Fused Pentacyclic Imidazole Derivatives

Abstract

A series of fused pentacyclic imidazole derivatives, being potent modulators of human TNFa 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. In particular, the present invention is concerned with 6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one derivatives and analogs thereof.

Claims

1. A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, ##STR00386## wherein —X-Q-represents —O—, —O—C(O)—, —C(O)—O—, —O—C(CH—CN)—, —S—, —SO—, —SO.sub.2—, —N(R.sup.g)—, —N(R.sup.f)—CO—, —CO—N(R.sup.f)—, —N(R.sup.f)—SO.sub.2—, —SO.sub.2—N(R.sup.f)—, —S(O)(NR.sup.f)—, —CH.sub.2-CH.sub.2—, —O—CH.sub.2—, —CH.sub.2—O—, —S—CH.sub.2—, —SO—CH.sub.2—, —SO.sub.2—CH.sub.2—, CH.sub.2—S—, —CH.sub.2—SO—, —CH.sub.2—SO.sub.2—, —N(R.sup.g)—CH.sub.2—, —CH.sub.2—N(R.sup.g)—, —S(O)(NR.sup.f)—CH.sub.2—, —CH.sub.2—S(O)(NR.sup.f)—,—N(R.sup.f)—C(S)—, —N═S(O)(CH.sub.3)——O—C(═CH.sub.2)— or —S(═N—CN)—, any of which groups may be optionally substituted by one or more substituents; Z represents methylene; E represents a fused heteroaromatic ring system selected from the groups of formula (Ea), (Eb) and (Ec), ##STR00387## wherein the asterisk (*) represents the site of attachment of E to the remainder of the molecule; R.sup.1 represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, —OR.sup.a, —SR.sup.a, —SOR, —SO.sub.2R.sup.a, —NR.sup.bR.sup.c, —NR.sup.cCOR.sup.d, —NR.sup.cCO.sub.2R.sup.d, —NHCONR.sup.bR.sup.c, —NR.sup.cSO.sub.2R.sup.e, —COR.sup.d, —CO.sub.2R.sup.d, —CONR.sup.bR.sup.c, —SO.sub.2NR.sup.bR.sup.c, or —S(O)(N—R.sup.b)R.sup.e; or C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.4-7 cycloalkenyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkenyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl, (C.sub.3-7)heterocycloalkyl(C.sub.1-6)alkyl-aryl-, (C.sub.3-7)cycloalkyl-heteroaryl-, (C.sub.3-7)cycloalkyl(C.sub.1-6)alkyl-heteroaryl-, (C.sub.4-7)cycloalkenyl-heteroaryl-, (C.sub.4-9)bicycloalkyl-heteroaryl-, (C.sub.3-7)heterocycloalkyl-heteroaryl-, (C.sub.3-7)heterocycloalkyl(C.sub.1-6)alkyl-heteroaryl-, (C.sub.3-7)heterocycloalkenyl-heteroaryl-, (C.sub.4-9)heterobicycloalkyl-heteroaryl- or (C.sub.4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents; or R.sup.1 represents (C.sub.3-7)heterocycloalkenyl-aryl-, which group may be optionally substituted by one or more substituents; R.sup.2 represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or —OR.sup.a; or C.sub.1-6 alkyl optionally substituted by one or more substituents; R.sup.3 and R.sup.4 independently represent hydrogen,halogen or trifluoromethyl; or C.sub.1-6 alkyl, optionally substituted by one or more substituents; R.sup.5 and R.sup.8 independently represent hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OR.sup.a, or C.sub.1-6 alkylsulphonyl; or C.sub.1-6 alkyl optionally substituted by one or more substituents; R.sup.6 and R.sup.7 independently represent hydrogen, halogen, trifluoromethyl, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; R.sup.12 represents hydrogen or C.sub.1-6 alkyl; R.sup.a represents C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 heterocycloalkyl, aryl, aryl(C.sub.1-6)alkyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R.sup.b and R.sup.c independently represent hydrogen or trifluoromethyl; or C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or R.sup.b and R.sup.c, when taken together with the nitrogen atom to which they are both attached, represent a heterocyclic moiety selected from azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl, homopiperazin-1-yl, (imino)(oxo)thiazinan-4-yl, (oxo)thiazinan-4-yl and (dioxo)thiazinan-4-yl, any of which groups may be optionally substituted by one or more substituents; R.sup.d represents hydrogen; or C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, aryl, C.sub.3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; R.sup.e represents C.sub.1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; R.sup.f represents hydrogen; or C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, or C.sub.3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents; and R.sup.g represents hydrogen; or C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 heterocycloalkyl, —CO— (C.sub.1-6)alkyl, or —SO.sub.2—(C.sub.1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or R.sup.g represents —CO—(C.sub.3-7)heterocycloalkyl, —SO.sub.2—(C.sub.3-7)cycloalkyl, —SO.sub.2—(C.sub.3-7)heterocycloalkyl, —SO.sub.2-aryl or —SO.sub.2-heteroaryl, any of which groups may be optionally substituted by one or more substituents; or R.sup.g represents heteroaryl or (C.sub.2-6)alkoxycarbonyl, either of which groups may be optionally substituted by one or more substituents

2. A compound as claimed in claim 1 wherein (E) represents (Ea) or (Eb); and/or wherein R.sup.12 represents hydrogen.

3. (canceled)

4. A compound as claimed in claim 1 represented by formula (IB), or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, ##STR00388##

5. A compound as claimed in claim 1 represented by formula (IC), or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, ##STR00389##

6. A compound as claimed in claim 1 wherein —X-Q-represents —O—, —O—C(O)—, —O—C(CH—CN)—, —S—, —SO—, —SO.sub.2—; or —N(R.sup.g)—, —N(R.sup.f)—CO—, —N(R.sup.f)—SO.sub.2—, O—CH.sub.2—, —, CH.sub.2—S—, —CH.sub.2—SO—, —CH.sub.2—SO.sub.2—, —N(R.sup.g)—CH.sub.2—, —N(R.sup.f)—C(S)—, —N═S(O)(CH.sub.3)—, —O—C(═CH.sub.2)— or —S(═N—CN)—, any of which groups may be optionally substituted; R.sup.f represents hydrogen; or C.sub.1-6 alkyl, which group may be optionally substituted by one or more substituents; and R.sup.g represents hydrogen; or C.sub.1-6 alkyl, —CO—(C.sub.1-6)alkyl, —SO.sub.2—(C.sub.1-6)alkyl. —CO— (C.sub.3-7)heterocycloalkyl, —SO.sub.2—(C.sub.3-7)cycloalkyl, —SO.sub.2-aryl, —SO.sub.2-heteroaryl, heteroaryl or (C.sub.2-6)alkoxycarbonyl, any of which groups may be optionally substituted by one or more substituents.

7. A compound as claimed in claim 6 wherein X-Q-include —O—,—O—CO—, —O—C(CH—CN)—, —S—, —SO—, SO.sub.2—, —NH—, —N(CO—CH.sub.3)—, —N(SO.sub.2—CH.sub.3)—, —N(CH.sub.2—CO—O—CH.sub.2-CH.sub.3)—, —N[(CO—CH.sub.2-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)], —N[CO-(azetidin-3-yl)]—, —N[CO-(methylsulphonyl)azetidin-3-yl)]—, —N(CH.sub.2—COOH), —N[(tert-butyl)(dimethyl)silyloxyethyl]—, —N(SO.sub.2-pyridine-3-yl)—, —N-(SO.sub.2-cyclopropyl)—, —N(CH.sub.3)—CH.sub.2—, —N(CH.sub.2-CH.sub.2—OH)—, —N(SO.sub.2-phenyl)—, —N[SO.sub.2-(6-methoxy-pyridin-3-yl)]—, NH—CO—, —N(CH.sub.3)—CO—, —N(CH.sub.2CH.sub.3)—CO—, —N(CH(CH.sub.3)2)—CO—, —N(CH.sub.2—COOH)—CO—, —N(CH.sub.2-CF.sub.3)—CO—, —N(CH.sub.2-CH.sub.2—OH)—CO—, —N(CH.sub.2—C(OH)(CH.sub.3).sub.2)—CO—, —N(CD.sub.3)—CO—, —NH—CH.sub.2—N(CH.sub.2—COOH)—CH.sub.2—, —NH—CH(CF.sub.3)—, —NH—CH(CH.sub.3)—, —NH—C(S)—, —N(CO—CH.sub.3)—CH(CH.sub.3)—, —N(SO.sub.2—CH.sub.3)—CH.sub.2—, —N(CO—CH.sub.3)—CH(CH.sub.3)—, —N═S(O)(CH.sub.3)—, O—CH(CF.sub.3)—, —CH(COOC.sub.2H.sub.5)—S—, —CH.sub.2—S(O)—, —CH.sub.2—S(O).sub.2—, —CH(CH(OH)(CH.sub.3).sub.2)—S—, —CH(CH.sub.2OH)—S—, —O—C(═CH.sub.2)—, —N[S(O).sub.2-(pyridin-1H-2-one)], —NH—S(O).sub.2—, —N(pyrimidinyl)-, —N(COOC.sub.2H.sub.5)—, —S(═N—CN)—,N(SO.sub.2-CH.sub.3)— or N(C.sub.2H.sub.5)—CO—.

8. A compound as claimed in claim 6 wherein X-Q-represents represents —N(R.sup.f)—C(O).

9. A compound of formula (IIB) or an N-oxide thereof, or a pharmaceutical acceptable salt thereof, ##STR00390##

10. A compound as claimed in claim 8 wherein (i) R.sup.1 represents halogen or cyano; or aryl, heteroaryl, (C.sub.3-7)cycloalkyl-heteroaryl, (C.sub.3-7)heterocycloalkyl-heteroaryl, (C.sub.4-9)heterobicycloalkyl-heteroaryl, (C.sub.3-7)heterocycloalkyl, (C.sub.3-7)heterocycloalkenyl, or (C.sub.3-7)heterocycloalkenyl-aryl, any of which groups may be optionally substituted by one or more substituents, and/or (ii) R.sup.1 represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents; and/or (iii) R.sup.2 represents hydrogen or halogen; and/or (iv) wherein R.sup.3 represents hydrogen or trifluoromethyl; and/or (v) R.sup.4 represents hydrogen or trifluoromethyl; and/or (vi) R.sup.5 represents halogen, —OR.sup.a, difluoromethoxy or trifluoromethoxy; and R.sup.a represents C.sub.1-6 alkyl; and/or (vii) R.sup.6 represents hydrogen, halogen or trifluoromethyl; and/or (viii) R.sup.7 represents hydrogen or trifluoromethyl; and/or (ix) R.sup.8 represents hydrogen, halogen or trifluoromethyl.

11. (canceled)

12. (canceled)

13. (canceled)

14. (canceled)

15. (canceled)

17. (canceled)

18. (canceled)

19. A compound as claimed in claim 1 represented by formula (IIB-A), or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, ##STR00391## wherein R.sup.1represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents; R.sup.2 represents hydrogen; R.sup.5 represents halogen, —OR.sup.a, difluoromethoxy or trifluoromethoxyis as defined in claim; and R.sup.f represents hydrogen; or C.sub.1-6 alkyl, which group may be optionally substituted by one or more substituents.

20. A compound as claimed in claim 9 wherein R.sup.1 represents a substituted heteroaryl selected from the groups represented by formula (i), (ii), (iii), (iv) and (v), and their respective corresponding salts represented by formula (ia), (ib), (iia), (iiia), (iva), (va), and (vb): ##STR00392## ##STR00393## wherein the asterisk (*) represents the site of attachment of R.sup.1 to the remainder of the molecule; R.sup.10 represents hydrogen or C.sub.1-6 alkyl; R.sup.11 represents C.sub.1-6 alkyl; W represents N or C—H; M.sup.1 represents a monovalent cation; and M.sup.2 represents a divalent cation.

21. A compound as claimed in claim 19 represented by formula (IIB-AB-A), an N-oxide thereof, or pharmaceutically acceptable salt thereof, ##STR00394## wherein R.sup.9 represents amino(C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl, or (C.sub.1-6) alkoxy(C.sub.1-6)alkyl; R.sup.10 represents hydrogen or C.sub.1-6 alkyl; R.sup.2 represents hydrogen or halogen; R.sup.5 represents halogen, —OR.sup.a, difluoromethoxy or trifluoromethoxy; and R.sup.f represents hydrogen; or C.sub.1-6 alkyl, which group may be optionally substituted by one or more substituents; and W represents N or C—H.

22. A compound as claimed in claim 21 wherein W represents N; and/or R.sup.10 represents hydrogen.

23. (canceled)

24. A compound as claimed in claim 21 wherein R.sup.9 represents 2-hydroxy-prop-2-yl.

25. A compound as claimed in any claim 9 wherein R.sup.2 represents fluoro; and/or (ii) R.sup.5 represents difluoromethoxy; and/or (iii) R.sup.f represents hydrogen.

26. (canceled)

27. (canceled)

28. A compound as claimed in claim 1 as herein specifically disclosed in any one of the Examples.

29. (canceled)

30. (canceled)

31. (canceled)

32. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

33. (canceled)

34. (canceled)

35. 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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

36. A method for the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neuro-degenerative 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 an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

37. A compound as claimed in claim 1 wherein (i) R.sup.1 represents halogen or cyano; or aryl, heteroaryl, (C.sub.3-7)cycloalkyl-heteroaryl, (C.sub.3-7)heterocycloalkyl-heteroaryl, (C.sub.4-9)heterobicycloalkyl-heteroaryl, (C.sub.3-7)heterocycloalkyl, (C.sub.3-7)heterocycloalkenyl, or (C.sub.3-7)heterocycloalkenyl-aryl, any of which groups may be optionally substituted by one or more sub stituents; and/or (ii) R.sup.1 represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents; and/or (iii) R.sup.2 represents hydrogen or halogen; and/or (iv) wherein R.sup.3 represents hydrogen or trifluoromethyl; and/or (v) R.sup.4 represents hydrogen or trifluoromethyl; and/or (vi) R.sup.5 represents halogen, —OR.sup.a, difluoromethoxy or trifluoromethoxy; and R.sup.a represents C.sub.1-6 alkyl; and/or (vii) R.sup.6 represents hydrogen, halogen or trifluoromethyl; and/or (viii) R.sup.7 represents hydrogen or trifluoromethyl; and/or (ix) R.sup.8 represents hydrogen, halogen or trifluoromethyl.

38. A compound as claimed in claim 1 wherein le represents a substituted heteroaryl selected from the groups represented by formula (i), (ii), (iii), (iv) and (v), and their respective corresponding salts represented by formula (ia), (ib), (iia), (iiia), (iva), (va), and (vb): ##STR00395## ##STR00396## wherein the asterisk (*) represents the site of attachment of R.sup.1 to the remainder of the molecule; R.sup.10 represents hydrogen or C.sub.1-6 alkyl; R.sup.11 represents C.sub.1-6 alkyl; W represents N or C—H; M.sup.1 represents a monovalent cation; and M.sup.2 represents a divalent cation.

39. A compound as claimed in claim 38 wherein W represents N; and/or R.sup.10 represents hydrogen.

40. A compound as claimed in claim 1 wherein (i) R.sup.2 represents fluoro; and/or (ii) R.sup.5 represents difluoromethoxy; and/or (iii) R.sup.f represents hydrogen.

Description

EXAMPLES

[0475] Abbreviations [0476] DCM: Dichloromethane EtOAc: Ethyl acetate [0477] DMF: N,N-Dimethylformamide MeOH: Methanol [0478] DMSO: Dimethylsulfoxide SiO2: Silica [0479] Et2O: Diethyl ether h: Hour [0480] THF: Tetrahydrofuran AcOH: Acetic acid

[0481] r.t.: Room temperature b s.: Broad singlet [0482] M: Mass [0483] Brine: Saturated aqueous sodium chloride solution [0484] HPLC: High Performance Liquid Chromatography [0485] LCMS: Liquid Chromatography Mass Spectrometry [0486] ES+: Electrospray Positive Ionisation [0487] TEA: Triethylamine [0488] DIPEA: N,N-di-iso-propylethylamine [0489] DIAD: Diisopropyl (E)-1,2-diazenedicarboxylate [0490] RT: retention time [0491] TBAF: tetrabutyl ammonium fluoride [0492] TLC: Thin Layer Chromatography [0493] MeCN: Acetonitrile [0494] DIBAL-H: Diisobutylaluminium hydride [0495] TMSCN: Trimethylsilyl cyanide [0496] DEA: Diethanolamine [0497] pTSA para-toluene sulphonic acid monohydrate [0498] TFA: trifluoroacetic acid [0499] DMA: dimethyl acetamide [0500] HATU: N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-ethylmethanaminium hexafluorophosphate N-oxide [0501] KHMDS: Potassium bis(trimethylsilyl)amide [0502] COMU: (1-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholino carbenium hexafluorophosphate [0503] PdCl.sub.2(dcypp): dichloro-bis(dicyclohexylphosphino)propane] palladium(II) [0504] [Ir{dF(CF.sub.3)ppy}.sub.2(dtbpy)]PF.sub.6 [4,4′-Bis(tert-butyl)-2,2′-bipyridine]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl]phenyl]iridium(III) hexafluorophosphate

[0505] Analytical Conditions

[0506] All NMRs were obtained either at 300 MHz or 400 MHz.

[0507] All reactions involving air-or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware.

[0508] All compound LCMS data was determined by using the method below:

[0509] Method 1: For Intermediates 1 to 7 and 15 to 17.

[0510] Shimadzu 2010—YMC Triart C18, 4.6×50 mm, 3 μm column

[0511] Mobile phase A: 10 mM Ammonium Formate+0.1% Ammonia+water

[0512] Mobile phase B: 5% of mobile phase A+95% MeCN+0.1% Ammonia

[0513] Gradient program (Flow Rate 1.4 mL/min, Column Temperature 40° C.):

TABLE-US-00001 Time A % B % 0.1 70 30 2.5 5 95 3.5 5 95 5.0 70 30 5.5 70 30

[0514] Method 2: For Intermediate 8 and 18

[0515] Shimadzu 2010—X-bridge C18 Waters 2.1×20 mm, 2.5 μm column

[0516] Mobile phase A: 10 mM Ammonium Formate+0.1% Ammonia+water

[0517] Mobile phase B: 5% of mobile phase A+95% MeCN+0.1% Ammonia

[0518] Gradient program (Flow Rate 1.0 mL/min, Column Temperature 40° C.):

TABLE-US-00002 Time A % B % 0.1 95 5 4.0 5 95 5.0 5 95 5.1 95 5 6.5 95 5

[0519] Method 3 for All Analytical LCMS Done in Basic Conditions: LCMS Basic:

[0520] A QDA Waters simple quadrupole mass spectrometer is used for LC-MS analysis.

[0521] This spectrometer is equipped with an ESI source and an UPLC Acquity Classic with diode array detector (210 to 400 nm.)

[0522] Data are acquired in a full MS scan from m/z 50 to 1000 in positive mode with an acidic elution

[0523] The reverse phase separation is carried out at 45° C. on a Waters Acquity UPLC BEH C18 1.7 μm (2.1×50 mm) column for basic elution

[0524] Gradient Elution is Done With:

[0525] H2O/ACN/Ammonium_formate (95/5/63 mg/l)+50 μl NH4OH (solvent A)

[0526] ACN/H2O/Ammonium_formate (95/5/63 mg/l)+50 μl NH4OH (solvent B).

[0527] Acidic Gradient Program:

[0528] HPLC flow rate: 0.6 ml/min to 0.7 ml/min,

[0529] injection volume: 1 μl

[0530] Full flow in MS.

TABLE-US-00003 Flow Time (min) A (%) B (%) (ml/min) 0 99 1 0.4 0.3 99 1 0.4 3.2 0 100 0.4 3.25 0 100 0.5 4 0 100 0.5 4.1 99 1 0.4 4.8 90 1 0.4

[0531] Method 4 for All Analytical LCMS in Acid Conditions: LCMS Acid:

[0532] A QDA Waters simple quadrupole mass spectrometer is used for LC-MS analysis.

[0533] This spectrometer is equipped with an ESI source and an UPLC Acquity Hclass with diode array detector (210 to 400 nm).

[0534] Data are acquired in a full MS scan from m/z 50 to 1000 in positive mode with an acidic elution. The reverse phase separation is carried out at 45° C. on a Waters Acquity UPLC HSS T3 1.8 μm (2.1×50 mm) column for acidic elution

[0535] Gradient Elution is Done With:

[0536] Water (solvent A)

[0537] Acetonitrile (solvent B)

[0538] Water/Acetonitrile/Formic Acid 0.5% (solvent C)

[0539] Acidic Gradient Program:

[0540] HPLC flow rate: 0.6 ml/min to 0.7 ml/min, injection volume: 1 μl

[0541] Full flow in MS.

TABLE-US-00004 Flow Time (min) A (%) B (%) C (%) (ml/min) 0 90 0 10 0.6 0.3 90 0 10 0.6 3.2 0 90 10 0.6 3.25 0 90 10 0.7 4 0 90 10 0.7 4.1 90 0 10 0.6 5.4 90 0 10 0.6

[0542] Method 5 for All Examples:

[0543] Waters Acquity-SQD, Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm column

[0544] Mobile phase A: 10 mM Ammonium Formate+0.1% Ammonia

[0545] Mobile phase B: 95% MeCN+5% H.sub.2O+0.1% Ammonia

[0546] Gradient Program (Flow Rate 1.0 mL/min, Column Temperature 40° C.):

TABLE-US-00005 Time A % B % 0.00 95 5 0.50 95 5 1.75 5 95 2.00 5 95 2.25 95 5

[0547] It will be apparent to the person skilled in the art that different retention times (RT) may be obtained for LCMS if different analytical conditions are used.

Additional Analytical HPLC Methods

[0548] Method 6

[0549] Column: Waters Atlantis dC18 (2.1×100 mm, 3 μm column)

[0550] Flow rate: 0.6 mL/min

[0551] Solvent A: 0.1% Formic acid/water

[0552] Solvent B: 0.1% Formic acid/acetonitrile

[0553] Injection Volume: 3 μL

[0554] Column temperature: 40° C.

[0555] UV Detection wavelength: 215 nm

[0556] Eluent: 0 to 5 minutes, constant gradient from 95% solvent A+5% solvent B to 100% solvent B; 5 to 5.4 minutes, 100% solvent B; 5.4 to 5.42 minutes, constant gradient from 100% solvent B to 95% solvent A+5% solvent B; 5.42 to 7.00 minutes, 95% solvent A+5% solvent B.

[0557] Method 7

[0558] Column: Waters Atlantis dC18 (2.1×30 mm, 3 μm column)

[0559] Flow rate: 1 ml/min

[0560] Solvent A: 0.1% Formic acid/water

[0561] Solvent B: 0.1% Formic acid/acetonitrile

[0562] Injection volume: 3 μL

[0563] UV Detection wavelength: 215 nm

[0564] Eluent: 0 to 1.5 minutes, constant gradient from 95% solvent A+5% solvent B to 100% solvent B; 1.5 to 1.6 minutes, 100% solvent B; 1.60 to 1.61 minutes, constant gradient from 100% solvent B to 95% solvent A+5% solvent B; 1.61 to 2.00 minutes, 95% solvent A+5% solvent B.

[0565] Method 8

[0566] Column: Phenomenex Gemini C18 (2.0 mm×100 mm, 3 μm column)

[0567] Flow rate: 0.5 mL/min

[0568] Solvent A: 2 mM Ammonium bicarbonate/water

[0569] Solvent B: Acetonitrile

[0570] Injection volume: 3 μL

[0571] Column temperature: 50° C.

[0572] UV Detection wavelength: 215 nM

[0573] Eluent: 0 to 5.5 minutes, constant gradient from 95% solvent A+5% solvent B to 100% solvent B; 5.5 to 5.9 minutes, 100% solvent B; 5.90 to 5.92 minutes, constant gradient from 100% solvent B to 95% solvent A+5% solvent B.

[0574] Method 9

[0575] Column: Phenomenex Gemini C18 (2.0 mm×50 mm, 3 μm column)

[0576] Flow rate: 1.0 mL/min

[0577] Solvent A: 2 mM Ammonium bicarbonate/water

[0578] Solvent B: Acetonitrile

[0579] Injection volume: 3 μL

[0580] Column temperature: 60° C.

[0581] UV Detection wavelength: 215 nM

[0582] Eluent: 0 to 1.8 minutes, constant gradient from 99% solvent A+1% solvent B to 100% solvent B; 1.8 to 2.1 minutes, 100% solvent B; 2.1 to 2.3 minutes, constant gradient from 100% solvent B to 99% solvent A+1% solvent B.

[0583] Method 10

[0584] Column: Waters XSelect (C18, 50×2.1 mm, 3.5μ)

[0585] Flow: 0.8 ml/min Column temp; 35° C.

[0586] Eluent A: 0.1% formic acid in acetonitrile

[0587] Eluent B: 0.1% formic acid in water

[0588] Lin. Gradient: t=0 min 5% A, t=3.5 min 98% A, t=6 min 98% A

[0589] Detection: DAD (220-320 nm)

[0590] Detection: MSD (ESI pos/neg) mass range: 100-800

[0591] Method 11

[0592] Column: Waters XSelect (C18, 30×2.1 mm, 3.5μ)

[0593] Flow: 1.0 ml/min Column temp; 35° C.

[0594] Eluent A: 0.1% formic acid in acetonitrile

[0595] Eluent B: 0.1% formic acid in water

[0596] Lin. Gradient: t=0 min 5% A, t=1.6 min 98% A, t=3 min 98% A

[0597] Detection: DAD (220-320 nm)

[0598] Detection: MSD (ESI pos/neg) mass range: 100-800

[0599] Method 12

[0600] Column: Waters XSelect (C18, 30×2.1 mm, 3.5μ)

[0601] Flow: 1.0 ml/min Column temp; 35° C.

[0602] Eluent A: 0.1% formic acid in acetonitrile

[0603] Eluent B: 0.1% formic acid in water

[0604] Lin. Gradient: t=0 min 5% A, t=1.6 min 98% A, t=4 min 98% A

[0605] Detection: DAD (220-320 nm)

[0606] Detection: MSD (ESI pos/neg) mass range: 100-800

[0607] Method 13

[0608] Column: Waters XSelect (C18, 30×2.1 mm, 3.5μ)

[0609] Flow: 1.0 ml/min Column temp; 35° C.

[0610] Eluent A: 0.1% formic acid in acetonitrile

[0611] Eluent B: 0.1% formic acid in water

[0612] Lin. Gradient: t=0 min 5% A, t=1.6 min 98% A, t=3 min 98% A

[0613] Detection: DAD (220-320 nm)

[0614] Detection: MSD (ESI pos/neg) mass range: 400-1600

[0615] Method 14 for the Purification of Examples 107 to 112

[0616] Semi preparative HPLC column: Sunfire prep C18 5 μm 10×150 mm

[0617] Isocratic elution: 25% of Solvent A (Water/Acetonitrile/formic acid (v/v/v; 95/5/0.05)) and 75% Solvent B (acetonitrile/formic acid (v/v; 100/0.075))

[0618] Flow rate: 7 mL/min

[0619] Method 15 for the Analysis of Examples 107 to 112

[0620] The LCMS control was performed with a QM Waters triple quadrupole mass spectrometer coupled with an HPLC Alliance Waters 2795 quaternary pump. The reverse phase separation is carried out at 45° C. on a Waters Sunfire MS C18 column 5 μm (4.6×15 mm) for acidic elution.

[0621] Gradient elution is performed with water (Solvent A), acetonitrile (Solvent B) and water/acetonitrile/formic acid (Solvent C v/v/v 50/50/5).

[0622] Solution pH 3-4, gradient table as below:

TABLE-US-00006 Time A % B % C % Flow 0 90 0 10 1.9 1.5 90 0 10 1.9 7.15 2 88 10 2.4 10.5 2 88 10 2.4 10.6 90 0 10 1.9 13 90 0 10 1.9

[0623] Method 16:

[0624] Waters UPLC-SQD apparatus; ionization: electrospray in positive and/or negative mode (ES+/−); chromatographic conditions: column: Acquity CSH C18 1.7 μm—1×30 mm; solvents: A: H.sub.2O (0.1% formic acid) B: CH.sub.3CN (0.1% formic acid); column temperature: 45° C.; flow rate: 0.6 ml/min; gradient (2.0 min): from 5 to 50% of B in 1.0 min; 1.3 min: 100% of B; 1.45 min: 100% of B; 1.75 min: 5% of B; retention time=RT (min).

[0625] Method 17:

[0626] Waters HPLC-ZQ apparatus; ionization: electrospray in positive and/or negative mode (ES+/−); chromatographic conditions: column: XSelect CSH C18 3.5 μm—3.0×75 mm; solvents: A: H.sub.2O (0.1% formic acid) B: CH.sub.3CN (0.1% formic acid); column temperature: 60° C.; flow rate: 0.8 ml/min; gradient (6.0 min): 6% of B during 0.8 min; From 6% to 100% of B in 3.9 min; 4.8 min: 100% of B; 5.0 min: 6% of B; 6.0 min: 6% of B; retention time=RT (min).

[0627] Method 18:

[0628] Waters HPLC-ZQ apparatus; ionization: electrospray in positive and/or negative mode (ES+/−); chromatographic conditions: column: XSelect CSH C18 3.5 μm—3.0×75 mm; solvents: A: H.sub.2O (0.1% formic acid) B: CH.sub.3CN (0.1% formic acid); column temperature: 60° C.; flow rate: 1.0 ml/min; gradient (7.0 min): 10% of B during 0.2 min; From 10 to 100% of B in 4.3 min; 4.85 min: 100% of B; 6.5 min: 10% of B; 7.0 min: 10% of B; retention time=RT (min).

[0629] Method 19:

[0630] Waters UPLC-SQD apparatus; ionization: electrospray in positive and/or negative mode (ES+/−); chromatographic conditions: column: Acquity CSH C18 1.7 μm—1×30 mm; solvents: A: H.sub.2O (0.1% formic acid) B: CH.sub.3CN (0.1% formic acid); column temperature: 45° C.; flow rate: 0.6 ml/min; gradient (4.0 min): 5% of B during 0.15 min; 1.3 min: From 5 to 100% of B in 3.15 min; 3.45 min: 100% of B; 3.85 min: 5% of B; 4.00 min: 5% of B; retention time=RT (min).

[0631] Method 20:

[0632] Waters UPLC-SQD apparatus; ionization: electrospray in positive and/or negative mode (ES+/−); chromatographic conditions: column: Acquity BEH C18 1.7 μm—2.1×50 mm; solvents: A: H.sub.2O (0.1% formic acid) B: CH.sub.3CN (0.1% formic acid); column temperature: 50° C.; flow rate: 0.8 ml/min; gradient (2.5 min): from 5 to 100% of B in 1.8 min; 2.4 min: 100% of B; 2.45 min: 100% to 5% of B in 0.05 min; retention time=RT (min).

Intermediate 1

2-chloro-6-(difluoromethoxy)benzaldehyde

[0633] To 2-chloro-6-hydroxy-benzaldehyde (20 g, 128.2 mmol) in MeCN (150 mL) was added an aqueous solution of potassium hydroxide (71.7 g, 1282 mmol) in water (50 mL) at 0° C. and the reaction mixture was stirred at 0° C. for 10 min. Diethyl (bromodifluoro methyl) phosphonate (36.4 mL, 205.1 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 min. After completion of reaction (monitored by TLC), the reaction mixture was poured into water (500 mL). The aqueous layer was extracted with ethyl acetate (1 L×2). The organic layer was washed with water (500 mL), brine (500 mL) and dried over anhydrous sodium sulphate. The organic layer was evaporated under reduced pressure to yield the crude product which was purified by column chromatography (SiO2, 5% EtOAc in hexane) yielding the title compound (13.9 g, 53% yield) as a yellow oil.

[0634] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.46 (s, 1H), 7.49 (t, J 8.2 Hz, 1H), 7.37 (dd, J 8.1, 1.1 Hz, 1H), 7.20 (m, 1H), 6.61 (t, 1H).

Intermediate 2

N-[[2-chloro-6-(difluoromethoxy)phenyl]methylene]-(S)-2-methyl-propane-2-sulfinamide

[0635] To a solution of Intermediate 1 (20 g, 97.08 mmol) in dry THF (100 mL) at 0° C. was added (S)-(−)-t-butyl sulfinamide (12.92 g, 106.79 mmol), K.sub.3PO.sub.4 (61.73 g, 291.2 mmol) and K.sub.2HPO.sub.4 (50.6 g, 291.2 mmol). Then the reaction mixture was stirred at r.t. for 18 h. After completion of reaction (monitored by TLC), the reaction mixture was filtered through celite and washed with ethyl acetate (1 L). The organic layer was washed with water (500 mL), brine (500 mL) and dried over anhydrous sodium sulphate. The organic layer was evaporated under reduced pressure and the residue was purified chromatography (SiO2, 10% EtOAc in hexane)to afford the title compound (20 g, 87% yield) as a yellow oil.

[0636] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.90 (s, 1H), 7.45-7.32 (m, 2H), 7.29-7.15 (m, 1H), 6.82-6.34 (m, 1H), 1.29 (s, 9H). LCMS (ES+) RT 2.73 min, 309.90 (M+H).sup.+

Intermediate 3

Ethyl (3R)-3-[[(S)-tert-butylsulfinyl]amino]-3-[2-chloro-6-(difluoromethoxy)phenyl]propanoate

[0637] This procedure used activated zinc and THF dried over sodium and benzophenone complex. Activated zinc was prepared using the following procedure: 150 g of zinc powder was taken in 1N HCl (500 mL), stirred for 10 min and decanted. The zinc dust powder was further washed with water (3×500 mL) and decanted. The powder was further washed with acetone (3×500 mL), decanted and dried under vacuum to afford 105 g of activated zinc.

[0638] To activated zinc dust (105 g, 1618 mmol) in dry THF (150 mL) was added CuCl (19.2 g, 194 mmol) and the reaction mixture was refluxed for 30 min. The reaction mixture was cooled to room temperature and ethyl bromoacetate (45 mL, 404 mmol in THF 100 mL) was added drop wise. The reaction mixture was stirred at 50° C. for 30 min. The reaction mixture was cooled to 0° C. and Intermediate 2 (50 g, 161 mmol in THF 100 mL) was added. The reaction mixture was warmed to r.t. and stirred for 3 h. After completion of reaction (monitored by TLC), the reaction mixture was filtered through celite and washed with ethyl acetate (700 mL). The organic layer was washed with 1N citric acid (500 mL), saturated solution of sodium bicarbonate (500 mL), water (500 mL) and brine (500 mL). The organic layer was separated, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography (SiO.sub.2, 40% EtOAc in hexane) to afford the title compound (59 g, 92% yield) as a yellow oil.

[0639] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.29-7.21 (m, 2H), 7.05 (d, J 7.3 Hz, 1H), 6.82-6.34 (m, 1H), 5.59 (m, 1H), 4.36 (s, 1H), 4.18-4.02 (m, 2H), 3.25 (dd, J 15.6, 7.5 Hz, 1H), 3.01 (dd, J 15.3, 7.5 Hz, 1H), 1.31-1.11 (m, 12H).

Intermediate 4

Ethyl (3R)-3-amino-3-[2-chloro-6-(difluoromethoxy)phenyl]propanoate hydrochloride

[0640] To a solution of Intermediate 3 (32 g, 80.6 mmol) in an Ether:EtOH (75 mL, 2:1) mixture was added 4M HCl in 1,4-dioxane (70 mL) and the reaction mixture was stirred at r.t. for 1 h. After completion of reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was washed with diethyl ether (500 mL) to afford the title compound as a yellow solid (22 g, 93% yield).

[0641] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.93 (d, J 6.2 Hz, 2H), 7.32-7.10 (m, 3H), 6.96 (s, 1H), 5.42 (m, 1H), 4.08 (q, J 7.0 Hz, 2H), 3.36 (dd, J 16.5, 7.0 Hz, 1H), 3.14 (dd, J 16.5, 7.8 Hz, 1H), 1.34 (t, J 7.1 Hz, 3H).

Intermediate 5

Ethyl (3R)-3-(5-bromo-4-fluoro-2-nitro-anilino)-3-[2-chloro-6-(difluoromethoxy)phenyl]propanoate

[0642] To a solution of Intermediate 4 (5 g, 17.06 mmol) in MeCN (50 mL) was added potassium carbonate (7.06 g, 51.18 mmol) and 1-bromo-2,5-difluoro-4-nitrobenzene (4.86 g, 20.47 mmol). The reaction mixture was stirred at 80° C. for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (SiO.sub.2, 20% EtOAc in hexane) to afford the title compound (6 g, 69% yield) as a yellow viscous liquid.

[0643] LCMS (ES+) RT 3.42 min, 510.90/512.90/514.90 (M+H).sup.+

Intermediate 6

(3R)-3-(5-bromo-4-fluoro-2-nitro-anilino)-3-[2-chloro-6-(difluoromethoxy)phenyl]propanal

[0644] To a solution of Intermediate 5 (6 g, 11.7 mmol) in THF (60 mL) at −78° C. was added DIBAL-H (23 mL, 23.5 mmol) drop wise. The reaction mixture was stirred for 2 h at −78° C. After completion of reaction (monitored by TLC), the reaction mixture was quenched with an aqueous solution of ammonium chloride (200 mL). The reaction mixture was diluted with ethyl acetate (200 mL) and filtered through celite. The filtrate was washed with water (200 mL) and the organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to afford the title compound (3 g, 57% yield) as a yellow oil, which was used in the next step without purification.

Intermediate 7

(4R)-4-(5-bromo-4-fluoro-2-nitro-anilino)-4-[2-chloro-6-(difluoromethoxy)phenyl]-2-trimethylsilyloxy-butanenitrile

[0645] To a solution ofIntermediate 6 (3 g, 6.42 mmol) in DCM (50 mL) was added ZnI.sub.2 (0.2 g, 0.64 mmol), TEA (0.09 mL, 0.64 mmol) and TMSCN (1.6 mL, 12.84 mmol). The reaction mixture was stirred at r.t. for 3 h. After completion of reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL) and the organic layer was separated. The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (3.25 g crude material) which was used for the next step without purification.

Intermediate 8

(1R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0646] ##STR00039##

[0647] To a solution of Intermediate 7 (3 g, 5.3 mmol) in EtOH (50 mL) was added SnCl.sub.2 (5 g, 26.46 mmol) and the reaction mixture was heated at 80° C. for 2 h. After completion of reaction (monitored by TLC), the reaction mixture was quenched with water (50 mL) and basified to pH-8 using 1N KOH (100 mL). The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through celite. The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (SiO.sub.2, 0-70% EtOAc in hexane) to afford the title compound (1.1 g, 47% yield) as a pale brown solid.

[0648] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.52 (m, 1H), 7.49-7.30 (m, 2H), 7.04-6.67 (m, 2H), 6.42 (m, 1H), 6.24-5.91 (m, 1H), 5.79-5.52 (m, 1H), 3.71-3.46 (m, 1H), 3.19 (m, 2H).

[0649] LCMS (ES+) RT 2.39 min, 447.0/449.0/451.0 (M+H).sup.+

Intermediate 9 and 10

(1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol and (1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0650] ##STR00040##

[0651] The title compounds were isolated by chiral purification of Intermediate 8 (15 g) under SFC conditions on Chirapak AD (column size: 50*216 mm*mm, flow 360 mL/min, 300 mg/injection/frequency: 8.5 minutes, 25° C., CO.sub.2+20% MeOH). Chiral analysis was done on Chiralpak AD-H (column size: 250*4.6 mm, 5 μm, flow 1 mL/min at 30° C. using 80/20 heptane/ethyl acetate containing 0.1% DEA). Under analytical conditions the first eluting diastereoisomers (5.8 and 9.5 minutes) were a mixture of (1R,3S) and (1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol.

[0652] (1S,3R) and (1S,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol were isolated at 12.5 minutes and 21.5 minutes.

[0653] The mixture of a mixture of (1R,3S) and (1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol was separated by chiral separation under SFC conditions on Chiracel OD (column size: 50*266 mm*mm, flow 360 mL/min, 80 mg/injection/frequency: 4 minutes, 25° C., CO.sub.2+20% MeOH). Chiral analysis was done on Chiralpak AD-H (column size: 250*4.6 mm, Sum, flow 1 mL/min at 30° C. using 70/30 heptane/ethyl acetate containing 0.1% DEA). Under analytical conditions the first eluting diastereoisomer (4.9 minutes) was the trans isomer, (1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol. Combined fractions were evaporated to yield Intermediate 10 (12.7 g, 50%). .sup.1H NMR (400 MHz, CDCl3) δ 7.41 (m, 3H), 7.23 (d, J 8.0 Hz, 0.4H), 6.97 (m, 1.2H), 6.85 (d, J 5.8 Hz, 0.4H), 6.73 (t, J 72.3 Hz, 0.4H), 6.41 (m, 1H), 5.95 (dd, J 74.2, 70.8 Hz, 0.6H), 5.71 (m, 0.6H), 5.62 (d, J 7.4 Hz, 0.4H), 3.22 (m, 2H), as a mixture of rotamers 6/4. LCMS basic (ES.sup.+) 2.50 min., 446.96/448.95/450.95 (M+H).sup.+.

[0654] Under analytical conditions the second eluting diastereoisomer (6.6 minutes) was the cis isomer, (1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol. Combined fractions were evaporated to yield Intermediate 9 (6.6 g, 26%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.45 (d, J 8.5 Hz, 1H), 7.31 (m, 1.8H), 7.20 (m, 0.6H), 7.08 (d, J 7.9 Hz, 0.6H), 6.88 (d, J 5.5 Hz, 0.6H), 6.74 (d, J 5.2 Hz, 0.4H), 6.61 (t, J 72.5 Hz, 0.4H), 6.15 (t, J 72.0 Hz, 0.6H), 6.08 (m, 1H), 5.63 (m, 1H), 3.56 (m, 0.6H), 3.43 (m, 0.4H), 2.98 (m, 0.4H), 2.80 (m, 0.6H), as a mixture of rotamers 6/4. LCMS acid (ES.sup.+) 2.20 min, 446.96/448.95/450.91 (M+H).sup.+.

[0655] Under preparative conditions the order of elution was reversed.

Intermediate 10

(1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0656] ##STR00041##

[0657] The title compound can also be prepared by the following procedure: Intermediate 9 (3.65 g, 8.146 mmol, 1 eq) and triphenylphosphine (2.62 g, 9.775 mmol, 1.2 eq) were solubilized in 8 mL of dry THF, under an inert atmosphere of nitrogen. Acetic acid (513 μL, 8.960 mmol, 1.1 eq) was added and the mixture cooled to 0° C. A solution of DIAD (2.42 mL, 12.220 mmol, 1.5 eq) in 8 mL of dry THF was added drop wise. The reaction was slowly warmed to r.t. and the reaction continued for 2 hours at this temperature. 20 mL of ethyl acetate were added to the reaction mixture before washing with 3×10 mL of a saturated solution of NaHCO.sub.3. The organic layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography (SiO.sub.2, 5% MeOH in DCM) giving 4.8 g (94% yield) of the inverted acetate intermediate which was used directly used in the next step. [(1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl] acetate (4.8 g, 9.800 mmol, 1 eq) was solubilized in 48 mL of methanol. Potassium carbonate (1.4 g, 9.800 mmol, 1 eq) was added and the reaction continued for 1 hour at r.t. The reaction was evaporated and the residue was taken up in ethyl acetate (50 mL) and water (20 mL). The organic layer was washed by water (2×20 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give 4.7 g of the crude title compound as a slightly beige solid.

Intermediate 11

tert-butyl-dimethyl-[1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]ethoxy]silane

[0658] 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (10 g, 37.8601 mmol), tert-butyldimethylchlorosilane (11.76 g, 75.72 mmol) and imidazole (7.890 g, 115.89 mmol) were dissolved in anhydrous DMF (150 mL). The reaction was stirred at 85° C. for 4 days. EtOAc (100 mL) and water (250 mL) were added, the aqueous layer was extracted with 3×20 mL of EtOAc then the combined organic layers were washed with brine (3×20 mL), and dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 0-100% EtOAc in heptane) to afford the title compound as a transparent oil (12.0 g, 83.76%).

[0659] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.04 (s, 2H), 1.70 (s, 6H), 1.40 (s, 12H), 0.94 (s, 9H), 0.01 (s, 6H). LCMS acid (ES.sup.+) RT 3.04 min, 297.20 (M+H).sup.+.

