H), 2.49-2.43 (m, 2 H), 2.14 (d, J 12.6 Hz, 2 H), 0.94 (s, 3 H). LCMS (ES+) [M+H].sup.+ 550.0, RT 1.68 minutes (Method 1). LCMS (ES+) [M+H].sup.+ 550.2, RT 1.46 minutes (Method 2).

    Example 11

    [0234] ##STR00079##

    (7R,14R)-11-{6-[Cis-1-Amino-3-Hydroxy-3-(Trifluoromethyl)Cyclobutyl]-5-Fluoropyridin-3-Yl}-1-(Difluoromethoxy)-6-Methyl-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b][2,5]-Benzodiazocin-5(14H)-One

    [0235] Hydrogen chloride in 1,4-dioxane (4 M, 8.72 mL) was added to a stirred solution of Intermediate 43 (823 mg, 1.16 mmol) in 1,4-dioxane (15 mL) at r.t. The mixture was stirred for 0.5 h, then concentrated in vacuo. The resulting off-white solid was dissolved in MeOH (10 mL) and loaded onto an ion-exchange cartridge (SCX-2), which was washed with MeOH (2 × 15 mL). The material was eluted with 2.0 M ammonia in MeOH (3 × 15 mL). The filtrate was concentrated in vacuo. Flash column chromatography of the crude residue (mixture of trans and cis isomers, 642 mg) on reverse phase silica (gradient elution with 10-23% acetonitrile in water spiked with 0.1% formic acid) afforded the first eluting fraction (trans isomer, 295 mg) as an opaque gum, which was suspended in 1:1 acetonitrile-water (4 mL) and treated with 1 M aqueous hydrochloric acid solution (538 .Math.L). The resulting solution was freeze-dried to afford the trans isomer (298 mg, 42%) as a colourless solid. The second eluting fraction (cis isomer) was concentrated in vacuo and re-purified via preparative HPLC (eluting with 0-100% acetonitrile in water spiked with 0.1% formic acid). The resulting off-white solid (mono-formate salt) was dissolved in MeOH (15 mL) and loaded onto an ion-exchange column (SCX-2). The material was washed with MeOH (2 × 15 mL) and eluted with 2.0 M ammonia in MeOH (3 × 15 mL). The filtrate was concentrated in vacuo. The resulting opaque glass (free base, 147 mg) was suspended in 1:1 acetonitrile-water (4 mL) and treated with 1 M aqueous hydrochloric acid solution (268 .Math.L). The resulting solution was freeze-dried to afford the title compound (cis isomer, 144 mg, 21%) as a colourless solid. δ.sub.H (500 MHz, CD.sub.3OD) 8.84 (d, J 1.5 Hz, 1 H), 8.46-8.39 (m, 1 H), 8.07 (dd, J 12.1, 1.8 Hz, 1 H), 8.04 (d, J 1.3 Hz, 1 H), 7.90 (d, J 8.6 Hz, 1 H), 7.83 (dd, J 8.6, 1.6 Hz, 1 H), 7.57-7.52 (m, 2 H), 7.51-7.21 (m, 1 H), 6.64 (d, J 7.2 Hz, 1 H), 5.48 (d, J 7.2 Hz, 1 H), 3.75-3.65 (m, 1 H), 3.58 (d, J 15.1 Hz, 2 H), 3.51 (s, 3 H), 3.05 (d, J 13.9 Hz, 1 H), 2.76 (d, J 15.3 Hz, 2 H). LCMS (ESI) [M+H].sup.+ 604.2, RT 2.04 minutes (Method 11).

    Example 12

    [0236] ##STR00080##

    (7R,14R)-11-{2-[Cis-1-Amino-3-Hydroxy-3-(Trifluoromethyl)Cyclobutyl]Pyrimidin-5-Yl}-1-(Difluoromethoxy)-6-Methyl-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-6][2,5]-Benzodiazocin-5(14H)-One