Intermediate 12

(1R,3S)-7-[2-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0660] ##STR00042##

[0661] Intermediate 10 (5.12 g, 11.44 mmol), Intermediate 11 (5.19 g, 13.73 mmol) and cesium carbonate (5.59 g, 17.16 mmol, 1.5 eq) were placed in a tube, and filled with argon. Degassed 1,4-dioxane (41.2 mL, 3.6 mL/mmol) and degassed water (4.1 mL, 0.36 mL/mmol) were added and the resulting slurry was stirred at r.t. for 5 minutes before addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (418.7 mg, 0.572 mmol, 0.05 eq). The reaction mixture was placed on a pre-heated stirring plate at 90° C. and stirred at this temperature for 2 h. Reaction mixture was cooled down to r.t. before addition of 50 mL of ethyl acetate and 50 mL of water. The aqueous layer extracted with 3×20 mL of ethyl acetate. Combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by chromatography (SiO.sub.2, 30-100% EtOAc in heptane) to afford the title compound (3.8 g, 53% yield).

[0662] LCMS basic (ES.sup.+) RT 3.54 min., 619.20/621.16 (M+H).sup.+.

Intermediate 13

(1R,3R)-7-[2-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

[0663] ##STR00043##

[0664] Intermediate 12 (3.369 g, 5.441 mmol) was suspended in 11 mL of dry toluene. At 0° C., diphenylphosphoryl azide (1.58 mL, 7.071 mmol) was added followed by addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.139 mL, 7.616 mmol). The reaction was allowed to reach r.t. and stirred at this temperature for 2 h then heated at 50° C. for 18 h.

[0665] The reaction mixture was diluted by 100 mL of water and 100 mL of ethyl acetate. The aqueous layer was extracted by ethyl acetate (3×20 mL). Combined organic layers were washed with successivelly 20 mL of a saturated solution of NH.sub.4Cl and 20 mL of a saturated solution of NaHCO.sub.3, dried over anhydrous magnesium sulfate and concentrated in vacuum.

[0666] The crude azide intermediate was solubilized in a solution of tetrahydrofuran (50 mL, 10 mL/mmol) and water (5 mL, 1 mL/mmol) before addition of 1 M solution of trimethylphosphine in toluene (11 mL, 11 mmol). The reaction mixture was stirred at r.t. for 2 h. Solvents were evaporated and the residue was purified by chromatography (SiO.sub.2, 5-8% MeOH in DCM) to afford the title compound (2.8 g, 83% yield).

[0667] LCMS basic (ES.sup.+) RT=3.52 min., 618.20/620.20 (M+H).sup.+.

Intermediate 14

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0668] ##STR00044##

[0669] Intermediate 13 (2.78 g, 4.50 mmol, 1 eq), sodium carbonate (2.38 g, 22.5 mmol, 5 eq) and dichloro bis(dicyclohexylphosphino)propane] palladium(II) [Pd-133 from Johnson Matthey] (552 mg, 0.899 mmol, 0.2 eq) were solubilized/suspended in degassed (nitrogen) 1,4-dioxane (54 mL, 12 mL/mmol). The reaction mixture was heated overnight at 150° C. under 5 atmosphere of CO gas. The reaction mixture was filtered over celite, which was thoroughly washed with ethanol. Solvents were evaporated and the residue was purified by chromatography (SiO.sub.2, 80-100% EtOAc in heptane), giving the title compound (1.39 g, 50% yield).

[0670] LCMS basic (ES.sup.+) RT 3.47 min., 610.25/611.25 (M+H).sup.+

Intermediate 15

ethyl (3R)-3-(5-bromo-2-nitro-anilino)-3-[2-chloro-6-(difluoromethoxy)phenyl]propanoate

[0671] Intermediate 15 was prepared, using the same procedure described for preparation of Intermediate 5, from Intermediate 4 (9.3 g, 28.3 mmol) and 4-bromo-2-fluoro-nitrobenzene (7.4 g, 34 mmol). The reaction was stirred overnight at 80° C. and purified by chromatography (SiO.sub.2, 10% EtOAc in hexane). Intermediate 15 was obtained as a yellow oil (12.5 g, 90% yield).

[0672] LCMS (ES.sup.+) 495 (M+H).sup.+

Intermediate 16

(3R)-3-(5-bromo-2-nitro-anilino)-3-[2-chloro-6-(difluoromethoxy)phenyl]propanal

[0673] Intermediate 16 was prepared from Intermediate 15 (12.5 g, 25.4 mmol) using the same procedure described for preparation of Intermediate 6. Following work-up the crude Intermediate 16 was purified by chromatography (SiO.sub.2, 15% EtOAc in hexane) yielding Intermediate 16 (9 g, 80% yield) as a yellow oil.

[0674] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.80 (d, J 1.3 Hz, 1H), 8.78 (d, J 9.0 Hz, 1H), 7.99 (d, J 9.0 Hz, 1H), 7.27 (d, J 3.2 Hz, 2H), 7.21-7.08 (m, 1H), 6.81-6.66 (m, 2H), 5.93 (m,1H), 3.56-3.38 (m, 2H), 3.12 (dd, J 17.9, 5.2 Hz, 1H).

Intermediate 17

(4R)-4-(5-bromo-2-nitro-anilino)-4-[2-chloro-6-(difluoromethoxy)phenyl]-2-trimethylsilyloxy-butanenitrile

[0675] Intermediate 17 was prepared from Intermediate 16 (9 g, 20 mmol) using the same procedure described for preparation of Intermediate 7. The reaction was stirred at r.t. for 2 h. After completion of reaction (monitored by TLC), water (200 mL) was added and extracted with DCM (500 mL). After evaporation of organic layer, the crude product, obtained as a yellow oil (9 g), was used directly for the next step without any purification.

Intermediate 18

(1R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0676] ##STR00045##

[0677] Intermediate 18 was prepared from Intermediate 17 (9 g, 16.4 mmol) using the same procedure described for preparation of Intermediate 8. The crude product was purified by chromatography (SiO.sub.2, 60% EtOAc in hexane) then triturated with hexane:ethyl acetate to yield the title compound (3 g, 43% yield) as a yellow solid.

[0678] LCMS (ES.sup.+) 431 (M+H).sup.+

Intermediate 19 and 20

(1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol and (1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0679] ##STR00046##

[0680] The title compounds were isolated by chiral purification of Intermediate 18 (12.5 g) by 2 successive chiral separation.

[0681] First Chiral Separation:

[0682] Under SFC conditions on Chiracel OD (column size: 50*266 mm*mm, flow 360 mL/min, 20 mg/injection/frequency: 4 minutes, 25° C., CO.sub.2+20% MeOH). Chiral analysis was done on Chiralcel OD-H (column size: 250*4.6 mm, flow 1 mL/min at 30° C. using 100% methanol containing 0.1% DEA). Under analytical conditions the first eluting diastereoisomer (3.9 minutes) was either (1S,3R) or (1S,3S) 7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol. The second eluting diastereoisomers (4.7 minutes) were a mixture of (1R,3S) along with either (1S, 3R) or (1S,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol and the third eluting diastereoisomer (5.4 minutes) was (1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol. Combined fractions of the third eluting diastereomer were evaporated to yield to Intermediate 19 (3.63 g, 29%). .sup.1H NMR (400 MHz, DMSO) δ 7.57 (m, 2.3H), 7.45 (m, 0.8H), 7.35 (d, J 8.0 Hz, 0.6H), 7.26 (m, 1H), 7.17 (m, 0.3H), 6.83 (t, J 72.5 Hz, 1H), 6.69 (bs, 1H), 6.15 (m, 1H), 6.07 (m, 1H), 5.38 (m, 1H), 3.38 (m, 1H), 2.67 (m, 1H) as a mixture of rotamers 7/3. LCMS acid (ES.sup.+) RT 4.31 min., 429.10/431.08/433.05 (M+H).sup.+.

[0683] Second Chiral Separation:

[0684] Under SFC conditions on Whelko 01 (R,R) (column size: 50*227 mm*mm, flow 360 mL/min, 690 mg/injection/frequency: 5.5 minutes, 25° C., CO.sub.2+20% EtOH). Chiral analysis was done on Chiralcel OD-H (column size: 250*4.6 mm, flow 1 mL/min at 30° C. using 50/50 heptane/isopropyl alcohol containing 0.1% DEA).

[0685] Under analytical conditions, the first eluting diastereomer (4.1 minutes) was either (1S, 3R) or (1S,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol.

[0686] Under analytical conditions, the second eluting diastereomer (5.9 minutes) was the trans isomer, (1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol. Combined fractions were evaporated to yield Intermediate 20 (4.46 g, 36%). .sup.1H NMR (400 MHz, DMSO) δ 7.55 (m, 3.4H), 7.31 (m, 1.4H), 7.12 (d, J 7.8 Hz, 0.6H), 7.03 (t, J 73.0 Hz, 0.6H), 6.89 (s, 0.6H), 6.81 (s, 0.4H), 6.32 (dd, J 8.4, 5.9 Hz, 1H), 6.10 (d, J 6.6 Hz, 1H), 5.32 (m, 0.6H), 5.26 (t, J 6.9 Hz, 0.4 H), 3.13 (m, 1H), 2.93 (m, 1H). as a mixture of rotamers 6/4. LCMS acid (ES.sup.+) RT 4.40 min., 429.05/431.08/433.05 (M+H).sup.+.

[0687] Under preparative conditions the order of elution was reversed.

Intermediate 20

(1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0688] ##STR00047##

[0689] The title compound was prepared from the same procedure as the preparation of Intermediate 10 starting from Intermediate 19 (3.63 g, 8.450 mmol), triphenylphosphine (2,66 g, 10.14 mmol), and acetic acid (0.5 mL, 9.295 mmol) THF (34 mL), DIAD (2.62 mL, 12.67 mmol) in 5 ml of dry THF giving 3.6 g (91%) of the inverted acetate intermediate which was used directly in the next step. Using the following conditions. [(1R,3S)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2a]benzimidazol-3-yl] acetate (4.0 g, 8.480 mmol) was solubilized in 40 mL of methanol. Potassium carbonate (1.1 g, 8.48 mmol, 1 eq) was added and the reaction continued for 1 hour at rt. The methanol was evaporated and the residue was taken up in ethyl acetate (50 mL) and water (20 mL). The organic layer was washed by water (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 4.9 g of crude title compound as a brown oil use without further purification.

[0690] LCMS basic (ES.sup.+) RT 2.46 min., 428.94/430.96/433.16 (M+H).sup.+.

Intermediate 21

(1R,3S)-7-[2-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0691] ##STR00048##

[0692] Intermediate 20 (4.46 g, 10.38 mmol), Intermediate 11 (3.92 g, 10.38 mmol) following the protocol described for intermediate 12 using cesium carbonate (5.07 g, 15.57 mmol), 1,4-dioxane (37.1 mL, 3.6 mL/mmol), water (3.7 mL, 0.36 mL/mmol), [1,1′ bis(diphenylphosphino)ferrocene]dichloropalladium(II) (379.8 mg, 0.5191 mmol, 0.05 eq). The crude was purified by chromatography (SiO.sub.2, 30-100% EtOAc in hexane) to yield the title compound (5.7 g, 92% yield).

[0693] LCMS acid (ES.sup.+) RT 3.64 min., 601.29/603.21 (M+H).sup.+

Intermediate 22

(1R,3R)-7-[2-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

[0694] ##STR00049##

[0695] Intermediate 22 was prepared from Intermediate 21 following the protocol described for intermediate 13, using toluene (34 mL), diphenylphosphoryl azide (5.0 mL, 24.22 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (3.62 mL, 24.22 mmol) for the first step and tetrahydrofuran (172 mL), water (17 mL), 1 M solution of trimethylphosphine in toluene (34.6 mL, 20.8 mmol) for the second step.

[0696] The crude residue was purified by chromatography (SiO.sub.2, 0-5% MeOH in DCM, 1% NH.sub.4) to afford the title compound (7 g, 61% yield).

[0697] LCMS basic (ES.sup.+) RT 3.49 min., 600.25/602.25 (M+H).sup.+

Intermediate 23

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0698] ##STR00050##

[0699] Intermediate 23 was prepared from Intermediate 22 (7.00 g, 7.931 mmol) following the protocol described for Intermediate 14 using sodium carbonate (6.181 g, 58.31 mmol), dichloro bis(dicyclohexylphosphino)propane] palladium(II) [Pd-133 from Johnson Matthey] (1.43 g, 0.254 mmol), 1,4-dioxane (95 mL, 12 mL/mmol) and 5 atmosphere of CO gas.

[0700] The crude was purified by chromatography (SiO.sub.2, 50-100% EtOAc in heptane) to afford the title compound (3.2 g, 62% yield) as a white solid.

[0701] .sup.1H NMR (400 MHz, DMSO) δ 9.23 (d, J 6.8 Hz, 1H), 9.16 (s, 2H), 8.32 (dd, J 5.9, 3.5 Hz, 1H), 7.88 (dd, J 51.9, 43.2 Hz, 1H), 7.84 (s, 1H), 7.71 (dd, J 8.3, 1.8 Hz, 1H), 7.60 (m, 3H), 6.47 (d, J 7.1 Hz, 1H), 4.99 (t, J 6.8 Hz, 1H), 3.58 (m, 1H), 2.85 (d, J 13.4 Hz, 1H), 1.76 (s, 6H), 0.95 (s, 9H), 0.01 (s, 6H). LCMS basic (ES.sup.+) RT 3.43 min., 592.27 (M+H).sup.+.

Intermediate 24

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0702] ##STR00051##

[0703] Intermediate 23 (1.0 g, 1.690 mmol) was dissolved in dry THF (10 mL/g) and tetrabutylammonium iodate (0.250 g, 0.676 mmol) was added. At 0° C., sodium hydride (60% in mineral oil) (0.081 g, 2.028 mmol) was added and the reaction mixture was stirred at r.t. for 35 minutes. Iodomethane (0.727 g, 5.070 mmol) was added and the reaction mixture was stirred at r.t. for 18 h. Distilled water (200 mL) was added, the mixture was extracted by of ethyl acetate (3×150 mL). Combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 50-100% EtOAc in heptane) to afford the title compound (0.868 g, 85% yield).

[0704] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.95 (s, 2H), 8.54 (d, 8.2 Hz, 1H), 7.93 (d, J 8.5 Hz, 1H), 7.80 (s, 1H), 7.59 (d, J 8.5 Hz, 1H), 7.49 (t, J 8.2 Hz, 1H), 7.37 (d, J 8.2 Hz, 1H), 6.89 (t, J 72.5 Hz, 1H), 6.42 (d, J 6.9 Hz, 1H), 5.30 (d, J 6.7 Hz, 1H), 3.63 (m, 4H), 2.99 (d, J 13.6 Hz, 1H), 1.75 (s, 6H), 0.92 (s, 9H), 0.00 (s, 6H). LCMS basic (ES.sup.+) RT 3.51 min., 606.25 (M+H).sup.+

Intermediate 25

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-ethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0705] ##STR00052##

[0706] Intermediate 23 (0.075 g, 0.127 mmol, 1 eq) was dissolved in dry THF (10 mL). At 0° C., sodium hydride (60% in mineral oil) (0.008 g, 0.190 mmol) was added and the reaction mixture was heated at 65° C. for 2.5 h, then was allowed to reach r.t. and iodoethane (0.059 g, 0.380 mmol) was added. The reaction mixture was then stirred at r.t. for 60 h. Additional Iodoethane (50 μL) was added and the reaction mixture was stirred at r.t.for 2 h. Distilled water (20 mL) was added, the mixture was extracted with 3×20 mL of ethyl acetate. Combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was purified by chromatography (SiO.sub.2, 50-100% EtOAc in heptane) to afford the title compound as a white solid (0.069 g, 88% yield).

[0707] LCMS basic (ES.sup.+) RT 2.24 min. 506.23 (M+H).sup.+.

Intermediate 26

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-(propan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0708] ##STR00053##

[0709] A solution of Intermediate 23 (25 mg, 0.0423 mmoL), potassium hydroxide (2.85 mg, 0.0507 mmoL), tetrabutylammonium bromide (12.26 mg, 0.0380 mmoL) and 2-iodopropane (14.36 mg, 0.0845 mmoL) in dry THF (0.8 mL) was stirred at r.t. for 24 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulphate and concentrated to dryness to afford the title compound (10 mg) which was used in the next step without further purification.

[0710] LCMS basic (ES.sup.+) RT 3.60 min. 534.30 (M+H).sup.+.

Intermediate 27

(1R,3S)-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0711] ##STR00054##

[0712] Intermediate 27 was prepared from Intermediate 20 (4.61 g, 10.30 mmol), following the protocol described for Intermediate 12, using 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (3.00 g, 11.330 mmol), cesium carbonate (5.03 g, 15.450 mmol), 1,4-dioxane (37.1 mL), water (3.7 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (376.8 mg, 0.5150 mmol). The crude was purified by chromatography (SiO.sub.2, 30-100% EtOAc in heptane) to afford the title compound (3.6 g, 69%).

[0713] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.77 (s, 1.2H), 8.73 (s, 0.8H), 7.59 (d, J=11.0 Hz, 1H), 7.37 (m, 2.8H), 7.23 (m, 0.6H), 6.99 (d, J=8.2 Hz, 0.6H), 6.84 (d, J=6.5 Hz, 0.6H), 6.74 (t, J=72.5 Hz, 0.6H), 6.70 (d, J=6.5 Hz, 0.4H), 6.51 (m, 1H), 6.02 (dd, J1=74.0 Hz, J2=71.0 Hz, 0.4H), 5.77 (dd, J1=7.8 Hz, J2=3.3 Hz, 0.6H), 5.68 (d, J=7.1 Hz, 0.4H), 4.60 (bs, 1H), 3.27 (m, 2H), 1.64 (s, 3.60H), 1.62 (s, 2.40). LCMS acid (ES.sup.+) RT 1.91 min. 505.15/507.15 (M+H).sup.+.

Intermediate 28

Butyl 3-(difluoromethoxy)-2-[(1R,3S)-6-fluoro-3-hydroxy-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]benzoate

[0714] ##STR00055##

[0715] A solution of Intermediate 27 (900 mg, 1.783 mmoL), sodium carbonate (944 mg, 8.913 mmoL), dichloro [bis(dicyclohexylphosphino)propane] palladium(II) (54.7 mg, 0.08913 mmol) in 10 mL of 1-butanol was heated for 16 h at 150° C. under 4 atm of CO gas. The reaction mixture was concentrated in vacuo, the residue was taken up in 50 mL of ethyl acetate and washed with 3×20 mL of NaOH 0.1 M. The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The crude material was purified by chromatography (SiO.sub.2, 80% EtOAc in hexane), to afford the title compound (490 mg, 48.2% yield).

[0716] LCMS acid (ES.sup.+) RT 2.66 min. 571.25 (M+H).sup.+.

Intermediate 29

3-(difluoromethoxy)-2-[(1R,3S)-6-fluoro-3-hydroxy-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]benzoic acid

[0717] ##STR00056##

[0718] Intermediate 28 (470 mg, 0.8237 mmoL) was dissolved in 4.7 mL of methanol. A 5 N solution of sodium hydroxide (0.3295 mL, 1.647 mmol) was added and the mixture was stirred at room temperature for 48 h. The reaction mixture was neutralized with HCl 1N and the solvent was evaporated. The aqueous phase was extracted with ethyl acetate (3×25 mL), the combined organic layers were dried over magnesium sulphate and concentrated in vacuo to afford crude 511 mg of the title compound used without further purification.

[0719] LCMS acid (ES.sup.+) RT 2.05 min., 515.17 (M+H).sup.+.

Intermediate 30

Ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate

[0720] ##STR00057##

[0721] The title compound was prepared according to the procedure provided in international patent application WO 2014/009295.

Intermediate 31

3-(6-bromo-2-ethoxycarbonyl-imidazo[1,2-a]pyridin-3-yl)-3-(2-chlorophenyl)propanoic acid

[0722] ##STR00058##

[0723] Intermediate 30 (8 g, 29.73 mmol), 2-chlorobenzaldehyde (6.7 ml, 59.58 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (8.6 g, 59.67 mmol), L-proline (170 mg, 1.48 mmol) and MgSO.sub.4 (11 g, 91.39 mmol) in acetonitrile (80 mL) was heated at 90° C. for 33 h, followed by 100° C. 15 h. The reaction cooled to r.t., and the solid filtered off, and washed with methanol (2×50 mL). The filtrate was concentrated in vacuo and triturated with diethyl ether (50 mL) and sonicated for 10 min and resulting gum was filtered off and rinsed with diethyl ether (2×50 mL) yielding the title compound as beige solid (10.2 g, 76%). .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.79 (s, 1H), 7.74 (d, J 7.7 Hz, 1H), 7.67-7.55 (m, 2H), 7.43-7.34 (m, 2H), 7.34-7.20 (m, 1H), 5.56 (dd, J 9.5, 6.0 Hz, 1H), 4.35 (qt, J 7.4, 3.7 Hz, 2H), 3.70 (dd, J 16.7, 9.5 Hz, 1H), 3.40 (dd, J 16.7, 6.0 Hz, 1H), 1.34 (t, J 7.1 Hz, 3H). LCMS (ES.sup.+) RT 1.24 min, 451.0/453.0 (M+H).sup.+.

Intermediate 32

Ethyl 6-bromo-3-[1-(2-chlorophenyl)-3-ethoxy-3-oxo-propyl]imidazo[1,2-a]pyridine-2-carboxylate

[0724] ##STR00059##

[0725] Thionyl chloride (4 ml, 55.14 mmol) was added to the stirred solution of Intermediate 31 (10.2 g, 20.1 mmol) in EtOH (100 mL) at 0° C. The reaction mixture warmed to r.t. and stirred for 20 h. The reaction mixture was concentrated in vacuo and resulting residue was triturated with EtOAc (100 mL) and washed with sat. NaHCO.sub.3 (100 mL) and further extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 0-100% EtOAc in heptane) yielding the title compound as an orange gum (8.2 g, 85%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.40 (s, 1H), 7.65 (dd, J 7.8, 1.5 Hz, 1H), 7.55 (d, J 9.5 Hz, 1H), 7.34 (dd, J 7.9, 1.4 Hz, 1H), 7.28 (dd, J 9.5, 1.8 Hz, 1H), 7.27-7.23 (m, 1H), 7.20 (td, J 7.6, 1.6 Hz,1H), 5.44 (dd, J 9.8, 5.6 Hz, 1H), 4.42 (q, J 7.1 Hz, 2H), 4.09-3.94 (m, 2H), 3.82 (dd, J 16.6, 9.9 Hz, 1H), 3.26 (dd, J 16.6, 5.5 Hz, 1H), 1.40 (t, J 7.1 Hz, 3H), 1.12 (t, J 7.1 Hz, 3H). LCMS (ES.sup.+) RT 1.44 min, 479.0/481.0 (M+H).sup.+.

Intermediate 33

Ethyl 7-bromo-1-(2-chlorophenyl)-3-oxo-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridine-2-carboxylate

[0726] ##STR00060##

[0727] Intermediate 32 (4 g, 8.34 mmol) was co-evaporated twice with toluene (50 mL) and the residue dissolved in dry toluene (400 mL) and degassed with N.sub.2(g) for 5 min. The mixture was cooled to −10° C. (external temp) and a 25% w/w solution of potassium 2-methylbutan-2-olate in toluene (7.5 mL, 13.37 mmol) was then added drop wise and stirred for 30 min at −10° C. The reaction mixture was quenched with acetic acid (2 mL) and diluted with water (200 mL), extracted with EtOAc (2×200 mL). The combined organic layer was washed with sat. aq. sodium bicarbonate (100 mL), brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo yielding the title compound as a pale yellow solid (3.3 g, 82%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.77 (s, 1H), 7.65 (d, J 9.8 Hz, 1H), 7.52 (d, J 6.7 Hz, 1H), 7.40 (dd, J 9.8, 1.5 Hz, 1H), 7.32 (t, J 8.3 Hz, 1H), 7.25-7.15 (m, 1H), 6.67 (s, 1H), 5.59 (s, 1H), 4.30 (q, J 7.1 Hz, 2H), 3.89 (s, 1H), 1.33 (t, J 7.1 Hz, 3H). LCMS (ES.sup.+) RT 1.35 min, 433.0/435.0 (M+H).sup.+.

Intermediate 34

7-bromo-1-(2-chlorophenyl)-1,2-dihydro-3H-cyclopenta[4,5]imidazo[1,2-a]pyridin-3-one

[0728] ##STR00061##

[0729] Intermediate 33 (3.2 g, 6.64 mmol) was dissolved in DMSO (50 mL) and water (10 mL) then heated at 100° C. for 48 h. The reaction was cooled to r.t. and poured on to ice and left to stand for 1 h. The resulting residue was filtered off and washed with water yielding the title compound as a pale yellow solid (2.5 g, 99%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.81 (s, 1H), 7.65 (dd, J 9.8, 0.8 Hz, 1H), 7.52 (d, J 8.0 Hz, 1H), 7.38 (dd, J 9.8, 1.8 Hz, 1H), 7.29 (td, J 7.8, 1.6 Hz, 1H), 7.21 (t, J 7.4 Hz, 1H), 6.77 (s, 1H), 5.22 (s,1H), 3.73 (dd, J 18.4, 7.1 Hz, 1H), 2.92 (d, J 19.0 Hz, 1H). LCMS (ES.sup.+) RT 1.27 min, 361.0/363.0 (M+H).sup.+.

Intermediate 35

1-(2-chlorophenyl)-7-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-1,2-dihydro-3H-cyclopenta[4,5]imidazo[1,2-a]pyridin-3-one

[0730] ##STR00062##

[0731] Intermediate 34 (1 g, 2.65 mmol), 2-[5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (0.84 g, 3.19 mmol) were dissolved in dioxane (40 mL) then 2M disodium carbonate (4 mL) was added and the mixture was degassed with N.sub.2 for 5 min. Bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; dichloropalladium (108 mg, 0.13 mmol) was added and the reaction was heated to 80° C. for 1.5 hours. The reaction mixture was then cooled to r.t. and diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by chromatography, (SiO.sub.2, 10-100% EtOAc in heptane) yielding the title compound as a light brown solid (1.1 g, 96%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.81 (s, 2H), 7.91 (d, J 9.6 Hz, 1H), 7.87 (s, 1H), 7.53 (dd, J 9.5, 1.6 Hz, 2H), 7.29 (td, J 7.8, 1.5 Hz, 1H), 7.21 (t, J 7.4 Hz, 1H), 6.84 (s, 1H), 5.31 (s, 1H), 4.45 (s, 1H),3.77 (dd, J 18.3, 7.0 Hz, 1H), 2.99 (d, J 18.9 Hz, 1H), 1.63 (s, 6H). LCMS (ES.sup.+) RT 1.14 min, 419.0/421.0 (M+H).sup.+.

Intermediate 36

2-{5-[(1-(2-chlorophenyl)-3-(methoxyimino)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl]pyrimidin-2-yl}propan-2-ol

[0732] ##STR00063##

[0733] Intermediate 35 (500 mg, 1.11 mmol), O-methylhydroxylamine hydrochloride (185 mg, 2.22 mmol) and sodium acetate (182 mg, 2.22 mmol) in ethanol (20 mL) were heated at 85° C. for 6 h. The reaction mixture was cooled to r.t., concentrated in vacuo then diluted with sat. aq. sodium bicarbonate (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered, concentrated in vacuo yielding the title compound as beige solid (500 mg, 95%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.80 (d, J 1.1 Hz, 2H), 7.98-7.73 (m, 2H), 7.54-7.36 (m, 2H), 7.26 (s, 2H), 6.94-6.64 (m, 1H), 5.31-5.09 (m, 1H), 4.48 (d, J 9.5 Hz, 1H), 4.07 (d, J 53.7 Hz, 3H), 3.97(dd, J 18.2, 7.9 Hz, 1H), 3.23-3.10 (m, 1H), 1.56 (s, 6H). LCMS (ES.sup.+) RT 1.17 and 1.29 min, 448.0/450.0 (M+H).sup.+.

Intermediate 37

2-{5-[3-amino-1-(2-chl orophenyl)-2,3-dihydro-1 H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl]pyrimidin-2-yl}propan-2-ol

[0734] ##STR00064##

[0735] A solution of Intermediate 36 (500 mg, 1.12 mmol), 7M ammonia in MeOH (0.64 mL) in methanol (50 mL) was passed over a Raney Nickel cartridge at a flow-rate of 1 ml/min, 60 bar hydrogen pressure at 80° C. in a H-Cube® continuous-flow hydrogenation reactor. This process was repeated three times and mixture was concentrated in vacuo. The residue was purified by preparative HPLC yielding the title compound as an off white solid (300 mg, 64%). A 1.6:1 cis/trans mixture of distereosiomers was isolated. .sup.1H NMR, cis distereoisomer, (500 MHz, CDCl.sub.3) δ 8.78 (s, 2H), 7.74 (d, J 20.0 Hz, 2H), 7.51-7.44 (m, 1H), 7.40-7.33 (m, 1H), 7.24-7.17 (m, 2H), 7.14 (t, J 7.5 Hz, 1H), 7.00 (dd, J 7.6, 1.6 Hz, 1H), 4.96 (dd, J 8.1,6.0 Hz, 1H), 4.59 (dd, J 7.4, 5.7 Hz, 3H), 3.69 (dt, J 13.5, 8.1 Hz, 1H), 2.11 (dt, J 13.4, 5.6 Hz, 1H), 1.61 (s, 6H). LCMS (ES.sup.+) RT 1.60 min (cis) and 1.65 min (trans), 420.0/422.0 (M+H).sup.+.

Intermediate 38

[0736] ##STR00065##

(1R,3S)-7-chloro-1-[2-bromo-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0737] The title compound was prepared in a sequence of steps analogous to those described for Intermediate 10 starting from 2-bromo-6-hydroxy-benzaldehyde and utilising 4-chloro-2-fluoro-nitrobenzene instead of 1-bromo-2,5-difluoro-4-nitrobenzene in the fifth synthetic step.

Intermediate 39

[0738] ##STR00066##

(1R,3S)-7-chloro-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0739] The title compound was prepared in a sequence of steps analogous to those described for Intermediate 10 starting from 2-bromo-6-hydroxy-benzaldehyde and utilising 1-chloro-2,5-difluoro-4-nitrobenzene, instead of 1-bromo-2,5-difluoro-4-nitrobenzene in the fifth synthetic step.

Intermediate 40

[0740] ##STR00067##

(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

[0741] Intermediate 38 (5 g, 11.64 mmol) was suspended in toluene (22 mL) and cooled to 0° C. before addition of diphenylphosphoryl azide (3.4 mL, 15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 mL, 16 mmol). The mixture was allowed to warm up to r.t and stirred for 2 hours and subsequently at 45° C. overnight. The reaction mixture was diluted with EtOAc (150 mL) and the organic phase washed with a saturated aqueous solution of ammonium chloride (50 mL) then a saturated solution of aqueous sodium bicarbonate (50 mL), and concentrated in vacuo. The crude residue thus obtained was solubilized in THF (100 mL) and water (10 mL), trimethylphosphine (17.46 mL, 17.46 mmol) was added and the reaction mixture stirred overnight. The mixture was concentrated in vacuo, partitioned between EtOAc (200 mL) and water (150 mL). The organic layer was extracted with 0.2M HCl aq (3×200 mL). The combined acid layer was stirred in an ice bath, whilst 10% NaOH solution was added with stirring until pH increased to 10. The stirred was continued for further 15 minutes to complete precipitation. The precipitate was filtered, rinsed with water (20 mL), then dried under suction for 10 minutes before drying under high vacuum overnight to afford 3.92 g (78%) of the title compound as an off white solid. LCMS basic: RT 1.96 min. (ES+) 428/430 (M+H).sup.+

Intermediate 41

[0742] ##STR00068##

(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

[0743] The title compound was prepared from Intermediate 39 using the experimental protocol described for the preparation of Intermediate 40. The crude material was purified by column chromatography over silica gel using EtOAc/MeOH (100/0 to 70/30) as eluent, yielding 15 g (83%) of the title compound as an amorphous solid. LCMS basic: RT 2.04 min. (ES+) 446/448 (M+H).sup.+.

Intermediate 42

[0744] ##STR00069##

tert-butyl {(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

[0745] To a solution of Intermediate 40 (700 mg, 2 mmol) in DCM (10 mL), at 0° C., was added dropwise triethylamine (500 μL, 4 mmol) and di-tert-butyl dicarbamate (400 mg, 2 mmol) portionwise. The reaction was stirred at 0° C. for 1 hour and at r.t overnight. The reaction mixture was poured into ice-water (20 mL) and the aqueous layer was extracted by DCM (3×10 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (heptane/EtOAc 2/8), yielding 626 mg (70%) of the title compound. LCMS basic (ES+) RT 2.92 min., 528.0/530.0 (M+H)+

Intermediate 43

[0746] ##STR00070##

tert-butyl {(1R,3R)-7-chloro-1-[2-(difluoromethoxy)-6-ethenylphenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

[0747] Intermediate 42 (250 mg, 0.473 mmol), potassium vinyltrifluoroborate (92.3 mg, 0.662 mmol), cesium carbonate (308 mg, 0.944 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19.3 mg, 0.0236 mmol) were placed in a tube, and filled with argon. Degassed 1,4 dioxane (5 mL) and water (0.5 mL) were added and the resulting slurry was stirred at 110° C. overnight. The reaction mixture was cooled to ambient temperature, filtered and concentrated in vacuo. The crude material was purified by preparative reverse phase HPLC (basic conditions) to afford 175 mg (78%) of the title compound. LCMS basic (ES+) RT 2.91 min., 476/478(M+H)+.

Intermediate 44

[0748] ##STR00071##

tert-butyl {(1R,3R)-7-chloro-1-[2-(difluoromethoxy)-6-formylphenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

[0749] Intermediate 43 (25 mg, 0.0526 mmol) was dissolved in 1,4 dioxane (0.4 mL) and water (0.1 mL). At 0° C., sodium periodate (34 mg, 0.158 mmol) followed by osmium tetroxide (26 μl, 0.0021 mmol) were added. The reaction mixture was allowed to warm to r.t and stirred overnight. The reaction was then diluted with EtOAc (2 mL) and water (2 mL). The aqueous layer was extracted with EtOAc (2×2 mL). The combined organic layers were washed with a saturated solution of sodium thiosulfate (2 mL), brine, dried over magnesium sulphate, filtered and concentrated under vacuum to afford the title compound which was used without further purification. LCMS basic (ES+) RT 2.65 min., 478/480(M+H)+

Intermediate 45

[0750] ##STR00072##

(7R,14R)-11-chloro-1-(difluoromethoxy)-7,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

[0751] Intermediate 44 (0.0525 mmol) was dissolved in DCM/TFA (1/1). The reaction mixture was stirred at r.t for one hour. The reaction mixture was then concentrated under reduced pressure to afford the title compound as a TFA salt which was used without further purification. LCMS basic (ES+) RT 2.29 min., 360/362 (M+H)+

Intermediate 46

[0752] ##STR00073##

Ethyl [(7R,14R)-11-chloro-1-(difluoromethoxy)-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]acetate

[0753] Example 12 (120 mg, 0.332 mmol) was dissolved in DMF (1 mL). Potassium carbonate (2 equiv., 0.663 mmol) and ethyl bromoacetate (1.2 equiv., 0.398 mmol) were added and the reaction mixture was stirred at r.t for 1 hour.

[0754] The mixture was filtered, rinsed with EtOAc and the volatiles removed in vacuo. The residue was taken up with EtOAc, washed with water, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude compound was purified by reverse phase chromatography to afford 34 mg (23%) of the title compound. LCMS (ES+) 448/450 (M+H).sup.+

Intermediate 47

[0755] ##STR00074##

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine-5(14H)-thione

[0756] Intermediate 23 (150 mg, 0.254 mmol) was solubilized in toluene (6 mL) before addition of Lawessons reagent (114 mg, 0.28 mmol). The slurry was heated overnight at 120° C. The reaction mixture was concentrated in vacuo, and the residue taken up in DCM and filtered through a pad of silica gel eluting with DCM/MeOH (1/1) to afford 195 mg of the title compound as a brown solid used without further purification. LCMS acidic (ES+) RT 3.74 min. 608(M+H).sup.+.

Intermediate 49

(S)—N-[(1Z)-(2-Chloro-6-methoxyphenyl)methylidene]-2-methylpropane-2-sulfinamide

[0757] To a cooled (0° C.) solution of 2-chloro-6-methoxybenzaldehyde (15 g, 87.93 mmol) in tetrahydrofuran (180 mL) was added sequentially (S)-2-methylpropane-2-sulfinamide (11.7 g, 96.7 mmol), tripotassium phosphate (56 g, 264 mmol) and dipotassium hydrogen phosphate (46 g, 263.8 mmol). The cooling bath was removed and the resultant suspension was stirred at r.t. for 18 hours. The reaction mixture was filtered through a pad of celite. The filtrate was diluted with EtOAc (250 mL), washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to a crude residue. The crude material was purified by flash column chromatography (0-50% EtOAc/heptanes) to afford 22.7 g (94%) of the title compound as a pale yellow solid. LCMS Method 6 (ES+) RT 1.61 min., 274.1 (M+H).sup.+. .sup.1H NMR (500 MHz, Chloroform-d) δ 8.95 (m, 1H), 7.33 (t, J=8.3 Hz, 1H), 7.07 (dd, J=8.1, 0.8 Hz, 1H), 6.95-6.84 (m, 1H), 3.88 (s, 3H), 1.29 (s, 9H).

Intermediate 50

(S)—N-[(1R)-1-(2-chloro-6-methoxyphenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

[0758] To a suspension of zinc powder (27.9 g, 426.5 mmol) in anhydrous THF (100 mL) was added 1,2-dibromoethane (620 μL, 7.19 mmol) and the mixture heated to 70° C. After 10 minutes at this temperature, the heating was switched off and the reaction stirred for a further 30 minutes (internal temperature ca. 50° C.) and allowed to cool slowly to r.t. over 20 minutes. Chloro(trimethyl)silane (910 μL, 7.17 mmol) was then added dropwise. Effervescence and an exotherm to ˜40° C. was observed, along with coagulation of the zinc. The reaction was heated to 50° C. for 10 min then allowed to cool to r.t. 3-Bromoprop-1-ene (18.5 mL, 213.8 mmol) was then added drop-wise at r.t. An exotherm to ˜50° C. was observed during addition and the addition rate controlled to maintain the exotherm. After completion of addition, the resultant grey suspension was heated to 70° C. for 15 minutes, then cooled first to r.t. over 30 min, then to −40° C. Anhydrous THF (350 ml) was added, then a pre-cooled solution of Intermediate 49 (19.5 g, 71.1 mmol) in dry THF (100 mL) was added dropwise whilst maintaining an internal reaction temperature of between −35 and −40° C., then the resultant mixture stirred at −40° C. for 1 hour. The reaction was allowed to warm to r.t., decanted and filtered through a sinter funnel to remove excess zinc. The solids were washed with THF (2×80 mL). The filtrate was poured into saturated aqueous ammonium chloride solution (500 mL) and shaken well, then extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford ˜56 g crude yellow oil. This material was purified by reverse-phase flash column chromatography (elution 0-100% MeCN (+0.1% NH.sub.4OH)/H.sub.2O (+0.1% NH.sub.4OH)). The clean fractions were extracted with EtOAc (2×3 L). The combined organics were dried over sodium sulfate, filtered and concentrated to dryness under vacuum to yield 16.8 g (74%) of the title compound as colourless viscous oil. LCMS Method 6 (ES+) RT 1.63 min., 316.1 (M+H)+. .sup.1H NMR (250 MHz, Chloroform-d) δ 7.14 (t, J=8.2 Hz, 1H), 6.97 (dd, J=8.1, 0.9 Hz, 1H), 6.87-6.72 (m, 1H), 5.70 (ddt, J=17.1, 10.1, 7.2 Hz, 1H), 5.26-4.91 (m, 2H), 4.53 (s, 1H), 3.86 (s, 3H), 2.81 (dtt, J=21.4, 13.8, 7.6 Hz, 2H), 1.10 (s, 9H).

Intermediate 51

(1R)-1-(2-chloro-6-methoxyphenyl)but-3-en-1-amine

[0759] Intermediate 50 (12.7 g, 40.21 mmol) was dissolved in diethyl ether (40 mL) and ethanol (20 mL) then 4M hydrogen chloride in 1,4-dioxane (31 mL) was added and the reaction mixture was stirred for 45 minutes. The reaction mixture was partitioned between water (150 mL) and diethyl ether (150 mL). The organic layer was re-extracted with 1M aq HCl solution (150 mL). The aqueous layers were combined, basified to pH 10 by addition of 6M aq NaOH solution and extracted with EtOAc (2×200 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated to dryness under vacuum to yield 9.19 g (97%) of the title compound as a pale yellow viscous oil. LCMS Method 6 (ES+) RT 1.49 min., 212.3 (M+H).sup.+. .sup.1H NMR (500 MHz, Chloroform-d) δ 7.10 (t, J=8.2 Hz, 1H), 6.96 (dd, J=8.1, 0.9 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 5.77 (ddt, J=17.2, 10.2, 7.2 Hz, 1H), 5.11-4.92 (m, 2H), 4.56 (t, J=7.6 Hz, 1H), 3.86 (s, 3H), 2.61 (hept, J=7.3, 6.9 Hz, 2H).

Intermediate 52

tert-butyl-[1-[5-(2,5-difluoro-4-nitro-phenyl)pyrimidin-2-yl]-1-methyl-ethoxy]-dimethyl-silane

[0760] The title compound can be prepared from Intermediate 11 and 1-bromo-2,5-difluoro-4-nitro-benzene by a palladium catalyzed Suzuki coupling following an analogous method to that described for Intermediate 12.

Intermediate 53

5-(2-{2-[(tert-butyldimethylsilyl)oxy]propan-2-yl}pyrimidin-5-yl)-N-[(1R)-1-(2-chloro-6-methoxyphenyl)but-3-en-1-yl]-4-fluoro-2-nitroaniline

[0761] Intermediate 51 (2.51 g, 10.67 mmol) and Intermediate 52 7 (4.96 g, 10.9 mmol) were dissolved in acetonitrile (40 mL) and K.sub.2CO.sub.3 (4.4 g, 31.84 mmol) was added. The reaction mixture was stirred at 80° C. overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2×75 mL), then brine (75 mL), dried (Na.sub.2SO.sub.4) and concentrated to dryness under vacuum to yield 7 g (98%) of the title compound as an orange gum. LCMS Method 6 (ES+) RT 2.64 min., 601.1 (M+H).sup.+. .sup.1H NMR (500 MHz, Chloroform-d) δ 8.94-8.74 (m, 3H), 7.99 (d, J=10.7 Hz, 1H), 7.18 (t, J=8.2 Hz, 1H), 7.00 (d, J=7.9 Hz, 2H), 6.83 (d, J=8.2 Hz, 1H), 5.80 (ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.48-5.25 (m, 1H), 5.16 (d, J=16.8 Hz, 1H), 5.07 (d, J=10.0 Hz, 1H), 3.88 (s, 3H), 3.04-2.86 (m, 1H), 2.79 (dt, J=13.3, 6.5 Hz, 1H), 1.70 (d, J=4.4 Hz, 6H), 0.90 (s, 9H), −0.02 (s, 6H).

Intermediate 54

(3R)-3-{[5-(2-{2-[(tert-butyldimethylsilyl)oxy]propan-2-yl}pyrimidin-5-yl)-4-fluoro-2-nitrophenyl]amino}-3-(2-chloro-6-methoxyphenyl)propanal

[0762] Potassium dioxido(dioxo)osmium hydrate (2:1:2) (75 mg, 0.2 mmol) was added in one portion to a stirred solution of Intermediate 53 (6.85 g, 10.25 mmol), sodium periodate (13.1 g, 61.25 mmol) and 2,6-dimethylpyridine (2.4 mL, 20.67 mmol) in a 3:1 mixture of 1,4-dioxane and water (240 mL). The mixture was stirred overnight then sodium thiosulfate (11.3 g, 71.47 mmol) was added and the resulting mixture was stirred for 30 minutes before diluting with DCM (200 mL) and water (200 mL). The biphasic mixture was stirred for a further 15 minutes then the two layers were separated and the aqueous layer was re-extracted with DCM (2×100 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to yield 8.5 g of the title compound as an orange gum. LCMS Method 6 (ES+) RT 2.74 min., 603.1 (M+H).sup.+. .sup.1H NMR (250 MHz, Chloroform-d) δ 9.81 (s, 1H), 8.87 (d, J=1.6 Hz, 2H), 8.24-8.07 (m, 1H), 7.99 (d, J=10.7 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 7.02 (dd, J=8.1, 1.0 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.03 (td, J=9.3, 5.0 Hz, 1H), 5.62-5.45 (m, 1H), 3.94 (s, 3H), 3.53 (ddd, J=17.6, 8.9, 1.6 Hz, 1H), 3.01 (dd, J=17.8, 4.8 Hz, 1H), 1.71 (s, 6H), 0.91 (s, 9H), −0.01 (s, 6H).

Intermediate 55

(R)—N-[(1Z,3R)-3-{[5-(2-{2-[(tert-butyldimethylsilyl)oxy]propan-2-yl}pyrimidin-5-yl)-4-fluoro-2-nitrophenyl]amino}-3-(2-chloro-6-methoxyphenyl)propylidene]-2-methylpropane-2-sulfinamide

[0763] To a solution of Intermediate 54 (8.5 g, 10.29 mmol) and (R)-2-methylpropane-2-sulfinamide (1.25 g, 10.3 mmol) in DCM (50 mL) was added dropwise titanium(4+) tetrapropan-2-olate (6.1 mL, 20.6 mmol) and the reaction mixture was stirred at 40° C. under nitrogen for 3 hours and 20 minutes. The reaction was diluted with DCM (100 mL) then quenched by the addition of brine (50 mL). The resultant sticky suspension was filtered through celite and the celite washed with further DCM (2×100 mL) and water (100 mL). The filtrate was separated and the aqueous layer was re-extracted with DCM (100 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated to dryness under vacuum to yield approximately 8 g of a crude orange gum. The crude product was purified on slica gel (DCM/EtOAc 100/0 to 95/5) to yield 3.61 g (50%) of the title compound as an orange gum. LCMS Method 6 (ES+) RT 2.56 min., 706.1 (M+H).sup.+. .sup.1H NMR (500 MHz, Chloroform-d) δ 8.96-8.79 (m, 3H), 8.10 (dd, J=5.7, 3.6 Hz, 1H), 7.99 (d, J=10.6 Hz, 1H), 7.21 (t, J=8.2 Hz, 1H), 7.11 (s, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 5.88 (td, J=9.3, 4.9 Hz, 1H), 3.92 (s, 3H), 3.63-3.46 (m, 1H), 3.11 (d, J=16.3 Hz, 1H), 1.71 (d, J=3.8 Hz, 6H), 1.13 (s, 9H), 0.91 (s, 9H), −0.02 (s, 6H).

Intermediate 56

N-[(1R,3R)-3-{[5-(2-{2-[(tert-butyldimethylsilyl)oxy]propan-2-yl}pyrimidin-5-yl)-4-fluoro-2-nitrophenyl]amino}-3-(2-chloro-6-methoxyphenyl)-1-cyanopropyl]-2-methylpropane-2-sulfinamide

[0764] Intermediate 55 (2.8 g, 3.96 mmol) was dissolved in anhydrous THF (50 mL) under nitrogen and scandium triflate (400 mg, 0.81 mmol) was added, followed by sodium cyanide (220 mg, 4.5 mmol). The reaction mixture was stirred under a flow of nitrogen overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with a saturated solution of NaHCO.sub.3 (75 mL). The aqueous layer was re-extracted with EtOAc (75 mL) and the combined organics were washed with saturated brine (75 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness under vacuum. The crude product was purified on silica gel (heptane/EtOAc 100/0 to 60/40) to yield to 1.52 g (44%) of the title compound as an orange gum. LCMS Method 6 (ES+) RT 2.41 min., 733.1 (M+H).sup.+. .sup.1H NMR (500 MHz, Chloroform-d) δ 8.94-8.62 (m, 3H), 8.02 (d, J=10.5 Hz, 1H), 7.26-7.14 (m, 2H), 7.03 (d, J=8.0 Hz, 1H), 6.85 (d, J=7.9 Hz, 1H), 5.81-5.61 (m, 1H), 4.49-4.26 (m, 1H), 3.92 (s, 3H), 3.86 (d, J=9.4 Hz, 1H), 2.93 (ddd, J=14.4, 9.7, 4.6 Hz, 1H), 2.48-2.23 (m, 1H), 1.71 (d, J=2.4 Hz, 6H), 1.19 (s, 9H), 0.90 (s, 9H), −0.03 (s, 6H).

Intermediate 57

[0765] ##STR00075##

2-{5-[(1R,3R)-3-amino-1-(2-chloro-6-methoxyphenyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl}propan-2-ol

[0766] Intermediate 56 (1.52 g, 2.07 mmol) was dissolved in ethanol (16 mL) and tin (II) chloride (2.4 g, 12.66 mmol) was added, followed by 12M HCl (1.4 mL). The reaction mixture was stirred at 80° C. for 90 minutes. The reaction mixture was cooled to r.t., concentrated in vacuo to approximately 1 mL. The concentrated solution was dissolved in DCM (50 mL), basified with 2M aqueous NaOH solution until pH=10 and finally treated with 10% aqueous KF solution (25 mL). The mixture was filtered and the solids were washed with DCM (2×20 mL). The filtrate was separated and the aqueous layer was re-extracted with DCM (30 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness under vacuum to yield the title compound (134 mg 14%) as an off-white solid.

[0767] The original solids can be washed with further EtOAc to yield a second crop of the title compound after removal of the volatiles in vacuo. If required additional purification can be performed by flash chromatography on silica gel (eluted with 0 to 100% EtOAc in heptane, followed by 0 to 20% MeOH in EtOAc). LCMS Method 6 (ES+) RT 3.76 min., 468.1 (M+H).sup.+. .sup.1H NMR (500 MHz, Chloroform-d) Major atropisomer—δ 8.71 (d, J=1.3 Hz, 2H), 7.56 (t, J=10.2 Hz, 1H), 7.33-7.27 (m, 1H), 7.16 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 6.66 (d, J=6.6 Hz, 1H), 6.19 (t, J=7.7 Hz, 1H), 4.74 (s, 1H), 4.60 (s, 2H), 3.61-3.52 (m, 1H), 3.38 (s, 3H), 2.67 (dt, J=14.4, 7.6 Hz, 1H), 1.62 (s, 6H).

Intermediate 58

[0768] ##STR00076##

2-{5-[(1R,3R)-3-amino-1-(2-chloro-6-fluorophenyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl}propan-2-ol

[0769] Intermediate 58 was prepared following an analogous 8 steps procedure to that described for Intermediate 41 through to Intermediate 57, starting from 2-chloro-6-fluoro-benzaldehyde, to afford 1.1 g of the title compound as a beige solid. LCMS basic Method 3 (ES+) RT 2.02 min., 456.2/458.1 (M+H)+.

Intermediate 59

[0770] ##STR00077##

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]methanesulfonamide

[0771] To a mixture of Intermediate 40 (2.5 g, 5.8 mmol), N,N-diisopropylethylamine (1.22 mL, 6.97 mmol) in DCM (58.3 mL), methanesulfonyl chloride (0.6 mL, 8 mmol) was added at 0° C. and the mixture was stirred at r.t for 2 hours. Water (30 mL) was added to the reaction mixture and extracted with CH.sub.2Cl.sub.2 (2×30 mL). The organic phase was washed with saturated brine (20 mL) and the combined organic phases was dried with sodium sulphate, filtered and concentrated in vacuo to give a solid. The crude was triturated in diethylether, filtered, washed twice with diethylether then hexane and dried to give the title compound (2.8 g, 5.53 mmol, 95% yield) as a brown solid. LC/MS Method 3: RT 2.11 mins (pH 10), m/z 506 and 508.

Intermediate 60

[0772] ##STR00078##

(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[0773] Intermediate 38 (5 g, 11.64 mmol) and triphenylphosphine (3.7 g, 14 mmol) were added to a round bottom flask followed by acetic acid (0.7 mL, 10 mmol) and THF (12 mL). The reaction mixture was cooled down to 0° C. and DIAD (3.4 mL, 17 mmol) in THF (12 mL) was added dropwise. The mixture was stirred at 0° C. for 2 hours. The reaction mixture was warmed to ambient temperature and the crude mixture was extracted with EtOAc (3×20 mL). The organic phase was washed with saturated NaHCO.sub.3 (20 mL) and saturated brine (20 mL), the combined organic phases was dried with sodium sulphate, filtered and concentrated in vacuo to give an oil which was purified by flash chromatography in silica gel (0 to 80% EtOAc in Hexane) to afford [(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl] acetate. The material was dissolved in MeOH (6.3 mL) and stirred with potassium carbonate (1.6 g, 12 mmol) for 45 minutes, the solid was filtered and washed with MeOH (30 mL) and water (10 mL) to give the title compound (4.3 g, 10 mmol, 86% yield) as a white solid. LC/MS Method 3: RT 2.07 mins (pH 10), m/z 429 and 431.

Intermediate 61

2-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol

[0774] 2-(5-bromo-4-methyl-pyrimidin-2-yl)propan-2-ol (1 g, 4.33 mmol), bis(pinacolato)diboron (2 equiv., 8.65 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.05 equiv., 0.22 mmol), potassium acetate (4 equiv., 17.31 mmol) and 1,4-dioxane (5 mL) were placed in vial and then degassed. The mixture was then heated at 105° C. for 2 hours.

[0775] The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was dried over Na.sub.2SO.sub.4 and evaporated to give a dark brown solid, stored at 0° C. and used successfully in ensuing reactions after a period of several days.

[0776] Alternatively, Intermediate 61 may be Prepared by Applying the Following Procedure:

[0777] 2-(5-bromo-4-methylpyrimidin-2-yl)propan-2-ol (8 g, 34.6 mmol), BISPIN (9.23 g, 36.3 mmol) and potassium acetate (10.2 g, 104 mmol) were combined in 1,4-dioxane (300 mL). Argon was bubbled through the mixture over 10 minutes. Then PdCl.sub.2(dppf) (0.76 g, 1.04 mmol) was added and the mixture was stirred at 100° C. The reaction mixture was cooled to room temperature and filtered over a plug of celite and rinsed with EtOAc. The combined filtrate was concentrated under reduced pressure to give the title compound as dark brown oil (16.9 g) which was used as such.

[0778] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.90 (s, 1H), 5.04 (s, 1H), 2.71 (s, 3H), 1.57 (s, 6H), 1.36 (s, 12H). LC/MS Method 9: 2.15 minutes, [M+H].sup.+: 278/279/280.

Intermediate 62

6-bromo-7-fluoroimidazo[1,2-c]pyridine-2-carboxylate

[0779] 5-bromo-4-fluoropyridin-2-amine (100 g, 0.52 mol) was dissolved in dioxane (200 mL) and added slowly to a solution of ethyl 3-bromo-2-oxopropanoate (70 mL, 0.54 mol) in 1,4-dioxane (800 mL) and stirred at r.t for 1.5 hours. Further 1,4-dioxane (400 mL) was added and the mixture heated to 95° C. and stirred overnight. The mixture was cooled to r.t and concentrated in vacuo. The residue was dissolved in water (700 mL) and basified to pH 9 with saturated aqueous sodium bicarbonate solution. The resulting solid was filtered and washed with water (2×200 mL) and diethyl ether (300 mL). The solid was dried in vacuo at 40° C. overnight to give the title compound (133 g, 86%) as a peach coloured solid. Method 7 HPLC-MS: MH+ m/z=288/290, RT=1.08 min (96%). .sup.1H NMR (500 MHz, Chloroform-d) δ 8.35 (d, J=6.3 Hz, 1H), 8.11 (s, 1H), 7.39 (d, J=8.5 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H).

Intermediate 63

{6-bromo-7-fluoroimidazo[1,2-a]pyridin-2-yl}methanol

[0780] Intermediate 62 (28.5 g, 95.3 mmol) was dissolved in anhydrous THF (500 mL) and cooled to −10° C. under nitrogen. 1M diisobutylaluminum hydride in heptane (200 mL) was added dropwise over ˜30 minutes and the reaction mixture was stirred at −10° C. under nitrogen for 30 minutes then allowed to warm to 10° C. under nitrogen over 1 hour. The reaction mixture was cooled to −50° C. and quenched by dropwise addition of saturated aqueous solution of Rochelle's salt (150 mL), stirred at −50° C. for 30 minutes, then allowed to warm to ambient temperature. The mixture was diluted with water (250 mL) and extracted with EtOAc (3×1 L). The aqueous layer was filtered through celite and extracted with EtOAc (3×500 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated under vacuum to yield the title compound (22.5 g, 93%) as a yellow solid. Method 8 HPLC-MS: MH+ m/z=245/247, RT=2.93 min (94%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.03 (d, J=6.7 Hz, 1H), 7.74 (s, 1H), 7.54 (d, J=9.8 Hz, 1H), 5.23 (t, J=5.2 Hz, 1H), 4.56 (d, J=4.4 Hz, 2H).

Intermediate 64

3-[6-bromo-7-fluoro-2-(hydroxymethyl)imidazo[1,2-a]pyridin-3-yl]-3-[2-chloro-6-(difluoromethoxy)phenyl]propanoic acid

[0781] Intermediate 63 (22.4 g, 84.02 mmol), 2-chloro-6-(difluoromethoxy)benzaldehyde (20.1 g, 92.4 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (13.3 g, 92.4 mmol), L-proline (532 mg, 4.62 mmol) and MgSO.sub.4 (15.2 g, 126 mmol) were suspended in anhydrous acetonitrile (110 mL), warmed to 100° C. and stirred under N.sub.2(g) overnight. The mixture was cooled to RT, diluted with acetonitrile (100 mL) and filtered over a sintered glass funnel. The filter cake was further washed with acetonitrile (50 mL) and the combined filtrate treated with 6M sodium hydroxide in water (42 ml) and stirred at ambient temperature for 1 hour. The mixture was acidified (to pH 4) by treatment with 6M HCl (aq) then concentrated under vacuum to give a tan solid. The solid thus obtained was slurried in water (100 mL) for 2 hours then filtered to give the title compound (41.8 g, 83%) as a beige powder. Method 7 HPLC-MS: MH+ m/z 493/495, (M−H).sup.− m/z 491/493 RT 0.91 min (84%), .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.44 (d, J=6.5 Hz, 1H), 7.65 (d, J=9.3 Hz, 1H), 7.41-7.37 (m, 2H), 7.19 (t, J=75.0 Hz, 1H), 7.17 (d, J=4.9 Hz, 1H), 5.37 (dd, J=8.7, 6.8 Hz, 1H), 4.64-4.51 (m, 2H), 3.47 (dd, J=16.5, 6.7 Hz, 1H), 3.29 (dd, J=16.5, 8.8 Hz, 1H).

Intermediate 65

6-bromo-3-{2-carboxy-1-[2-chloro-6-(difluoromethoxy)phenyl]ethyl}-7-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid

[0782] Chromium trioxide (167 mg, 1.66 mmol) and periodic acid (81.0 g, 355 mmol) were suspended in MeCN:H.sub.2O (800 mL:8 mL). The resulting mixture was added to a stirred suspension of Intermediate 64 (41.8 g, 71.0 mmol) in MeCN:H.sub.2O (312 mL:2.4 mL). The resulting mixture was stirred at r.t overnight then filtered through a sintered glass funnel. The resulting pale green filter cake was washed with acetonitrile (4×50 mL) and the filtrate concentrated under vacuum to give a gummy orange solid. This was partitioned between EtOAc (500 mL) and water (250 mL). The layers were separated and the aqueous phase further extracted with EtOAc (2×150 mL). The combined organic phase was washed with water (3×250 mL), dried (MgSO.sub.4), filtered and concentrated under vacuum to leave an orange paste. This was slurried with water (200 mL) for 72 hours (weekend period) and filtered. The resulting yellow solid was washed with water (100 mL) and dried in vacuo at 40° C. to give the title compound (39.1 g, 96%) as a pale yellow powder. Method 7 HPLC-MS: MH+ m/z 507/509, RT 1.00 minutes. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.39 (s, 2H), 8.73 (d, J=6.6 Hz, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.39-7.30 (m, 2H), 7.16-7.11 (m, 1H), 7.10 (t, J=75.0 Hz, 1H), 5.79 (t, J=8.4 Hz, 1H), 3.46 (dd, J=17.3, 9.2 Hz, 1H), 3.20 (dd, J=17.3, 7.7 Hz, 1H).

Intermediate 66

Ethyl 6-bromo-3-{1-[2-chloro-6-(difluoromethoxy)phenyl]-3-ethoxy-3-oxopropyl}-7-fluoroimidazo[1,2-a]pyridine-2-carboxylate

[0783] Potassium carbonate (25.0 g, 180 mmol) and iodoethane (14.6 ml, 181 mmol) were added to a stirred solution of Intermediate 65 (34 g, 60.3 mmol) in anhydrous DMF (350 mL) at r.t. The mixture was stirred under an atmosphere of nitrogen overnight then added slowly to vigorously stirred mixture of ice/water (1.2 L). After stirring at RT for a further 4 hours, the resulting light beige solid was filtered under vacuum and the filter cake slurried with water (50 mL). The solid was dried in vacuo at 40° C. to give the title compound (31.5 g, 88%) as a light beige powder. Method 7 HPLC-MS: MH+ m/z 564 RT 1.29 mins. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.74 (d, J=6.5 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.40-7.33 (m, 2H), 7.30-6.96 (m, 2H), 5.82 (t, J=8.5 Hz, 1H), 4.23 (qq, J=7.0, 3.8 Hz, 2H), 3.98 (q, J=7.0 Hz, 2H), 3.49 (dd, J=17.1, 8.9 Hz, 1H), 3.27 (dd, J=14.8, 7.7 Hz, 1H), 1.24 (t, J=7.1 Hz, 3H), 1.03 (t, J=7.1 Hz, 3H).

Intermediate 67

[0784] ##STR00079##

Ethyl 11-bromo-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-5-oxo-1,7-diazatricyclo[6.4.0.0.SUP.2.,.SUP.6.]dodeca-2(6),7,9,11-tetraene-4-carboxylate

[0785] Intermediate 67 was prepared from Intermediate 66 according to the method described for Intermediate 33. The crude material was purified by flash column chromatography (SiO.sub.2, 800 g) eluting with a stepwise gradient in 500 mL vessels of 15-50% EtOAc in heptanes then 100% EtOAc to afford the title compound as a yellow/orange solid. (13.3 g, 50%). Method 7 HPLC-MS: MH+ m/z 517/519, RT 1.21 min (99%), .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.51-8.34 (m, 1H), 7.94-7.83 (m, 1H), 7.56-7.42 (m, 2H), 7.39-6.68 (m, 2H), 5.77-5.63 (m, 1H), 4.28-4.13 (m, 2H), 4.07-4.00 (m, 1H), 1.27-1.19 (m, 3H).

Intermediate 68

[0786] ##STR00080##

11-bromo-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-1,7-diazatricyclo[6.4.0.0.SUP.2.,.SUP.6.]dodeca-2(6),7,9,11-tetraen-5-one

[0787] Intermediate 68 was prepared from Intermediate 67 (13.3 g, 25.7 mmol) according to the method described for Intermediate 34 to give the title compound (11.3 g, 89%) as an orange foam. Method 7 HPLC-MS: MH+ m/z 444/446, RT 1.19 minutes.

[0788] .sup.1H NMR (500 MHz, Chloroform-d) δ 7.79-7.58 (m, 1H), 7.47-7.27 (m, 3H), 7.25-7.06 (m, 1H), 6.89-5.81 (m, 1H), 5.48-5.40 (m, 1H), 3.65-3.48 (m, 1H), 3.30-3.09 (m, 1H).

Intermediate 69

[0789] ##STR00081##

(3R)-11-bromo-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-1,7-diazatricyclo[6.4.0.0.SUP.2.,.SUP.6.]dodeca-2(6),7,9,11-tetraen-5-one

[0790] The title compound was prepared by chiral separation of Intermediate 68 into the constituent enantiomers and the isolation of the second eluting peak according to the conditions outlined below:

[0791] Analytical Method: Liquid Chromatography [0792] Column: Chiralcel OD 250×4.6 mm 5 μm [0793] Temperature: 30° C. [0794] Eluent: 100% MeOH+0.1% DEA [0795] Flow rate: 1 ml/min [0796] Enantiomer A: 4.943 min [0797] Enantiomer B (Intermediate 69): 11.887 min

[0798] Preperative Method, by SFC: [0799] Column: Chiralcel OD 266×50 mm [0800] Eluent: CO2+20% MeOH [0801] Flow rate: 360 ml/min [0802] Enantiomer A: depending on the amount injected (˜5.2 min) [0803] Enantiomer B (Intermediate 69): depending on the amount injected (˜8.5 min)

[0804] Optical rotation of Enantiomer B Intermediate 69: α.sub.D+117.6 (MeOH, conc 0.255 g/100 mL, T=25° C., wavelength 589 nM, cell path 10 cm).

Intermediate 70

[0805] ##STR00082##

(R)—N-[(3R,5E)-11-bromo-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-1,7-diazatricyclo[6.4.0.0.SUP.2.,.SUP.6.]dodeca-2(6),7,9,11-tetraen-5-ylidene]-2-methylpropane-2-sulfinamide

[0806] Ti(OEt).sub.4 (1.59 mL, 2.48 mmol) was added a stirred solution of Intermediate 69 (0.57 g, 1.22 mmol) in anhydrous THF (12 mL) at r.t then (R)-2-methylpropane-2-sulfinamide (0.29 g, 2.43 mmol) was added and mixture was heated at 65° C. for 17 hours. The mixture was cooled to r.t, diluted with brine (10 mL), EtOAc (50 mL) and water (5 mL) and stirred for 15 min. The resulting solids were removed by filtration and the aqueous layer was further extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product as a beige solid. Purification by column chromatography (SiO.sub.2 Biotage isolera), eluting with 0-100% EtOAc in heptanes afforded the title compound (600 mg, 90%) as a beige solid. Method 7 HPLC-MS: MH+ m/z 548, RT 1.20 min (99%), .sup.1H NMR (500 MHz, Chloroform-d) δ 7.76-7.58 (m, 1H), 7.43-7.39 (m, 1H), 7.39-7.27 (m, 2H), 7.25-7.02 (m, 1H), 6.84-5.82 (m, 1H), 5.47-5.30 (m, 1H), 4.52-4.33 (m, 1H), 3.61-3.47 (m, 1H), 1.36 (s, 9H).

Intermediate 71

[0807] ##STR00083##

(3R,5R)-11-bromo-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-1,7-diazatricyclo[6.4.0.0.SUP.2.,.SUP.6.]dodeca-2(6),7,9,11-tetraen-5-amine dihydrochloride

[0808] Sodium borohydride (90 mg, 2.38 mmol) was added in one portion to a stirred solution of Intermediate 70 (600 mg, 1.09 mmol) in THF:water (14.7 mL:0.3 mL) under an atmosphere of nitrogen at −50° C. and the reaction maintained at this temperature for 30 minutes. The mixture was slowly warmed to 0° C. over 2 hours then stirred for a further 1 hour. The mixture was quenched with MeOH (1 mL) and diluted with water (25 mL). The intermediate was extracted with EtOAc (2×25 mL) and the combined organic phases dried (MgSO.sub.4), filtered and concentrated in vacuo to leave an off-white foam (570 mg). This was dissolved in dioxane (10 mL) and treated with 4M HCl in dioxane (1.4 mL, 5.6 mmol). The mixture was stirred at RT for 30 minutes then concentrated to dryness to afford the title compound (480 mg, 67%) as an off-white solid. The title compound was used directly in the subsequent step without further purification. Method 9 HPLC-MS: MH+ m/z 446/448, RT 1.42 minutes.

Intermediate 72

[0809] ##STR00084##

2-{5-[(3R,5R)-5-amino-3-[2-chloro-6-(difluoromethoxy)phenyl]-10-fluoro-1,7-diazatricyclo[6.4.0.0.SUP.2.,.SUP.6.]dodeca-2(6),7,9,11-tetraen-11-yl]pyrimidin-2-yl}propan-2-ol

[0810] An aqueous solution of 2M K.sub.2CO.sub.3 (1.8 mL) was added to a stirred suspension of Intermediate 71 (480 mg, 0.73 mmol) and 2-[5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (232 mg, 0.88 mmol) in 1,4-dioxane (10 mL). The mixture was degassed under a flow of nitrogen for 10 minutes then treated with bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; DCM; dichloropalladium (60 mg, 0.07 mmol) and heated to 105° C. for 1.5 hours. The mixture was cooled to RT, diluted with EtOAc (30 mL) and filtered through a pad of Celite. The filter cake was further washed with EtOAc (2×20 mL). The filtrate was washed with water (25 mL) and the aqueous phase further extracted with EtOAc (2×25 mL). The combined organic phase was washed with brine (30 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give the crude product (750 mg) as a dark brown oil. Purification by column chromatography (KP-NH, SiO.sub.2, Biotage isolera) eluting with 50-100% EtOAc in heptane followed by 0-50% MeOH in EtOAc to give the title compound (260 mg, 71%) as an off white solid. The material was azeotroped twice with toluene prior to use in the subsequent step. Method 8 HPLC-MS: MH+ m/z 504, RT 3.86 minutes, .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.90-8.78 (m, 2H), 8.18-7.90 (m, 1H), 7.68-7.54 (m, 1H), 7.45-7.36 (m, 1H), 7.37-6.66 (m, 3H), 5.14-4.92 (m, 2H), 4.48-4.32 (m, 1H), 3.57-3.34 (m, 1H), 2.95-2.54(m, 2H), 2.23-1.93 (m, 1H), 1.51-1.47 (m, 6H).

Intermediate 73

2,2-Dichloro-3-oxocyclobutyl 2,2-dimethylpropanoate

[0811] To a stirred mixture of vinyl pivalate (30 g, 234 mmol) and zinc (31 g, 474 mmol) in ether (250 mL) was added a solution of 2,2,2-trichloroacetyl chloride (34 mL, 304 mmol) in ether (250 mL) dropwise over 2.5 hours in a water bath while maintaining the reaction temperature between 15-30° C. Reaction was filtered through Celite and washed through with EtOAc (200 mL). The filtrate was washed with water (200 mL), brine (200 mL), dried over sodium sulfate and concentrated under vacuum to afford the title compound (68 g, 97% at 80% purity) as an orange liquid.

[0812] δH (500 MHz, CDCl.sub.3) ppm 5.40 (dd, J=8.4, 6.2 Hz, 1H), 3.70 (dd, J=18.9, 8.4 Hz, 1H), 3.39 (dd, J=18.9, 6.2 Hz, 1H), 1.28 (s, 9H).

Intermediate 74

3-Oxocyclobutyl 2,2-dimethylpropanoate

[0813] Zinc (74 g, 1.1 mol) was added to acetic acid (200 mL) with stirring and the suspension was cooled in an ice bath. Intermediate 73 (80%, 68 g, 228 mmol) in acetic acid (300 mL) was added dropwise over 2 hours. Upon completion of addition, the reaction was warmed to r.t and stirred for 1.5 hours. The reaction was filtered washed with DCM (100 mL). The filtrate was diluted with EtOAc (800 mL) and washed sequentially with water (3×250 mL), saturated aqueous NaHCO.sub.3 solution (3×250 mL) and brine (50 mL). The organic phase was dried over sodium sulfate and concentrated under vacuum to give crude product as a brown oil (30 g) which was purified by dry flash chromatography on silica gel eluting with 0-10% EtOAc in heptanes to afford the title compound (11 g, 28%) as a clear colourless oil

[0814] δH (500 MHz, CDCl.sub.3) 5.26-5.19 (m, 1H), 3.51-3.40 (m, 2H), 3.19-3.07 (m, 2H), 1.22 (s, 9H).

Intermediate 75

3-(5-Bromopyrimidin-2-yl)-3-hydroxycyclobutyl 2,2-dimethylpropanoate

[0815] 5-bromo-2-iodopyrimidine (16.7 g, 58.8 mmol) was dissolved in DCM (200 mL) with stirring and cooled to −78° C. under N.sub.2. 2.5 M n-BuLi in hexane in hexane (23.5 mL) was added dropwise and stirred for 20 minutes at −78° C. Intermediate 74 (10 g, 58.8 mmol) in DCM (50 mL) was cooled in a dry ice bath and added in one portion. The reaction was stirred at −78° C. for 10 minutes. The reaction was quenched by addition of saturated aqueous NH.sub.4Cl solution (20 mL) and allowed to warm to r.t, saturated aqueous NH.sub.4Cl solution (50 mL) was added and the mixture was extracted with DCM (2×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using 0-30% EtOAc in heptane to afford the title compound (7.6 g, 35%) as a yellow solid.

[0816] δH (500 MHz, CDCl.sub.3) 8.78 (s, 2H), 5.22-5.14 (m, 1H), 3.03-2.93 (m, 2H), 2.67-2.58 (m, 2H), 1.22 (s, 9H).

Intermediate 76

1-(5-Bromopyrimidin-2-yl)cyclobutane-1,3-diol

[0817] Intermediate 75 (90%, 6 g, 16.4 mmol) was dissolved in MeOH (120 mL) and K.sub.2CO.sub.3 (11.3 g, 82 mmol) was added and the reaction stirred for 18 hours at r.t. The reaction was diluted with DCM (400 mL) and washed with water (150 mL). The aqueous phase was extracted with DCM (200 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum to afford the title compound (2.94 g, 73%) as an off-white solid.

[0818] δH (500 MHz, DMSO-d6) 8.98 (s, 2H), 5.63 (s, 1H), 5.08 (d, J=6.2 Hz, 1H), 4.09-3.92 (m, 1H), 2.87-2.79 (m, 2H), 2.28-2.14 (m, 2H).

Intermediate 77

3-(5-Bromopyrimidin-2-yl)-3-hydroxycyclobutan-1-one

[0819] To a stirred solution of Intermediate 76 (2 g, 8.1 mmol) in DCM (200 mL) was added Dess-Martin periodinane (4.1 g, 9.8 mmol). The reaction was stirred for 18 hours and the resulting suspension diluted with DCM (100 mL) and washed with saturated aqueous NaHCO.sub.3 solution (100 mL). The aqueous layer was re-extracted with DCM (100 mL) and the combined organic extracts dried over sodium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with 0-30% EtOAc in heptanes to afford the title compound (1.37 g, 69%) as an off white solid.

[0820] δH (500 MHz, DMSO-d6) 9.04 (s, 2H), 6.41 (s, 1H), 3.69-3.55 (m, 2H), 3.37-3.21 (m, 2H).

Intermediate 78

3-(5-Bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]cyclobutan-1-one

[0821] Intermediate 77 (1.37 g, 5.64 mmol) was dissolved in dry DMF (20 mL) with stirring under N.sub.2 and cooled to 0° C. 1H-imidazole (1.9 g, 28.18 mmol) was added followed by tert-butyl(chloro)dimethylsilane (2.0 g, 13.5 mmol) and reaction was stirred at r.t for 20 hours. The reaction was diluted with DCM (150 mL) and washed with water (3×50 mL). The aqueous phase was re-extracted with DCM (50 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with 0-20% EtOAc in heptanes to afford the title compound (1.6 g 79%) as a pale orange oil.

[0822] δH (500 MHz, DMSO-d6) 9.06 (s, 2H), 3.78-3.66 (m, 2H), 3.44-3.34 (m, 2H), 0.88 (s, 9H), 0.00 (s, 6H).

Intermediate 79

3-(5-Bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-1-methylcyclobutan-1-ol

[0823] Intermediate 78 (1.35 g, 3.78 mmol) was dissolved in dry ether (40 mL) under N.sub.2 with stirring and cooled to 0° C. using an ice bath. 3M MeMgBr in diethylether (2.52 mL) was added dropwise and reaction stirred for 30 minutes at 0° C. The reaction was quenched with saturated aqueous NH.sub.4Cl solution (20 mL) and then water (20 mL). The mixture was extracted with EtOAc (2×50 mL), dried over sodium sulfate and concentrated to give a yellow oil. This was purified by chromatography on silica gel eluting with 0-100% DCM in heptane followed by 0-20% EtOAc in DCM to afford the title compound as a mixture of separate cis and trans isomers (total yield, 1.19 g, 84%) as clear oils.

[0824] Major isomer—cis

[0825] δH (500 MHz, CDCl.sub.3) 8.79 (s, 2H), 3.10-3.03 (m, 2H), 2.59-2.51 (m, 2H), 1.18 (s, 3H), 0.87 (s, 9H), −0.14 (s, 6H).

[0826] Minor isomer—trans

[0827] δH (500 MHz, CDCl.sub.3) 8.79 (s, 2H), 2.78-2.63 (m, 4H), 1.49 (s, 3H), 0.95 (s, 9H), 0.04 (s, 6H).

Intermediate 80

1-Chloro-2,5-difluoro-4-nitrobenzene

[0828] A suspension of 2-chloro-1,4-difluorobenzene (98 g, 660 mmol) in concentrated sulphuric acid (250 ml, 4.69 mol) was cooled with an ice/salt mixture after which a solution of nitric acid (29.1 ml, 693 mmol) in sulphuric acid (100 ml, 1.88 mol) was added drop-wise over 1.5 hours whilst maintaining the temperature between −5 and +2° C. After 30 minutes, the reaction mixture was allowed to warm to ˜17° C. and slowly poured onto ice with stirring. The formed solid was isolated by filtration and the residue washed several times with water and air dried yielding the title compound (112 g, 88%) as a pale yellow powder.

[0829] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.94 (dd, J=7.9, 6.5 Hz, 1H), 7.45 (dd, J=9.8, 5.9 Hz, 1H).

Intermediate 81

2-(5-(2,5-difluoro-4-nitrophenyl)pyrimidin-2-yl)propan-2-ol

[0830] A mixture of Intermediate 80 (50 g, 258 mmol), 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propan-2-ol (69.6 g, 264 mmol) and sodium carbonate (54.8 g, 517 mmol) in 1,4-dioxane (700 mL) and water (100 mL) was flushed with argon 3 times. Subsequently, tris(dibenzylideneacetone)dipalladium (5.91 g, 6.46 mmol) and tri-tert-butylphosphine tetrafluoroborate (7.50 g, 25.8 mmol) were added and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to r.t, filtered over celite and washed with EtOAc (1 L). The filtrate was washed with water (100 mL) and brine (2×200 mL) and the combined aqueous layers back-extracted with EtOAc (200 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; 30% EtOAc in heptane). The product containing fractions were combined, concentrated in vacuo and crystallised from iPrOH to give the title compound as an orange solid (55 g) which can be further purified if required by trituration with di-isopropyl ether.

[0831] LCMS Method 11 RT=1.806 (99.5%); [M+H].sup.+=296.

[0832] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.95 (d, J=1.5 Hz, 2H), 8.02 (dd, J=9.2, 6.1 Hz, 1H), 7.46 (dd, J=10.4, 6.0 Hz, 1H), 4.47 (s, 1H), 1.66 (s, 6H).

Intermediate 82

(S)—N-(2-bromo-6-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide.

[0833] (S)-2-methylpropane-2-sulfinamide (30 g, 248 mmol), potassium phosphate, dibasic (129 g, 743 mmol) and phosphoric acid, potassium salt (158 g, 743 mmol) were added to a cooled solution of 2-bromo-6-(difluoromethoxy)benzaldehyde (68.3 g, 272 mmol) in anhydrous THF (500 mL) at 0° C. The reaction mixture was allowed to warm to r.t and stirred overnight. The bulk of the THF was removed in vacuo and water and Et.sub.2O were added to the residue. The layers were separated and the aqueous phase extracted with Et.sub.2O. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo yielding the title compound (90 g) as a dark oil which was used as such in the next reaction.

[0834] LCMS Method 11: RT=2.084 (97.6%); [M+H].sup.+=354/356 (Br pattern).

[0835] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.84 (s, 1H), 7.58 (dd, J=7.9, 1.2 Hz, 1H), 7.33 (t, J=8.1 Hz, 1H), 7.28-7.20 (m, 1H), 6.57 (t, J=73.8 Hz, 1H), 1.30 (s, 9H).

Intermediate 83

(S)—N—((R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

[0836] Under a nitrogen atmosphere, 1,2-dibromoethane (2.19 ml, 25.4 mmol) was added to a suspension of zinc (100 g, 1.52 mol) in anhydrous THF (250 mL). The suspension was warmed to mild reflux, allowed to cool down and heated to reflux again. This cycle was repeated twice more after which TMSCl (3.24 mL, 25.4 mmol) was added causing an exothermic reaction. After 15 minutes, 3-bromoprop-1-ene (55.2 mL, 635 mmol) was added dropwise at such a rate that the very light reflux was maintained without external heating. The suspension was stirred for an additional 30 minutes while allowing to cool to r.t. Stirring was stopped and excess zinc allowed to separate. The grey supernatant solution was transferred to a dropping funnel and the flask rinsed twice with anhydrous THF. This solution was added relatively fast to a solution of crude Intermediate 82 (89.9 g, 254 mmol) in anhydrous THF (1000 ml) which was pre-cooled to −60° C. (dry ice/acetone). After the addition was complete, the cooling bath was removed and the reaction mixture allowed to slowly warm to r.t overnight. The reaction mixture was quenched by adding saturated aqueous NH.sub.4Cl solution (20 mL) and some ice. The bulk of the THF was removed in vacuo and saturated aqueous NH.sub.4Cl solution was added to the residue until almost no solids remained. This mixture was extracted with Et.sub.2O (3×200 mL). The combined organic layers were washed with saturated aqueous NH.sub.4Cl solution, water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo yielding the title compound (98.9 g) as a yellow-orange oil which was used as such in the next reaction.

[0837] LCMS Method 10: RT=3.183 (84.1%); [M+H].sup.+=396/398 (Br pattern); d.e.: 94.5% (the other diastereomer elutes at 3.43 minutes).

[0838] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.43 (d, J=7.9 Hz, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.13-6.98 (m, 1H), 6.56 (t, J=73.8 Hz, 1H), 5.82-5.62 (m, 1H), 5.19 (q, J=8.0 Hz, 1H), 5.10-4.95 (m, 2H), 4.40-4.03 (m, 1H), 3.00-2.65 (m, 2H), 1.14 (s, 9H).

Intermediate 84

(R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-amine

[0839] At 0° C., HCl (1 M in Et.sub.2O, 666 mL, 666 mmol) was added to a solution of crude Intermediate 83 (88.0 g, ˜222 mmol) in ethanol (240 mL). After 3 hours, the reaction mixture was diluted with water and the layers were separated. The organic layer was extracted twice with aqueous HCl ((0.2 M). The combined aqueous layers were made alkaline (pH=˜10) by slowly adding saturated aqueous Na.sub.2CO.sub.3 solution and the aqueous mixture thus obtained was extracted 3 times with Et.sub.2O. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo yielding the title compound (56.4 g) as a dark orange oil which was used as such in the next reaction.

[0840] LCMS Method 11: RT=1.360 (93.7%); [M+H].sup.+=292/294 (Br pattern).

[0841] .sup.1H NMR (300 MHz, Chloroform-d) δ 7.41 (dd, J=7.6, 1.6 Hz, 1H), 7.14-6.98 (m, 2H), 6.56 (t, J=73.5 Hz, 1H), 5.86-5.68 (m, 1H), 5.13-4.97 (m, 2H), 4.59 (t, J=7.6 Hz, 1H), 2.61 (t, J=7.1 Hz, 2H), 1.85 (br s, 2H).

Intermediate 85

(R)-2-(5-(5-((1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)amino)-2-fluoro-4-nitrophenyl)pyrimidin-2-yl)propan-2-ol

[0842] Under a N.sub.2 atmosphere, Intermediate 81 (54.2 g, 183 mmol), Intermediate 84 (56.4 g, ˜183 mmol), and potassium carbonate (50.7 g, 367 mmol) were mixed in acetonitrile (anhydrous, 500 mL) and stirred at 80° C. for 2 days. After cooling to r.t, the reaction mixture was filtered through sand and rinsed with EtOAc. The filtrate was evaporated to give the title compound (106.1 g) as a dark red oil that was used as such in the next reaction.

[0843] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.83 (s, 2H), 8.70 (br d, J=7.0 Hz, 1H), 8.03 (d, J=10.7 Hz, 1H), 7.49 (dd, J=7.0, 2.2 Hz, 1H), 7.24-7.10 (m, 2H), 6.92 (br d, J=6.0 Hz, 1H), 6.58 (t, J=72.3 Hz, 1H), 5.91-5.73 (m, 1H), 5.36 (q, J=8.1 Hz, 1H), 5.22 (dd, J=17.0, 1.4 Hz, 1H), 5.13 (d, J=10.1 Hz, 1H), 4.67-4.50 (m, 1H), 3.09-2.70 (m, 2H), 1.65 (s, 6H).

Intermediate 86

(R)—N-(1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)-5-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyrimidin-5-yl)-4-fluoro-2-nitroaniline

[0844] Imidazole (60.1 g, 883 mmol) and tert-butyldimethylsilyl chloride (80 g, 531 mmol) were added to a solution of crude Intermediate 85 (99.8 g, ˜176 mmol) in anhydrous N,N-dimethylformamide (250 mL). The mixture was warmed to 100° C. and stirred for 19 hours. After cooling to r.t, the reaction mixture was diluted with brine (1 L) and extracted with mixture of heptane and EtOAc (1:1, 500+200 mL). The combined organic layers were washed with water (2×100 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; 5-15% EtOAc in heptane) to give the title compound (107.1 g, 72% (over 5 steps)) as a red oil.

[0845] LCMS Method 12: RT=3.01 (94.9%); [M+H].sup.+=681/683 (Br pattern).

[0846] .sup.1H NMR (300 MHz, Chloroform-d) δ 8.78 (s, 2H), 8.65 (br s, 1H), 8.00 (d, J=10.7 Hz, 1H), 7.44 (dd, J=6.8, 2.4 Hz, 1H), 7.19-7.08 (m, 2H), 6.92-6.81 (m, 1H), 6.54 (t, J=72.4 Hz, 1H), 5.88-5.74 (m, 1H), 5.33 (q, J=8.0 Hz, 1H), 5.20 (dd, J=17.0, 1.4 Hz, 1H), 5.11 (d, J=10.1 Hz, 1H), 3.01-2.71 (m, 2H), 1.69 (s, 3H), 1.68 (s, 3H), 0.89 (s, 9H), −0.05 (s, 6H).

Intermediate 87

(4R)-4-(2-bromo-6-(difluoromethoxy)phenyl)-4-((5-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyrimidin-5-yl)-4-fluoro-2-nitrophenyl)amino)butane-1,2-diol

[0847] Osmium tetroxide (4 wt % in water, 4.80 mL, 0.786 mmol) and 4-methylmorpholine-4-oxide (50 wt % in water, 94 mL, 393 mmol) were added to a solution of Intermediate 86 (107.1 g, 157 mmol) in a mixture of acetone (330 mL) and water (45 mL). The reaction mixture was stirred overnight at ambient temperature and concentrated in vacuo. The residue was mixed with aqueous Na.sub.2S.sub.2O.sub.3 solution (10 wt %, 200 mL) and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo yielding the title compound (120.1 g) as a dark red sticky oil that was used as such in the next reaction.

[0848] LCMS Method 12: RT=2.58 (95.3%); [M+H].sup.+=715/717 (Br pattern).

Intermediate 88

(R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyrimidin-5-yl)-4-fluoro-2-nitrophenyl)amino)propanal

[0849] A solution of crude Intermediate 87 (119 g, ˜155 mmol) in THF (250 mL) was diluted with water (200 mL). To the resulting suspension, sodium periodate (68 g, 318 mmol) was added and another portion of sodium periodate (10.3 g, 48.2 mmol) after 3 hours. Stirring was continued for another hour after which the reaction mixture was quenched with aqueous Na.sub.2S.sub.2O.sub.3 (10 wt %, 300 mL). The solids were filtered off and washed with EtOAc (500 mL). The organic layers were separated (some NaCl (s) added to enable layer separation) and the aqueous phase was extracted with EtOAc (200 mL). The combined organic layers were washed with a mixture of water (100 mL) and brine (50 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give the title compound (106.6 g) as a dark red thick syrup that was used as such in the next reaction.

[0850] LCMS Method 12: RT=2.73 (72.9%); [M+H].sup.+=683/685 (Br pattern) and RT=2.57 (19.5%); [M+H].sup.+=701/703 (Br pattern) product as hydrate.

[0851] .sup.1H NMR (300 MHz, Chloroform-d) δ 9.81 (s, 1H), 8.86 (d, J=1.5 Hz, 2H), 8.68 (br d, J=8.6 Hz, 1H), 7.99 (d, J=10.6 Hz, 1H), 7.45 (dd, J=6.8, 2.4 Hz, 1H), 7.22-7.09 (m, 3H), 6.66 (t, J=72.2 Hz, 1H), 6.00 (td, J=9.0, 4.7 Hz, 1H), 3.55 (dd, J=17.9, 9.0 Hz, 1H), 3.08 (br d, J=16.9 Hz, 1H), 1.71 (s, 3H), 1.70 (s, 3H), 0.89 (s, 9H), −0.03 (s, 6H).