    [0237] Hydrogen chloride in 1,4-dioxane (4 M, 5.15 mL) was added to a stirred solution of Intermediate 46 (474 mg, 0.69 mmol) in 1,4-dioxane (10 mL) at ambient temperature. The mixture was stirred for 2 h, then concentrated in vacuo. The resulting crude off-white solid was dissolved in MeOH (10 mL) and loaded onto an ion exchange column (SCX-2), which was washed with MeOH (2 × 25 mL). The material was eluted with 2.0 M ammonia in MeOH (3 × 15 mL). The filtrate was concentrated in vacuo. Purification of the crude residue (mixture of trans and cis isomers, 396 mg) by preparative HPLC (eluting with 0-100% formic acid in acetonitrile) afforded the first eluting fraction (trans isomer), which was concentrated in vacuo, then dissolved in MeOH (5 mL) and loaded onto an ion-exchange column (SCX-2). The column was washed with MeOH (2 × 15 mL) and the material was eluted with 2.0 M ammonia in MeOH (3 × 15 mL). The filtrate was concentrated in vacuo. The resulting opaque glass (free base, 215 mg) was suspended in 1:1 acetonitrile-water (4 mL) and treated with 1 M aqueous hydrochloric acid solution (400 .Math.L). The resulting solution was freeze-dried to give the trans isomer (203 mg, 47%) as a colourless solid. The second eluting fraction (cis isomer) was concentrated in vacuo, then dissolved in MeOH (5 mL) and loaded onto an ion exchange column (SCX-2). The column was washed with MeOH (2 × 15 mL) and the material was eluted with 2.0 M ammonia in MeOH (3 × 15 mL). The filtrate was concentrated in vacuo. The resulting opaque glass (free base, 118 mg) was suspended in 1:1 acetonitrile-water (2 mL) and treated with 1 M aqueous hydrochloric acid solution (222 .Math.L). The resulting solution was freeze-dried to give the title compound (cis isomer, 118 mg, 24%) as a colourless solid. δ.sub.H (500 MHz, CD.sub.3OD) 9.19 (s, 2 H), 8.44-8.36 (m, 1 H), 8.00 (d, J 1.2 Hz, 1 H), 7.89 (d, J 8.6 Hz, 1 H), 7.81-7.72 (m, 1 H), 7.54-7.49 (m, 2 H), 7.49-7.21 (m, 1 H), 6.59 (d, J 7.1 Hz, 1 H), 5.42 (d, J 7.2 Hz, 1 H), 3.72-3.64 (m, 1 H), 3.58-3.53 (m, 2 H), 3.51 (s, 3 H), 3.01 (d, J 13.9 Hz, 1 H), 2.67-2.59 (m, 2 H). LCMS (ESI) [M+H].sup.+ 587.2, RT 1.95 minutes (Method 11).

    Example 13

    [0238] ##STR00081##

    (7R,14R)-11-{6-[Cis-1-Amino-3-Hydroxy-3-(Trifluoromethyl)Cyclobutyl]-5-Fluoropyridin-3-Yl}-1-(Difluoromethoxy)-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b][2,5]-Benzodiazocin-5(14H)-One

    [0239] To a solution of Intermediate 48 (440 mg, 0.55 mmol) in 1,4-dioxane (8 mL) was added 4 M hydrogen chloride in 1,4-dioxane (4.14 mL). The reaction mixture was stirred at r.t. for 1 h, then concentrated in vacuo. The crude residue was loaded onto an ion-exchange column (SCX-2) in DCM/MeOH. The column was washed with MeOH (50 mL), and the product was eluted with 2 M ammonia in MeOH (50 mL). The crude material (mixture of trans and cis isomers, 350 mg) was purified by preparative HPLC. The fraction containing cis isomer was suspended in 1:1 acetonitrile-water (4 mL) and treated with 4 M hydrogen chloride in 1,4-dioxane (300 .Math.L). The solution was freeze-dried to afford the title compound (hydrochloride salt, 132 mg, 38%) as an off-white powder. δ.sub.H (500 MHz, CD.sub.3OD) 8.82 (t, J 1.6 Hz, 1 H), 8.36 (dd, J 7.2, 2.2 Hz, 1 H), 8.04 (dd, J 12.2, 1.8 Hz, 1 H), 7.95 (d, J 1.3 Hz, 1 H), 7.82 (d, J 8.5 Hz, 1 H), 7.70 (dd, J 8.6, 1.7 Hz, 1 H), 7.58-7.17 (m, 3 H), 6.60 (d, J 7.1 Hz, 1 H), 5.15-5.05 (m, 1 H), 3.66-3.53 (m, 3 H), 2.93 (d, J 13.5 Hz, 1 H), 2.79-2.71 (m, 2 H). LCMS (ESI) [M+H].sup.+ 590.1, RT 1.65 minutes (Method 11).

    Example 14

    [0240] ##STR00082##

    (7R,14R)-11-(2-{Cis-1-Amino-3-[Hydroxy(Dideutero)Methyl]-3-Methylcyclobutyl}-Pyrimidin-5-Yl)-1-(Difluoromethoxy)-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b][2,5]-Benzodiazocin-5(14H)-One