Intermediate 89

(R)—N—((R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyrimidin-5-yl)-4-fluoro-2-nitrophenyl)amino)propylidene)-2-methylpropane-2-sulfinamide

[0852] Titanium (IV) isopropoxide (87 g, 307 mmol, 91 mL) was added to a solution of crude Intermediate 88 (105 g, ˜154 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (18.63 g, 154 mmol) in DCM (180 mL). After stirring overnight, the reaction mixture was poured out into a mixture of water (300 mL) and kieselguhr (30 g), stirred for 10 minutes, and filtered. The yellow solid was washed several times with DCM. The layers of the filtrate were separated and the organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo yielding the title compound (114.5 g) as a yellow-orange glass that was used as such in the next reaction.

[0853] LCMS Method 12: RT=2.88 minutes; [M+H].sup.+=786/788 (Br pattern).

Intermediate 90

(R)—N—((R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-(2-(2-((tertbutyldimethylsilyl)oxy)propan-2-yl) pyrimidin-5-yl)-4-fluoro-2-nitrophenyl) amino)propylidene)-2-methylpropane-2-sulfinamide

[0854] To a stirred solution of crude Intermediate 89 (103.6 g, ˜139 mmol) in DCM (500 mL) was added yttrium(III) trifluoromethanesulfonate (3.53 g, 6.58 mmol). The flask was sealed with a suba seal and to the resulting mixture, trimethylsilyl cyanide (15.68 g, 158 mmol, 19.77 mL) was added by syringe in a steady stream. After stirring for 5 days, the reaction mixture was concentrated in vacuo and co-evaporated with EtOAc yielding the title compound (101 g) as a yellow-red foaming oil that was used as such in the next reaction.

[0855] LCMS Method 13: RT=2.70 minutes; [M+H].sup.+=813/815 (Br pattern).

Intermediate 91

(R)—N-((3R)-3-((2-amino-5-(2-(2-((tertbutyldimethylsilyl)oxy)propan-2-yl)pyrimidin-5-yl)-4-fluorophenyl)amino)-3-(2-bromo-6-(difluoromethoxy)phenyl)-1-cyanopropyl)-2-methylpropane-2-sulfinamide

[0856] Under a N.sub.2 atmosphere, platinum on charcoal (10 wt %, 13.88 g, 7.11 mmol) was added to a mixture of crude Intermediate 90 (106 g, 147 mmol) and zinc(II) bromide (12.46 g, 55.3 mmol) in EtOAc (1000 mL). Subsequently, the reaction was purged with H.sub.2 and stirred under atmospheric H.sub.2 pressure for 3 days. The reaction mixture was flushed with N.sub.2, filtered over kieselguhr and rinsed with EtOAc. The filtrate (˜1.5 L) was washed with water (500 mL) and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo yielding the title compound (109 g) as a brown-yellow foaming oil that was used as such in the next reaction.

[0857] LCMS Method 11: RT=1.360 (76.5%); [M+H].sup.+=783/785 (Br pattern).

Intermediate 92

[0858] ##STR00085##

2-(5-((1R,3R)-3-amino-1-(2-bromo-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1Hbenzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol

[0859] To a stirred solution of crude Intermediate 91 (109 g, 147 mmol) in ethanol (1000 mL) was added HCl (4 M in dioxane, 69.5 mL, 278 mmol). The resulting mixture was stirred at reflux for 8 hours and allowed to cool to r.t overnight. The reaction mixture was concentrated in vacuo and co-evaporated with ethanol. The residue was triturated in Et.sub.2O (1.5 L) and the formed precipitate was isolated by filtration, washed with Et.sub.2O, and dried on the filter. This material was taken up in iPrOH (250 mL) and stirred at reflux for 15 minutes. The resulting suspension was stirred under N.sub.2 while allowing to cool to r.t. The resulting thick viscous suspension was diluted with iPrOH (250 mL) and filtered through a glass filter. The residue thus obtained was dissolved in water (1.5 L) and Et.sub.2O (500 mL) while stirring. The layers were separated and the organic layer was extracted with aqueous HCl (0.1 M, 200 mL). The combined aqueous layers were washed with Et.sub.2O (500 mL), made alkaline (pH=10) with NaOH (s, 40 g), and extracted with DCM (2×500 mL). The combined DCM layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue thus obtained was co-evaporated with iPr.sub.2O and Et.sub.2O yielding the title compound (40.6 g, 48%) as a green foam.

[0860] LCMS Method 10: RT=2.37 minutes; [M+H].sup.+=548/550 (Br pattern).

[0861] .sup.1H NMR (300 MHz, Chloroform-d): 3:2 mixture of rotamers δ 8.74-8.70 (m, 2H), 7.61 (d, J=8.2 Hz, 0.6H), 7.57 (d, J=11.2 Hz, 1H), 7.45 (dd, J=6.6, 2.6 Hz, 0.4H), 7.37-7.28 (m, 1.4H), 7.04 (d, J=8.3 Hz, 0.6H), 6.71 (t, J=72.4 Hz, 0.4H), 6.59 (dd, J=12.0, 6.6 Hz, 1H), 6.23-6.13 (m, 1H), 5.92 (dd, J=74.5, 70.9 Hz, 0.6H), 4.72 (br s, 1H), 4.61 (br s, 1H), 3.70-3.41 (m, 1H), 2.77 (dt, J=13.5, 8.6 Hz, 0.4H), 2.63 (dt, J=13.7, 7.6 Hz, 0.6H), 2.03 (br s, 2H), 1.62 (s, 3.6H), 1.61 (s, 2.4H).

Intermediate 93

[0862] ##STR00086##

Ethyl 2-[[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]amino]acetate

[0863] Ethyl bromoacetate (91.3 mg, 0.54 mmol) was added to a solution of potassium carbonate (252 mg, 1.82 mmol), and Intermediate 92 (250 mg, 0.45 mmol) in DMF (1.5 mL). The reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to ambient temperature and the crude mixture was quenched with water and extracted with EtOAc (2×5 mL). The organic phase was washed with saturated brine (5 mL), the combined organic phases were dried with sodium sulphate, filtered and concentrated in vacuo to give an oil which was purified by flash chromatography in silica gel (0 to 100% EtOAc in hexanes) to afford the title compound (220 mg, 76% yield) as a brown solid.

[0864] LC/MS Method 3: RT 2.06 mins (pH 10), m/z 634/636.

Intermediate 94

[0865] ##STR00087##

tert-butyl 3-[[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]carbamoyl]azetidine-1-carboxylate

[0866] Intermediate 92 (550 mg, 1.00 mmol) was added to a solution of 1-tert-butoxycarbonylazetidine-3-carboxylic acid (222 mg, 1.10 mmol), HATU (432 mg, 1.10 mmol) and N,N-di-isopropylethylamine (0.38 mL, 2.2 mmol) in DMF (20 mL). The reaction mixture was stirred at ambient temperature for 3 hours. Water was added and the reaction mixture extracted with EtOAc and the organic phases removed in vacuo to yield a crude product. The crude material was purified by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) as eluent, yielding 640 mg (87%) of the title compound as an amorphous solid. LCMS basic Method 3: RT 2.25 min, [M+H-BOC].sup.+=631.

Intermediate 95

[0867] ##STR00088##

tert-Butyl 3-{[(6R,12R)-11-(difluoromethoxy)-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]carbonyl}azetidine-1-carboxylate

[0868] To Intermediate 94 was added cesium acetate anhydrous (420 mg, 2.18 mmol), cuprous iodide (170 mg, 0.87 mmol) and dimethyl sulfoxide (0.9 mL). The mixture was seal and purged 3 times with nitrogen. The reaction mixture was stirred for 18 hours at 100° C. Water and ethyl acetate were added to the reaction mixture and the two layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organics were filtered through a phase separator and the solvent was evaporated. The crude material was purified by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) as eluent, yielding 158 mg (28%) of the title compound as a brown solid. LCMS Method 3: RT 2.72 min, [M+H].sup.+=651

Intermediate 96

[0869] ##STR00089##

tert-butyl 3-[[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]carbamoyl]azetidine-1-carboxylate

[0870] Intermediate 40 (250 mg, 0.58 mmol) was added to a solution of 1-tert-butoxycarbonylazetidine-3-carboxylic acid (130 mg, 0.65 mmol), HATU (252 mg, 0.643 mmol) and N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) in DMF (11 mL). The reaction mixture was stirred at room temperature for 3 hours. Water was added to the reaction and the mixture extracted with EtOAc (×3), dried (sodium sulphate), filtered and concentrated in vacuo. The crude material was purified by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) as eluent, yielding 280 mg (78%) of the title compound as an amorphous solid.

[0871] LCMS Method 3: RT 2.48 minutes, [M+H].sup.+=611/613.

Intermediate 97

[0872] ##STR00090##

tert-butyl 3-{[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]carbonyl}azetidine-1-carboxylate

[0873] To Intermediate 96 (165 mg, 0.27 mmol) was added cesium acetate (130 mg, 0.67 mmol), cuprous iodide (52 mg, 0.27 mmol) and dimethyl sulfoxide (0.3 mL). The mixture was sealed in a pressure tube and purged 3 times with nitrogen. The reaction mixture was stirred at 100° C. overnight. Water and ethyl acetate were added to the reaction mixture and the two layers were separated. The aqueous layer was extracted with further ethyl acetate. The combined organic layer was filtered through a phase separator and the solvent was evaporated. The crude material was purified by column chromatography on silica gel using hexane/ethyl acetate (0 to 100%) as eluent, yielding 85 mg (59%) of the title compound as a brown solid. LCMS Method 3: RT 2.63 min., [M+H].sup.+=531/533.

Intermediate 98

[0874] ##STR00091##

cis-3-{[tert-butyl(dimethyl)silyl]oxy}-3-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}-1-methylcyclobutanol

[0875] The title compound was prepared from 3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl], and Example 23 according to a method involving the same procedural steps as those described for Example 20, to give, following purification by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) as eluent the title compound as a white solid (83 mg, 37% yield).

[0876] LC/MS Method 3: RT 2.73 minutes, [M+H].sup.+=684.

Intermediate 99

[0877] ##STR00092##

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]pyridine-3-sulfonamide

[0878] Pyridine-3-sulfonyl chloride (1.1 eq, 0.6 mmol) was added to a solution of Intermediate 92 (300 mg, 0.55 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.3 mmol) in dichloromethane (2.8 mL) at room temperature. The mixture was stirred for 1 hour before solvent was partially evaporated. The crude material was purified by column chromatography on silica gel using hexane/ethyl acetate (0 to 100%) as eluent, yielding 276 mg (73%) of the title compound. LCMS Method 3: RT 1.91 min. (pH 10), [M+H]+=689.

Intermediate 100

1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-3-(trifluoromethyl)azetidin-3-ol

[0879] To a solution of the trifluoroacetate salt of (trifluoromethyl)-3-aziditin-3-ol (5.8 g, 22.75 mmol) and 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (5 g, 20.75 mmol) in acetonitrile (80 mL) was added dropwise triethylamine (9.5 mL, 68.5 mmol) and the resultant mixture stirred overnight. LC/MS showed completion of reaction, concentrated to an off-white solid, ice-water was added, triturated, filtered, washed with cold water and dried by suction to give the title compound (6.1 g, 50%) as cream solid. .sup.1H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 2H), 7.46 (s, 1H), 4.32 (m, 2H), 4.10 (d, J=10.3 Hz, 2H), 1.29 (s, 12H). LC/MS Method 3: m/z 346, RT 1.09 min (pH=10).

Intermediate 101

[0880] ##STR00093##

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]methanesulfonamide

[0881] To a solution of Intermediate 92 (202 mg, 0.37 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) in DCM (4 mL) at 0° C. was added N,N-diisopropylethylamine (76 μL, 0.43 mmol) followed by methanesulfonyl chloride (30 μL, 0.38 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and then at room temperature for 45 minutes, after which time the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 25-100% EtOAc in hexane) to give the title compound (193 mg, 83%) as a yellow solid.

[0882] LCMS Method 3: (ES+) 626/628 (M+H).sup.+, RT 1.90 minutes.

[0883] LCMS Method 4: (ES+) 626/628 (M+H).sup.+, RT 1.86 minutes.

Intermediate 102

[0884] ##STR00094##

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]cyclopropanesulfonamide

[0885] To a solution of Intermediate 92 (151 mg, 0.28 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in DCM (3 mL) at 0° C. was added N,N-diisopropylethylamine (58 μL, 0.33 mmol) followed by cyclopropanesulfonyl chloride (172 μL, 1.65 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and then at room temperature for 18 hours, after which time the reaction mixture was partitioned between DCM (30 mL) and water (20 mL), the layers separated and the aqueous extracted with DCM (3×20 mL). The combined organics were dried (phase separator), and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 25-100% EtOAc in hexane) to give the title compound (110 mg, 61%) as a purple solid.

[0886] LCMS (ES+) Method 3: 652/654 (M+H).sup.+, RT 2.20 minutes.

[0887] LCMS (ES+) Method 4: 652/654 (M+H).sup.+, RT 2.01 minutes.

Intermediate 103

[0888] ##STR00095##

2-[5-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-3-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]propan-2-ol

[0889] To a solution of Intermediate 92 (251 mg, 0.46 mmol) and potassium carbonate (252 mg, 1.82 mmol) in DMF (2 mL) was added (2-bromoethoxy)-tert-butyldimethylsilane (99 μL, 0.46 mmol) and reaction mixture stirred at 70° C. for 18 hours. The reaction mixture was partitioned between EtOAc (25 mL) and water (25 mL), layers separated and aqueous extracted with EtOAc (2×25 mL), the combined organics dried (phase separator) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-100% EtOAc in hexane) to give the title compound (128 mg, 39%) as a brown oil.

[0890] LCMS (ES+) Method 3: 706/708 (M+H).sup.+, RT 3.10 minutes.

Intermediate 104

[0891] ##STR00096##

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]benzenesulfonamide

[0892] To a solution of Intermediate 92 (202 mg, 0.37 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in DCM (4 mL) at 0° C. was added N,N-diisopropylethylamine (77 μL, 0.44 mmol) followed by benzenesulfonyl chloride (49 μL, 0.38 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and then at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (SiO.sub.2, 0-60% EtOAc in hexane) to give the title compound (178 mg, 70%) as a yellow solid.

[0893] LCMS (ES+) Method 3: 688/690 (M+H).sup.+, RT 2.20 minutes.

[0894] LCMS (ES+) Method 4: 688/690 (M+H).sup.+, RT 2.01 minutes.

Intermediate 105

[0895] ##STR00097##

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]-6-methoxy-pyridine-3-sulfonamide

[0896] To a solution of Intermediate 92 (150 mg, 0.27 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in DMF (3 mL) at 0° C. was added N,N-diisopropylethylamine (57 μL, 0.33 mmol) followed by 6-methoxypyridine-3-sulfonyl chloride (62 mg, 0.29 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and then at room temperature 30 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-100% EtOAc in hexane) to give the title compound (148 mg, 75%) as a dark beige solid. LCMS (ES+) Method 3: 719/721 (M+H).sup.+, RT 2.30 minutes. LCMS (ES+) Method 4: 719/721 (M+H).sup.+, RT 2.42 minutes. δ.sub.H (300 MHz, DMSO-d.sub.6) 8.77-8.97 (m, 1H), 8.71-8.77 (m, 3H), 8.19-8.26 (m, 1H), 7.59-7.68 (m, 1H), 7.39-7.50 (m, 2H), 7.38 (t, 1H, J 73.4 Hz), 7.07 (d, 1H, J 8.7 Hz), 6.65-6.71 (m, 1H), 6.04-6.21 (m, 1H), 5.22-5.44 (m, 1H), 5.05-5.07 (m, 1H), 3.96 (s, 3H), 3.05-3.24 (m, 1H), 2.59-2.79 (m, 1H), 1.47-1.52 (m, 6H).

Intermediate 106

[0897] ##STR00098##

Ethyl [(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5-oxo-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]acetate

[0898] To a solution of Intermediate 23 (100 mg, 0.169 mmol) in THF (4 mL) was added potassium bis(trimethylsilyl)amide (0.2 mL, 0.2 mmol, 1M in THF) at −78° C. and stirred for 40 minutes before the addition of ethyl bromoacetate (25.0 μL, 0.225 mmol). The reaction mixture was stirred at −78° C. for 30 mins before being quenched with water. The mixture was extracted with DCM (2×20 mL), and the organics were combined, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was columned on silica eluting with 0-5% MeOH/DCM to give the title compound (88 mg). LC/MS: Method 3: RT 3.53 minutes.

Intermediate 107

[0899] ##STR00099##

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-(2,2,2-trifluoro ethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0900] To a solution of Intermediate 23 (90.0 mg, 0.152 mmol) in DMF (3.5 mL) were added cesium carbonate (250 mg, 0.767 mmol) and 2-iodo-1,1,1-trifluoroethane (0.06 mL, 0.60 mmol) at ambient temperature. The reaction mixture was heated at 150° C. for 3 hours. The reaction mixture was partitioned between EtOAc (2×10 mL) and water (20 mL), and the organics were combined, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was progressed to the next step without further purification.

[0901] LC/MS: Method 3 MH.sup.+ 674, retention time 2.03 minutes.

Intermediate 108

[0902] ##STR00100##

(7R,14R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0903] To a solution of Intermediate 23 (100.0 mg, 0.169 mmol) in THF (4.0 mL) was added potassium bis(trimethylsilyl)amide (0.20 mL, 0.20 mmol, 1M in THF) at −78° C. followed by the addition of (2-bromoethoxyl)-tert-butyldimethylsilane (50.0 μL, 0.231 mmol). The reaction mixture was heated in a microwave at 70° C. for 24 hours before being quenched with aqueous saturated NH.sub.4Cl and extracted with EtOAc (2×10 mL). The organics were combined, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was progressed to the next step without further purification. LC/MS Method 3: ESI MH.sup.+ 750, retention time 4.23 minutes.

Intermediate 109

[0904] ##STR00101##

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-(2-hydroxyethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0905] To a solution of Intermediate 108 (80.0 mg, 0.107 mmol) in THF (5.0 mL) was added a solution of tetrabutylammonium fluoride (0.20 mL, 0.20 mmol, 1M in THF) at ambient temperature and the mixture was stirred for 72 hours. The reaction mixture was partitioned between water (10 mL) and DCM (3×10 mL), and the organics were combined, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was progressed to the next step.

[0906] LC/MS Method 3: ESI MH.sup.+ 636, retention time 3.21 minutes.

Intermediate 110

[0907] ##STR00102##

(7R,14R)-11-chloro-1-(difluoromethoxy)-6-(trideutero)methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0908] To a solution of Example 11 (90.0 mg, 0.24 mmol) in THF (4 mL) was added a solution of KHMDS in THF (1M, 0.25 mL, 0.25 mmol) dropwise at −78° C. and the mixture was stirred for 30 minutes before the addition of CD.sub.3I (30.1 μL, 0.48 mmol). The reaction mixture was warmed to 0° C. and stirred for 3 hours. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl solution, extracted with EtOAc, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with 0-10% MeOH/EtOAc to give the title compound (95 mg, 99%). LC/MS Method 3: ESI MH.sup.+ 393, retention time 1.93 minutes.

Intermediate 111

[0909] ##STR00103##

tert-butyl (2-{5-[(7R,14R)-1-(difluoromethoxy)-6-(trideutero)methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate

[0910] To a solution of tert-butyl N-[1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]ethyl]carbamate (260 mg, 0.72 mmol) and Intermediate 110 (94 mg, 0.24 mmol) in 1,4-dioxane (3 mL) were added K.sub.3PO.sub.4 (294 mg, 1.40 mmol), tricyclohexyl phosphonium tetrafluoroborate (15 mg, 0.04 mmol) and tris(dibenzylideneacetone) dipalladium(0) (28 mg, 0.03 mmol) were added. The mixture was degassed for 10 minutes with nitrogen before heating at 110° C. for 18 hours. The reaction mixture was quenched with water and extracted with EtOAc (2×10 mL), dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with 0-10% MeOH/DCM to give the title compound (40 mg, 28%). LC/MS Method 3: ESI MH.sup.+ 594, retention time 2.10 minutes.

Intermediate 112

[0911] ##STR00104##

rac 2-(5-{(1R,3R)-3-amino-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl}-4-methylpyrimidin-2-yl)propan-2-ol

[0912] Intermediate 61 (0.15 g, 0.6 mmol) and potassium acetate (0.15 g, 1.5 mmol) were suspended in anhydrous 1,4-dioaxane (5 mL) in a sealable vessel. The mixture was stirred and degassed thoroughly under a stream of N.sub.2(g) for 15 min then treated with bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; dichloropalladium (0.02 g, 0.02 mmol), and a solution of Intermediate 71 (82%, 0.25 g, 0.4 mmol) in a mixture of dioxane (1 mL) and 2M K.sub.2CO.sub.3 in water (1.24 ml) was added and the mixture warmed to 100° C. overnight. After cooling to room temperature the mixture was diluted with EtOAc (25 mL) and filtered over a pad of celite. The filtrated was washed with water (10 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give the crude product (0.4 g) as a brown gum. Column chromatography (C18, biotgae isolera, 60 g) eluting with 0 to 50% acetonitrile in water spiked with 0.1% NH.sub.4OH afforded the title compound (0.15 g, 58%) as an orange glass. The material was azeotroped twice with toluene prior to use in the subsequent step. Method 8 HPLC-MS: MH+ m/z 518, RT 1.43 minutes. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.56-8.51 (m, 1H), 7.99-7.77 (m, 1H), 7.63-7.53 (m, 1H), 7.43-7.31 (m, 2H), 7.29-7.24 (m, 1H), 7.06-6.73 (m, 1H), 5.10-4.90 (m, 2H), 4.47-4.31 (m, 1H), 3.52-3.40 (m, 1H), 2.34-2.27 (m, 3H), 2.03-1.81 (m, 3H), 1.52-1.45 (m, 6H).

Intermediate 113

[0913] ##STR00105##

(7R,14R)-11-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)-4-methylpyridin-3-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0914] The title compound was prepared from Example 11 (450 mg, 1.20 mmol) and tert-butyl-dimethyl-[1-methyl-1-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]ethoxy]silane (483 mg, 1.86 mmol), by a palladium catalyzed Suzuki coupling according to a method involving the same procedural steps as those described for Example 20. The crude product was purified by flash chromatography (SiO.sub.2, 0 to 100% EtOAc in DCM and then 1 to 10% MeOH in EtOAc) to obtain the title compound (650 mg, 81%) as a brown solid. LCMS Method 3 (ES+) RT 3.20 min, 605 (M+H).sup.+.

Intermediate 114

tert-butyl N-[1-(5-bromopyrimidin-2-yl)-1-methyl-ethyl]carbamate

[0915] 2-(5-bromopyrimidin-2-yl)propan-2-amine (200 mg, 0.92 mmol) was dissolved in THF (5 mL) and di-tert-butyl dicarbonate solution (1.0M) (1.3 mL, 1.3 mmol) in THF added. After 2 hours the solvents were removed in vacuo to afford the title compound as an orange gum (300 mg, 92%). LCMS Method 3 (ES+) RT 1.88 min, 338.0/340.0 (M+Na).sup.+.

Intermediate 115

[0916] ##STR00106##

tert-butyl (2-{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}propan-2-yl)carbamate

[0917] The title compound was prepared from Example 11 (300 mg, 0.80 mmol) and Intermediate 114 (252 mg, 0.80 mmol) in accordance with the Method described for Example 70. The crude product was purified by flash chromatography in (SiO.sub.2, 0 to 100% EtOAc in DCM and then 1 to 10% MeOH in EtOAc) to obtain the title compound (154 mg, 33%).

[0918] LCMS Method 3 (ES+) RT 1.43 min, 577.2 (M+H).sup.+

Intermediate 116

[0919] ##STR00107##

tert-butyl (2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate

[0920] The title compound was prepared from Example 10 (50 mg, 0.13 mmol) and Intermediate 114 (100 mg, 0.32 mmol) in accordance with the Method described for Example 70. The product was purified by flash chromatography (SiO.sub.2, 0 to 100% EtOAc in DCM and then 1 to 10% MeOH in EtOAc) to obtain the title compound (55 mg, 71%). LCMS Method 3 (ES+) RT 2.16 min, 595.2 (M+H).sup.+

Intermediate 117

[0921] ##STR00108##

tert-butyl {(1R,3R)-1-[2-acetyl-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

[0922] To a degassed solution of Intermediate 42 (1.4 g, 2.6 mmol) in dry toluene (30 mL) under argon were added tributyl(1-ethoxyvinyl)tin (1.1 mL g, 3.2 mmol) and bis(triphenylphosphine)-palladium(II)dichloride (100 mg, 0.141 mmol). The reaction mixture was heated at 105° C. for 48 hours. Further Tributyl(1-ethoxyvinyl)tin (0.7 g, 2.0 mmol) and bis(triphenylphosphine)palladium(II)-dichloride (64 mg, 0.0912 mmol) were added and the reaction mixture was heated for an additional 5 hours at 105° C. The reaction mixture was cooled to room temperature and poured onto a saturated aqueous solution of KF. The mixture was extracted with ethyl acetate, filtered over celite, dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude compound was re-dissolved in THF (50 mL), p-toluene sulfonic acid (200 mg) and water (5 mL) was added and the mixture was heated at 45° C. for 5 hours. The mixture was poured onto ice, neutralized with solid NaHCO.sub.3 and extracted with ethyl acetate (×3). The combined organic layers were dried over MgSO.sub.4, filtered and evaporated to dryness. The crude compound was purified by flash chromatography with ethyl acetate 50%-heptane 50% to afford 1.27 g of the title compound as a yellow solid. LCMS Method 3 basic (ES+) RT 2.75 min. 492.1 (M+H).sup.+.

Intermediate 118

[0923] ##STR00109##

(7R,14R)-11-chloro-1-(difluoromethoxy)-5-methyl-7,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

[0924] A solution of Intermediate 117 (0.48 g, 0.976 mmol) in dichloromethane (10 mL) was cooled to 0° C. and trifluoroacetic acid (10 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. The mixture was poured on ice, brought to neutral pH with solid NaHCO.sub.3 and extracted with dichloromethane (×3). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo to afford 0.25 g (65%) of the title compound. LCMS basic Method 3 (ES+) RT 2.42 min., 374.1 (M+H).sup.+.

Intermediate 119

[0925] ##STR00110##

(7R,14R)-11-chloro-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

[0926] To a solution of Intermediate 118 (350 mg, 0.893 mmol) in a mixture of THF (8 mL) and EtOH (8 mL) were added macroporous polymer-supported cyanoborohydride (1.12 g, 4.4 mmol, 4.0 mmol/g loading) and acetic acid (50 μL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered over celite and concentrated in vacuo. The residue was poured onto ice/water and solid NaHCO.sub.3 was added till pH=9. The aqueous phase was extracted with DCM (×3), the combined organic layers dried over MgSO.sub.4, filtered and concentrated to dryness. The crude compound was purified by normal phase chromatography (DCM 95%-MeOH 5%) to afford 237 mg (71%) of the title compound as a mixture of diastereomers. LCMS Method 3 basic (ES+) RT 1.99 min., 376.1 (M+H).sup.+.

Intermediates 120 and 121

[0927] ##STR00111##

(5R,7R,14R)-11-chloro-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

(5S,7R,14R)-11-chloro-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

[0928] The title compounds were isolated from Intermediate 119 (0.118 g) by purification under SFC conditions on Chiralpak OD-A20 column (50*266, 360 mL/min, 25° C., CO.sub.2+20% iPrOH, con: 24 g/l), yielding 37 mg (31%) of Intermediate 120 (RT 3.65 min) and 40.0 mg (34%) of Intermediate 121 (RT 7.57 min) respectively.

[0929] Intermediate 120: LCMS Method 4 (ES+) RT 2.18 min., 376.2 (M+H)+.

[0930] Intermediate 121: LCMS Method 4 (ES+) RT 2.14 min., 376.2 (M+H)+.

Intermediate 122

[0931] ##STR00112##

tert-butyl {(1R,3R)-7-[2-(2-{[tert-butyl(dimethyl) silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

[0932] Intermediate 22 (5 g, 8,331 mmol) was suspended in DCM (10 mL) and cooled on an ice bath. Triethylamine (2.6 mL, 18,33 mmol) and di-tert-butyl dicarbonate (2.2 g, 10.0 mmol) were added. The reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was quenched by addition of water (10 mL). The aqueous layer was extracted by DCM (3×10 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuum. The residue was purified over silica gel (eluting with heptane/ethyl acetate 7/3) to afford 5.1 g (87%) of the title compound as a white solid.

[0933] LCMS Method 3 (ES+) RT 3.64 min., 700.3/702.3 (M+H).sup.+

Intermediate 123

[0934] ##STR00113##

Ethyl 2-{(1R,3R)-3-[(tert-butoxycarbonyl)amino]-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl}-3-(difluoromethoxy)benzoate

[0935] Intermediate 122 (5 g, 7.14 mmol), potassium carbonate (1.50 g, 10.71 mmol), molecular sieve 4 A° powder (2 g) and dichloro[bis(dicyclohexylphosphino)propane]-palladium(II) (350 mg, 0.57 mmol) were suspended in dry dimethyl sulfoxide (50 mL) and ethanol (1.8 mL, 32 mmol). The slurry was stirred under 5 bars of CO gas at 100° C., overnight. The slurry was filtered through a pad of celite and rinsed with ethyl acetate (30 mL). The filtrate was washed successively by a saturated solution of aqueous NH.sub.4Cl (20 mL), brine (20 mL), dried over MgSO.sub.4, filtetred and concentrated in vacuum affording 5.1 g of the crude title compound as a brown solid, used without further purification. LCMS Method 3 (ES+) RT 3.64 min., 738.1 (M+H).sup.+.

Intermediate 124

[0936] ##STR00114##

tert-butyl {(1R,3R)-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-(difluoromethoxy)-6-(hydroxymethyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2 a]benzimidazol-3-yl}carbamate

[0937] Intermediate 123 6 (3 g) was dissolved in ethanol (30 mL). At 0° C., sodium borohydride (1.2 g) was added, followed by calcium chloride (1.805 g). The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was filtered through a pad of celite, and rinsed with ethyl acetate (2×20 mL). The filtrate was washed with water (2×20 mL) and brine (20 mL), and dried over MgSO.sub.4. The residue was purified by basic reverse phase preparative HPLC yielding 948 mg (33%) of the title compound as a white solid. LCMS Method 3 (ES+) RT 3.45 minutes 696.3 (M+H).sup.+.

Intermediate 125

[0938] ##STR00115##

tert-butyl {(1R,3R)-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-(difluoromethoxy)-6-formylphenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

[0939] Intermediate 124 (750 mg, 1.08 mmol) was dissolved in 1,4-dioxane (16 mL) before addition of manganese dioxide (2.3 g, 27 mmol) at room temperature. The reaction was stirred overnight. The crude reaction mixture was filtered through a pad of celite and rinsed with 20 mL of chloroform. The filtrate was concentrated to dryness in vacuum yielding to a crude 860 mg of title compound used without further purification. LCMS Method 3 basic (ES+) RT 5.85 minutes. 694.4 (M+H).sup.+.

Intermediate 126

[0940] ##STR00116##

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-7,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

[0941] Intermediate 125 (860 mg, 1.24 mmol) was treated in accordance with the procedure described for the synthesis of Intermediate 118 to afford 710 mg (99%) of the title compound as a yellow glass.

[0942] LCMS Method 3 basic (ES+) RT 5.76 min., 576.2 (M+H).sup.+.

Intermediate 127

[0943] ##STR00117##

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

[0944] Intermediate 126 (710 mg, 1.23 mmol) was treated in accordance with the synthetic method described for Intermediate 119 to afford the title compound 655 mg (92%) as a yellow oil.

[0945] LCMS Method 3 basic (ES+) RT 5.84 min., 578.7 (M+H).sup.+.

Intermediate 128

[0946] ##STR00118##

1-[(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone

[0947] To a solution of Intermediate 127 (655 mg, 1.13 mmol) in dichloromethane (11 mL) was added successively pyridine (0.28 mL, 3.4 mmol) and acetic anhydride (0.22 mL, 2.27 mmol). The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was washed by a saturated aqueous solution of NH.sub.4Cl (2×20 mL) and a saturated aqueous solution of NaHCO.sub.3 (2×10 mL). The aqueous phases were extracted by DCM (2×10 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by chromatography over silica gel (eluting with ethyl acetate 100% to ethyl acetate/ethanol 9/1), yielding to 300 mg (43%) of title compound as a yellow glass.

[0948] LCMS Method 3 basic (ES+) RT 5.84 min., 620.3 (M+H).sup.+

Intermediate 129

[0949] ##STR00119##

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

[0950] Intermediate 127 (30 mg, 0.051 mmol) in 2,2,2-trifluoroethanol (3 mL) and formaldehyde (1 mL, 25.97 mmol) was stirred at room temperature for 30 minutes before addition of sodium borohydride (20 mg, 0.52 mmol). The reaction mixture was heated at 70° C. for 2 hours. At room temperature, additional sodium borohydride (20 mg, 0.52 mmol) was added, and the reaction mixture heated at 70° C. for addition 1 hour. The reaction mixture was filtered through a pad of celite, and the residual solid washed by 2,2,2-trifluoroethanol (2×4 mL). The filtrate was concentrated in vacuum. The residue was used without further purification.

[0951] LCMS Method 3 basic (ES+) RT 5.97 min., 592.2 (M+H).sup.+.

Intermediate 130

[0952] ##STR00120##

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

[0953] To a solution of Intermediate 126 (0.074 mmol) in acetonitrile (1 mL) and N,N dimethylformamide (17 μl) was added successively at 0° C., trifluoroacetic acid (7 μL, 0.092 mmol), potassium hydrogen fluoride (4.4 mg, 0.055 mmol) and (trifluoromethyl)trimethylsilane (16 μL, 0.11 mmol). The resulting slurry was allowed to warm to ambient temperature overnight. The reaction mixture was then evaporated and purified by preparative basic reverse phase HPLC. This was followed by a second acidic preparative HPLC to afford the TFA salt of the title compound which was solubilized in EtOAc (2 mL) and washed with a saturated solution of NaHCO.sub.3. The aqueous layer was extracted with EtOAc (2×2 mL). The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo to afford 7 mg (15%) of the title compound as a mixture of diastereoisomers.

[0954] LCMS Method 3 (ES+) RT 6.08 min., 646.2 (M+H).sup.+.

Intermediate 131 and Intermediate 132

[0955] ##STR00121##

(5R,7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine and

(5S,7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

[0956] To a solution of Intermediate 126 (0.72 mmol) in acetonitrile (5 mL) and DMF (166 μL) was added successively at 0° C., trifluoroacetic acid (69 μL, 0.90 mmol), potassium hydrogen fluoride (43 mg, 0.54 mmol) and (trifluoromethyl)trimethylsilane (159 μL, 1.08 mmol). The resulting slurry was allowed to warm to room temperature for 3 hours. The reaction mixture was then diluted with EtOAc and a saturated aqueous solution of NaHCO.sub.3. The two phases were separated and the aqueous layer further extracted with EtOAc (×2). The combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure.

[0957] The crude was purified over silica gel (eluting with dichloromethane-methanol-aqueous ammonia/97:2.7:0.3). This was followed by a second purification by reverse phase preparative HPLC to give the following diastereoisomers:

[0958] 4.8 mg (1%) of Intermediate 131:

[0959] LCMS Method 3 (ES+) RT 3.65 min., 646.2 (M+H).sup.+.

[0960] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.72 (m, 2H), 7.19 (m, 1H), 7.05 (s, 2H), 7.00 (m, 1H), 6.85 (m, 2H), 6.35 (m, 1H), 5.33 (m, 1H), 4.52 (d, 1H, J=7.0 Hz), 3.48 (m, 1H), 2.83 (m, 1H), 2.42 (m, 1H), 1.67 (s, 6H), 0.87 (s, 9H), −0.07 (d, 6H, J=1.2 Hz).

[0961] 2.8 mg (5%) of Intermediate 132:

[0962] LCMS Method 3 (ES+) RT 3.66 min., 646.2 (M+H).sup.+.

[0963] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.93 (m, 2H), 7.94 (m, 1H), 7.53 (m, 2H), 7.31 (m, 2H), 7.23 (m, 1H), 6.76 (m, 1H), 6.32 (m, 1H), 4.88 (m, 1H), 3.39 (m, 1H), 3.19 (m, 1H), 2.67 (m, 1H), 2.54 (m, 1H), 1.70 (s, 6H), 0.89 (s, 9H), −0.04 (s, 6H)

Intermediate 133

1-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-3-(trifluoromethyl)azetidin-3-ol

[0964] 1-(5-bromo-4-methyl-pyrimidin-2-yl)-3-(trifluoromethyl)azetidin-3-ol (700 mg, 2.24 mmol), bis(pinacolato)diboron (1.15 g, 4.49 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (92 mg, 0.112 mmol), potassium acetate (890 mg, 8.97 mmol) and 1,4-dioxane (10 mL) were placed in a small RB flask, degassed and placed under nitrogen. The mixture was then heated at 105° C. for 2 hours. The mixture was cooled and partitioned between EtOAc and water. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuo to give the title compound as a dark brown solid 1.60 g. LC/MS Method 3: RT 1.93 minutes, m/z 360.

Intermediate 134

1-(5-bromo-6-methyl-2-pyridyl)-3-(trifluoromethyl)azetidin-3-ol

[0965] 2,5-dibromo-6-methylpyridine (1.30 g, 5.18 mmol) and 3-(trifluoromethyl)azetidin-3-ol hydrochloride (1.00 g, 5.63 mmol) were added to a small RB flask with stirrer bar. N,N-diisopropylethylamine (0.90 mL, 5.2 mmol) was added and the mixture heated to 130° C. for 4 hours. The mixture was cooled, diluted with dichloromethane (50 mL) and washed with sodium bicarbonate solution (50 mL). The organic layer was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. Chromatography (silica, DCM gradient to 15% EtOAc in DCM) gave the title compound as a white solid (210 mg, 13.0% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.70 (d, J=8.7 Hz, 1H), 7.32 (s, 1H), 6.32 (dd, J=8.7, 0.7 Hz, 1H), 4.19 (dd, J=9.6, 1.0 Hz, 2H), 3.93 (dt, J=9.4, 1.3 Hz, 2H), 2.42 (s, 3H).

[0966] LC/MS Method 3: RT 2.02 minutes, m/z 313/315.

Intermediate 135

1-[6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3-(trifluoromethyl)azetidin-3-ol

[0967] Intermediate 134 was treated in accordance with the synthetic procedure described for Intermediate 133 to afford the title compound as pale brown gum which was used without further purification. LC/MS Method 3: RT 2.29 minutes, m/z 359.

Intermediate 136

[0968] ##STR00122##

2-ethylhexyl 3-[2-[(1R,3S)-7-chloro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)phenyl]sulfanylpropanoate

[0969] N,N-di-iso-propylethylamine (1.63 mL, 9.31 mmol) was added to a solution of Intermediate 38 (2.00 g, 4.66 mmol) in 1,4-dioxane (10 mL). The mixture was evacuated and refilled with nitrogen. The catalyst, tris(dibenzylideneacetone)dipalladium(0) (213 mg, 0.233 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (275 mg, 0.466 mmol) and 3-mercaptopropionic acid 2-ethylhexyl ester (1.86 mL, 7.93 mmol) were added and the mixture was evacuated and filled with nitrogen and heated under nitrogen at 105° C. for 18 hours. The mixture was partitioned between EtOAc (250 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo to leave a yellow oil, 4.00 g. Purification by chromatography (silica, dichloromethane gradient up to 5% methanol in dichloromethane) afforded the title product as a pale yellow foam (2.10 g, 80% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.62 (dd, J=8.6, 1.9 Hz, 1H), 7.54-7.41 (m, 1H), 7.36-7.21 (m, 1H), 7.21-7.09 (m, 1H), 7.06-6.86 (m, 1H), 6.74-6.52 (m, 1H), 6.46-6.21 (m, 1H), 6.03 (dd, J=6.7, 3.7 Hz, 1H), 5.36-5.07 (m, 1H), 4.05-3.80 (m, 2H), 3.35 (td, J=6.8, 2.6 Hz, 2H), 3.25-2.64 (m, 4H), 2.24 (ddt, J=24.0, 16.6, 8.4 Hz, 1H), 1.50 (dd, J=12.5, 6.4 Hz, 1H), 1.37-1.08 (m, 8H), 0.92-0.68 (m, 6H). LC/MS Method 3: RT 3.00 minutes, m/z 381/383.

Intermediate 137

1-(5-bromo-4-methyl-2-pyridyl)-3-(trifluoromethyl)azetidin-3-ol

[0970] The title compound was synthesised from 2,5-dibromo-4-methylpyridine and 3-(trifluoromethyl)azetidin-3-ol hydrochloride in accordance with the synthetic procedure described for Intermediate 134.

Intermediate 138

1-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3-(trifluoromethyl)azetidin-3-ol

[0971] Intermediate 137 was treated in accordance with the synthetic procedure described for Intermediate 135 to afford the title compound which was used without further purification.

Intermediate 139

Ethyl 5-bromo-4-methylpyrimidine-2-carboxylate

[0972] 5-bromo-4-methylpyrimidine-2-carboxylic acid (17.8 g, 82 mmol) dissolved in ethanol (185 mL). Sulfuric acid (38.6 g, 394 mmol, 21 mL) was added and the resulting suspension was placed in a preheated oil bath of 80° C. Additional sulfuric acid (3.68 g, 37.5 mmol, 2 mL) added and heating continued for a further hour before cooling to room temperature. The solid was filtered and residue washed with EtOH. The filtrate was evaporated and the residue taken up in EtOAc (300 mL) and sat. aqueous NaHCO.sub.3 solution (300 mL). The layers were separated and the aqueous phase extracted with EtOAc (300 mL). The combined organics were washed with brine (300 mL), dried (Na.sub.2SO.sub.4), filtered and evaporated to give a dark solid which was purified by column chromatography 300 g silica (20%.fwdarw.50% EtOAc in heptane) to give the title compound as a yellow solid (12.24 g, 44%). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.87 (s, 1H), 4.53 (q, J=7.1 Hz, 2H), 2.76 (s, 3H), 1.46 (t, J=7.1 Hz, 3H). LC/MS Method 11 RT 1.57 minutes, [M+H].sup.+: 245/247 Br-isotope.

Intermediate 140

2-(5-bromo-4-methylpyrimidin-2-yl)propan-2-ol

[0973] Under a nitrogen atmosphere methyl magnesium bromide solution (3M in Et.sub.2O 109 mmol, 36.4 ml) was added dropwise to a stirred mixture of Intermediate 139 (10.7 g, 43.7 mmol) in diethyl ether (300 mL) while cooled in an ice/water bath. During addition a suspension formed. When addition was completed the mixture was stirred at room temperature. The reaction mixture was carefully quenched with saturated aqueous NH.sub.4Cl solution (300 mL). The resulting organic layer was separated and the aqueous phase was extracted with Et.sub.2O (300 mL). The combined organics were washed with brine, dried (Na.sub.2SO.sub.4), filtered and evaporated to dryness to give an orange oil.

[0974] Purification by flash chromatography (300 g silica, 10%.fwdarw.50% EtOAc in heptane) gave the title compound as a light yellow oil (7.5 g, 74%). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.67 (s, 1H), 4.51 (s, 1H), 2.65 (s, 3H), 1.58 (s, 6H). LC/MS Method 9: [M+H].sup.+ 231/233 Br-isotope.

Intermediate 141

[0975] ##STR00123##

(1R,3R)-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-(difluoromethoxy)-6-(methylsulfanyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

[0976] To a solution of Intermediate 22 (415 mg, 0.69 mmol) in DMSO (2 mL) was added sodium thiomethoxide (64 mg, 0.83 mmol). The reaction mixture was stirred for 25 minutes at 100° C. Water (20 mL) and ethyl acetate (40 mL) were added to the reaction mixture, and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2×40 mL) and the combined organics layers were dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude material was purified over silica gel using DCM/MeOH/NH.sub.4OH (100% DCM to 90/10/1) as eluent, yielding 310 mg (73%) of the title compound as a brown solid. LCMS Method 3 (ES+): RT 2.72 min, [M+H]+=612.2

Intermediate 142

[0977] ##STR00124##

(7R,14R)-11-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-5-methyl-7,14-dihydro-7,14-methano-5λ-4-benzimidazo[2,1-d][1,2,5]benzothiadiazocine 5-oxide

[0978] To a degassed solution of Intermediate 141 (87 mg, 0.14 mmol) in MeOH (5 mL) was added a solution of bromine (19 mg, 0.12 mmol) in MeOH (0.5 mL). The reaction mixture was evaporated after 1 hour and the residue was solubilised in DCM (5 mL). The solution was degassed by bubbling of argon through the solution for 5 minutes. Potassium carbonate (63 mg, 0.45 mmol) and 3-chloroperbenzoic acid (74 mg, 0.43 mmol) were then added to the mixture. The mixture was stirred overnight at ambient temperature before dilution with DCM (40 mL) and the organic layer washed with water (2×20 mL), dried by passage through a phase separator cartridge and concentrated in vacuo. The crude material was purified over silica gel using DCM/MeOH/NH.sub.4OH (100% DCM to 90/10/1) as eluent, yielding 8 mg (9%) of the title compound as a dark oil. LCMS Method 3 (ES.sup.+): RT 3.27 minutes, [M+H]+=626.2.

Intermediate 143

5-bromo-2-(1-methylsulfonylcyclopropyl)pyridine

[0979] 5-bromo-2-[(methylsulfonyl)methyl]pyridine (300 mg, 1.20 mmol), 1,2-dibromoethane (0.12 mL, 1.40 mmol), benzyltributylammonium chloride (377 mg, 1.20 mmol) and sodium hydroxide 50% aqueous solution (7.5 mL, 94 mmol) were mixed in acetonitrile (8 mL). The reaction mixture was stirred at room temperature for 24 hours. Aqueous saturated NaCl solution and ethyl acetate were added to the reaction mixture and the two layers were separated. The organic layer was dried over MgSO.sub.4, filtered and the solvent evaporated. The crude was purified by reverse phase basic preparative LCMS to yield 32 mg (10%) of the title compound as an off-white solid. LCMS Method 3 (ES+): RT 1.86 min, [M+H]+=276.

Intermediate 144

[0980] ##STR00125##

(1R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]benzimidazol-3-one

[0981] To a solution of Intermediate 19 (3 g, 6.98 mmol) in chloroform (60 mL), was added manganese dioxide (3.64 g, 42 mmol) and the reaction mixture was stirred at room temperature for 3 hours, after which additional manganese dioxide (2 g, 23 mmol) was added and stirred overnight. The reaction mixture was filtered over celite, rinsed with chloroform (2×60 mL) and the filtrate concentrated in vacuo to yield 2.91 g (97%) of the title compound as a beige solid. LCMS Method 3 (ES+): RT 4.88 min, [M+H]+=427.

Intermediate 145

[0982] ##STR00126##

N-{(1R,3E)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]benzimidazol-3-ylidene}-2-methylpropane-2-sulfinamide

[0983] Titanium(IV) isopropoxide (1.86 mL, 9.52 mmol) was added to a solution of Intermediate 144 (1.85 g, 4.33 mmol) in dry THF (43 mL). The mixture was stirred at room temperature for 10 minutes before addition of (R)-(+)-2-methyl-2-propanesulfinamide (642 mg, 5.2 mmol). The reaction mixture was stirred at 50° C. overnight. Further (R)-(+)-2-methyl-2-propanesulfinamide (320 mg, 2.58 mmol) was added and the reaction mixture stirred at 50° C. overnight. The reaction mixture was cooled to 0° C. and methanol was added followed by a saturated aqueous solution of NaHCO.sub.3 until precipitation was observed. The slurry was diluted by EtOAc (50 mL) and filtered over celite. The filtrate was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified over silica gel (gradient EtOAc/heptane 20 to50%) yielding 770 mg (34%) of the title compound as a brown solid. LCMS Method 3 (ES+): RT 2.82 min, [M+H].sup.+=530.

Intermediate 146

[0984] ##STR00127##

N-{(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-3-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}-2-methylpropane-2-sulfinamide

[0985] To a solution of Intermediate 145 (8 g, 15.1 mmol) in dry DCM (90 mL), cooled at −70° C., was added dropwise a solution of methyl magnesium bromide 3 M in diethyl ether (17.6 mL, 52.8 mmol). The reaction mixture was stirred at −70° C. for 10 minutes and at 0° C. for 2 hours before quenching by addition of a saturated solution of NH.sub.4Cl (100 mL). The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with saturated brine and dried over MgSO4, filtered and concentrated in vacuo. The residue was purified over silica gel (gradient ethyl heptane/acetate 50 to 100%), yielding to 2.91 g (35%) of the title compound as a beige solid. LCMS Method 3 (ES+): RT 2.68 min, [M+H].sup.+=546.10

Intermediate 147

[0986] ##STR00128##

(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-3-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

[0987] Intermediate 146 (2.91 g, 5.32 mmol) was dissolved in dry 1,4-dioxane (150 mL). HCl/dioxane (4M) (6.65 mL, 27 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was taken up in EtOAc (50 mL) and a saturated aqueous solution of NaHCO.sub.3 (20 mL) added. The organic layer was washed with saturated brine, dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was dissolved in diethyl ether and evaporated yielding to 2.2 g (93%) of the title compound as a yellow solid. LCMS Method 3 (ES+): RT 2.43 min, [M+H].sup.+=442.1.

Intermediate 148

[0988] ##STR00129##

(7R,14R)-11-chloro-1-(difluoromethoxy)-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0989] Intermediate 147 (50 mg, 0.11 mmol), potassium carbonate (23 mg, 0.170 mmol), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (4 mg, 0.006 mmol) were mixed in degassed 1,4-dioxane (2 mL). The mixture was stirred under CO gas (3 bar) at 120° C. for 4 hours. Additional bis(diphenylphosphino)xanthene]palladium(II) (4 mg, 0.006 mmol) was introduced in the reactor at room temperature and the reaction continued under stirring under CO (3 bar) at 120° C. for 16 hours. The crude mixture was purified over silica gel (ethyl acetate as eluent), yielding 71 mg (37%) of the title compound as an off-white solid. LCMS Method 3 (ES+): RT 2.34 min, [M+H]+=390.

Intermediate 149

[0990] ##STR00130##

(7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dimethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[0991] Intermediate 148 (80 mg, 0.21 mmol) and tetrabutylammonium iodide (30 mg, 0.08 mmol) were mixed in dry THF (2 mL). At 0° C., sodium hydride (60% in mineral oil) (9 mg, 0.246 mmol) was added. The reaction mixture was stirred at room temperature for 35 minutes. Iodomethane (0.08 mL, 1.24 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was quenched by addition of water (1 mL). The aqueous layer was extracted by EtOAc (3×2 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified over silica gel (heptane/DCM 50% to 100%), yielding 60 mg (72%) of the title compound as a white solid. LCMS Method 4 (ES+): RT 2.63 min, [M+H].sup.+ 404.

Intermediate 150

[0992] ##STR00131##

tert-butyl (2-{5-[(7R,14R)-1-(difluoromethoxy)-7-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate

[0993] tert-butyl N-[1-(5-bromopyrimidin-2-yl)-1-methyl-ethyl]carbamate (36 mg, 0.11 mmol), bis(pinacolato)diboron (36 mg, 0.14 mmol), potassium acetate (11 mg, 0.12 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg, 0.008 mmol), were mixed in dioxane (3 mL). The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered through a 45 μM filter, and concentrated in vacuo. The residue was dissolved in n-butanol (5 mL) and Intermediate 148 (15 mg, 0.038 mmol), tricyclohexylphosphonium tetrafluoroborate (4 mg, 0.009 mmol), tris(dibenzenylideneacetone)dipaladium(0) (4 mg, 0.0038 mmol), potassium triphosphate (17 mg, 0.077 mmol) and water (50 μL) were added. The reaction mixture was stirred at 140° C. in a microwave for 25 minutes. The reaction mixture was filtered and purified by reverse phase basic preparative HPLC-MS to yield 13 mg (57%) of the title compound as a beige solid. LCMS Method 3 (ES+): RT 2.42 minutes, [M+H].sup.+=591.

Intermediate 151

[0994] ##STR00132##

(1R,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

[0995] To a solution of Intermediate 21 (2 g, 3.33 mmol) in DMF (12 mL) was added imidazole (283 mg, 4.16 mmol) and tert-butyldimethylchlorosilane (543 mg, 3.49 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction was then diluted with diethyl ether (30 mL) and water (30 mL). The aqueous layer was extracted with diethyl ether (2×20 mL). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to afford the title compound which was used in the next step without further purification. LCMS Method 3 (ES+): RT 7.09 min.

Intermediate 152

[0996] ##STR00133##

Ethyl 2-{(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl}-3-(difluoromethoxy)benzoate

[0997] Intermediate 151 (2.05 g, 2.87 mmol), potassium carbonate (1.5 equiv., 4.30 mmol), molecular sieve 4 Å powder (860 mg) and dichloro[bis(dicyclohexylphosphino)propane]palladium(II) (0.08 equiv., 0.23 mmol) were suspended in dry dimethylsulfoxide (20 mL) and ethanol (0.75 mL). The reaction mixture was stirred at 100° C. under 5 bars of CO gas for 16 hours. After this time, another portion of dichloro[bis(dicyclohexylphosphino)propane]palladium(II) was added and the reaction stirred overnight at 100° C. under 5bars of CO gas to complete the reaction. The reaction mixture was allowed to cool to ambient temperature, filtered over celite and partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with water (2×20 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (DCM:MeOH 99.5%:0.5%), yielding 824 mg (38%) of the title compound. LCMS Method 3 (ES+): RT 3.92 min, 753 (M+H).sup.+.

Intermediate 153

[0998] ##STR00134##

[2-{(1R,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl}-3-(difluoromethoxy)phenyl]methanol

[0999] Intermediate 152 (780 mg, 1.04 mmol) was dissolved in dry ethanol (8 mL). At 0° C., sodium borohydride (317 mg, 8.30 mmol) followed by calcium chloride (460 mg, 4.15 mmol) were added. The reaction was allowed to warm to ambient temperature and stirred for 4 hours. The reaction was then diluted with EtOAc (20 mL) and water (10 mL). The organic layer was washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (hexane:ethyl acetate 80:20), yielding 233 mg (32%) of the title compound. LCMS Method 3 (ES+): RT 3.69 min, 711 (M+H).sup.+.

Intermediate 154

[1000] ##STR00135##

2-{(1R,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl}-3-(difluoromethoxy)benzaldehyde

[1001] Intermediate 153 (233 mg, 0.33 mmol) was dissolved in DCM (5 mL) before the addition of Dess-Martin periodinane (157 mg, 0.36 mmol). The slurry was stirred overnight at ambient temperature. Additional Dess-Martin periodinane (72 mg, 0.16 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours to complete the reaction. The slurry was filtered and the filtrate was diluted with DCM (20 mL) and washed by a saturated aqueous solution of NaHCO.sub.3 (10 mL). The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (hexane:ethyl acetate 80:20), yielding 190 mg (82%) of the title compound. LCMS Method 3 (ES+): RT 3.79 min, 709 (M+H).sup.+.

Intermediate 155

[1002] ##STR00136##

(1R,3S)-1-[2-(difluoromethoxy)-6-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-7-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

[1003] Intermediate 154 (190 mg, 0.27 mmol) was dissolved in tetrahydrofuran (3 mL). At 0° C., tetrabutylammonium fluoride (54 μL, 0.054 mmol) followed by (trifluoromethyl)trimethylsilane (79 μL, 0.54 mmol) were added. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was then diluted with EtOAc (10 mL) and water (5 mL). The aqueous layer was extracted with further EtOAc (2×5 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (1 ml) and p-toluenesulfonic acid monohydrate (255 mg, 1.34 mmol) was added. The reaction was stirred overnight at room temperature. Additional p-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol) was added and the reaction mixture was stirred at ambient temperature overnight to complete the reaction. The reaction mixture was diluted with EtOAc (10 mL) and a saturated aqueous solution of NaHCO.sub.3 (5 mL). The aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase basic preparative HPLC-MS to afford 97 mg (66%) of the title compound as a white solid. LCMS Method 3 (ES+): RT 2.03 min, 551 (M+H).sup.+.

Intermediate 156

[1004] ##STR00137##

(1R,3R)-7-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-3-amine

[1005] To a solution of Intermediate 72 (212 mg, 0.42 mmol) and 4-dimethylaminopyridine (4 mg, 0.033 mmol) in DCM (4 mL) at 0° C. was added N,N-di-isopropylethylamine (441 μL, 2.52 mmol), followed by tert-butyldimethylsilyl-trifluoromethanesulfonate (395 μL, 1.69 mmol). The reaction mixture was stirred at 0° C. for 20 minutes before the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature. After 45 minutes the reaction mixture was diluted with DCM (100 mL) and washed with water (2×50 mL), brine (50 mL), dried (by passage through a phase separator cartridge) and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 60-100% EtOAc in hexane, followed by 0-25% MeOH in EtOAc) and freeze dried from acetonitrile/water to give the title compound (190 mg, 73%) as an off-white solid.

[1006] LCMS Method 3 (ES+) 618 (M+H).sup.+, RT 3.44 minutes.

[1007] LCMS Method 4 (ES+) 618 (M+H).sup.+, RT 3.04 minutes.

Intermediate 157

[1008] ##STR00138##

(6R,12R)-2-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)pyrimidin-5-yl]-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanopyrido[1′,2′:1,2]imidazo[4,5-c][1]benzazepine

[1009] To a microwave vial was added tris(dibenzylideneacetone)dipalladium(0) (9.5 mg, 0.01 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (10.2 mg, 0.021 mmol), followed by degassed 1,4-dioxane (2 mL), and the microwave vial then sealed and degassed and stirred at room temperature for 30 minutes. After this time Intermediate 156 (125 mg, 0.20 mmol) and sodium tert-butoxide (41 mg, 0.40 mmol) then added and reaction mixture degassed and heated to 110° C. for 18 hours. The reaction mixture was partitioned between EtOAc (25 mL) and water (25 mL), the layers separated and aqueous extracted with EtOAc (25 mL). The combined organics were washed with brine (25 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 0-20% MeOH in DCM) to give the title compound (69 mg, 59%) as a dark brown glass.

[1010] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.95 (d, J=1.6 Hz, 2H), 8.37 (d, J=7.3 Hz, 1H), 7.38 (d, J=11.2 Hz, 1H), 6.96 (t, J=75 Hz, 1H), 6.88 (t, J=8.1 Hz, 1H), 6.40-6.26 (m, 2H), 4.89-4.73 (m, 2H) 3.45-3.32 (m, 1H), 2.21 (d,J=10.5 Hz, 1H), 1.73 (s, 6H), 0.91 (s, 9H), −0.01 (s, 6H).

[1011] LCMS: Method 3 (ES+) 582 (M+H).sup.+, RT 3.39 minutes.

[1012] LCMS Method 4 (ES+) 582 (M+H).sup.+, RT 3.48 minutes.

Intermediate 159

[1013] ##STR00139##

(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-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

[1014] To a solution of Intermediate 110 (2.01 g, 5.12 mmol) in 1,4-dioxane (18 mL) was added bis-(pinacolato)diboron (1.97 g, 7.8 mmol), potassium acetate, (1.5 g, 15.1 mmol), tricyclohexylphosphonium tetrafluoroborate (197 mg, 0.15 mmol) and tris(dibenzylideneacetone)dipalladium(0) (242 mg, 0.25 mmol). The reaction mixture was degassed for 10 minutes before heating to 140° C. in the microwave for 3 hours. Water and EtOAc was added to the reaction mixture and the aqueous phase extracted with further EtOAc. The combined organic layers were evaporated to give a crude residue which was purified by column chromatography on silica (eluent Hexane:EtOAc gradient from 0 to 100% followed by DCM:MeOH to 10% MeOH) to provide the title compound as a white solid (2.2 g, 89% yield). LC/MS: Method 3 RT 2.27 mins, [M+H].sup.+=485.

Intermediate 160

[1015] ##STR00140##

(7R,14R)-11-[2-(cis-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-3-methylcyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1016] Intermediate 159 (401 mg, 0.83 mmol) and Intermediate 79 (403 mg, 1.08 mmol) in 1,4-dioxane (10 mL) were degassed, 1,1′-bis(diphenylphospino)ferrocene-palladium(II)dichloride dichloromethane complex (35 mg, 0.043 mmol) and K.sub.3PO.sub.4 (282 mg, 1.33 mmol) were added and reaction mixture degassed and then heated at 110° C. for 18 hours, or until LCMS analysis showed the reaction to be completed. The reaction mixture was allowed to cool to room temperature, partitioned between EtOAc (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL), the layers were separated and the aqueous phase extracted with further EtOAc (3×25 mL). The combined organics were dried over sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, 0-100% EtOAc in hexane, followed by 0-15% MeOH in DCM) to give the title compound (221 mg, 41%) as a yellow foam.

[1017] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.12 (s, 2H), 8.27 (dd, J=5.9, 3.6 Hz, 1H), 7.78 (d, J=8.5 Hz, 2H), 7.69 (t, J=73.6 Hz, 1H), 7.65 (dd, J=8.3, 1.8 Hz, 1H), 7.52-7.44 (m, 2H), 6.31 (d, J=7.2 Hz, 1H), 5.25 (d, J=6.9 Hz, 1H), 5.03 (s, 1H), 3.58-3.45 (m, 1H), 3.10-3.02 (m, 1H), 2.84 (d, J=13.6 Hz, 1H), 2.56-2.45 (m, 2H), 2.48-2.40 (m, 1H), 0.93 (s, 3H), 0.80 (s, 6H), −0.19 (d, J=1.4 Hz, 9H).

[1018] LCMS: Method 3 (ES+) 651 (M+H).sup.+, RT 2.51 minutes.

Intermediate 161

[1019] ##STR00141##

Ethyl 2-[2-[(1R,3S)-7-chloro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)phenyl]sulfanylacetate

[1020] The title compound was prepared from Intermediate 38 (2.02 g, 4.7 mmol), N,N-di-iso-propylethylamine (1.63 mL, 9.31 mmol), tris(dibenzylideneacetone)dipalladium(0) (213 mg, 0.23 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (275 mg, 0.47 mmol) and ethyl thioglycolate (980 mg, 7.99 mmol) by the method of Intermediate 136. Crude material was purified by column chromatography (SiO.sub.2, 20-100% EtOAc in hexane) to give the title compound (1.76 g, 80%) as a yellow solid.

[1021] LCMS: Method 3 (ES+) 469 (M+H).sup.+, RT 2.08 minutes.

[1022] LCMS: Method 4 (ES+) 469 (M+H).sup.+, RT 2.05 minutes.

Intermediate 162

[1023] ##STR00142##

Ethyl (7S,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate 5,5-dioxide

Intermediate 163

[1024] ##STR00143##

Ethyl (7R,14S)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate 5-oxide

[1025] To a solution of Example 115 (150 mg, 0.33 mmol) in DCM (5 mL) was added 3-chloroperoxybenzoic acid (149 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 18 hours, after which time the reaction mixture was partitioned between DCM (25 mL) and water (25 mL), layers separated and organics washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with DCM (20 mL), the combined organics filtered through a phase separator and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-60% EtOAc in DCM) and freeze dried from acetonitrile/water to give Intermediate 162 (65 mg, 40%) as an off-white solid and Intermediate 163 (47 mg, 30%) as a white solid.

[1026] Intermediate 162

[1027] LCMS: Method 3 (ES+) 483 (M+H).sup.+, RT 2.12 minutes (minor diastereoisomer) and 2.26 minutes (major diastereoisomer)

[1028] LCMS: Method 4 (ES+) 483 (M+H).sup.+, RT 2.09 minutes (minor diastereoisomer) and 2.26 minutes (Major diastereoisomer).

[1029] Intermediate 163

[1030] LCMS: Method 3 (ES+) 467 (M+H).sup.+, RT 2.22 minutes (major diastereoisomer)

[1031] LCMS: Method 4 (ES+) 467 (M+H).sup.+, RT 2.20 minutes (Major diastereoisomer).

Intermediate 164

[1032] ##STR00144##

2-[(7S,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-6-yl]propan-2-ol

[1033] To a solution of Example 115 (98 mg, 0.22 mmol) in THF (5 mL) at 0° C. was added methylmagnesium bromide (3M in diethylether, 0.16 mL, 0.48 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. After this time the reaction was quenched with methanol, concentrated in vacuo and the residue partitioned between EtOAc (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL), the layers separated and the aqueous phase extracted with EtOAc (3×30 mL), the combined organics were washed with brine (60 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. Purification by column chromatography (SiO.sub.2, 0-20% MeOH in DCM) and freeze drying from acetonitrile/water gave the title compound (28 mg, 29%).

[1034] LCMS: Method 3 (ES+) 437 (M+H).sup.+, RT 2.44 minutes.

[1035] LCMS: Method 4 (ES+) 437 (M+H).sup.+, RT 2.38 minutes.

Intermediate 165

[1036] ##STR00145##

[(7S,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-6-yl]methanol

[1037] To a solution of Example 115 (88 mg, 0.15 mmol) in THF (1.5 mL) at −10° C. was added lithium aluminium hydride (2M solution in THF, 0.1 mL, 0.20 mmol). The reaction mixture was stirred below 0° C. for 1 hour after which time the reaction was quenched with a few drops of 2 M HCl, stirred and then basified with 10% NaOH (aq) (20 mL) and extracted with EtOAc (4×25 mL). The combined organic phases were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. Purification by column chromatography (SiO.sub.2, 50-100% EtOAc in DCM, followed by 0-20% MeOH in EtOAc) and freeze drying from acetonitrile/water gave the title compound (35 mg, 57%) as a white solid.

[1038] LCMS: Method 3 (ES+) 409 (M+H).sup.+, RT 2.18 minutes (major diastereoisomer) and 2.22 minutes (minor diastereoisomer)

[1039] LCMS: Method 4 (ES+) 409 (M+H).sup.+, RT 2.14 minutes.

Intermediate 166

[1040] ##STR00146##

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-trimethylsilyloxypropan-2-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1041] Example 11 (750 mg, 2.00 mmol), 6-(2-(trimethylsilyloxy)propan-2-yl)pyridine-3-boronic acid pinacol ester (1.41 g, 4.00 mmol), tris(dibenzylideneacetone)dipalladium(0) (94 mg, 0.1 mmol) and tricyclohexylphosphonium tetrafluoroborate (91 mg, 0.24 mmol, 97 mass %) were added to a round bottom flask, evacuated & refilled with nitrogen and 1,4-dioxane (10 mL) added followed by potassium phosphate (1.27 g, 6.00 mmol) in water (1 mL). The mixture was degassed, placed under nitrogen and heated to 105° C. overnight. The mixture was partitioned between EtOAc and water, the organic layer dried over sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by chromatography, (EtOAc to 15% MeOH gradient). The product fractions were concentrated in vacuo to give the title compound as an off-white solid, (1.05 g, 96% yield). LC/MS Method 3: RT 1.61 minutes, m/z 549.

Intermediate 167

tert-Butyl 3-(5-bromo-2-pyridyl)-3-hydroxy-pyrrolidine-1-carboxylate

[1042] 2,5-dibromopyridine (2.00 g, 8.27 mmol) was dissolved in toluene (40 mL), cooled to −78° C. and n-butyllithium (7.1 mL, 9.9 mmol, 1.40 M) solution in n-hexane added dropwise and stirred for 10 minutes before the addition of N-BOC-3-pyrrolidinone (1.61 g, 8.69 mmol) in toluene (3 mL). The mixture was stirred at −60° C. for 1 hour, quenched with methanol (2 mL) and partitioned between EtOAc and saturated aqueous ammonium chloride solution. The organic layer was concentrated in vacuo to yield a crude residue. Purification by chromatography (silica, 0 to 60% EtOAc gradient in iso-hexane) gave the title compound as an off-white solid (1.05 g, 3.06 mmol, 37% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.65 (dd, J=2.5, 0.7 Hz, 1H), 8.07 (dd, J=8.5, 2.4 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 5.76 (s, 1H), 3.63 (t, J=11.3 Hz, 1H), 3.56-3.37 (m, 4H), 2.43-2.21 (m, 1H), 1.98-1.86 (m, 1H), 1.41 (s, 9H). LC/MS Method 3: RT 1.57 minutes, m/z 341/343 (−ve ion).

Intermediate 168

Methyl N-[1-(5-bromopyrimidin-2-yl)-1-methyl-ethyl]carbamate

[1043] To a cooled (0° C.) solution of 2-(5-bromopyrimidin-2-yl)propan-2-amine (2 g, 9.25 mmol) in dichloromethane (50 mL) was added N,N-diisopropylethylamine (2.2 equiv., 20.3 mmol) followed by methyl chloroformate (1 equiv., 9.25 mmol) and the mixture stirred at room temperature for 4 hours. The dichloromethane solution was extracted with 2M HCl (×2) washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulphate, filtered and the solvents removed in vacuo to give 2.6 g of a pale reddish solid which was used without further purification.

[1044] LCMS Method 3 RT=1.15 minutes

Intermediate 169

[1045] ##STR00147##

1-[2-[(1R,3S)-3-bromo-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoro methoxy)phenyl]ethanone

[1046] Intermediate 181 (58.0 mg, 0.148 mmol) and triphenylphosphine (43.0 mg, 0.162 mmol) were dissolved in DCM (2 mL), and at 0° C. was added carbon tetrabromide (54.0 mg, 0.163 mmol). The reaction mixture was warmed up to ambient temperature and stirred for 3 hours, partitioned between water and DCM, and the organics, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude material was purified by column chromatography (0%-5% MeOH in DCM) to afford the title compound (74 mg, 77%). LC/MS: Method 3 ESI MH.sup.+ 455/457, retention time 2.18 minutes.

Intermediate 170

2-(5-bromopyrimidin-2-yl)-N,N-dimethyl-propan-2-amine

[1047] To a solution of 1-(5-bromopyrimidin-2-yl)-1-methylethylamine (500 mg, 2.20 mmol) in THF (15 mL) was added sodium hydride (97 mg, 2.43 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min before the addition of iodomethane (0.17 mL, 2.64 mmol) dropwise. The mixture was stirred at 0° C. for 30 mins before warming to room temperature and stirred for 16 hours. Iodomethane (0.165 mL, 2.64 mmol) was added and stirred for additional hour before being quenched with saturated aqueous NH.sub.4Cl solution and extracted with DCM (3×10 mL). The organics were combined, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-5% MeOH in DCM) to give the title compound (120 mg, 22%).

[1048] LC/MS: Method 3 retention time 1.23 minutes.

Intermediate 171

[1049] ##STR00148##

(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

[1050] Example 11 (150 mg, 0.40 mmol) in 1,4-dioxane (1.5 mL) was added to bis(pinacolato)diboron (150 mg, 0.59 mmol), potassium acetate, (117 mg, 1.19 mmol), tricyclohexylphosphonium tetrafluoroborate (15 mg, 0.040 mmol) and tris(dibenzylideneacetone)dipalladium(0) (19 mg, 0.02 mmol) were added. The reaction mixture was degassed for 10 minutes before heating to 140° C. in the microwave for 3 hours. The reaction mixture was partitioned between EtOAc and water and extracted with further EtOAC (×3). The combined organic phases were filtered through a phase separator and the solvents removed in vacuo to give the title compound which was used without further purification. LC/MS: Method 3 RT 2.09 mins, [M+H].sup.+=468.

Intermediate 172

[1051] ##STR00149##

N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]-6-methoxy-pyridine-3-sulfonamide

[1052] To a solution of Intermediate 40 (500 mg, 1.17 mmol) and N,N-di-isopropylethylamine (0.24 mL, 1.4 mmol, 180 mg) in dichloromethane (12 mL) was added 6-methoxypyridine-3-sulfonyl chloride (325 mg, 1.52 mmol). The reaction mixture was stirred at room temperature for 3 hours before the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-100% EtOAc in hexane) to give the title compound (600 mg, 86%) as a dark beige solid. LCMS (ES+) Method 3: 600/602 (M+H).sup.+, RT 2.4 minutes

Intermediate 173

[1053] ##STR00150##

2-[(1R,3S)-7-chloro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)benzenesulfonamide

[1054] To a solution of Intermediate 136 (1.0 g, 1.67 mmol) in dimethyl sulfoxide (2.8 mL), sodium ethoxide solution (3M in EtOH, 1.13 mL, 3.3 mmol) was added. The reaction mixture was stirred for 10 minutes before additional sodium ethoxide solution (3M in ethanol, 1.13 mL, 3.3 mmol) was added and the mixture stirred for 5 minutes. Hydroxylamine-O-sulfonic acid (1.0 g, 8.58 mmol) and sodium acetate (550 mg, 6.70 mmol) in 2 mL of water were added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. EtOAc and water were added to the reaction mixture and the two phases were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were filtered through a phase separator and the solvent was evaporated. The crude material was purified by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) then DCM:MeOH (0 to 20%) as eluent, yielding 300 mg (42%) of the title compound as a pale yellow solid. LCMS Method 3: RT 1.57 min, [M−H].sup.+=430/432.

Intermediate 174

[1055] ##STR00151##

2-[(1R,3S)-3,7-dichloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)benzenesulfonamide

[1056] To a solution of Intermediate 173 (130 mg, 0.30 mmol) in THF (3 mL), DMAP (4 mg, 0.033 mmol) and N,N-di-isopropylethylamine (0.04 mL, 0.39 mmol) were added. The mixture was stirred at 0° C. before methanesulfonyl chloride (47 μL, 0.61 mmol) was added. The reaction mixture was stirred for 1 hour 30 minutes. Sodium hydride (18 mg, 0.45 mmol) was added at 0° C. and stirred for 1 hour before the mixture was heated to reflux overnight. The reaction was quenched by the addition of water and extracted with EtOAc (×3). The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. Purification by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) as eluent, the title compound was obtained as a mixture of diasterisomers which were separated by Achiral SFC purification, yielding 14 mg (11% yield) of the title compound as a white solid. LCMS Method 3: RT 1.63 min, [M−H].sup.+=448/450.

Intermediate 175

[1057] ##STR00152##

(7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,2,5]benzothiadiazocine 5,5-dioxide

[1058] To a solution of Intermediate 174 (14 mg, 0.031 mmol) in N,N-dimethylformamide (0.6 mL) was added sodium hydride (60 mass %, 1.87 mg, 0.047 mmol) and the reaction mixture was heated at 80° C. for 1 hour. Water and EtOAc were added and the two phase were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine and filtered through a phase separator. The solvent was evaporated, yielding 10 mg (78% yield) of the title compound as a green solid. LCMS Method 3: RT 1.70 min, [M−H].sup.+=412/414

Intermediate 176

[1059] ##STR00153##

(1 R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-N-pyrimidin-2-yl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

[1060] To a solution of Intermediate 40 (600 mg, 1.40 mmol) and 2-bromopyrimidine (334 mg, 2.10 mmol) in N,N-dimethylformamide (2.8 mL) was added N,N-di-isopropylethylamine. The reaction mixture was heated at 80° C. for 4 hours and then at 110° C. overnight. Water and EtOAc were added and the reaction mixture was extracted with further ethyl acetate. The combined organic layer was filtered through a phase separator and the solvent evaporated. The crude material was purified by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) then DCM:MeOH (0 to 20%) as eluent, yielding 205 mg (29% yield) of the title compound as a pale yellow solid. LCMS Method 3: RT 2.24 min, [M−H].sup.+=506/508.

Intermediate 177

[1061] ##STR00154##

Ethyl-N-[(1R,3R)-1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]carbamate

[1062] To a solution of Intermediate 40 (400 mg, 0.93 mmol) in dichloromethane (4.6 mL). N,N-diisopropylethylamine (0.24 mL, 1.4 mmol) followed by ethyl chloroformate (116 μL, 1.21 mmol) were added and the reaction mixture was stirred for 1 hour. The solvent was evaporated and the residue was purified by column chromatography (SiO.sub.2, 0-100% EtOAc in hexane) to give the title compound (350 mg, 75% yield) as a pale yellow solid. LCMS (ES+) Method 3: 500/502 (M+H).sup.+, RT 2.23 minutes.

Intermediate 178

[1063] ##STR00155##

N-[1-(5-bromo-2-pyridyl)cyclobutyl]-2-methyl-propane-2-sulfinamide

[1064] 2,5-dibromopyridine (1.4 g, 5.8 mmol) was dissolved in toluene (15 mL) and the reaction mixture was cooled to −60° C. after which time n-butyllithium (4 mL, 6.4 mmol) was added dropwise and the mixture was stirred at this temperature for 10 minutes. N-cyclobutylidene-2-methyl-propane-2-sulfinamide (1 g, 5.77 mmol) in 1 mL of toluene was added to the reaction mixture and stirred at −60° C. for 15 minutes. A saturated solution of NH.sub.4Cl aq. was added and the reaction mixture was extracted with EtOAc and the combined organic layers was washed with brine and filtered through a phase separator and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, 0-100% EtOAc in hexane) to give the title compound (1.25 g, 65% yield) as a colourless oil. .sup.1H NMR (300 MHz, Chloroform-d) δ 8.64 (dd, J=2.4, 0.7 Hz, 1H), 7.83 (dd, J=8.4, 2.4 Hz, 1H), 7.42 (dd, J=8.5, 0.7 Hz, 1H), 4.31 (s, 1H), 2.72-2.57 (m, 3H), 2.63-2.44 (m, 1H), 2.10 (ddt, J=18.7, 9.0, 7.0 Hz, 1H), 1.96-1.75 (m, 1H), 1.22 (s, 9H).

Intermediate 179

[1065] ##STR00156##

N-[3-(5-bromo-2-pyridyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide

[1066] 2,5-dibromopyridine (500 mg, 2.07 mmol) was dissolved in toluene (5 mL) and the reaction mixture was cooled to −60° C. before n-butyllithium (1.4 mL, 2.2 mmol) was added dropwise and the mixture stirred for 10 minutes. 2-methyl-N-(oxetan-3-ylidine)propane-2-sulfinamide (420 mg, 2.2 mmol) in 0.5 mL of toluene was added and the reaction mixture stirred at −60° C. for 15 minutes. A saturated solution of aqueous NH.sub.4Cl was added and the reaction mixture extracted with EtOAc and the combined organic layers washed with brine, filtered through a phase separator and the solvent evaporated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, 0-100% EtOAc in hexane) to give the title compound (550 mg, 80% yield) as a colourless oil. LC/MS: RT 1.35 mins (pH 10), [M+H]+=333/335. 1H NMR (400 MHz, Chloroform-d) δ 8.63 (dd, J=2.4, 0.7 Hz, 1H), 7.93 (dd, J=8.5, 2.3 Hz, 1H), 7.71 (dd, J=8.5, 0.8 Hz, 1H), 5.41 (s, 1H), 5.33 (d, J=7.0 Hz, 1H), 5.05 (d, J=6.6 Hz, 1H), 4.94 (d, J=6.6 Hz, 1H), 4.84 (dd, J=7.0, 0.8 Hz, 1H), 1.28 (s, 9H).

Intermediate 180

5-(4-bromophenyl)-2,4-dimethyl-1H-imidazole

[1067] To a solution of 1-(4-bromophenyl)-2-nitropropene (750 mg, 3.09 mmol), acetamidine hydrochloride (313 mg, 3.31 mmol) and potassium carbonate (421 mg, 3.015 mmol) in ethanol (12 mL) was added indium (III) chloride (33 mg, 0.149 mmol) and the reaction mixture was stirred at 70° C. overnight. Ethanol was evaporated and the crude reaction mixture was diluted with water (2 mL), and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to give a yellow solid. The residue was purified by column chromatography (hexane/ethyl acetate) to afford the title compound (270 mg, 35%) as a pale yellow solid. LC/MS Method 3: RT 1.62 minutes, [M+H].sup.+=251/253.

Intermediate 181

[1068] ##STR00157##

1-[2-[(1R,3R)-7-chloro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)phenyl]ethanone

[1069] Intermediate 60 (1.50 g, 3.49 mmol) was dissolved in toluene (20 mL), and tributyl(1-ethoxyvinyl)tin (2.53 mL, 7.67 mmol) and bis(triphenylphosphine)palladium(II) dichloride (250 mg, 0.36 mmol) were added. The reaction mixture was degassed and purged with N.sub.2 3 times before heating at 105° C. for 18 hours. The reaction mixture was diluted with saturated aqueous KF solution and extracted with EtOAc (×3). The combined organics were, dried (sodium sulphate) and concentrated in vacuo. The crude compound was purified by column chromatography eluting with 0-10% MeOH:DCM to give the enol ether intermediate. The intermediate was dissolved in THF/1N HCl (1:1, 40 mL) and stirred at room temperature for 1 hour before neutralisation with saturated sodium bicarbonate solution and extraction with EtOAc (2×50 mL). The organics were combined and concentrated in vacuo to give the desired methyl ketone (1.22 g, 3.10 mmol, 89%). LC/MS: ESI MH.sup.+ 393, retention time 1.31 minutes Method 3.

Intermediate 182

[1070] ##STR00158##

tert-butyl 2-{4-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]phenyl}pyrrolidine-1-carboxylate

[1071] To a solution of Example 11 (500 mg, 1.33 mmol) and tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxylate (768 mg, 2.00 mmol) in 1,4-dioxane (10 mL) was added K.sub.3PO.sub.4 (566 mg, 2.67 mmol), tricyclohexylphosphonium tetrafluoroborate (52 mg, 0.14 mmol) and tris(dibenzylideneacetone)dipalladium(0) (108 mg, 0.11 mmol) with several drops of water. The reaction mixture was degassed and flushed with nitrogen and then heated at 120 degrees in a microwave for 6 hours. The cooled reaction was diluted with H.sub.2O (50 mL) and extracted with EtOAc×3. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by column chromatography, firstly with EtOAc in DCM (0 to 100%) and then with 0-10% MeOH/DCM gave the title compound (575 mg, 66%). LC/MS Method 3: RT 2.40 minutes, m/z 487.2 (-BOC).

Intermediate 182(a)

[1072] ##STR00159##

tert-Butyl (2-{4-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]phenyl}propan-2-yl)carbamate

[1073] The title compound can be prepared from Intermediate 171 (0.35 g, 0.93 mmol, 1 eq) and (tert-butyl 2-(4-bromophenyl)propan-2-ylcarbamate (1 eq) in accordance with the Method described for Example 137. Purification by flash chromatography on silica gel (0 to 100% EtOAc in DCM followed by 0 to 10% MeOH in DCM) afforded the title compound as a brown solid. LC/MS Method 3: RT 2.32 minutes, m/z 575.2

Intermediate 183

[1074] ##STR00160##

(1R,3R)-1-[2-chloro-6-(difluoromethoxy)phenyl]-7-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine

[1075] The title compound may be prepared from Intermediate 10 in accordance with the Method described for Intermediate 40.

Intermediate 184

[1076] ##STR00161##

tert-butyl {(1R,3R)-1-[2-chloro-6-(difluoromethoxy)phenyl]-7-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl}carbamate

[1077] The title compound may be prepared from Intermediate 183 in accordance with the Method described for Intermediate 42.

Intermediate 185

[1078] ##STR00162##

tert-butyl N-[(1R,3R)-7-bromo-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]-N-(trideuteriomethyl)carbamate

[1079] Intermediate 184 (300 mg, 0.549 mmol) was dissolved in tetrahydrofuran (10 mL). Potassium bis(trimethylsilyl)amide (0.6 mL, 0.6 mmol) was added dropwise at −78 degree and stirred for 30 minutes before the addition of iodomethane-d3 (0.06 mL, 1 mmol). The reaction mixture was stirred at −78° C. for 10 minutes before being left in an ice-water bath for 2 hours followed by 1 hour at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc, the organics dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by column chromatography, eluting with 0%-10% MeOH in DCM, to afford the title compound as an off white solid (320 mg, 99%). LC/MS Method 3: RT 2.75 minutes, m/z 563.0/565.0

Intermediate 186

[1080] ##STR00163##

tert-butyl-N-[(1R,3R)-1-[2-chloro-6-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]-N-trideuteriomethyl) carbamate

[1081] Intermediate 185 (310 mg, 0.49 mmol), [2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]boronic acid (0.55 mmol, 1.1 eq), potassium carbonate (115 mg, 0.83 mmol), palladium(II) acetate (7 mg, 0.03 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 mg, 0.033 mmol) were dissolved in DMSO (5 mL, 70 mmol) and a drop of water added. The mixture was degassed thoroughly and nitrogen flushed. The mixture was heated for 1 hour in a microwave at 110° C. The mixture was separated between EtOAc and brine (25 mL of each) and the aqueous extracted with EtOAc (25 mL) and the combined organics washed with 3×20 mL of brine, dried (phase separator)—and evaporated in vacuo. Purification by column chromatography on silica using a gradient EtOAc in DCM (0-100%) and then 1 to 15% MeOH in EtOAc to afford the title compound as an off white solid (210 mg, 64%). LC/MS Method 3: RT 2.28 minutes, m/z 661.2.

Intermediate 187

[1082] ##STR00164##

2-[(1R,3R)-3-[tert-butoxycarbonyl(trideuteriomethyl)amino]-6-fluoro-7-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy) benzoic acid

[1083] Into a 10 mL glass vial was placed Intermediate 186 (210 mg, 0.32 mmol), potassium carbonate (67 mg, 0.48 mmol), PdCl.sub.2(dcypp) (15 mg, 0.025 mmol), dimethyl sulfoxide (5 mL), water (0.1 mL, 6 mmol) and the vial equipped with a stirring bar was placed into a high pressure reactor. The headspace of the reactor was vacuum purge cycled with CO at 14 psi (×3) and then left with a headspace pressure of 5 Bar. The vessel was heated to 105° C., (heating block temp) for a period of 24 hrs. The reaction mixture was separated between ethyl acetate and water (20 mL of each) and the organic layer was extracted with a further 2×20 mL of 10% sodium carbonate solution. The combined aqueous layers were then treated with citric acid until no longer basic. The solution was then extracted with ethyl acetate (3×20 mL) and these organics washed with 4×20 mL of water. The organics were dried (sodium sulfate), filtered and evaporated in vacuo to afford the title compound as a white solid 90% pure. (120 mg, 56%). LC/MS Method 3: RT 1.51 minutes, m/z 671.2

Intermediate 188

[1084] ##STR00165##

Ethyl 2-[2-[(1R,3S)-7-chloro-3-methylsulfonyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl]-3-(difluoromethoxy)phenyl]sulfanylacetate

[1085] To a solution of Intermediate 161 (1.35 g, 2.88 mmol) in DCM (30 mL) at 0° C. was added 4-dimethylaminopyridine (40 mg, 0.33 mmol), N,N-diisopropylethylamine (1.01 mL, 5.77 mmol) and methane sulfonyl chloride (335 μL, 4.32 mmol) and stirred for 45 minutes. After this time the reaction mixture was partitioned between DCM (40 mL) and water (50 mL), layers separated and the aqueous phase extracted with DCM (3×50 mL). Combined organics were washed with saturated aqueous sodium bicarbonate solution (100 mL), dried (phase separator) and concentrated in vacuo to give the title compound as orange brown solid (1.57 g, quantitative yield). The crude product was progressed to the next synthetic step without further purification.

Intermediate 189

tert-Butyl N-[1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]ethyl]carbamate

[1086] Bis(pinacolato)diboron (4.55 g, 17.6 mmol), Intermediate 114 (3.70 g, 11.7 mmol), potassium acetate (4.64 g, 46.8 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1000 mg, 1.22 mmol) and 1,4-dioxane (35 mL) were placed in a RBF and then degassed. The mixture was then heated at 105° C. for 1 hour, LCMS showed the completion of the reaction. The reaction mixture was diluted with H.sub.2O and extracted with EtOAc (×3), and the organics combined, dried (MgSO.sub.4), filtered and evaporated in vacuo. The crude material was used in the subsequent Suzuki coupling (3.6 g, 80%). LC/MS Method 3: RT 1.04 minutes, m/z 378.