    [0241] To a stirred solution of Intermediate 56 (500 mg, 0.66 mmol) in 1,4-dioxane (5 mL) was added 4 M hydrogen chloride in 1,4-dioxane (0.66 mL). The reaction mixture was stirred at r.t. for 18 h, then concentrated under reduced pressure. The resulting off-white solid was purified using a 20 g SCX-2 cartridge (eluting with 2 M ammonia in methanol). The resulting off-white solid was further purified by reverse-phase column chromatography (10-60% acetonitrile in water (+ 0.1% formic acid)). The relevant fractions were combined and the solvent was removed under reduced pressure. The resulting colourless gum was suspended in 1: 1 acetonitrile:water and 1 M HCl (1.3 equivalents) was added. The resulting solution was freeze-dried to afford the title compound, hydrochloride salt (199 mg) as a white powder. δ.sub.H (500 MHz, DMSO-d.sub.6) 9.22 (s, 2 H), 9.19 (d, J 6.9 Hz, 1 H), 8.77 (s, 3 H), 8.26-8.20 (m, 1 H), 7.87-7.54 (m, 4 H), 7.55-7.49 (m, 2 H), 6.40 (d, J 7.1 Hz, 1 H), 4.96 (t, J 6.9 Hz, 1 H), 3.54-3.48 (m, 1 H), 2.78 (d, J 13.3 Hz, 1 H), 2.62 (d, J 14.0 Hz, 2 H), 2.53-2.51 (m, 2 H), 1.21 (s, 3 H). LCMS (ESI+) [M+H].sup.+ 535.3, RT 2.25 minutes (Method 1).

    Example 15

    [0242] ##STR00083##

    (7R,14R)-11-{2-[Cis-1-Amino-3-(Hydroxymethyl)-3-Methylcyclobutyl]Pyrimidin-5-Yl}-1-(Difluoromethoxy)-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b][2,5]Benzodiazocin-5(14H)-One

    [0243] To a solution of Intermediate 57 (180 mg, 0.24 mmol) in ethanol (12 mL) at 0° C. was added 4 M hydrochloric acid in 1,4-dioxane (2.5 mL, 10 mmol). The reaction mixture was warmed to r.t. and stirred overnight, then concentrated in vacuo. The residue was re-dissolved in 1 M aqueous HCl solution and washed with DCM (2 × 2.5 mL). The aqueous layer was basified to pH 10 with 2 M aqueous NaOH solution and extracted with DCM (2 × 2.5 mL). The organic phases were combined and concentrated in vacuo. The crude residue was purified by column chromatography (0-100% EtOAc in hexane, followed by 0-20% MeOH and 10% 7N ammonia in DCM) to give the title compound (62 mg, 49%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 9.15 (d, J 6.8 Hz, 1 H), 9.05 (s, 2 H), 8.23 (dd, J 5.9, 3.6 Hz, 1 H), 7.81-7.66 (m, 2 H), 7.77 (t, J 48 Hz, 1 H), 7.61 (dd, J 8.5, 1.8 Hz, 1 H), 7.55-7.41 (m, 2 H), 6.37 (d, J 7.1 Hz, 1 H), 5.50 (br s, 1 H), 4.90 (t, J 6.7 Hz, 1 H), 3.50 (dd, J 13.6, 6.9 Hz, 1 H), 3.45 (s, 2 H), 2.75 (d, J 13.5 Hz, 1 H), 2.44 (d, J 12.9 Hz, 2 H), 2.09 (d, J 12.9 Hz, 2 H), 1.07 (s, 3 H). LCMS (ESI+) [M+H].sup.+ 533, RT 1.51 minutes (Method 1).

    Example 16

    [0244] ##STR00084##

    (7R,14R)-11-(6-{Cis-1-Amino-3-[Hydroxy(Dideutero)Methyl]-3-Methylcyclobutyl}-5-fluoropyridin-3-Yl)-1-(Difluoromethoxy)-6,7-Dihydro-7,14-Methanobenzimidazo[1,2-b]-[2,5]Benzodiazocin-5(14H)-One

    [0245] Intermediate 59 (130 mg, 0.17 mmol) was dissolved in 1,4-dioxane (3 mL) and 4 M hydrochloric acid in 1,4-dioxane (0.9 mL) was added. The mixture was stirred for 10 minutes, then diluted with methanol (3 mL) and stirred for 2 h. The mixture was concentrated in vacuo and the residue was purified on a 10 g SCX cartridge (eluting with 2 M ammonia in methanol). The residue was dissolved in 1:1 acetonitrile:water (~5 mL), then treated with aqueous HCl (1.2 equivalents) and freeze-dried, to afford the title compound, hydrochloride salt (80 mg, 79%) as an off-white solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 9.16 (d, J 6.9 Hz, 1 H), 8.85-8.77 (m, 1 H), 8.67 (s, 3 H), 8.24 (dd, J 6.3, 3.1 Hz, 1 H), 8.15 (dd, J 12.7, 1.8 Hz, 1 H), 7.87-7.54 (m, 4 H), 7.54-7.48 (m, 2 H), 6.37 (d,J 7.1 Hz, 1 H), 4.93 (t, J 6.8 Hz, 1 H), 3.53-3.48 (m, 1 H), 2.77 (d, J 13.3 Hz, 1 H), 2.75-2.69 (m, 2 H), 2.57 (d, J 13.5 Hz, 2 H), 1.08 (s, 3 H). LCMS (ESI+) [M+H].sup.+ 552.5, RT 1.99 minutes (Method 1).