Intermediate 190

[1087] ##STR00166##

(7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-6-(trideutero)methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1088] Example 10 (650 mg, 1.65 mmol) was dissolved in tetrahydrofuran (15 mL, 184 mmol) and potassium bis(trimethylsilyl)amide (1.8 mL, 1.8 mmol, 1 mol/L in TNF) was added dropwise at −78° C. and stirred for 30 minutes before the addition of iodomethane-d.sup.3 (0.16 mL, 2.5 mmol). The reaction mixture was stirred at −78° C. for 10 minutes before being left in an ice-water bath for 1 hour. The reaction mixture was quenched with aqueous saturated NH.sub.4Cl solution and extracted with EtOAc (×3), the combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude material was purified by column chromatography eluting with 0%-10% MeOH/DCM to afford the title compound (570 mg, 84%). .sup.1H NMR (300 MHz, DMSO-d6) δ 8.27 (dd, J=5.3, 4.1 Hz, 1H), 7.93-7.26 (m, 5H), 6.24 (d, J=7.1 Hz, 1H), 5.23 (d, J=7.1 Hz, 1H), 3.49 (dt, J=14.3, 7.3 Hz, 1H), 2.81 (d, J=13.8 Hz, 1H). LC/MS Method 3: RT 2.00 minutes, m/z 411.0

Intermediate 191

[1089] ##STR00167##

tert-Butyl (2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-(trideutero)methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate

[1090] Intermediate 190 (570 mg, 1.38 mmol), Intermediate 189 (1.8 g, 4.0 mmol), potassium phosphate tribasic (1.05 g, 4.85 mmol) and tricyclohexylphosphonium tetrafluoroborate (65 mg, 0.17 mmol) were placed in a microwave vial and suspended in 1,4-dioxane (5 mL). The mixture was degassed and purged with N.sub.2 3 times, followed by the addition of tris(dibenzylideneacetone) dipalladium(0) (130 mg, 0.13 mmol) and three drops of water. The reaction mixture was heated at 140° C. for 2 hours in a microwave. The reaction cooled to room temperature and quenched with H.sub.2O (20 mL) and extracted with EtOAc (3×25 mL). The combined organics were dried over (Na.sub.2SO.sub.4), filtered and the solvents removed in vacuo. The residue was purified by column chromatography on silica eluting with 0 to 20% MeOH in EtOAc to afford the title compound (420 mg, 50%). LC/MS Method 3: RT 2.19 minutes, m/z 612.2

Intermediate 192

[1091] ##STR00168##

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl, di-O-benzyl phosphate

[1092] Example 1 (26.0 g, 52.5 mmol) was suspended in dichloromethane (450 mL), placed under nitrogen and 5-methyl-1H-tetrazole (8.38 g, 99.7 mmol) was added and the mixture cooled to 5° C. in an ice bath, evacuated and refilled with nitrogen twice then stirred for 5 minutes before adding dibenzyl N,N-di-isopropylphosphoramidite (28.2 mL, 83.9 mmol). The reaction was stirred for 5 minutes before warming to room temperature and stirred for one further hour. The mixture was cooled to 0° C. in an ice bath then hydrogen peroxide solution (5.96 mL, 105 mmol, 50.0% w/w in water) was added. The mixture was stirred for 1 hour and monitored by LCMS until oxidation was complete. The mixture was washed with 0.25M sodium metabisulphite solution (250 mL), then saturated aqueous sodium bicarbonate solution (150 mL) and saturated brine (200 mL). The organic phase was dried (sodium sulfate), filtered and concentrated in vacuo to a pale yellow gum. The crude product was purified by chromatography on silica (EtOAc to 15% MeOH in EtOAc) to give a crude residue which was azeotroped with toluene (×3) to give the title compound as a white solid, (31.0 g, 78%). .sup.1H NMR (d.sup.6-DMSO, 300 MHz) δ: 1.87 (s, 6H), 2.75 (d, 1H, J=13.4 Hz), 3.50 (m, 1H), 4.92 (t, 1H, J=6.8 Hz), 5.02-5.05 (m, 4H), 6.36 (d, 1H, J=7.1 Hz), 7.25 (m, 10H), 7.55 (m, 3H), 7.69 (d, 1H, J=11.5 Hz), 8.24 (dd, 1H, J=5.3, 4.2 Hz), 8.99 (s, 2H), 9.16 (d, 1H, J=6.8 Hz). LC/MS Method 3: RT 2.49 minutes, m/z 756.

Intermediate 193

[1093] ##STR00169##

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl, di-O-benzyl phosphate

[1094] To a solution of Intermediate 192 (4.00 g, 5.29 mmol) in THF (70 mL) was added a solution of KHMDS in THF (1M, 5.60 mL, 5.60 mmol) dropwise at −78° C. and the mixture was stirred for 45 minutes before the addition of iodomethane (0.37 mL, 5.90 mmol). The reaction mixture was warmed to 0° C. and stirred for 2.5 hours before the reaction completed. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl solution and extracted with EtOAc (×3), the combined organics were dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by column chromatography eluting with 0-10% MeOH in EtOAc gave the title compound (3.20 g, 4.2 mmol, 79%). LC/MS Method 3: ES.sup.+ (M+H).sup.+ 770, retention time 2.67 minutes.

Intermediate 194

[1095] ##STR00170##

(7R,14R)-11-chloro-1-(difluoromethoxy)-6-ethyl-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1096] Intermediate 148 (100 mg, 0.25 mmol) was dissolved in dry THF (2.5 mL), at the reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (12 mg, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 35 minutes. Iodomethane (0.27 mL, 3.34 mmol) was added and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was quenched by addition of water (2 mL). The aqueous layer was extracted by EtOAc (3×150 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified over silica gel (heptane/AcOEt 1/1), yielding to 35 mg (32%) of the title compound as a white solid. LCMS (Method 3 ES+): RT 2.60 min, [M+H]+ 418.

Intermediate 195

2-chloro-6-(trifluoromethoxy)benzaldehyde

[1097] N,N-Di-isopropylamine (38.4 ml, 271 mmol) was added dropwise to a solution of n-butyllithium (1.6 M, 169 ml, 271 mmol) in THF (180 ml) at 0° C. and the reaction mixture was stirred and allowed to warm to room temperature over 30 mins. The LDA solution was then added drop wise over 10 minutes to a solution of 1-chloro-3-(trifluoromethoxy)benzene (50 g, 246 mmol) in THF (500 ml) at −70° C. and the resulting mixture was stirred at −70° C. for 30 minutes. Finally N,N-dimethylformamide (23 ml, 296 mmol) was added dropwise and the resultant mixture stirred at −70° C. for 30 minutes.

[1098] The reaction was quenched at −70° C. by addition of NH.sub.4Cl (saturated aqueous solution) to pH 7-8 and the resulting mixture was extracted with EtOAc (3×75 ml). The combined organic phases were washed with water (100 ml), brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound (55 g, 99% yield).

[1099] LCMS (Method 16, ES+) RT 1.32 min., 224 [M+H].sup.+.

Intermediate 196

(S,E)-N-(2-chloro-6-(trifluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide

[1100] (S)-2-Methylpropane-2-sulfinamide (49.9 g, 411 mmol), potassium hydrogen phosphate (196 g, 1.12 mol) and potassium phosphate (238.2 g, 1.12 mol) were added to a solution of Intermediate 195 (84 g, 374 mmol) in THF (2000 ml) at room temperature. The resulting reaction mixture was stirred at room temperature over 20 hours, filtered and the solid was washed with EtOAc (3×200 ml). The filtrate was concentrated under reduced pressure to isolate the title compound (123 g).

[1101] LCMS (Method 16, ES+) RT 1.45 min., 328 [M+H].sup.+.

Intermediate 197

Ethyl (R)-3-(((S)-tert-butylsulfinyl)amino)-3-(2-chloro-6-(trifluoromethoxy)phenyl)-propanoate

[1102] A solution of ethyl bromoacetate (106.1 ml, 938.2 mmol) in THF (100 ml) was added dropwise over 2 hours to a solution of zinc (245.5 g, 3.75 mol) and cuprous chloride (44.6 g, 450 mmol) in THF (800 ml) at 20-25° C. (NB: prior to this addition, the solution of Zn and CuCl was heated at 70° C. over 30 mins and cooled down to room temperature). Once the addition was complete the reaction mixture was warmed to 50° C. over 1 hour. The reaction mixture was cooled to 0° C. and a solution of Intermediate 196 (123 g, 375.29 mmol) in THF (500 ml) was added dropwise over 60 mins. The resulting reaction mixture was warmed to room temperature over 20 hours and filtered over charcoal. The cake was washed with EtOAc (3×250 ml) and the combined filtrates were washed with water (500 ml), with 10% citric acid solution (1000 ml) and brine (500 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (155 g, 99% yield).

[1103] LCMS (Method 16, ES+) RT 1.36 min., 416 [M+H].sup.+.

Intermediate 198

Ethyl (R)-3-amino-3-(2-chloro-6-(trifluoromethoxy)phenyl)propanoate hydrochloride

[1104] 4M Hydrochloric acid solution in 1,4-dioxane (326.1 ml, 1.3 mol) was added dropwise over 30 mins to a solution of Intermediate 197 (155 g, 372.7 mmol) in a mixture of ethanol (107 ml) and diethyl ether (215 ml) at room temperature. The reaction mixture was then stirred for 2 hours and the resulting suspension was filtered. The cake was washed with Et.sub.2O (3×250 ml), with pentane (250 ml) and dried under suction to yield 49 g of the title compound. The filtrate was concentrated under reduced pressure to provide a viscous residue. Et.sub.2O was added to the residue, and the mixture was stirred over 20 hours. The resulting suspension was filtered and the isolated cake was washed with Et.sub.2O (3×250 ml), with pentane (250 ml), and dried to yield 70 g of the title compound as the hydrochloride salt. LCMS (Method 16, ES+) RT 0.59 min., 311 [M+H].sup.+.

Intermediate 199

Ethyl (R)-3-((5-bromo-4-fluoro-2-nitrophenyl)amino)-3-(2-chloro-6-(trifluoromethoxy)-phenyl)propanoate

[1105] 1-Bromo-2,5-difluoro-4-nitrobenzene (30.2 g, 126.7 mmol) was added to a solution of ethyl Intermediate 198 (49 g, 140.8 mmol) in N,N-dimethylformamide (200 ml) and N,N-diisopropylamine (46.76 ml, 281.5 mmol) was added. The reaction mixture was heated at 85° C. over two hours and, once cooled to room temperature, was then concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (500 ml), washed with water (500 ml), 10% citric acid solution (2×500 ml) and brine (500 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude was purified by SiO.sub.2 flash chromatography with EtOAc/n-Heptane (2/98) as eluent to provide the title compound (45 g, 60% yield).

[1106] LCMS (Method 16, ES+) RT 1.60 min., 531 [M+H].sup.+.

Intermediate 200

(R)-3-((5-bromo-4-fluoro-2-nitrophenyl)amino)-3-(2-chloro-6-(trifluoromethoxy)phenyl)-propanal

[1107] Diisobutylaluminium hydride was added dropwise over 2 hours to a solution of Intermediate 199 (10 g, 18.9 mmol) in THF (100 ml) at −70° C. under argon. The reaction mixture was stirred over 2 hours at −70° C. The reaction was quenched at −70° C. by addition of NH.sub.4Cl (saturated aqueous solution) to pH=6 and the resulting suspension was filtered over a charcoal pad washing with EtOAc (75 mL). The filtrate was extracted with EtOAc (3×75 mL. The combined organic phases were washed with water (100 ml), brine (100 ml), dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The resulting residue was purified by SiO.sub.2 flash chromatography with EtOAc/n-Heptane (1/4) as eluent to give the title compound (5.8 g, 63% yield).

[1108] LCMS (Method 17, ES+) RT 4.83 min., 487 [M+H].sup.+.

Intermediate 201

(R)—N—((R,Z)-3-((5-bromo-4-fluoro-2-nitrophenyl)amino)-3-(2-chloro-6-(trifluoromethoxy)-phenyl)propylidene)-2-methylpropane-2-sulfinamide

[1109] (R)-2-Methylpropane-2-sulfinamide (1.47 g, 11.9 mmol) was added to a solution of Intermediate 200 (5.8 g, 11.35 mmol) and titanium(IV) isopropoxide (3.36 ml, 11.35 mmol) in dichloromethane (100 ml) at room temperature. The reaction was heated at reflux for 20 hours.

[1110] After cooling to room temperature the reaction was quenched by addition of brine (50 ml) and the resulting mixture was stirred for 30 mins. The suspension was filtered over a charcoal pad, washed with dichloromethane until the filtrate is colourless. The filtrate was washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (6.6 g, 99% yield).

[1111] LCMS (Method 18, ES+) RT 5.31 min., 588 [M+H].sup.+.

Intermediate 202

(R)—N—((1R,3R)-3-((5-bromo-4-fluoro-2-nitrophenyl)amino)-3-(2-chloro-6-(trifluoromethoxy)phenyl)-1-cyanopropyl)-2-methylpropane-2-sulfinamide

[1112] Scandium(III) trifluoromethanesulfonate (1.30 g, 2.62 mmol) was added to a solution of Intermediate 201 (7.7 g, 13.08 mmol) in dichloromethane (75 ml) at room temperature followed by trimethylsilyl cyanide (3.44 ml, 26.16 mmol). The reaction mixture was then stirred over 92 hours at room temperature. The reaction was quenched by addition of water (100 ml) and the resulting mixture was extracted with dichloromethane (2×50 ml). Combined organic phases were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound (7.5 g, 93% yield).

[1113] LCMS (Method 18, ES+) RT 4.89 min., 615 [M+H].sup.+.

Intermediate 203

[1114] ##STR00171##

7-Bromo-1-(2-chloro-6-(trifluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-3-amine

[1115] Stannous chloride (11.78 g, 60.9 mmol) was added to a solution of Intermediate 202 (7.5 g, 12.18 mmol) in ethanol (75 ml). The reaction mixture was heated at reflux over 2 hours and water (40 ml) was then added. The resulting solution was heated to reflux for 16 hours.

[1116] Once cooled to room temperature water (100 ml) and 2M Sodium hydroxide aqueous solution was added until pH=9.0 while keeping the solution temperature below 30° C. The resulting suspension was filtered over a charcoal pad and washed through with dichloromethane (5×50 ml). The filtrate was extracted with further dichloromethane (5×50 ml). The combined organic phases were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as cis/trans mixture of isomers (4/1, 3.00 g, 53% yield).

[1117] LCMS (Method 18, ES+) RT 2.83 min., 464 [M+H].sup.+.

Intermediate 204

[1118] ##STR00172##

tert-butyl ((1R,3R)-7-bromo-1-(2-chloro-6-(trifluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-3-yl)carbamate

[1119] Di-tert-butyl carbonate (1.99 ml, 9.04 mmol) was added to a solution of Intermediate 203 (3.00 g, 6.46 mmol) in dichloromethane (20 ml) at room temperature. The reaction mixture was then stirred for 20 hours and concentrated under reduced pressure. The resulting residue was purified by SiO.sub.2 flash chromatography with EtOAc/n-Heptane (1/4) as eluent to give the title compound (1.8 g, 49% yield).

[1120] LCMS (Method 19, ES+) RT 2.51 min., 464 [M-BOC+H].sup.+.

Intermediate 205

[1121] ##STR00173##

tert-Butyl ((1R,3R)-1-(2-chloro-6-(trifluoromethoxy)phenyl)-6-fluoro-7-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-3-yl)carbamate

[1122] 2-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propan-2-ol (0.26 g, 0.97 mmol) was added to a solution of Intermediate 204 (0.50 g, 0.89 mmol) in 1,4-dioxane (5 ml) under argon. Potassium carbonate (0.370 g, 2.66 mmol) was added to the solution and the reaction mixture was purged with argon prior.

[1123] bis(diphenylphosphino)ferrocene palladium(II)dichloride dichloromethane complex (0.023 g, 0.026 mmol) was added and the reaction mixture was heated at 90° C. for 2 hours and then cooled to room temperature. The reaction was quenched by addition of iced water and the resulting mixture was extracted with EtOAc (2×30 ml). The combined organic phases were washed with brine (2×20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by SiO.sub.2 flash chromatography with DCM/MeOH (100/0 to 98/2) followed by SiO2 flash chromatography with EtOAc/n-Heptane (3/7 to 1/1) as eluent to give the title compound (0.350 g, 64% yield).

[1124] LCMS (Method 20, ES+) RT 1.38 min., 622 [M+H].sup.+.

Intermediate 206

[1125] ##STR00174##

2-(5-((1R,3R)-3-amino-1-(2-chloro-6-(trifluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidin-2-yl)propan-2-ol

[1126] 2N Hydrochloric acid solution in diethyl ether (2.8 ml, 5.63 mmol) was added to a solution of Intermediate 205 (0.35 g, 0.56 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature over 72 hours.

[1127] Water was added and the aqueous phase was treated with 2N sodium hydroxide aqueous solution until pH=12. The resulting mixture was extracted with dichloromethane (2×50 ml) and then with EtOAc (2×50 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (300 mg).

[1128] LCMS (Method 20, ES+) RT 0.67 min., 522 [M+H].sup.+.

Intermediate 207

[1129] ##STR00175##

tert-Butyl ((1R,3R)-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-7-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)carbamate

[1130] 2-(Azetidin-3-yl)propan-2-ol hydrochloride (0.208 g, 1.37 mmol) and cesium carbonate (0.890 g, 2.74 mmol) were added to a solution of Intermediate 184 (0.500 g, 0.91 mmol) in a mixture of toluene/DMF (99/1, 15 ml). The resulting mixture was purged with argon. (R/S)-(+/−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.018 g, 0.027 mmol) and tris(benzylideneacetone)dipalladium(0) (0.009 g, 0.009 mmol) were added. The reaction mixture was then heated in a microwave at 100° C. over 2 hours. As traces of the expected azetidinyl derivative were detected by LCMS, a second addition of all reagents [2-(azetidin-3-yl)propan-2-ol hydrochloride (0.208 g, 1.37 mmol), cesium carbonate (0.890 g, 2.74 mmol), (R/S)-(+/−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.018 g, 0.027 mmol) and tris(benzylideneacetone)-dipalladium(0) (0.009 g, 0.009 mmol)] was carried out. The reaction mixture was then heated in microwave at 100° C. for a further 2 hours.

[1131] Water (50 ml) was added and the resulting mixture was extracted with EtOAc (3×50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by SiO.sub.2 flash chromatography with DCM/MeOH (100/0 to 95/5) as eluent to give the title compound (0.249 g, 47% yield).

[1132] LCMS (Method 20, ES+) RT 1.09 min., 581 [M+H].sup.+.

Intermediate 208

[1133] ##STR00176##

2-(1-((1R,3R)-3-amino-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)azetidin-3-yl)propan-2-ol

[1134] Trifluoroacetic acid (0.33 ml, 4.29 mmol) was added to a solution of Intermediate 207 (0.249 g, 0.428 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature over 24 hours.

[1135] Water (30 ml) was added and the aqueous phase was treated with 2N sodium hydroxide aqueous solution until pH=12. The resulting mixture was extracted with dichloromethane (2×30 ml) and EtOAc (1×30 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (0.157 g, 76% yield).

[1136] LCMS (Method 20, ES+) RT 0.64 min., 481 [M+H].sup.+.

Intermediate 209

[1137] ##STR00177##

tert-butyl ((1R,3R)-7-(4-(2-aminopropan-2-yl)phenyl)-1-(2-chloro-6-(trifluoromethoxy)-phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-3-yl)carbamate

[1138] A solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-amine in 1,4-dioxane (10 ml) was added to a solution of Intermediate 204 (0.500 g, 0.885 mmol) in 1,4-dioxane (40 ml) under argon. Sodium carbonate (0.188 g, 1.77 mmol) and water (1 ml) were added to the solution and purged with argon prior to addition of tris(dibenzylideneacetone)dipalladium(0) (0.021 g, 0.022 mmol) and tri-tert-butylphosphonium tretrafluoroborate (0.026 g, 0.088 mmol) were added and the reaction mixture was heated at 90° C. for 3 hours and then cooled to room temperature over 15 hours. Water (30 ml added and the resulting mixture extracted with EtOAc (2×30 ml). The combined organic phases were washed with brine (2×20 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by SiO.sub.2 flash chromatography with DCM/MeOH (100/0 to 9/1) as eluent to give the title compound (0.250 g, 46% yield).

[1139] LCMS (Method 20, ES+) RT 0.91 min., 619 [M+H].sup.+.

Intermediate 210

[1140] ##STR00178##

(1R,3R)-7-(4-(2-aminopropan-2-yl)phenyl)-1-(2-chloro-6-(trifluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-3-amine

[1141] 2N Hydrochloric acid solution in diethyl ether (2.0 ml, 4.04 mmol) was added to a solution of Intermediate 209 (0.250 g, 0.404 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 72 hours. Water (30 ml) was added and the aqueous phase was treated with 2N sodium hydroxide aqueous solution until to pH=12. The resulting mixture was extracted with dichloromethane (2×50 ml) and then with EtOAc (2×50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (0.195 g, 93% yield).

[1142] LCMS (Method 20, ES+) RT 0.45 min., 519 [M+H].sup.+.

Intermediate 211

[1143] ##STR00179##

tert-butyl ((1R,3R)-7-(4-(2-aminopropan-2-yl)phenyl)-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-3-yl)carbamate

[1144] The title compound was prepared from Intermediate 184 (0.500 g, 0.91 mmol) in accordance with the synthetic procedure described for Intermediate 209 after purification by SiO.sub.2 flash chromatography with DCM/MeOH (100/0 to 95/5) as eluent to give (0.324 g, 59% yield).

[1145] LCMS (Method 20, ES+) RT 0.86 min., 601 [M+H].sup.+.

Intermediate 212

[1146] ##STR00180##

(1R,3R)-7-(4-(2-aminopropan-2-yl)phenyl)-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-c]imidazole-3-amine

[1147] The title compound was prepared from Intermediate (0.324 g, 0.54 mmol) in accordance with the synthetic procedure described for Intermediate 210 to afford the title compound (0.240 g, 89% yield).

[1148] LCMS (Method 20, ES+) RT 0.43 min., 501 [M+H].sup.+.

Intermediate 213

[1149] ##STR00181##

N,N-diallyl-2-(5-bromopyrimidin-2-yl)propan-2-amine

[1150] To a mixture of 2-(5-bromopyrimidin-2-yl)propan-2-amine (3.00 g, 13.9 mmol) and potassium carbonate (5.81 g, 41.6 mmol) in acetonitrile (50 mL) was added allyl bromide (3.56 g, 29.1 mmol) and the mixture heated to 50° C. for 4 hours. A further portion of allyl bromide (850 mg, 6.95 mmol) was added and the reaction allowed to stir at room temperature for 72 hours. The mixture was partitioned between diethyl ether (200 mL) and 2M HCl. The organic phase was further extracted with 2M HCl (×2) and the aqueous phase washed with diethylether (×2). The aqueous phase was cooled on ice and made basic with solid sodium hydroxide. The aqueous was then extracted with dichloromethane and the organic solvents dried over sodium sulphate, filtered and the volatiles removed in vacuo to give the title compound as a red oil, (3.40 g, 83% yield). LCMS Method 3 (ES+) RT 2.63 minutes, 296/298 (M+H)+. .sup.1H NMR (300 MHz, DMSO-d.sup.6) 8.96 (s, 2H), 5.80-5.60 (m, 2H), 5.10-4.85 (m, 4H), 3.20-3.10 (m, 4H), 1.50 (s, 6H).

Intermediate 214

[1151] ##STR00182##

tert-butyl ((1R,3R)-7-(2-(2-((tert-butyldimethylsilyl)oxy)butan-2-yl)pyrimidin-5-yl)-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)carbamate

[1152] A solution of 2-(2-((tert-butyldimethylsilyl)oxy)butan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine [prepared from 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)butan-2-yl)pyrimidine (0.500 g, 1.45 mmol), bis(pinacolato)diboron (0.450 g, 1.74 mmol) potassium acetate (0.426 g, 4.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium(II)dichloride dichloromethane complex (0.037 g, 0.043 mmol) in 1,4-dioxane (10 ml) at 95° C. during 2 hours] in 1,4-dioxane (10 ml) was added to a solution of Intermediate 184 (0.650 g, 1.19 mmol) in 1,4-dioxane (40 ml) under argon. Sodium carbonate (0.253 g, 2.38 mmol), water (1 ml) were added and the suspension purged with argon. tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.030 mmol) and tri-tert-butylphosphonium tretrafluoroborate (0.035 g, 0.119 mmol) were added and the reaction mixture was heated at 95° C. for 3 hours before cooling to room temperature.

[1153] Water (30 ml) was added and the resulting mixture was extracted with EtOAc (2×30 ml). The combined organic phases were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by SiO.sub.2 flash chromatography with DCM/MeOH (100/0 to 98/2) as eluent to give a brown viscous oil. Purification by preparative HPLC provided the title compound (0.310 g, 36% yield).

[1154] LCMS (Method 20, ES+) RT 1.98 min., 732 [M+H].sup.+.

Intermediate 215

[1155] ##STR00183##

(1R,3R)-7-(2-(2-((tert-butyldimethylsilyl)oxy)butan-2-yl)pyrimidin-5-yl)-1-(2-chloro-6-(difluoromethoxy)phenyl)-6-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine

[1156] 2N Hydrochloric acid solution in diethyl ether (1.9 ml, 3.82 mmol) was added to a solution of Intermediate 214 (0.280 g, 0.382 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 3 hours.

[1157] Water (30 ml) was added and the aqueous phase was treated with 2N sodium hydroxide aqueous solution until pH=12. The resulting mixture was extracted with dichloromethane (2×30 ml) and with EtOAc (1×30 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (0.200 g, 78% yield).

[1158] LCMS (Method 16, ES+) RT 1.34 min., 632 [M+H].sup.+.

Intermediate 216

[1159] ##STR00184##

(7R,14R)-11-(2-(2-((tert-butyldimethylsilyl)oxy)butan-2-yl)pyrimidin-5-yl)-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[1160] A 0.6M solution of phenol in anhydrous DMSO (0.63 ml, 0.38 mmol) was added to a solution of Intermediate 215 (0.200 g, 0.32 mmol) in anhydrous DMSO (6 ml). Potassium carbonate (0.066 g, 0.47 mmol), dried 4 Å molecular sieves (0.240 g), dichloro-[bis(dicyclohexylphosphino)propane]palladium(II) (0.019 g, 0.032 mmol) were added. The reaction mixture was heated at 100° C. under 3 bars of carbon monoxide over 24 hours.

[1161] EtOAc (100 ml) was added and the resulting mixture was washed with water (3×100 ml), brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by SiO.sub.2 flash chromatography with DCM/MeOH (98/2 to 95/5) as eluent to afford the title compound (0.176 g, 89% yield)

[1162] LCMS (Method 20, ES+) RT 1.84 min., 624 [M+H].sup.+.

Example 1

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1163] ##STR00185##

[1164] Intermediate 14 was dissolved with pTSA (2.092, 11.00 mmol, 5 eq) in methanol (60 mL) and the mixture was stirred overnight at r.t. The reaction mixture was diluted with EtOAC (200 mL) and a saturated solution of NaHCO.sub.3 (200 mL) was added. The aqueous layer was extracted by 3×50 mL of EtOAc and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained residue was taken up in a minimum of EtOAc, triturated, and filtered off. The obtained precipitate was washed with EtOAc and dried to afford the title compound (1.6 g, 76%).

[1165] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.89 (s, 2H), 8.46 (d, J 8.0 Hz, 1H), 7.59 (m, 2H), 7.48 (m, 2H), 7.38 (m, 1H), 6.84 (t, J 72.5 Hz, 1H), 6.37 (d, J 7.0 Hz, 1H), 5.00 (t, J 6.4 Hz, 1H), 4.68 (s, 1H), 3.51 (dt, J 13.4, 7.0 Hz, 1H), 2.90 (d, J 13.3 Hz, 1H), 1.67 (s, 6H). LCMS Method 3 (ES.sup.+) RT 1.28 min, 496.0 (M+H).sup.+.

Example 2

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-methoxypropan-2-yl)pyrimidin-5-yl]-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1166] ##STR00186##

[1167] Example 1 (8 mg, 0.01615 mmol) was dissolved in 0.2 mL of dry THF. Sodium hydride (60% in mineral oil, 1.6 mg, 0.04037 mmoL) was added and the reaction mixture was heated at 65° C. for 1.5 h. Methyliodide (2.3 mg, 0.01615 mmoL) was added at r.t. and the mixture stirred at r.t for 16 h.

[1168] An excess of methyliodide was then added to the mixture and stirred for 1 h. Water was added, the mixture was extracted with ethyl acetate, the combined organic layers were dried over magnesium sulphate and concentrated in vacuo to the title compound as an off white solid (3 mg, 35.7%).

[1169] .sup.1H NMR (400 MHz, DMSO) δ ppm 8.93 (s, 2H), 8.51 (d, J 8.2 Hz, 1H), 7.54 (m, 2H), 7.44 (t, J 8.2 Hz, 1H), 7.32 (d, J 8.1 Hz, 1H), 6.84 (t, J 72.8 Hz, 1H), 6.28 (d, J 7.2 Hz, 1H), 4.98 (d, J 7.1 Hz, 1H), 3.52 (s, 3H), 3.48 (m, 1H), 3.28 (s, 3H), 2.90 (d, J 13.6 Hz, 1H), 1.70 (s, 6H). LCMS Method 3 (ES.sup.+) RT 1.39 min, 524.0 (M+H).sup.+.

Example 3

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1170] ##STR00187##

[1171] Intermediate 23 (525 mg, 0.8873 mmoL) was dissolved in 60 mL of methanol and cooled to 0° C. pTSA (1 g, 0.7031 mmoL) was added and the mixture stirred at room temperature for 16 h. The mixture was cooled down to 0° C., pTSA (1 g, 0.7031 mmoL) was added and the reaction mixture was heated at 60° C. for 2 h. The solvent was evaporated, the residue was taken up in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with DCM, the combined layers were dried over anhydrous MgSO.sub.4, filtered and concentrated in vacuo. The crude compound was triturated with EtOAc filtered, washed with a minimum of cold ethyl acetate and dried in vacuo to afford the title compound as a white solid (318 mg, 75%).

[1172] .sup.1H NMR (400 MHz, DMSO) δ ppm 9.14 (d, J 6.9 Hz, 1H), 9.04 (s, 2H), 8.25 (dd, J 4.6 Hz, J 4.1 Hz, 1H), 7.86-7.50 (m, 6H), 6.38 (d J 7.0 Hz, 1H), 5.12 (s, 1H), 4.92 (t, J 6.8 Hz, 1H), 3.49 (m, 1H), 2.77 (d, J 13.3 Hz, 1H), 1.54 (s, 6H). LCMS Method 3 (ES.sup.+) RT 1.26 min, 478.0 (M+H).sup.+.

Example 4

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1173] ##STR00188##

[1174] Intermediate 24 was dissolved in methanol (20 mL/g), pTSA (0.600 g, 3.152 mmol, 2.2 eq) was added and the reaction mixture was stirred at r.t. overnight. APTS (0.300 g, 1.176 mmol, 1.1 eq) was added and the reaction mixture was heated at 40° C. for 2 h, then 45° C. for 1 h and following 50° C. for 15 minutes until disappearance of starting material in LCMS. EtOAc (600 mL) was added and the mixture was washed successively with a saturated solution of NaHCO.sub.3 (200 mL) and a saturated solution of NaCl (200 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, diluted with diethylether (150 mL) and concentrated in vacuo to afford the title compound as an off-white solid (0.701 g, 99%).

[1175] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.83 (s, 2H), 8.43 (d, J=8.2 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 6.79 (t, J=72.5 Hz, 1H), 6.33 (d, J=7.2 Hz, 1H), 5.25 (d, J=7.1 Hz, 1H), 3.55 (d, J=7.1 Hz, 1H), 3.53 (s, 3H), 3.38 (d, J=6.7 Hz, 1H), 2.89 (d, J=13.7 Hz, 1H), 1.57 (s, 6H). LCMS Method 3 (ES.sup.+) RT 1.30 min, 492.0 (M+H).sup.+.

Example 5

(7R,14R)-1-(difluoromethoxy)-6-ethyl-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1176] ##STR00189##

[1177] Intermediate 25 (69 mg, 0.1113 mmoL) was dissolved in 1 mL of methanol, pTSA (105.9 mg, 34.0908 mmoL) was added and the mixture was stirred at r.t. for 16 h. EtOAc was added, washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography (SiO2, 75% EtOAc in heptane) and triturated with diethyl ether to afford the title compound as an off white solid (23 mg, 40.9%).

[1178] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.95 (s, 2H), 8.56 (d, J=7.4 Hz, 1H), 7.93 (m, 1H), 7.81 (s, 1H), 7.54 (m, 1H), 7.48 (m, 1H), 7.35 (d, J=7.2 Hz, 1H), 6.89 (t, J=72.3 Hz, 1H), 6.41 (s, 1H), 5.25 (m, 1H), 4.17 (m, 1H), 3.95 (m, 1H), 3.59 (m, 1H), 2.93 (m, 1H), 1.68 (s, 6H), 1.49 (m, 3H). LCMS Method 3 (ES.sup.+) RT 1.36 min, 506.0 (M+H).sup.+.

Example 6

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-(propan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1179] ##STR00190##

[1180] Intermediate 26 (10 mg, 0.0158 mmoL) was dissolved in MeOH (0.2 mL) and pTSA (6.6 mg, 0.0347 mmoL) was added. The mixture was stirred at r.t. After 16 h, pTSA (6.6 mg, 0.0347 mmoL) was again added and the mixture heated at 50° C. for 1 h. The reaction mixture was concentrated, the residue dissolved in EtOAc washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous magnesium sulphate, concentrated in vacuo and triturated with diethyl ether to afford the title compound as a white solid (7 mg, 85.4% yield).

[1181] LCMS (ES.sup.+) Method 3 RT 1.42 min, 520.0 (M+H).sup.+.

Example 7

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazocin-5(14H)-one

[1182] ##STR00191##

[1183] To a suspension of Intermediate 29 (50 mg, 0.0972 mmoL) in 1 mL of toluene was added cyanomethylenetributylphosphorane (25.9 mg, 0.0282 mmoL) and the reaction mixture was heated at 100° C. for 16 h. The mixture was cooled to r.t., taken up with EtOAc and washed with 1N sodium hydroxide. The organic layer was dried over magnesium sulphate and concentrated in vacuo and triturated with diethyl ether to afford the title compound as an off-white solid (3 mg, 6.2% yield).

[1184] .sup.1H NMR (400 MHz, DMSO) δ ppm 8.96 (s, 2H), 8.08 (d, J=7.9 Hz, 1H), 7.76 (d, J=11.3 Hz, 1H), 7.65 (t, J=73.8 Hz, 1H), 7.61 (m, 2H), 7.55 (m, 1H), 6.47 (d, J=6.8 Hz, 1H), 6.10 (d, J=5.3 Hz, 1H), 5.17 (bs, 1H), 3.61 (m, 1H), 3.18 (d, J=14.7 Hz, 1H), 1.49 (m, 6H). LCMS Method 3 (ES.sup.+) RT 1.36 min, 497.0 (M+H).sup.+.

Example 8

(2Z)-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazocin-5(14H)-ylidene]acetonitrile and (2E)-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazocin-5(14H)-ylidene]acetonitrile

[1185] ##STR00192##

[1186] To a suspension of Intermediate 29 (50 mg, 0.0972 mmoL) in 1 mL of toluene was added cyanomethylenetributylphosphorane (25.9 mg, 0.0282 mmoL) and the reaction mixture was heated at 100° C. for 16 h. The reaction was concentrated in vacuo and the residue was purified by reverse phase preparative LCMS (basic conditions). The residue was dissolved in 2 mL of MeOH and passed through an acidic exchange-ion column (400 mg, conditioning: MeOH 10 mL), followed by washing of the column with 10 mL of methanol. The compound was discharged from the resin by elution of 10 mL of ammonia (1 M in methanol) and concentrated in vacuo. The residue was purified by preparative TLC with EtOAc-hexane (8/2), to afford the title compound as a colourless oil (2.5 mg, 4.95% yield) in a 6/4 mixture of Z/E isomers.

[1187] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.93 (s, 1.2H), 8.90 (s, 0.8H), 7.69 (t, J=11.5 Hz, 1H), 7.60 (d, J=7.6 Hz, 0.6H), 7.40 (m, 3H), 7.25 (d, J=7.4 Hz, 0.4H), 6.84 (t, J=72.5 Hz, 0.4H), 6.83 (t, J=72.3 Hz, 0.6H), 6.28 (m, 1H), 6.01 (d, J=4.3 Hz, 0.4H), 5.87 (d, J=4.1 Hz, 0.6H), 5.34 (s, 0.6H), 5.07 (s, 0.4H), 3.32 (m, 1H), 3.07 (d, J=14.1 Hz, 0.4H), 3.02 (d, J=13.9 Hz, 0.6H) 1.67 (s, 6H).

[1188] LCMS Method 3 (ES.sup.+) RT 1.39 min, 520.0 (M+H).sup.+.

Example 9

(7R,1 4R) and (7S,14S)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7,14-dihydro-7,14-methanopyrido[1′,2′:1,2]imidazo[4,5-d][2]benzazocin-5(6H)-one

[1189] ##STR00193##

[1190] The title compound was prepared from Intermediate 37 (300 mg, 0.71 mmol), Na.sub.2CO.sub.3 (378 mg, 3.57 mmol) and dichloro [bis(dicyclohexylphosphino)propane] palladium(II) [Pd-133 from Johnson Matthey] (40 mg, 0.06 mmol), 1,4-dioxane (9 mL) under CO gas (5 bars) at 150° C. for 15 h, following the protocol described for Intermediate 14 (5.5 mg, 2%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.10 (s, 2H), 8.90 (s, 1H), 8.70 (d, J 6.3 Hz, 1H), 8.28 (d, J 8.0 Hz, 1H), 7.95 (d, J 7.5 Hz, 1H), 7.66 (d, J 9.4 Hz, 1H), 7.61 (d, J 9.4 Hz, 1H), 7.48 (t, J 7.4 Hz, 1H), 7.27(t, J 7.7 Hz, 1H), 5.11 (s, 1H), 4.75 (d, J 6.1 Hz, 1H), 4.69 (t, J 6.3 Hz, 1H), 2.44 (d, J 12.6 Hz, 2H), 1.54 (s, 6H).

[1191] LCMS Method 3 (ES.sup.+) RT 1.64 min, 412.0 (M+H).sup.+.

Example 10

[1192] ##STR00194##

(7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1193] In a high pressure reactor, Intermediate 41 (927 mg, 2.076 mmol) was solubilized in dry 1,4-dioxane (21 mL). Potassium carbonate (1.4 g, 10.4 mmol) was added. A solution of palladium(II) acetate (23.3 mg, 0.1038 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (61.9 mg, 0.1038 mmol) in 1 mL of dry dioxane was then added. The reactor was closed and degassed by 3 successive vacuum/nitrogen cycles and then with CO by 3 successive vaccuum/CO cycles. The bomb was charged with CO to 8 psi and heated at 110° C. overnight. The reaction mixture was subsequently filtered through a pad of celite and the pad rinsed by 50 mL of EtOAc. The filtrate was concentrated in vacuo and the residue purified over silica gel using AcOEt/MeOH 10/0 to 9/1 to yield 534 mg (65%) of the title compound as a pale brown solid. LCMS basic: RT 1.97 min. (ES+) 394/396 (M+H).sup.+. 1H NMR (400 MHz, DMSO): 9.13 (d, J=6.8 Hz, 1H), 8.23 (dd, J1=6.9 Hz, J2=2.6 Hz, 1H), 7.70 (d, J=10.1 Hz, 1H), 7.60 (t, J=73.2 Hz, 1H), 7.51 (m, 3H), 6.30 (d, J=7.1 Hz, 1H), 4.88 (t, J=6.8 Hz, 1H), 3.45 (m, 1H), 2.73 (d, J=13.4 Hz, 1H).

Example 11

[1194] ##STR00195##

(7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1195] Intermediate 40 (3.7 g, 8.6 mmol), activated molecular sieve 4 A powder (1.2 g), potassium carbonate (1.5 equiv., 13 mmol) followed by dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (0.04 equiv., 0.35 mmol) were poured into the center of the 100 mL Glass Parr reaction vessel. 3 cycles of vacuum (˜20 mmHg) followed by Argon were applied to the closed reactor.

[1196] Anhydrous dimethyl sulfoxide (35 mL) was added, followed by phenol 5M in DMSO (1.1 equiv., 9.5 mmol). The solution was degassed by 3 vacuum (˜20 mmHg)/argon cycles followed by 3 cycles of vacuum/CO resulting in a final CO pressure of 1 bar.

[1197] The mixture was stirred and heated overnight at 100° C. under the CO atmosphere. The reaction was cooled to 30° C., the reactor vessel was opened and EtOAc (40 mL) was added. The resulting mixture was filtered on a pad of Celite, evaporated in vacuo to yield a green oil.

[1198] The residue thus obtained was taken up in EtOAc (100 mL) and the organic layer was washed with water, K.sub.2CO.sub.3 (saturated aqueous solution) and brine (saturated aqueous solution). The aqueous layer was then re-extracted with EtOAc (1×50 mL). The combined organic layers were dried over MgSO.sub.4, filtered and evaporated to dryness. The obtained green solid (3.65 g), was taken up in EtOAc, the insoluble material was filtered and rinsed with Et.sub.2O to afford 1.06 g (33.1%) of the title compound as a grey solid. The filtrate can be purified by flash chromatography to provide additional product if required:

[1199] LCMS basic: MH+ m/z=376, RT 1.90 minutes.

[1200] .sup.1H NMR (300 MHz, DMSO) δ 9.12 (d, 1H, J=6.7 Hz), 8.23 (dd, 1H, J=7.0, 2.4 Hz), 7.60 (m, 5H), 7.20 (dd, 1H, J=8.7, 2.1 Hz), 6.29 (d, 1H, J=7.1 Hz), 4.87 (dd, 1H, J=6.7 Hz, 6.7 Hz), 3.46 (m, 1H), 2.72 (d, 1H, J=13.4 Hz).

Example 12

[1201] ##STR00196##

(7R,14R)-11-chloro-1-(difluoromethoxy)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

[1202] Intermediate 45 (0.0525 mmol) was solubilized in THF (0.5 mL) and ethanol (0.5 mL). Polymer-supported cyanoborohydride (33 mg, 0.132 mmol, 4 mmol/g) was added. The reaction mixture was subjected to an orbital shaker for 2 hours. The reaction mixture was then filtered and evaporated under reduced pressure. The crude material was purified by preparative reverse phase HPLC (basic condition) to afford 7 mg (37%) of the title compound. LCMS basic (ES+) RT 3.5 min., 362/364(M+H)+. LCMS acidic (ES+) RT 2.12 min., 362/364(M+H)+.

[1203] .sup.1H NMR (400 MHz, CDCl3) δ 7.69 (m, 1H), 7.20 (m, 3H), 7.13 (m, 1H), 6.99 (m, 1H), 6.73 (m, 1H), 6.10 (m, 1H), 4.77 (m, 1H), 3.66 (m, 1H), 3.21 (m, 1H), 3.01 (d, 1H, J=15.3 Hz), 2.94 (m, 1H), 2.50 (m, 1H).

Example 13

[1204] ##STR00197##

[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]acetic acid

[1205] Intermediate 46 (34 mg, 0.076 mmol), 2-(1-hydroxy-1-methtylethyl) pyrimidine-5-boronic acid pinacol ester (2.5 equiv., 0.190 mmol), K.sub.3PO.sub.4 (2 equiv., 0.152 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.05 equiv., 0.0038 mmol), and tricyclohexylphosphonium tetrafluoroborate (0.12 equiv., 0.0091 mmol) were dissolved in a degassed mixture of 1,4 dioxane (0.9 mL) and water (0.1 mL). The reaction mixture was heated overnight at 105° C.

[1206] The mixture was cooled to r.t; water was added and the mixture extracted with EtOAc. The aqueous layer was brought to pH 2-3 with HCl 1N, extracted with EtOAc, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by reverse phase chromatography to afford 3 mg (7.5%) of the title compound as a white solid at 90% purity. LCMS (ES+) 522/523 (M+H).sup.+

Example 14

[1207] ##STR00198##

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine-5(14H)-thione

[1208] To a solution of Intermediate 47 5 (15 mg, 0.025 mmol) in MeOH (1 mL) was added p-toluenesulfonic acid monohydrate (23.5 mg, 0.124 mmol). The slurry was stirred overnight at r.t. The reaction mixture was quenched with NaHCO.sub.3 (10% aqueous solution) and extracted with EtOAc (3×5 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH 9/1) followed by a second purification by flash chromatography on silica gel (DCM/MeOH 100/0 to 95/5) to afford 9 mg (74%) of the title compound. LCMS acidic (ES+) RT 2.29 min., 494(M+H)+.

Example 15

[1209] ##STR00199##

(7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine

[1210] Example 10 (178 mg, 0.452 mmol) was solubilized in dry THF (5 mL). At 0° C., borane dimethyl sulfide complex (340 μL, 2M solution in THF, 0.68 mmol) was added. The reaction mixture was allowed to warm to r.t. and stirred overnight. The reaction mixture was concentrated in vacuo, the residue was taken up in MeOH, stirred and heated under reflux for 48 hours. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase preparative LCMS (basic condition) to afford 65 mg (38%) of the title compound. LCMS basic (ES+) RT 3.55 min., 380/382(M+H)+. LCMS acidic (ES+) RT 3.56 min., 380/382(M+H)+. .sup.1H NMR (400 MHz, CDCl3) δ ppm 7.52 (d, 1H, J=9.6 Hz), 7.23 (m, 2H), 7.12 (m, 1H), 6.97 (d, 1H, J=7.4 Hz), 6.71 (m, 1H), 6.09 (d, 1H, J=7.6 Hz), 4.70 (d, 2H, J=5.9 Hz), 3.64 (m, 1H), 3.21 (m, 1H), 2.98 (d, 1H, J=15.3 Hz), 2.48 (d, 1H, J=12.6 Hz).

Example 16

[1211] ##STR00200##

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1212] Example 15 (47 mg, 0.1237 mmol), 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (82 mg, 0.3105 mmol), tricyclohexylphosphonium tetrafluoroborate (5.524 mg, 0.01485 mmol), tris (dibenzylideneacetone)dipalladium(0) (5.6 mg, 0.0061 mmol), and K.sub.3PO.sub.4 (52.5 mg, 0.248 mmol) were placed in a tube, and filled with argon. Degassed 1,4 dioxane (1 mL) and water (100 μL) were added and the resulting slurry was stirred at 105° C. for 2 hours. The reaction mixture was cooled to r.t. before addition of EtOAc (2 mL) and water (2 mL). The aqueous layer extracted with EtOAc (2×2 mL). The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude was purified by reverse phase preparative LCMS (acidic condition) to afford the TFA salt of the title compound which was solubilized in EtOAc (2 mL) and washed with a saturated solution of NaHCO.sub.3. The aqueous layer was extracted with EtOAc (2×2 mL). The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo to afford 33 mg (55%) of the title compound as a white solid. LCMS basic (ES+) RT 3.69 min., 482(M+H)+. LCMS acidic (ES+) RT 1.91 min., 482(M+H)+. .sup.1H NMR (400 MHz, CDCl3) δ ppm 8.87 (m, 2H), 7.62 (m, 1H), 7.25 (s, 1H), 7.20 (m, 1H), 7.12 (m, 1H), 6.99 (m, 1H), 6.72 (m, 1H), 6.17 (m, 1H), 4.78 (m, 1H), 4.66 (m, 1H), 3.66 (m, 1H), 3.25 (m, 1H), 3.05 (m, 1H), 2.53 (m, 1H), 1.65 (s, 6H).

Example 17

[1213] ##STR00201##

(7R,14R)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-1-methoxy-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1214] Intermediate 57 (145 mg, 0.31 mmol) was dissolved in anhydrous DMA (3 mL) in a 25 mL pressure reactor and Na.sub.2CO.sub.3 (165 mg, 1.56 mmol) was added. The mixture was degassed with a stream of nitrogen for 10 minutes then the pressure vessel was sealed and subjected to three vacuum/nitrogen flush cycles, before repeating the process with carbon monoxide and charging the pressure to 3.0 bar. The mixture was stirred for 5 minutes then heated to 150° C. and stirred at this temperature overnight. The reactor was allowed to cool to r.t. The reaction mixture was diluted with EtOAc (20 mL) and filtered through a pad of celite, washing with excess EtOAc (20 mL). The filtrate was washed with water (15 mL), then brine (15 mL), dried (Na.sub.2SO.sub.4) and concentrated to dryness under vacuum to yield 160 mg of a crude residue. Purification by reverse phase chromatography (eluting with 0-100% MeCN (+0.1% NH.sub.4OH)/H.sub.2O (+0.1% NH.sub.4OH)) to yield 2.1 mg (1.5%) of the title compound as a beige solid. LCMS Method 6 (ES+) RT 3.52 min., 460.2 (M+H)+. .sup.1H NMR (500 MHz, MeOH-d4) δ 8.95 (d, J=1.5 Hz, 2H), 8.04 (dd, J=8.0, 1.1 Hz, 1H), 7.64 (d, J=6.8 Hz, 1H), 7.50 (d, J=11.2 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.37-7.29 (m, 1H), 6.62 (d, J=7.1 Hz, 1H), 4.96 (d, J=6.7 Hz, 1H), 4.13 (s, 3H), 3.51 (dt, J=13.5, 6.9 Hz, 1H), 2.80 (d, J=13.4 Hz, 1H), 1.65 (s, 6H), 1.63-1.57 (m, 1H).

Example 18

[1215] ##STR00202##

(7R,14R)-1,10-difluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1216] To a solution of Intermediate 58 (200 mg, 0.44 mmol) in 1,4-dioxane (5 mL) was added sodium carbonate (232 mg, 2.19 mmol) dichloropalladium; dicyclohexyl(3-dicyclohexyl-phosphanylpropyl)-phosphane (53.8 mg, 0.0877 mmol). The reaction mixture was stirred at 160° C. under 5 bar of CO pressure overnight. The reaction mixture was filtered through a celite pad and rinsed with ethanol (10 mL). The filtrate was evaporated and the crude was dissolved in DCM (10 mL) and treated with a saturated aqueous solution of NH.sub.4Cl (5 mL) The organic layer was concentrated in vacuo, and the residue purified on silica gel (DCM/iPrOH/aq NH.sub.3 90:9:1), yielding 32 mg (16%) of the title compound.

[1217] LCMS acidic Method 4 (ES+) RT 2.06 min., 448.2 (M+H).sup.+

Example 19

[1218] ##STR00203##

(6R,12R)-2-chloro-11-(difluoromethoxy)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

[1219] A mixture of Intermediate 40 (500 mg, 1.17 mmol), potassium carbonate (322 mg, 2.33 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (69 mg, 0.12 mmol) and palladium(II) acetate (26 mg, 0.12 mmol) in 1,4-dioxane (16 mL) was de-gassed and stirred at 110° C. under nitrogen for 15 hours. The reaction mixture was cooled to ambient temperature and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (69 mg, 0.12 mmol) and palladium(II) acetate (26 mg, 0.12 mmol) were added to the reaction mixture. The solvent was de-gassed and the mixture was stirred at 110° C. for 18 hours. The reaction mixture was cooled to ambient temperature, filtered through celite and the latter was washed with EtOAc. The combined filtrate and washings were evaporated to dryness using an oil pump to give an oil which was purified by flash chromatography on silica gel (25 to 100% EtOAc in hexanes) to afford the title compound (249 mg, 0.71 mmol, 61% yield) as a brown solid. LC/MS Method 3: RT 2.29 mins (pH 10), m/z 348 and 350.

[1220] .sup.1H NMR: (CD.sub.3OD, 300 MHz) δ: 2.48 (d, J=11.2 Hz, 1H), 2.99 (dt, J=11.2, 4.5 Hz, 1H), 4.87 (m, 1H (overlap with the residual water), 5.93 (d, J=4.5 Hz, 1H), 6.40 (d, J=8.1 Hz, 2H), 6.96 (t, J=74 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 7.17 (dd, J=8.6, 2.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H).

Example 20

[1221] ##STR00204##

2-{5-[(6R,12R)-11-(difluoromethoxy)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1222] A mixture of 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (purchased from commercial sources) (110.5 mg, 0.42 mmol), Example 19 (97 mg, 0.28 mmol), K.sub.3PO.sub.4 (118.3 mg, 0.56 mmol), and tricyclohexylphosphonium tetrafluoroborate (15.9 mg, 0.042 mmol) was solubilized in 1,4-dioxane (1.95 mL) and water (0.19 mL) and the mixture degassed with nitrogen before addition of tris(dibenzylideneacetone)dipalladium(0) (18.4 mg, 0.019 mmol). The reaction mixture was heated at 105° C. for 15 hours or until LCMS showed reaction to be complete. The reaction mixture was cooled to ambient temperature and the crude mixture was extracted with EtOAc (3×10 mL). The combined organic phases were washed with saturated brine (2×10 mL), dried over sodium sulphate, filtered and concentrated in vacuo to give an oil which was purified by preparative HPLC (pH=10) to afford the title compound (23 mg, 0.051 mmol, 18% yield) as a white solid. LC/MS Method 3: RT 2.09 mins (pH 10), m/z 450.

[1223] .sup.1H NMR: (DMSO-d.sub.6, 300 MHz) δ: 1.54 (s, 6H), 2.38 (d, J=11.3 Hz, 1H), 2.94 (dt, J=11.3, 4.3 Hz, 1H), 4.91 (t, J=3.5 Hz, 1H), 5.11 (bs, 1H), 5.91 (d, J=4.3 Hz, 1H), 6.34 (t, J=8.3 Hz, 2H), 6.97 (t, J=8.3 Hz, 1H), 7.15 (d, J=3.7 Hz, 1H), 7.38 Hz (dd, J=73, 1.7 Hz, 1H), 7.54 (dd, J=8.4, 1.7 Hz, 1H), 7.68-7.72 (m, 2H), 9.06 (s, 2H).

Example 21

[1224] ##STR00205##

1-[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]ethanone

[1225] Example 19 (245 mg, 0.7044 mmol) was dissolved in pyridine (2 mL) and acetic anhydride (2 mL). The mixture was stirred at 110° C. for 15 hours. The reaction mixture was cooled to ambient temperature and quenched with 2N NaOH aq. (2 mL). The crude mixture was extracted with EtOAc (2×10 mL). The organic phase was washed with saturated brine (10 mL), the combined organic phases was dried with sodium sulphate, filtered and concentrated in vacuo to give an oil which was purified by flash chromatography on silica gel (0 to 100% EtOAc in hexanes) to afford the title compound (177 mg, 65% yield) as a yellow solid. LC/MS Method 3: RT 2.08 mins (pH 10), m/z 390 and 392.

[1226] .sup.1H NMR: (CD.sub.3OD, 300 MHz) δ: 2.66 (d, J=11.9 Hz, 1H), 2.69 (s, 3H), 3.20 (dt, J=11.9, 4.5 Hz, 1H), 5.99 (d, J=3.9 Hz, 1H), 6.10 (d, J=4.5 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 7.08 (t, J=73.4 Hz, 1H), 7.20-7.28 (m, 2H), 7.53 (d, J=8.7 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 8.22 (d, J=8.7 Hz, 1H).

Example 22

[1227] ##STR00206##

1-[(6R,12R)-11-(difluoromethoxy)-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]ethanone

[1228] The title compound was prepared from 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (179.9 mg, 0.68 mmol), and Example 21 according to a method involving the same procedural steps as those described for Example 20, to give, following purification by preperative HPLC (pH=10), a white solid (13 mg, 0.026 mmol, 5.8% yield): LC/MS Method 3: RT 1.93 mins (pH 10), m/z 492.

[1229] .sup.1H NMR: (DMSO-d.sub.6, 300 MHz) δ: 1.54 (s, 6H), 2.61 (d, J=12.4 Hz, 1H), 2.69 (s, 3H), 3.20 (dt, J=12.1, 4.5 Hz, 1H), 5.75 (s, 1H), 6.00 (d, J=3.2 Hz, 1H), 6.08 (d, J=4.3 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 7.46 Hz (dd, J=72.1, 1.7 Hz, 1H), 7.61 (dd, J=8.5, 1.8 Hz, 1H), 7.76-7.80 (m, 2H), 8.21 (d, J=8.5 Hz, 1H), 9.07 (s, 2H).

Example 23

[1230] ##STR00207##

(6R,12R)-2-chloro-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

[1231] To a round bottom flask were added Intermediate 59 (2.80 g, 5.52 mmol), palladium(II) acetate (248 mg, 1.11 mmol), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.38 g, 2.21 mmol) and potassium carbonate (1.93 g, 13.8 mmol). The mixture was sealed and purged 3 times with nitrogen. Toluene (55 mL) was added to the reaction mixture and the vial was kept under nitrogen and stirred for 15 hours at 110° C. Then, the reaction mixture was cooled to ambient temperature, filtered through celite and the latter was washed with EtOAc. The combined filtrate and washings were evaporated to dryness using an oil pump to give an oil which was purified by flash chromatography in silica gel (0 to 100% EtOAc in Hexane) to afford the title compound (1.87 g, 4.39 mmol, 79.5% yield) as a brown solid. LC/MS Method 3: RT 2.15 mins (pH 10), m/z 426 and 428.

[1232] .sup.1H NMR: (DMSO-d.sub.6, 300 MHz) δ: 2.64 (d, J=12.0 Hz, 1H), 3.05 (s, 3H), 3.18 (dt, J=12.0, 4.2 Hz, 1H), 5.92 (d, J=3.6 Hz, 1H), 6.08 (d, J=4.2 Hz, 1H), 6.94 (dd, J=8.3, 0.7 Hz, 1H), 7.22 (dd, J=8.7, 2.1 Hz, 1H), 7.34 (t, J=8.5 Hz, 1H), 7.44 (t, J=73.2 Hz, 1H), 7.47 (d, J=1.8 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H).

Example 24

[1233] ##STR00208##

2-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1234] The title compound was prepared from 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol, and Example 23 according to a method involving the same procedural steps as those described for Example 20 to give, following purification by flash chromatography on silica gel (0 to 100% EtOAc in hexane), a white solid (542 mg, 84% yield). LC/MS Method 3: RT 2.04 mins (pH 10), m/z 528.

[1235] .sup.1H NMR: (DMSO-d.sub.6, 300 MHz) δ: 1.55 (s, 6H), 2.68 (d, J=12.1 Hz, 1H), 3.05 (s, 3H), 3.24 (dt, J=12.3, 4.5 Hz, 1H), 5.12 (s, 1H), 5.96 (d, J=3.6 Hz, 1H), 6.13 (d, J=4.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 7.34 (t, J=8.5 Hz, 1H), 7.50 Hz (dd, J=72.4, 1.5 Hz, 1H), 7.62-7.56 (m, 2H), 7.67 (d, J=1.5 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 9.07 (s, 2H).

Example 25

[1236] ##STR00209##

(6R,12R)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzoxazepine

[1237] A mixture of Intermediate 60 (287 mg, 0.668 mmol), cesium carbonate (440 mg, 1.33 mmol), 8-hydroxyquinoline (10 mg, 0.068 mmol), in toluene (0.7 mL) was degassed followed by the addition of copper (I) iodide (6.5 mg, 0.033 mmol). The reaction mixture was stirred at 100° C. for 15 hours. The reaction mixture was cooled to ambient temperature, filtered through celite and the latter was washed with CH.sub.2Cl.sub.2. The combined filtrate and washings were evaporated to dryness using an oil pump to give an oil which was purified by flash chromatography on silica gel (0 to 75% EtOAc in Hexane) to afford the title compound (40 mg, 0.1147 mmol, 17.17% yield) as a red solid. LC/MS Method 3: RT 2.51 mins (pH 10), m/z 349 and 351.

[1238] .sup.1H NMR: (CD.sub.3OD, 300 MHz) δ: 2.75 (d, J=12.4 Hz, 1H), 3.13 (ddd, J=12.4, 4.4, 1.4 Hz, 1H), 5.83 (d, J=1.4 Hz, 1H), 6.01 (d, J=4.4 Hz, 1H), 6.63 (dd, J=8.4 Hz, 1H), 6.70 (dd, J=8.3 Hz, 1H), 7.01 (t, J=73.4 Hz, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.21 (dd, J=8.6, 1.9 Hz, 1H), 7.53 (d, J=1.6 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H).

Example 26

[1239] ##STR00210##

2-{5-[(6R,12R)-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzoxazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1240] The title compound was prepared from 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol, and Example 25 according to a method involving the same procedural steps as those described for Example 20 to give, following purification by flash chromatography on silica gel (0 to 100% EtOAc in Hexane) a white solid (4.5 mg, 12% yield). LC/MS Method 3: RT 2.02 mins (pH 10), m/z 451.

[1241] .sup.1H NMR: (DMSO-d.sub.6, 300 MHz) δ: 1.48 (s, 6H), 2.68 (d, J=12.9 Hz, 1H), 3.09 (ddd, J=12.9, 4.2, 1.5 Hz, 1H), 5.05 (s, 1H), 5.92 (d, J=1.5 Hz, 1H), 5.92 (d, J=4.2 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 7.12 (t, J=8.3 Hz, 1H), 7.35(dd, J=72.4, 1.5 Hz, 1H), 7.55 (dd, J=8.6, 1.7 Hz, 1H), 7.74 (m, 2H), 9.01 (s, 2H).

Example 27

[1242] ##STR00211##

(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine-11-carbonitrile

[1243] To a mixture of Example 11 (100 mg, 0.266 mmol), zinc cyanide (35 mg, 0.298 mmol) and tetrakis (triphenylphosphine) palladium (31 mg, 0.0266 mmol) was added N,N-dimethyl-formamide (3 mL). The mixture was degassed for 3 minutes before being heated in microwave at 180° C. for 20 minutes. The reaction mixture was partitioned between EtOAc (30 mL) and water (40 mL), and the organics were washed with saturated brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (reverse phase) to give the title compound (5.1 mg, 5.2% yield) as a white solid. LC/MS Method 3: ESI MH.sup.+ 367, retention time 1.69 minutes (pH 10).

[1244] .sup.1H NMR: (DMSO-d6, 400 MHz) δ 9.17 (d, J=6.8 Hz, 1H), 8.23 (dd, J=7.5, 1.8 Hz, 1H), 7.79 (m, 2H), 7.7-7.4 (m, 4H), 6.38 (d, J=7.1 Hz, 1H), 4.94 (t, J=6.8 Hz, 1H), 3.50 (m, 1H), 2.77 (d, J=13.5 Hz, 1H).

Example 28

[1245] ##STR00212##

(7R,14R)-1-(difluoromethoxy)-11-[4-(methylsulfonyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1246] The title compound was prepared from 4-methylsulfonylphenyl-boronic acid, and Example 11 according to a method involving the same procedural steps as those described for Example 20, following purification by flash chromatography on a 100 g-SNAP Biotage silica cartridge eluting with 0%-10% MeOH/EtOAc followed by prep HPLC (reverse phase, 30%-50% MeCN/H.sub.2O, pH 10) to give (8.83 mg, 0.178 mmol, 48%) as a white solid.

[1247] LC/MS Method 3: ESI MH.sup.+ 496.0, retention time 1.82 minutes (pH 10).

[1248] .sup.1H NMR: (DMSO-d6, 300 MHz) δ 9.14 (d, J=6.6 Hz, 1H), 8.23 (dd, J=5.7, 3.8 Hz, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.9-7.4 (m, 9H), 6.37 (d, J=7.1 Hz, 1H), 4.89 (t, J=6.6 Hz, 1H), 3.49 (m, 1H), 3.27 (s, 3H), 2.75 (d, J=13.4 Hz, 1H).

Example 29

[1249] ##STR00213##

(7R,14R)-1-(difluoromethoxy)-11-(6-methoxypyridin-3-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1250] The title compound was prepared from 2-methoxy-5-pyridineboronic acid and Example 11, according to a method involving the same procedural steps as those described for Example 20, following purification by flash chromatography to give (29 mg, 24%) as a white solid.

[1251] LC/MS Method 3: ESI MH.sup.+ 449.0, retention time 2.07 minutes (pH 10).

[1252] .sup.1H NMR: (DMSO-d6, 400 MHz) δ 9.13 (d, J=6.8 Hz, 1H), 8.42 (d, J=2.32 Hz, 1H), 8.23 (dd, J=5.9, 3.4 Hz, 1H), 7.9-7.4 (m, 7H), 6.93 (d, J=8.6 Hz, 1H), 6.35 (d, J=7.1 Hz, 1H), 4.88 (t, J=6.8 Hz, 1H), 3.91 (s, 3H), 3.48 (m, 1H), 2.73 (d, J=13.3 Hz, 1H).

Example 30

[1253] ##STR00214##

(7R,14R)-1-(difluoromethoxy)-11-(6-oxo-1,6-dihydropyridin-3-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1254] A mixture of Example 29 (22.4 mg, 0.050 mmol) and pyridine hydrochloride (29.0 mg, 0.246 mmol) were heated at 160° C. for 5 minutes and allowed to cool to ambient temperature. The mixture was then diluted with DCM/MeOH, concentrated and purified by prep HPLC (reverse phase) to afford the desired product (22.0 mg, 0.051 mmol, 78%) as a white solid.

[1255] LC/MS Method 3: ESI MH.sup.+ 435.0, retention time 1.34 minutes (pH 10).

[1256] .sup.1H NMR: (DMSO-d6, 300 MHz) δ 11.8 (br s, 1H), 9.11 (d, J=6.7 Hz, 1H), 8.22 (m, 1H), 7.9-7.3 (m, 8H), 6.44 (d, J=9.5 Hz, 1H), 6.31 (d, J=7.1 Hz, 1H), 4.86 (t, J=6.7 Hz, 1H), 3.46 (m, 1H), 2.72 (d, J=13.4 Hz, 1H).

Example 31

[1257] ##STR00215##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1258] A degassed mixture of Example 10 (299 mg, 0.56 mmol), 6-(2-(trimethylsilyloxy)propan-2-yl)pyridine-3-boronic acid pinacol ester (295 mg, 0.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (26.0 mg, 0.03 mmol), potassium phosphate tribasic (296 mg, 1.40 mmol), and tricyclohexylphosphonium tetrafluoroborate (26.0 mg, 0.07 mmol) in 1,4-dioxane (4.5 mL) and water (0.5 mL) was heated to 105° C. overnight. The reaction mixture was cooled to r.t, diluted with EtOAc (50 mL) and washed with water (2×50 mL). The organic layer was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residues were dissolved in DCM (4 mL) and 4M HCl solution (1.5 mL) was added. The solution was stirred at r.t for 1 hour. Saturated aqueous sodium carbonate solution (50 mL) was added, and the aqueous layer separated. The organic layer was washed with brine (50 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give a crude oil. The crude material was purified by column chromatography, eluting with 0-100% EtOAc in DCM, followed by 0-10% MeOH in EtOAc to give the title compound as an off-white powder (105 mg, 38% yield).

[1259] .sup.1H NMR (400 MHz, DMSO) δ 9.15 (d, 1H, J=6.8 Hz), 8.61 (s, 1H), 8.26-8.21 (m, 1H), 7.90 (dt, 1H, J=1.9, 8.2 Hz), 7.77 (d, 1H, J=8.2 Hz), 7.61 (t, 1H, J=75 Hz), 7.61 (d, 1H, J=11.5 Hz), 7.52-7.50 (m, 3H), 6.34 (d, 1H, J=7.1 Hz), 5.27 (s, 1H), 4.91 (t, 1H, J=6.8 Hz), 3.52-3.45 (m, 1H), 2.75 (d, 1H, J=13.4 Hz), 1.49 (s, 6H). LCMS Method 3 ESI MH+ 495.1

Example 32

[1260] ##STR00216##

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)-6-methyl-pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1261] The title compound was synthesised from Example 11 (240 mg, 0.639 mmol), and Intermediate 61 (213.2 mg, 0.7664 mmol), according to a method involving the same procedural steps as those described for Example 20 to give, after purification by flash column chromatography, an oil, which was subsequently freeze dried to provide a white solid (115 mg, 0.234 mmol, 36%).

[1262] 1H NMR (400 MHz, DMSO) δ 9.15 (d, 1H, 6.6 Hz), 8.61 (s, 1H), 8.23 (dd, 1H, 4.8 Hz), 7.73 (d, 1H, 8.3 Hz), 7.56, (m, 1H),7.51 (m, 3H), 7.22 (dd, 1H, J=8.3, 1.7 Hz), 6.34 (d, 1H, J=7.1 Hz), 5.07 (s, 1H), 4.91 (t, 1H, J=6.6 Hz), 3.50 (m, 1H), 2.76 (d, 1H, J=13.3 Hz), 2.46 (s, 3H), 1.54 (s, 6H). HPLC-MS Method 3 (pH10): MH+ m/z=492.2, RT 1.81 minutes; Method 4 (pH3): MH+ m/z=492.2, RT 1.80 minutes.

Example 33

[1263] ##STR00217##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-6-methyl-pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1264] The title compound was synthesised from Example 10 (300 mg, 0.762 mmol), and Intermediate 61 (254.3 mg, 0.9142 mmol), according to a method involving the same procedural steps as those described for Example 20, to give, after purification by column chromatography, an oil, which was subsequently freeze dried to give a white solid (125 mg, 0.245 mmol, 32%).

[1265] 1H NMR (400 MHz, DMSO) δ 9.15 (d, 1H, J=6.8 Hz), 8.62 (s, 1H), 8.22 (dd, 1H, J=6.2, 3.2 Hz), 7.65 (d, 1H, J=10.8 Hz), 7.53 (d, 1H, 7.8 Hz), 7.52 (d, 1H, 7.8Hz,), 7.51 (t, 1H, 72 Hz) 7.39 (d, 1H, J=6.6 Hz), 6.33 (d, 1H, 7.1 Hz), 5.08 (s, 1H), 4.87 (t, 1H, J=6.8 Hz), 3.50 (dt, 1H, 13.6, 6.8 Hz), 2.75 (d, 1H, J=13.4 Hz), 2.33 (d, 3H, 1 Hz), 1.54 (s, 6H). HPLC-MS Method 3 (pH10): MH+ m/z=510.2, RT 1.88 minutes; Method 4 (pH3): MH+ m/z=510.2, RT 1.91 minutes.

Example 34

[1266] ##STR00218##

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1267] Example 11 (140 mg, 0.373 mmol) and 6-(2-(trimethylsilyloxy)propan-2-yl)pyridine-3-boronic acid pinacol ester (171 mg, 0.484 mmol) were added to a small microwave tube and tris(dibenzylideneacetone)dipalladium(0) (17.6 mg, 0.0186 mmol) and tricyclohexylphosphonium tetrafluoroborate (17.0 mg, 0.0447 mmol) were added with dioxane (2 mL), followed by K.sub.3PO.sub.4 (158 mg, 0.745 mmol) in water (1 mL). The mixture was degassed and heated to 105° C. for 18 hours. The mixture was diluted with EtOAc (30 mL) and washed with water (10 mL). The organic was concentrated in vacuo, re-dissolved in DCM (10 mL) and 4.0M HCl in dioxane (5 mL) added and the mixture was stirred at r.t for 1 hour. The mixture was partitioned between DCM and sodium carbonate (20 mL). The organic phase was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. Purification by preparative HPLC gave the title compound (35 mg, 20%) as a white solid.

[1268] .sup.1H NMR: (d6-DMSO, 300 MHz) δ:1.48 (s, 6H), 2.74 (d, 1H, J=13.3 Hz), 3.49 (m, 1H), 4.88 (t, 1H, J=6.7 Hz), 5.24 (s, 1H), 6.35 (d, 1H, J=7.0 Hz), 7.49-7.53 (m, 3H), 7.69-7.72 (m, 3H), 7.66 (t, 1H, J.sub.H-F=73.2 Hz), 7.97 (dd, 1H, J=5.6, 8.2 Hz), 8.21-8.24 (m, 1H), 8.73 (d, 1H, J=1.8 Hz), 9.13 (d, 1H, 6.8 Hz). LC/MS Method 3: RT 1.76 mins (pH 10), m/z 477.

Example 35

[1269] ##STR00219##

(7R,14R)-1-(difluoromethoxy)-11-[4-(S-methylsulfonimidoyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1270] Example 11 (200 mg, 0.532 mmol) and imino-methyl-oxo-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-sulfane (210 mg, 0.745 mmol), tris(dibenzylideneacetone)-dipalladium(0) (25.1 mg, 0.0266 mmol) and tricyclohexylphosphonium tetrafluoroborate (24.2 mg, 0.0639 mmol) were added to a small microwave tube. 1,4-Dioxane (2 mL) was added, followed by K.sub.3PO.sub.4 (226 mg, 1.06 mmol) in water (0.3 mL). The mixture was degassed, placed under nitrogen and heated to 105° C. for 18 hours. LCMS showed a poor conversion. Another identical portion of catalyst, ligand and the boronate as above were added along with more dioxane (0.5 mL) and water (0.2 mL) and the mixture heated to 110° C. for a further 18 hours. The mixture was partitioned between EtOAc and water (50 mL each) The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The material was subjected to column chromatography (silica, 0 to 20% MeOH in DCM) and the product containing fractions were concentrated in vacuo to give a brown solid, which, after further purification by prep HPLC provided the title compound (9.1 mg, 3.5%) as a white solid. .sup.1H NMR: (d6-DMSO, 300 MHz) δ: 2.74 (d, 1H, J=13.3 Hz), 3.11 (d, 3H, J=0.8 Hz), 3.49-3.54 (m, 1H), 4.24 (s, 1H), 4.89 (t, 1H, J=6.7 Hz), 6.36 (d, 1H, J=7.0 Hz), 7.49-7.56 (m, 3H), 7.67 (dt, 1H, J.sub.H-F=73.3, 1.0 Hz), 7.71-7.74 (m, 2H), 7.80-7.83 (m, 2H), 7.98-8.01 (m, 2H), 8.21-8.24 (m, 1H), 9.14 (d, 1H, 6.7 Hz). LC/MS Method 3: RT 1.54 mins (pH 10), m/z 495.

Example 36

[1271] ##STR00220##

(1R,11R)-18-(difluoromethoxy)-6-fluoro-5-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-3,9,12-triazapentacyclo[9.8.1.0.SUP.2.,.SUP.1..SUP.0.0.SUP.3.,.SUP.8..0.SUP.1..SUP.4,.SUP.1..SUP.9]icosa-2(10),4,6,8,14(19),15,17-heptaen-13-one hydrochloride

[1272] Intermediate 72 (260 mg, 0.52 mmol), Na.sub.2CO.sub.3 (274 mg, 2.59 mmol) and 2,2-dichloro-1,1,3,3-tetracyclohexyl-1λ.sup.5,3λ.sup.5-diphospha-2-palladacyclohexane (28 mg, 0.04 mmol) were suspended in degassed anhydrous dimethylacetamide (6 mL) in a 25 mL pressure vessel. The vessel was sealed and degassed thoroughly under vacuum then placed under an atmosphere of nitrogen. This process was repeated then the vessel was evacuated and charged with 3 bar CO gas. The mixture was heated to 140° C. overnight whereon the internal pressure reached 4.8 bar. On cooling to r.t, the mixture was diluted with DCM:MeOH (50 mL) and washed with water (30 mL). The aqueous layer was back extracted with DCM:MeOH (2×30 mL). The combined organic layer was filtered through Celite and concentrated under reduced pressure to afford a beige solid. Purification by column chromatography (KP-NH, Biotage isolera) eluting with 0-100% MeOH in DCM followed by purification using achiral SFC (20% MeOH:80% CO.sub.2 with Phenomenex Synergi 4u Polar RP 25 cm column at 15 ml/min) gave the free base 65 mg (25%) as an off white solid. Suspension in 1:1 MeCN:water (3 mL) and treatment with 1N aqueous HCl (129.5 μL, 1 eq) followed by freeze drying gave the title compound (67.5 mg, 25%) as a fluffy colourless solid. Method 6 HPLC-MS: MH+ m/z 496, RT 2.27 min (100%), .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.98 (s, 2H), 8.88 (d, J=6.1 Hz, 1H), 8.27 (d, J=7.1 Hz, 1H), 8.22 (d, J=7.8 Hz, 1H), 7.78-7.68 (m, 1H), 7.67-7.38 (m, 1H), 7.46-7.32 (m, 2H), 5.19 (d, J=6.4 Hz, 1H), 4.73 (t, J=6.4 Hz, 1H), 3.77-3.15 (m, 2H), 2.43 (d, J=13.0 Hz, 1H), 1.54 (s, 6H).

Example 37

[1273] ##STR00221##

(7R,14R)-1-(difluoromethoxy)-11-[2-(cis-1,3-dihydroxy-3-methylcyclobutyl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1274] Intermediate 79 (500 mg, 1.34 mmol), bis(pinacolato)diboron (408.0 mg, 1.61 mmol), tricyclohexylphosphonium tetrafluoroborate (61.00 mg, 0.161 mmol), potassium carbonate (22 mg, 0.161 mmol), potassium acetate (398 mg, 4.02 mmol) were placed in a 8 mL vial filled with nitrogen. 1,4-dioxane (4.8 mL) was added and the solution homogenized for 5 minutes before addition of tris(dibenzylideneacetone)dipalladium(0) (63 mg, 0.067 mmol). The reaction mixture was heated at 100° C., using a preheated oil bath, for 1 hour. The reaction mixture was filtered giving a clear crude solution of boronic acid used without further treatment. LCMS basic RT 0.920 min. (ES+) 339.0 (M+H).sup.+ To Example 11 (127 mg, 0.338 mmol), tricyclohexylphosphonium tetrafluoroborate (15.4 mg, 0.04055 mmol), potassium phosphate (143 mg, 0.676 mmol) in a vial was added the above described crude solution of 3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]cyclobutanol, and water (0.12 mL). The slurry was degassed before addition of tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.0169 mmol). The resulting solution was heated at 100° C. overnight. The reaction mixture was filtered through sodium sulfate and rinsed with EtOAc (10 mL). The filtrate was evaporated, and the residue was purified over silica gel (100% EtOAc) yielding a slightly yellow glass (192 mg). LCMS basic (ES+) RT 2.35 min, 635.0 (M+H).sup.+

[1275] The above intermediate (192 mg, 0.3029 mmol) was solubilised in THF (1.8 mL) and tetrabutylammonium fluoride (1 M in THF) (0.9 mL, 0.9 mmol) was added drop-wise. The reaction mixture was stirred at r.t for 2 hours. The volatiles were removed in vacuo and the residue was partitioned between dichloromethane (20 mL) and water (20 mL). The DCM layer was washed by 2×20 mL of water. The combined aqueous layers were extracted by 2×20 mL of DCM. The combined organic layers were washed by 4×20 mL of water and brine (1×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 109 mg of white solid. The white solid was recrystallized with 3 mL of isopropanol yielding 40 mg (26%) of the title compound as a white solid. LCMS basic Method 3 (ES+) RT 1.49 min, 520.4 (M+H).sup.+

Example 38

[1276] ##STR00222##

Ethyl [(6R,12R)-11-(difluoromethoxy)-3-fluoro-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]acetate

[1277] A solution of Intermediate 93 (250 mg, 0.39 mmol), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (36 mg, 0.058 mmol), cesium carbonate (261 mg, 0.80 mmol) and palladium acetate (12 mg, 0.053 mmol) in toluene (8 mL) was degassed and heated to 110° C. for 15 hours. The reaction mixture was cooled to ambient temperature, partitioned between EtOAc (30 mL) and water (30 mL) and the phases were separated. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phases were washed with saturated brine (10 mL), dried with sodium sulphate, filtered and concentrated in vacuo to give an oil which was purified by flash chromatography in silica gel (0 to 100% EtOAc in hexanes) to afford the title compound (169 mg, 78% yield) as a brown solid.

[1278] LC/MS Method 3: RT 2.26 mins (pH 10), m/z 554.

[1279] .sup.1H NMR: (CD.sub.3OD, 300 MHz) δ: 1.20 (t, J=7.1 Hz, 3H), 1.66 (s, 6H), 2.69 (d, J=11.7 Hz, 1H), 3.01 (dt, J=11.7, 4.5 Hz, 1H), 4.44-4.15 (m, 4H), 4.96 (d, J=3.4 Hz, 1H), 6.11 (d, J=4.5 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 6.54 (d, J=8.3 Hz, 1H), 7.12 (t, J=8.4 Hz, 1H), 7.05 Hz (t, J=73.8, 1.5 Hz, 1H), 7.50 (d, J=11.2 Hz, 1H), 7.65 (d, J=6.7 Hz, 1H), 8.97 (d, J=1.6 Hz, 2H).

Example 39

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1280] ##STR00223##

[1281] The title compound can be synthesised from Intermediate 158 and [2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]boronic acid in accordance with the Method described for Example 20.

[1282] .sup.1H NMR: (DMSO-d6, 300 MHz) δ 8.95 (d, J=1.7 Hz, 1H), 8.23 (dd, J=6.7, 2.8 Hz, 1H), 7.9-7.3 (m, 5H), 6.29 (d, J=7.1 Hz, 1H), 5.27 (d, J=7.1 Hz, 1H), 5.15 (s, 1H), 3.52 (m, 1H), 3.36 (s, 3H), 2.84 (d, J=13.9 Hz, 1H), 1.55 (s, 6H).

[1283] LC/MS: Method 3: MH.sup.+ 510.3, RT 2.04 minutes.

Preparative Example 40

[1284] ##STR00224##

1-[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]-2-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)ethanone

[1285] To a solution of Example 19 (50 mg, 0.14 mmol) in dichloromethane (1 mL), was added triethylamine (24 μL, 0.17 mmol) followed by chloroacetyl chloride (12 μL, 0.015 mL). After stirring for 1 hour, a further 0.11 equiv of chloroacetyl chloride (1.2 μL, 0.014 mmol) was added and the reaction mixture was stirred for an additional 20 min. Triethylamine (24 μL, 0.17 mmol) was added to the reaction mixture followed by 3,7-dioxa-9-azabicyclo[3.3.1]nonane (11.5 mg, 0.168 mmol) and the reaction was stirred at room temperature for 18 h. The reaction mixture was directly purified by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) and then DCM/MeOH (from 0 to 20%) as eluent. A second purification by Prep-HPLC (basic conditions) afforded 20 mg (27%) of the title compound. LCMS Method 3 (ES+) RT 2.91 min. [M+H].sup.+=517/519. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J=8.7 Hz, 1H), 7.68-7.59 (m, 1H), 7.51-7.41 (m, 1H), 7.34-7.19 (m, 2H), 6.97 (d, J=8.3 Hz, 1H), 6.25 (s, 1H), 6.07 (d, J=4.3 Hz, 1H), 4.14 (s, 3H), 4.06 (s, 1H), 3.83 (s, 4H), 3.22 (d, J=12.1 Hz, 1H), 2.63 (d, J=12.1 Hz, 1H).

Example 41

[1286] ##STR00225##

tert-butyl (2-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-yl)carbamate

[1287] The title compound was prepared from tert-butyl N-[1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]ethyl]carbamate, and Example 23 according to a method involving the same procedural steps as those described for Example 20, to give, following purification by Prep-HPLC the title compound as a white solid (100.5 mg, 48% yield). LC/MS Method 3: RT 2.46 mins, [M+H].sup.+=627. .sup.1H NMR (300 MHz, DMSO-d6) δ 9.02 (s, 2H), 7.80 (d, J=8.5 Hz, 1H), 7.77-7.70 (m, 1H), 7.64-7.52 (m, 2H), 7.50 (t, J=73.5 Hz, 1H), 7.38 (d, J=73.0 Hz, 1H), 7.34 (t, J=8.5 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.13 (d, J=4.3 Hz, 1H), 5.95 (d, J=4.0 Hz, 1H), 3.29-3.16 (m, 1H), 3.07 (s, 3H), 2.68 (d, J=12.1 Hz, 1H), 1.60 (s, 6H), 1.32 (bs, 9H).

Example 42

[1288] ##STR00226##

2-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-amine

[1289] To a solution of Example 41 (98 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in dioxane (6 mL). The reaction was stirred for 1 hour at room temperature and then the solvent was evaporated and the crude was dissolved in dichloromethane (5 mL) and a saturated aqueous solution of Na.sub.2CO.sub.3 was added until pH=8-9. The two phases were separated and the aqueous layer was extracted with dichloromethane (2×5 mL) the combined organic layers were washed with brine, filtered through a phase separator and the solvent was evaporated. The solid obtained was triturated in ether and filtered to give the title compound as a white solid (49.2 mg, 60% yield). LC/MS Method 3: RT 1.65 mins (pH 10), [M+H].sup.+=527. .sup.1H NMR (300 MHz, DMSO-d6) δ 9.04 (s, 2H), 7.85-7.71 (m, 2H), 7.64-7.46 (m, 2H), 7.50 (t, J=73.4 Hz, 1H), 7.34 (t, J=8.5 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.13 (d, J=4.3 Hz, 1H), 5.95 (d, J=3.9 Hz, 1H), 3.23 (dt, J=12.2, 4.5 Hz, 1H), 3.07 (s, 3H), 2.68 (d, J=12.3 Hz, 1H), 2.31 (bs, 2H), 1.47 (s, 6H).

Example 43

[1290] ##STR00227##

Azetidin-3-yl[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]methanone

[1291] To Intermediate 95 (158 mg, 0.24 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (2 mL) and the reaction was stirred for 10 minutes. Methanol (2 mL) was added to keep the mixture in solution. The reaction mixture was stirred for 3 hours before the solvent was evaporated. The crude material was purified by preparative HPLC, yielding 22 mg (15%) of the title compound as a white solid. LCMS Method 3: RT 1.57 min., [M+H].sup.+=551. .sup.1H NMR (300 MHz, DMSO-d6) δ 8.97 (d, J=1.7 Hz, 2H), 8.22 (d, J=8.6 Hz, 1H), 7.70 (d, J=11.5 Hz, 1H), 7.61 (d, J=6.9 Hz, 1H), 7.43 (t, J=73.8 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.07 (d, J=4.2 Hz, 1H), 5.61 (bs, 1H), 5.15 (bs, 1H), 4.38 (bs, 1H), 4.07 (bs, 1H), 3.84 (bs, 4H), 3.20-3.08 (m, 1H), 2.64 (d, J=12.1 Hz, 1H), 1.56 (s, 6H).

Example 44

[1292] ##STR00228##

[(6R,12R)-11-(difluoromethoxy)-3-fluoro-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl][1-(methylsulfonyl)azetidin-3-yl]methanone

[1293] Methanesulfonyl chloride (3 μL, 0.038 mmol) was added to a solution of Example 43 (17 mg, 0.03 mmol), N,N-diisopropylethylamine (6 μL, 0.034 mmol) in DCM (0.3 mL) at 0° C. The reaction mixture was stirred at this temperature for 10 minutes and then at room temperature for 3 hours. The solvent was evaporated and the crude material was purified by preparative HPLC, yielding 1.5 mg (8%) of the title compound as a white solid. LCMS Method 3: RT 2.04 min., [M+H].sup.+=629. .sup.1H NMR (300 MHz, Methanol-d4) δ 8.98 (d, J=1.6 Hz, 2H), 8.19 (s, 1H), 7.70 (d, J=6.6 Hz, 1H), 7.55 (d, J=11.1 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 7.15 (t, J=73.5 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.21 (d, J=4.4 Hz, 1H), 5.80 (s, 1H), 4.46 (dq, J=13.6, 6.2 Hz, 2H), 4.31 (td, J=13.6, 12.0, 5.9 Hz, 2H), 3.30-3.18 (m, 1H), 3.04 (s, 3H), 2.73 (d, J=12.1 Hz, 1H), 1.66 (s, 6H). OH signal is exchanged with water. One proton is missing due to overlapping with the solvent residual peak.

Example 45

[1294] ##STR00229##

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1295] A mixture of Intermediate 92 (500 mg, 0.9117 mmol), cesium carbonate (594 mg, 1.82 mmol), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (80 mg, 0.13 mmol) and palladium(II) acetate (25 mg, 0.11 mmol) in toluene (18 mL) was de-gassed and stirred at 110° C. under nitrogen for 15 hours. The reaction mixture was cooled to ambient temperature, filtered through a pad of celite and washed with ethyl acetate. The combined filtrate and washings were evaporated to dryness using an oil pump to give an oil which was purified by flash chromatography on silica gel (25 to 100% EtOAc in hexanes) to afford the title compound (165 mg, 0.35 mmol, 39% yield) as a brown solid. LC/MS Method 3: RT 1.99 mins, [M+H].sup.+=468. .sup.1H NMR (300 MHz, DMSO-d6) δ 8.97 (d, J=1.7 Hz, 2H), 7.61 (d, J=11.7 Hz, 1H), 7.53 (d, J=6.9 Hz, 1H), 7.21-7.13 (m, 1H), 7.17 (t, J=74.2 Hz, 1H), 6.98 (t, J=8.2 Hz, 1H), 6.35 (t, J=8.6 Hz, 1H), 5.90 (d, J=4.3 Hz, 1H), 5.14 (s, 1H), 4.92 (t, J=3.7 Hz, 1H), 2.95 (dt, J=9.0, 4.3 Hz, 1H), 2.37 (d, J=11.4 Hz, 1H), 1.55 (s, 6H).

Example 46

[1296] ##STR00230##

Azetidin-3-yl[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]methanone

[1297] HCl 4M in dioxane was added To Intermediate 97 (10 mg, 0.019 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxan (2 mL) and the reaction stirred for 5 hours before the solvent was evaporated. The crude material was purified by preparative HPLC, yielding 3 mg (39%) of the title compound as a white solid.

[1298] LCMS Method 3: RT 2.12 min, [M+H].sup.+=431. .sup.1H NMR (300 MHz, DMSO-d6) δ 8.21 (d, J=8.7 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.42 (t, J=74.2 Hz, 1H), 7.27 (t, J=8.5 Hz, 1H), 7.20 (dd, J=8.7, 2.1 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.03 (d, J=4.3 Hz, 1H), 5.56 (d, J=3.9 Hz, 1H), 4.41-4.30 (m, 1H), 4.10-3.65 (m, 4H), 3.09 (dt, J=12.1, 4.3 Hz, 1H), 2.60 (d, J=12.0 Hz, 1H).

Example 47

[1299] ##STR00231##

cis-1-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}-3-methylcyclobutane-1,3-diol

[1300] A solution of tetrabutylammonium fluoride (1M in THF, 0.36 mL, 0.36 mmol) was added to a solution of Intermediate 98 (82 mg, 0.12 mmol) in tetrahydrofuran (0.72 mL) and the reaction was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was partitioned between dichloromethane (20 mL) and brine (20 mL). The two layers were separated and the aqueous phase was extracted with dichloromethane (2×20 mL) and the combined organic layers were washed with brine, filtered through a phase separator and the solvent was removed in vacuo. The crude material was purified by column chromatography on silica gel with hexane/ethyl acetate (0 to 100%) as eluent, yielding 47 mg (68%) of the title compound as a brown solid. LCMS Method 3: RT 1.61 min. (pH 10), [M+H].sup.+=570. .sup.1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 2H), 7.81 (dd, J=8.5, 0.7 Hz, 1H), 7.78-7.76 (m, 1H), 7.62 (dd, J=8.5, 1.8 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.50 (t, J=73,7 Hz, 1H), 7.34 (t, J=8.5 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.13 (d, J=4.4 Hz, 1H), 5.96 (d, J=3.8 Hz, 1H), 5.61 (s, 1H), 4.95 (s, 1H), 3.32-3.18 (m, 1H), 3.07 (s, 3H), 2.97-2.85 (m, 2H), 3.05 (s, 3H), 2.68 (d, J=12.1 Hz, 1H), 2.41 (d, 1.09 J=12.9 Hz, 2H).

Example 48

[1301] ##STR00232##

(6R,12R)-11-(difluoromethoxy)-2-{2-[(1s,5s)-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl]pyrimidin-5-yl}-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

[1302] The title compound was prepared from 9-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-3,7-dioxa-9-azabicyclo[3.3.1]nonane and Example 23 according to a method involving the same procedural steps as those described for Example 20, to give, following purification by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) as eluent, the title compound as a white solid (114 mg, 58% yield). LC/MS Method 3: RT 1.88 mins (pH 10), [M+H].sup.+=597. .sup.1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 2H), 7.77-7.68 (m, 1H), 7.65-7.53 (m, 2H), 7.49 (t, J=1.6 Hz, 1H), 7.46 (t, J=73.5 Hz, 1H), 7.33 (t, J=8.5 Hz, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.10 (d, J=4.3 Hz, 1H), 5.93 (d, J=3.9 Hz, 1H), 4.52 (s, 2H), 4.10-3.93 (m, 4H), 3.77 (dd, J=11.1, 2.7 Hz, 4H), 3.21 (dt, J=12.3, 4.4 Hz, 1H), 3.06 (s, 3H), 2.66 (d, J=12.1 Hz, 1H).

Example 49

[1303] ##STR00233##

[(6R,12R)-11-(difluoromethoxy)-3-fluoro-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]acetic acid

[1304] A solution of 1M sodium hydroxide in water (30 μL, 0.03 mmol) was added to a solution of Example 38 (17 mg, 0.031 mmol) in ethanol (30 μL). The mixture was stirred for 3 hours and then purified directly by preparative HPLC affording the title compound as a white solid (9 mg, 54%). LC/MS Method 3: RT 1.68 minutes, [M+H].sup.+=526. .sup.1H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J=1.7 Hz, 2H), 7.66-7.58 (m, 1H), 7.54 (d, J=6.9 Hz, 1H), 7.35 (t, J=74.2 Hz, 1H), 7.04 (t, J=8.3 Hz, 1H), 6.37 (dd, J=8.3, 4.7 Hz, 2H), 5.95 (d, J=4.3 Hz, 1H), 5.15 (s, 1H), 4.95 (d, J=3.4 Hz, 1H), 3.86 (d, J=4.1 Hz, 2H), 2.95 (dt, J=11.3, 4.3 Hz, 1H), 1.55 (s, 6H). COOH signal interchange with the water of the DMSO and one proton is missing due to overlapping with the residual signal of DMSO.

Example 50

[1305] ##STR00234##

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(pyridin-3-ylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1306] To Intermediate 99 (275 mg, 0.40 mmol), in a Schlenk tube were added cesium acetate (383 mg, 1.99 mmol), cuprous iodide (155 mg, 0.79 mmol) and dimethylsulfoxide (0.4 mL) and the mixture was sealed and purged 3 times with nitrogen. The reaction mixture was stirred at 100° C. for 18 hours before water and ethyl acetate was added to the reaction mixture and the two layers were separated. The aqueous layer was extracted with ethyl acetate (×2) and the combined organic layers were filtered through a phase separator and the solvent evaporated. The crude material was purified by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) as eluent, yielding 8 mg (3%) of the title compound as a white solid. LCMS Method 4: RT 2.15 min. (pH 3), [M+H]+=609. .sup.1H NMR (300 MHz, DMSO-d6) δ 9.24 (dd, J=2.5, 0.8 Hz, 1H), 8.95 (d, J=1.7 Hz, 2H), 8.81 (dd, J=4.8, 1.5 Hz, 1H), 8.58 (ddd, J=8.2, 2.5, 1.6 Hz, 1H), 7.75 (d, J=11.3 Hz, 1H), 7.64 (ddd, J=8.2, 4.8, 0.8 Hz, 1H), 7.56 (d, J=6.8 Hz, 1H), 7.42 (d, J=11.6 Hz, 1H), 7.41 (t, J=74.7 Hz, 1H), 7.27 (t, J=8.5 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.36 (d, J=3.7 Hz, 1H), 6.08 (d, J=4.3 Hz, 1H), 5.15 (s, 1H), 3.28-3.18 (m, 1H), 2.61 (d, J=12.3 Hz, 1H), 1.55 (s, 6H).

Example 51

[1307] ##STR00235##

1-{5-[(6R,12R)-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}-3-(trifluoromethyl)azetidin-3-ol

[1308] The title compound was prepared from Example 23 (149 mg, 0.35 mmol), and Intermediate 100 (186 mg, 0.54 mmol), according to a method involving the same procedural steps as those described for Example 20. The crude material was purified by column chromatography (SiO.sub.2, 40-100% EtOAc in hexane) and freeze dried from acetonitrile/water to give the title compound (119 mg, 56%) as a pale yellow solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 8.70 (s, 2H), 7.71-7.75 (m, 1H), 7.61 (d, 1H, J 1.3 Hz), 7.57 (d, 1H, J 8.7 Hz), 7.49 (dd, 1H, J 73.9, 72.5 Hz), 7.46 (dd, 1H, J 8.5, 1.7 Hz), 7.42 (s, 1H), 7.33 (t, 1H, J 8.5 Hz), 6.92 (d, 1H, J 8.2 Hz), 6.10 (d, 1H, J 4.4 Hz), 5.93 (d, 1H, J 3.5 Hz), 4.34 (m, 2H), 4.12 (d, 2H, J 9.9 Hz), 3.17-3.25 (m, 1H), 3.06 (s, 3H), 2.63-2.70 (m, 1H). LCMS (ES+) Method 4: 609 (M+H).sup.+, RT 2.21 minutes. LCMS (ES+) Method 5: 609 (M+H).sup.+, RT 2.17 minutes.

Example 52

[1309] ##STR00236##

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1310] The title compound was prepared from Intermediate 101 (192 mg, 0.31 mmol), potassium carbonate (107 mg, 0.77 mmol), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (92 mg, 0.15 mmol), palladium(II) acetate (24 mg, 0.11 mmol) and toluene (3 mL) in accordance with the Method described for Example 23. The crude material was purified by column chromatography (SiO.sub.2, 20-100% EtOAc in hexane) and further purified by preparative HPLC to give the title compound (40 mg, 24%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 8.97 (d, 2H, J 1.7 Hz), 7.70-7.75 (m, 1H), 7.62 (d, 1H, J 6.8 Hz), 7.58 (d, 1H, J 8.6 Hz), 7.46 (dd, 1H, J 74.1, 72.6 Hz), 7.35 (t, 1H, J 8.5 Hz), 6.94 (d, 1H, J 8.1 Hz), 6.12 (d, 1H, J 4.3 Hz), 5.97 (d, 1H, J 3.6 Hz), 5.15 (s, 1H), 3.19-3.28 (m, 1H), 3.09 (s, 3H), 2.68 (d, 1H, J 12.1 Hz), 1.56 (s, 6H).

[1311] LCMS (ES+) Method 5: 546 (M+H).sup.+, RT 2.07 minutes.

[1312] LCMS (ES+) Method 4: 546 (M+H).sup.+, RT 2.13 minutes.

Example 53

[1313] ##STR00237##

2-{5-[(6R,12R)-7-(cyclopropylsulfonyl)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1314] The title compound was prepared from Intermediate 102 (110 mg, 0.17 mmol), potassium carbonate (60 mg, 0.43 mmol), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (44 mg, 0.07 mmol), palladium(II) acetate (10 mg, 0.045 mmol) and toluene (2 mL) in accordance with the synthetic Method of Example 23. The crude material was purified by by column chromatography (SiO.sub.2, 20-100% EtOAc in hexane) and further purified by preparative HPLC to give the title compound (6 mg, 6%) as an off-white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 8.98 (d, 2H, J 1.7 Hz), 7.71 (d, 1H, J 11.4 Hz), 7.63 (s, 1H), 7.60 (d, 1H, J 2.1 Hz), 7.47 (dd, 1H, J 74.3, 72.3 Hz), 7.33 (t, 1H, J 8.5 Hz), 6.92 (d, 1H, J 8.1 Hz), 6.11 (d, 1H, J 4.3 Hz), 5.98 (d, 1H, J 3.5 Hz), 5.15 (s, 1H), 3.16-3.25 (m, 1H), 2.85-2.95 (m, 1H), 2.63-2.70 (m, 1H), 1.56 (s, 6H), 1.21-1.31 (m, 2H), 0.94-1.05 (m, 2H).

[1315] LCMS (ES+) Method 5: 572 (M+H).sup.+, RT 2.71 minutes.

[1316] LCMS (ES+) Method 4: 572 (M+H).sup.+, RT 2.22 minutes.

Example 54

[1317] ##STR00238##

2-{5-[(6R,12R)-7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1318] The title compound was prepared from Intermediate 103 (125 mg, 0.18 mmol), cesium carbonate (117 mg, 0.36 mmol), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (16 mg, 0.026 mmol) and palladium(II) acetate (6 mg, 0.027 mmol) and toluene (5 mL) by the method of Example 38. The crude material was purified by column chromatography (SiO.sub.2, 20-50% EtOAc in hexane) and freeze dried from acetonitrile/water to give the title compound (84 mg, 76%) as an off-white solid.

[1319] δ.sub.H (300 MHz, DMSO-d.sub.6) 8.89 (d, 2H, J 1.7 Hz), 7.55 (d, 1H, J 11.4 Hz), 7.47 (d, 1H, J 6.9 Hz), 7.29 (dd, 1 H J 74.3, 73.0 Hz), 7.01 (t, 1H, J 8.4 Hz), 6.54 (d, 1H, J 8.6 Hz), 6.36 (d, 1H, J 7.9 Hz), 5.88 (d, 1H, J 4.4 Hz), 5.07 (s, 1H), 4.93 (d, 1H, J 3.3 Hz), 3.70-3.92 (m, 2H), 3.33-3.52 (m, 2H), 2.90-2.98 (m, 1H), 2.31 (d, 1H, J 11.7 Hz), 1.48 (s, 6H), 0.81 (s, 9H), 0.00 (s, 6H).

[1320] LCMS (ES+) Method 5: 626 (M+H).sup.+, RT 3.37 minutes.

[1321] LCMS (ES+) Method 4: 626 (M+H).sup.+, RT 3.41 minutes.

Example 55

[1322] ##STR00239##

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(2-hydroxyethyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1323] To a solution of Example 54 (78 mg) in THF (5 mL) was added tetrabutylammonium fluoride (1M in THF, 0.26 mL, 0.26 mmol) and the reaction stirred at room temperature for 1 hour. After which time the reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (20 mL) and brine (20 mL), layers separated and organics washed with brine (2×20 mL), the combined aqueous extracted with DCM (2×20 mL). The combined organics were dried (phase separator) and the volatiles concentrated in vacuo. The crude material was purified by preparative HPLC to give the title compound (45 mg, 71%) as a white solid.

[1324] δ.sub.H (300 MHz, DMSO-d.sub.6) 8.96 (d, 2H, J 1.7 Hz), 7.64 (d, 1H, J 11.5 Hz), 7.55 (d, 1H, J 6.8 Hz), 7.36 (dd, 1H, J 74.5, 72.8 Hz), 7.08 (t, 1H, J 7.6 Hz), 6.59 (d, 1H, J 8.5 Hz), 6.42 (d, 1H, J 8.0 Hz), 5.95 (d, 1H, J 4.4 Hz), 5.05-5.22 (m, 1H), 5.01 (d, 1H, J 3.2 Hz), 3.69-3.79 (m, 1H), 3.54-3.65 (m, 1H), 3.36-3.53 (m, 2H), 3.12-3.21 (m, 1H), 2.94-3.03 (m, 1H), 2.44 (d, 1H, J 11.3 Hz), 1.55 (s, 6H).

[1325] LCMS (ES+) Method 5: 512 (M+H).sup.+, RT 1.91 minutes.

[1326] LCMS (ES+) Method 4: 512 (M+H).sup.+, RT 1.91 minutes.

Example 56

[1327] ##STR00240##

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-(phenylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1328] The title compound was prepared from Intermediate 104 (174 mg, 0.25 mmol), potassium carbonate (90 mg, 0.64 mmol), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (62 mg, 0.10 mmol), palladium(II) acetate (14 mg, 0.062 mmol) and toluene (3 mL) by the method of Example 23. The crude material was purified by column chromatography (SiO.sub.2, 0-100% EtOAc in hexane) and further purified by preparative HPLC to give the title compound (6 mg, 4%) as a white solid.

[1329] δ.sub.H (300 MHz, DMSO-d.sub.6) 8.96 (d, 2H, J 1.6 Hz), 8.10-8.16 (m, 2H), 7.77 (d, 1H, J 11.3 Hz), 7.55-7.71 (m, 4H), 7.40 (dd, 1H, J 74.3, 72.1 Hz), 7.31-7.36 (m, 1H), 7.21 (t, 1H, J 8.4 Hz), 6.84 (d, 1H, J 8.1 Hz), 6.34 (d, 1H, J 3.6 Hz), 6.07 (d, 1H, J 4.1 Hz), 5.03-5.27 (m, 1H), 3.17-3.27 (m, 1H), 2.51-2.56 (m, 1H), 1.55 (s, 6H).

[1330] LCMS (ES+) Method 5: 608 (M+H).sup.+, RT 2.45 minutes.

[1331] LCMS (ES+) Method 4: 608 (M+H).sup.+, RT 2.48 minutes.

Example 57

[1332] ##STR00241##

2-(5-{(6R,12R)-11-(difluoromethoxy)-3-fluoro-7-[(6-methoxypyridin-3-yl)sulfonyl]-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-2-yl}pyrimidin-2-yl)propan-2-ol

[1333] To a microwave vial was added Intermediate 105 (146 mg, 0.20 mmol), potassium carbonate (71 mg, 0.51 mmol), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (51 mg, 0.08 mmol), palladium(II) acetate (11 mg, 0.05 mmol) and toluene (2.5 mL). The reaction mixture was sealed and degassed with nitrogen and heated to 120° C. in a microwave for 2 hours. After which time the reaction was cooled to room temperature, filtered through celite and washed with EtOAc and DCM. The filtrate was concentrated in vacuo and the crude material purified by column chromatography (SiO.sub.2, 0-100% EtOAc in hexane) and further purified by preparative HPLC to give the title compound (6 mg, 5%) as an off-white solid.

[1334] δ.sub.H (300 MHz, DMSO-d.sub.6) 8.95 (d, J 1.7 Hz, 2H), 8.88 (dd, J 2.7, 0.7 Hz, 1H), 8.45 (dd, J 8.9, 2.7 Hz, 1H), 7.74 (d, J 11.3 Hz, 1H), 7.56 (d, J 6.8 Hz, 1H), 7.47 (d, J 8.6 Hz, 1H), 7.41 (dd, J 74.1, 72.2 Hz, 1H), 7.28 (t, J 8.5 Hz, 1H), 7.00 (dd, J 8.9, 0.7 Hz, 1H), 6.87 (d, J 8.2 Hz, 1H), 6.32 (d, J 3.8 Hz, 1H), 6.07 (d, J 4.3 Hz, 1H), 5.15 (s, 1H), 3.89 (s, 3H), 3.23 (dt, J 12.3, 4.4 Hz, 1H), 2.57 (d, J 12.3 Hz, 1H), 1.55 (s, 6H).

[1335] LCMS (ES+) Method 5 639 (M+H).sup.+, RT 2.36 minutes.

[1336] LCMS (ES+) Method 4 639 (M+H).sup.+, RT 2.48 minutes.

Example 58

[1337] ##STR00242##

[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-oxo-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]acetic acid

[1338] To a solution of Intermediate 106 (20.0 mg, 0.03 mmol) in THF (1 mL) was added a solution of tetrabutylammonium fluoride (0.4 mL, 0.4 mmol, 1M in THF) at ambient temperature and the reaction stirred for 72 hours. The reaction mixture was partitioned between water (10 mL) and DCM (2×10 mL), and the organics were combined, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by preparative HPLC afforded the title compound (3.0 mg, 19%).

[1339] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.06 (s, 2H), 8.27 (dd, J=6.3, 3.2 Hz, 1H), 7.84-7.56 (m, 3H), 7.55-7.40 (m, 2H), 6.82 (s, 1H), 6.31 (d, J=7.0 Hz, 1H), 5.22 (d, J=7.2 Hz, 1H), 5.12 (s, 1H), 4.56 (d, J=16.3 Hz, 1H), 3.86 (d, J=16.1 Hz, 1H), 3.56 (dt, J=14.0, 7.2 Hz, 1H), 2.89 (d, J=13.8 Hz, 1H), 1.55 (s, 6H). LC/MS Method 3: MH.sup.+ 536, retention time 1.19 minutes.

Example 59

[1340] ##STR00243##

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6-(2,2,2-trifluoroethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1341] To a solution of Intermediate 107 (100.0 mg, 0.148 mmol) in THF (10 mL) were added HCl (20 mL, 40 mmol, 2M in 1,4 dioxan), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralised with NaOH (10% aqueous solution) and extracted with DCM (2×10 mL), the organics were combined, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by preparative HPLC afforded the desired product (15.0 mg, 18%).

[1342] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.06 (s, 2H), 8.26 (dd, J=7.0, 2.5 Hz, 1H), 8.03-7.37 (m, 6H), 6.38 (d, J=7.0 Hz, 1H), 5.45 (d, J=7.3 Hz, 1H), 5.12 (s, 1H), 4.94-4.70 (m, 1H), 4.59 (dt, J=15.3, 9.3 Hz, 1H), 3.60 (dt, J=14.3, 7.3 Hz, 1H), 2.90 (d, J=13.9 Hz, 1H), 1.55 (s, 6H). LC/MS Method 3: ESI MFI.sup.+ 560, retention time 2.19 minutes.

Example 60

[1343] ##STR00244##

(7R,14R)-1-(difluoromethoxy)-6-(2-hydroxyethyl)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1344] To a solution of Intermediate 109 (60.0 mg, 0.094 mmol) in THF (5.0 mL) were added aqueous HCl (10 mL, 20 mmol, 2M), and the mixture was stirred at room temperature for 18 hours before the completion of the reaction. The reaction mixture was neutralised with 10% aqueous NaOH solution and extracted with DCM (2×10 mL). The organics were combined, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by preparative HPLC (reverse phase) afforded the title compound (27.0 mg, 55%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.06 (s, 2H), 8.31 (dd, J=5.5, 4.1 Hz, 1H), 7.99-7.39 (m, 6H), 6.32 (d, J=7.0 Hz, 1H), 5.38 (d, J=7.2 Hz, 1H), 4.01-3.88 (m, 2H), 3.88-3.71 (m, 4H), 3.54 (dt, J=14.1, 7.2 Hz, 1H), 2.85 (d, J=13.8 Hz, 1H), 1.55 (s, 6H). LC/MS Method 3: ESI MH.sup.+ 522, retention time 1.69 minutes.

Example 61

[1345] ##STR00245##

(7R,14R)-1-(difluoromethoxy)-6-(2-hydroxy-2-methylpropyl)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1346] To a solution of Intermediate 23 (120 mg, 0.2 mmol) in DMF (4 mL) were added cesium carbonate (320 mg, 1.01 mmol) and 1-iodo-2-methylpropan-2-ol (50.0 μL, 0.41 mmol), and the mixture was heated in a microwave at 150° C. for 22 hours. The reaction mixture was partitioned between water and DCM (2×10 mL), and the organics were combined, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by preparative HPLC (reverse phase) afforded the title compound (12.0 mg, 11%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.06 (s, 2H), 8.32 (dd, J=5.5, 4.0 Hz, 1H), 7.99-7.37 (m, 6H), 6.34 (d, J=6.9 Hz, 1H), 5.65 (d, J=7.5 Hz, 1H), 4.05 (d, J=13.7 Hz, 1H), 3.72 (d, J=13.7 Hz, 1H), 3.58 (dd, J=14.0, 7.0 Hz, 1H), 2.86 (d, J=13.8 Hz, 1H), 1.55 (s, 6H), 1.21 (d, J=5.7 Hz, 6H). LC/MS Method 3: ESI MH.sup.+ 550, retention time 1.57 minutes.

Example 62

[1347] ##STR00246##

(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-(trideutero)methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1348] Intermediate 111 (36.0 mg, 0.06 mmol) was dissolved in a solution of HCl in dioxane (4 mL, 4 M) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified on silica eluting with 0-10% MeOH/DCM to give the title compound (10 mg, 34%). .sup.1H NMR (400 MHz, D.sub.2O) δ 8.97 (s, 2H), 8.21 (dd, J=7.4, 2.0 Hz, 1H), 7.94 (dd, J=1.7, 0.7 Hz, 1H), 7.74 (dd, J=8.7, 0.7 Hz, 1H), 7.59 (dd, J=8.7, 1.7 Hz, 1H), 7.50-7.36 (m, 1H), 7.15 (d, J=2.4 Hz, 2H), 6.64 (d, J=7.1 Hz, 1H), 5.51 (d, J=7.2 Hz, 1H), 3.59 (dt, J=14.4, 7.3 Hz, 1H), 3.03 (d, J=14.2 Hz, 1H), 1.75 (s, 6H). LC/MS Method 3: ESI MH.sup.+ 494, retention time 1.45 minutes.

Example 63

[1349] ##STR00247##

(7R,14R)-1-(difluoromethoxy)-11-{6-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methylpyridin-3-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1350] To a solution of Intermediate 138 (300 mg, 0.84 mmol) and Example 11 (350 mg, 0.93 mmol) in 1,4-dioxane (5 mL) and water (0.4 mL) were added K.sub.3PO.sub.4 (540 mg, 2.55 mmol), tricyclohexylphosphonium tetrafluoroborate (38 mg, 0.1 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (40 mg, 0.042 mmol) were added. The mixture was degassed for 10 minutes before heating at 105° C. for 17 hours. The reaction mixture was quenched with water and extracted with EtOAc (3×10 mL), dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with 0 to 10% MeOH in DCM to give the title compound, which was then treated with HCl (1.1 eq., 0.5M) to form the HCl salt (107 mg, 21%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.16 (d, J=6.8 Hz, 1H), 8.24 (dd, J=6.4, 3.1 Hz, 1H), 7.94 (s, 1H), 7.82-7.25 (m, 7H), 7.19 (dd, J=8.4, 1.7 Hz, 1H), 6.83 (s, 1H), 6.32 (d, J=7.1 Hz, 1H), 4.92 (t, J=6.7 Hz, 1H), 4.44 (d, J=10.2 Hz, 1H), 4.21 (d, J=10.1 Hz, 1H), 3.58-3.37 (m, 1H), 2.75 (d, J=13.2 Hz, 1H), 2.30-2.16 (s, 3H). LC/MS Method 3: ESI MFI.sup.+572, retention time 1.86 minutes.

Example 64

[1351] ##STR00248##

(6R,12R)-3,10-dibromo-2-chloro-11-(difluoromethoxy)-7-(methylsulfonyl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

[1352] N-Bromosuccinimide (19 mg, 0.11 mmol) was added to a solution of Example 23 (35 mg, 0.08 mmol) in DMF (3 mL) at room temperature. The reaction was left to stir overnight. Further N-bromosuccinimide (19 mg, 0.11 mmol) was added and the reaction mixture heated at 80° C. for 2 hours. The reaction mixture was cooled and concentrated in vacuo to a yellow oil, azeotroping with heptane to remove excess DMF. The crude material was purified by chromatography on silica, eluting with 0-50% EtOAc in hexanes to afford a clear oil. The material was freeze-dried (MeCN/water) to afford the title compound as a white solid (20 mg, 42% yield). .sup.1H NMR: (DMSO-d.sup.6, 400 MHz) δ: 2.66 (d, J=12.4 Hz, 1H), 3.10 (s, 3H), 3.18 (dt, J=25.0, 8.3, 4.5 Hz, 1H), 5.93 (d, J=3.6 Hz, 1H), 6.10 (d, J=4.6 Hz, 1H), 7.31 (t, J=74.1 Hz, 1H), 7.62 (d, J=9.3 Hz, 1H), 7.65 (d, J=19.5 Hz, 1H), 7.70 (s, 1H), 8.11 (s, 1H). LC/MS Method 5 RT 2.87 mins, m/z 584 and 586.

Example 65

[1353] ##STR00249##

(6R,12R)-2,8,10-trichloro-11-(difluoromethoxy)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

[1354] N-Chlorosuccinimide (21 mg, 0.16 mmol) was added to a solution of Example 19 (43 mg, 0.12 mmol) in DMF (3 mL) at RT. The reaction was stirred at 60° C. for 6 hours. The reaction mixture was cooled and concentrated in vacuo to a yellow oil, azeotroping with heptane to remove the DMF. The crude material was subjected to chromatography on silica (0-50% EtOAc in hexanes) and evaporated to afford a clear oil. The material was freeze-dried (MeCN/water) to afford the title compound as an off white solid (9 mg, 17% yield). .sup.1H NMR: (DMSO-d6, 400 MHz) δ: 2.35 (d, J=11.8 Hz, 1H), 3.00 (dt, J=16.0, 8.0, 4.0 Hz, 1H), 5.00 (d, J=3.7 Hz, 1H), 5.92 (d, J=4.4 Hz, 1H),), 7.20 (dd, J=8.6, 2.0 Hz, 1H), 7.26 (t, J=73.9 Hz, 1H), 7.29 (d, J=4.1 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.50 (s, 1H), 7.60 (d, J=7.6 Hz, 1H). LC/MS Method 5 RT 2.60 mins (pH 10), m/z 417

Example 66

[1355] ##STR00250##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4-methylpyrimidin-5-yl]-7,14-dihydro-7,14-methanopyrido[1′,2′:1,2]imidazo[4,5-d][2]benzazocin-5(6H)-one

[1356] Intermediate 112 (150 mg, 0.29 mmol), Na.sub.2CO.sub.3(s) (0.15 g, 1.45 mmol) and 2,2-dichloro-1,1,3,3-tetracyclohexyl-1λ.sup.5,3λ.sup.5-diphospha-2-palladacyclohexane (0.02 g, 0.02 mmol) were suspended in degassed anhydrous dimethylacetamide (3.0 mL) in a 25 mL pressure vessel. The vessel was sealed and degassed thoroughly under vacuum then placed under an atmosphere of nitrogen. This process was twice repeated then the vessel was evacuated and charged with 3 bar CO gas. The mixture was heated to 150° C. overnight whereon the internal pressure reached 5 bar. On cooling to room temperature, the mixture was thoroughly evacuated, diluted with EtOAc (20 mL) and filtered over a pad of celite, washing the filter cake with further EtOAc (2×50 mL). The filtrate was washed with water (25 mL) and the aqueous phase re-extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (50 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to give the crude product (165 mg) as a brown glass. Column chromatography (C18, biotage isolera, 30 g) eluting with 0 to 45% acetonitrile in water spiked with 0.1% formic acid afforded the racemic target (30 mg, 19%) as a tan solid.

[1357] Preparative chiral SFC employing a Chiralcel OD-H 25 cm eluting with 15% Methanol: 85% CO.sub.2 eluting at 15 ml/min, gave the desired enantiomer eluting at 4.88 minutes. Freeze drying from 1:1 MeCN-water afforded the title compound (6.9 mg, 5%, 92% chiral purity) as a colourless solid. .sup.1H NMR (500 MHz, DMSO-d6) 1H NMR (500 MHz, DMSO-d6) δ 8.87 (d, J=6.4 Hz, 1H), 8.69 (s, 1H), 8.23 (dd, J=7.9, 1.4 Hz, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.64 (d, J=11.1 Hz, 1H), 7.44 (t, J=75.0 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 5.13 (d, J=6.3 Hz, 1H), 5.11 (s, 1H), 4.68 (t, J=6.4 Hz, 1H), 2.43-2.39 (m, 1H), 2.37 (s, 3H), 1.53 (s, 6H). LCMS Method 6: MH+ m/z 510, RT 2.37 min

Example 67

[1358] ##STR00251##

(7R,14R)-1-(difluoromethoxy)-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]pyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1359] The title compound was prepared from Example 11 (350 mg, 0.933 mmol) and Intermediate 100 (642 mg, 1.86 mmol), according to a method involving the same procedural steps as those described for Example 20. The crude product was purified by flash chromatography (SiO.sub.2, 0 to 100% EtOAc in DCM and then 1 to 12% MeOH in EtOAc) to give the title compound (305 mg, 59%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.13 (d, J=6.8 Hz, 1H), 8.68 (s, 2H), 8.22 (q, J=4.5 Hz, 1H), 7.73-7.64 (m, 1H), 7.60 (dd, J=1.9, 0.7 Hz, 1H), 7.57-7.38 (m, 4H), 6.34 (d, J=7.0 Hz, 1H), 4.88 (t, J=6.7 Hz, 1H), 4.39-4.29 (m, 2H), 4.17-3.96 (m, 2H), 3.60-3.39 (m, 1H), 2.73 (d, J=13.3 Hz, 1H). LCMS basic Method 5 (ES+) RT 1.87 min, 557 (M-H).sup.+

Example 68

[1360] ##STR00252##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]pyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1361] The title compound was prepared from Example 10 (75 mg, 0.19 mmol) and Intermediate 100 (138 mg, 0.40 mmol), according to a method involving the same procedural steps as those described for Example 20. The crude product was purified by flash chromatography (SiO.sub.2, 0 to 100% EtOAc in DCM and then 1 to 12% MeOH in EtOAc) to obtain the title compound (61 mg, 53%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.06 (d, J=6.8 Hz, 1H), 8.49 (d, J=1.7 Hz, 2H), 8.16 (dd, J=6.0, 3.4 Hz, 1H), 7.59-7.28 (m, 5H), 6.26 (d, J=7.0 Hz, 1H), 4.82 (t, J=6.8 Hz, 1H), 4.28 (d, J=10.3 Hz, 2H), 4.06 (d, J=10.1 Hz, 2H), 3.41 (dd, J=13.5, 6.8 Hz, 1H), 2.66 (d, J=13.4 Hz, 1H). LCMS Method 5: (ES+) RT 1.96 min, 575 (M-H).sup.+

Example 69

[1362] ##STR00253##

(7R,14R)-1-(difluoromethoxy)-11-{2-[(1s,5s)-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl]pyrimidin-5-yl}-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1363] The title compound was prepared from Example 10 (75 mg, 0.19 mmol) and [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-3,7-dioxa-9-azabicyclo[3.3.1]nonane (126 mg, 0.38 mmol), by a palladium catalysed Suzuki coupling according to a method involving the same procedural steps as those described for Example 20. The crude compound was purified by preparative reverse phase HPLC to afford the title compound (5 mg, 5%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.14 (d, J=6.9 Hz, 1H), 8.57 (d, J=1.7 Hz, 2H), 8.24 (dd, J=5.6, 3.9 Hz, 1H), 7.65-7.56 (m, 1H), 7.54-7.42 (m, 4H), 6.33 (d, J=7.1 Hz, 1H), 4.90 (t, J=6.6 Hz, 1H), 4.53 (s, 2H), 4.03 (d, J=11.3 Hz, 4H), 3.82-3.74 (m, 4H), 3.48 (dt, J=13.5, 7.0 Hz, 1H), 2.74 (d, J=13.4 Hz, 1H). LCMS basic Method 5 (ES+) RT 1.79 min, 565 (M+H).sup.+

Example 70

[1364] ##STR00254##

(7R,14R)-1-(difluoromethoxy)-11-[2-methyl-4-(methylsulfonyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1365] (1-bromo-4-methanesulfonyl-2-methylbenzene (483 mg, 1.86 mmol), bis(pinacolato)diboron (525 mg, 2.0 mmol), and potassium acetate (369 mg, 3.7 mmol) were dissolved in 1,4-dioxane (15 mL) and the mixture degassed thoroughly with nitrogen. 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (38 mg, 0.05 mmol) was then added and the mixture heated for 2.5 hours under nitrogen. The reaction mixture was separated between EtOAc (25 mL) and water (25 mL). The organic layer was passed through a phase separator and evaporated in vacuo.

[1366] The crude product was engaged in a Suzuki reaction with Example 11 (350 mg, 0.93 mmol), tricyclohexylphosphonium tetrafluoroborate (42 mg, 0.11 mmol), tris(dibenzylideneacetone)-dipalladium(0) (56 mg, 0.060 mmol), and K.sub.3PO.sub.4 (592 mg, 2.79 mmol) in dioxane (5 ml) plus 2 drops of water. The mixture was heated in microwave for 18 hours at 110 degrees. After this time the reaction mixture was separated between EtOAc (25 mL) and water (25 mL) and the organic layer was passed through a phase separator and evaporated in vacuo. The resultant residue was then purified by flash chromatography (SiO.sub.2, 0 to 100% EtOAc in DCM and then 1 to 10% MeOH in EtOAc) to obtain mostly pure product (350 mg as brown solid 90% pure). Further purification by flash chromatography on silica gel 1-10% MeOH in DCM gave the title compound as off white powder (45 mg, 10%).

[1367] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.15 (d, J=6.9 Hz, 1H), 8.31-8.18 (m, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.87-7.65 (m, 2H), 7.59-7.38 (m, 4H), 7.45 (t, J=73 Hz, 1H), 7.36-7.15 (m, 1H), 6.31 (d, J=7.1 Hz, 1H), 4.89 (t, J=6.7 Hz, 1H), 3.49 (dt, J=13.6, 7.1 Hz, 1H), 3.26 (s, 3H), 2.74 (d, J=13.4 Hz, 1H), 2.30 (s, 3H). LCMS basic Method 5 (ES+) RT 1.83 min, 510 (M+H).sup.+.

Example 71

[1368] ##STR00255##

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1369] Intermediate 113 (650 mg, 0.97 mmol) was dissolved in tetrahydrofuran (6 mL) and treated with a solution of tetrabutylammonium fluoride (1M in THF, 2.90 mL, 2.90 mmol) dropwise and the reaction stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and separated between water and DCM. The organic phase was evaporated in vacuo and treated with 2M HCl (aq) (20 mL) and THF (5 mL). The reaction was stirred overnight and a further 20 mL of 2M HCl (aq) added. After a further 18 hours the reaction mixture was diluted with water (75 mL) and then evaporated in vacuo to remove volatiles. The aqueous was washed with DCM (4×50 mL) to remove impurities and then the solution was then made basic with saturated sodium carbonate solution and extracted into DCM (2×75 mL). The combined organics were washed with water (50 mL) dried (sodium sulphate), filtered and evaporated in vacuo. The solid was then dissolved in 0.5N HCl (aq) and freeze dried to afford the title compound as the HCl salt. (332 mg, 70%).

[1370] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.20 (d, J=6.9 Hz, 1H), 8.48 (s, 1H), 8.25 (dt, J=8.6, 4.3 Hz, 1H), 8.17 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.52 (m, 4H), 7.40-7.32 (m, 1H), 6.37 (d, J=7.1 Hz, 1H), 4.97 (t, J=6.8 Hz, 1H), 3.58-3.43 (m, 1H), 2.78 (d, J=13.4 Hz, 1H), 2.50 (s, 3H), 1.65 (s, 6H). LCMS basic Method 5 (ES+) RT 1.62 min, 491 (M+H).sup.+

Example 72

[1371] ##STR00256##

(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1372] Intermediate 115 (154 mg, 0.21 mmol) was dissolved in a solution of 4M HCl in dioxane (10 mL) and stirred for 3 hours at room temperature. After this time the mixture was evaporated in vacuo and separated between EtOAc (50 mL) and sodium carbonate (50 mL), the aqueous layer was extracted with EtOAc (50 mL) and the combined organics were dried (though a phase separator) and evaporated in vacuo. The crude compound was purified by preparative reverse phase HPLC to afford the title compound (27 mg, 27%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.14 (d, J=6.8 Hz, 1H), 9.02 (s, 2H), 8.23 (dd, J=6.0, 3.4 Hz, 1H), 7.80-7.65 (m, 3H), 7.59 (dd, J=8.5, 1.8 Hz, 1H), 7.55-7.41 (m, 2H), 6.36 (d, J=7.1 Hz, 1H), 4.90 (t, J=6.8 Hz, 1H), 3.49 (dt, J=13.9, 7.1 Hz, 1H), 2.75 (d, J=13.4 Hz, 1H), 2.10 (s, 2H), 1.46 (s, 6H). LCMS basic Method 5 (ES+) RT 1.30 min, 477.2 (M+H).sup.+

Example 73

[1373] ##STR00257##

(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1374] Intermediate 116 was dissolved in a mixture of dioxane (5 mL) and 4M HCl in dioxane (5 mL). The mixture was stirred for 3 hours at room temperature before being evaporated in vacuo. The reaction mixture was then separated between EtOAc (25 mL) and 1M HCl (20 mL). The acid layer made basic with saturated sodium carbonate solution and extracted with DCM (3×25 mL). The combined organic layers were dried (phase separator) and evaporated in vacuo to afford the title compound as an off white solid (25 mg, 40% over two steps). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.16 (d, J=6.9 Hz, 1H), 8.92 (d, J=1.7 Hz, 2H), 8.24 (p, J=4.2 Hz, 1H), 7.71-7.60 (m, 1H), 7.58-7.46 (m, 4H), 6.35 (d, J=7.0 Hz, 1H), 4.92 (t, J=6.8 Hz, 1H), 3.50 (dt, J=13.5, 7.0 Hz, 1H), 2.75 (d, J=13.4 Hz, 1H), 2.15 (s, 2H), 1.48 (s, 6H). LCMS basic Method 5 (ES+) RT 1.45 min, 495.2 (M+H).sup.+

Example 74

[1375] ##STR00258##

2-{5-[(7R,14R)-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1376] Intermediate 119 (150 mg, 0.3991 mmol), 245-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (105 mg, 0.3976 mmol), cesium carbonate (0.260 g., 0.797 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.3 mg., 0.020 mmol), and tricyclohexylphosphonium tetrafluoroborate (17.8 mg., 0.0479 mmol) were dissolved in a degassed mixture of 1,4-dioxane (2 mL) and water (0.5 mL). The reaction mixture was heated for 3 hours at 105° C. The mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate, the combined organic layers dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC-LCMS (basic conditions; Gr 5-70 (NH.sub.4).sub.2CO.sub.3) to afford 36 mg (19%) of the title compound as a white solid. LCMS Method 3 (ES+) RT 1.76 min., 478.2 (M+H)+.

Example 75

[1377] ##STR00259##

2-{5-[(SR or 5S,7R,14R)-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1378] The title compound was prepared from Intermediate 120 (40 mg, 0.106 mmol) and 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol according to a method involving the same procedural steps as those described for Example 20, to afford the title compound 24 mg (47%).

[1379] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.91 (s, 2H), 7.91 (d, 1H, J=9.2 Hz), 7.46 (m, 2 H), 7.27 (t, 1H, J=8.3 Hz), 7.15 (m, 2H), 6.74 (t, 1H, J=73.8 Hz), 6.29 (d, 1H, J=7.5 Hz), 4.73 (d, 1H, J=5.8 Hz), 4.68 (s, 1H), 3.18 (m, 1H), 2.90 (q, 1H, J=6.3 Hz), 2.47 (d, 1H, J=12.4 Hz), 2.42 (s, 1H), 1.64 (s, 6H), 1.41 (d, 3H, J=6.4 Hz). LCMS Method 3 (ES+) RT 2.36 min., 478.2 (M+H).sup.+.

Example 76

[1380] ##STR00260##

2-{5-[(5R or 5S,7R,14R)-1-(difluoromethoxy)-5-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1381] The title compound was prepared from Intermediate 121 (40 mg, 0.106 mmol) and 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol according to a method involving the same procedural steps as those described for Example 20, to afford the title compound 25 mg (49%).

[1382] .sup.1H NMR (400 MHz, CDCl3) δ ppm 8.94 (s, 2H), 7.87 (d, 1H, J=8.4 Hz), 7.56 (d, 1H, J=1.4 Hz), 7.45 (dd, 1H, J=8.5, 1.7 Hz), 7.23 (t, 1H, J=8.1 Hz), 7.09 (d, 1H, J=8.1 Hz), 7.02 (d, 1H, J=7.6 Hz), 6.77 (t, 1H, J=73.5 Hz), 6.25 (d, 1H, J=7.6 Hz), 4.71 (m, 2H), 4.50 (q, 1H, J=7.5 Hz), 3.24 (ddd, 1H, J=13.0, 7.5, 6.0 Hz), 2.61 (d, 1H, J=12.6 Hz), 2.01 (s, 1H), 1.65 (s, 6H), 0.45 (d, 3H, J=7.4 Hz). LCMS Method 4 (ES+) RT 1.83 min., 478.2 (M+H).sup.+.

Example 77

[1383] ##STR00261##

1-[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6 (7H) -yl]ethanone

[1384] To a solution of Example 74 (30 mg, 0.063 mmol) in dichloromethane (0.5 mL) was added pyridine (50 μL). The reaction mixture was cooled to 0° C. and acetic anhydride (0.5 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. Water and solid NaHCO.sub.3 were added and the mixture was extracted with dichloromethane. The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo to afford 24 mg (74%) of the title compound as a mixture of diastereomers. LCMS Method 3 (ES+) RT 3.53 min and 3.70 min., 520.3 (M+H).sup.+.

Example 78

[1385] ##STR00262##

1-[(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone

[1386] To a solution of Intermediate 128 1 (300 mg, 0.48 mmol) in methanol (7 mL) was added p-toluenesulfonic acid monohydrate (460 mg, 2.42 mmol). The reaction mixture was stirred at room temperature for 4 hours. The methanol was evaporated at in vacuo. The residue was dissolved in DCM (2 mL). The organic layer was washed with a saturated solution of NaHCO.sub.3 (3×1 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude material was purified by preparative basic reverse phase HPLC-MS to afford 150 mg (61%) of the title compound as a white powder.

[1387] LCMS Method 3 basic (ES+) RT 3.71 min., 506 (M+H).sup.+.

[1388] LCMS Method 4 acidic (ES+) RT 3.88 min., 506 (M+H).sup.+.

Example 79

[1389] ##STR00263##

2-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1390] Intermediate 129 (80 mg, 0.135 mmol) was treated in accordance with the synthetic procedure described for Example 78. The crude material was purified by preparative basic reverse phase HPLC-MS affording 2.4 mg (4%) of the title compound as an off white solid.

[1391] LCMS Method 3 basic (ES+) RT 3.83 min., 478.1 (M+H).sup.+.

Example 80

[1392] ##STR00264##

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-(methylsulfonyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1393] Example 16 (14.3 mg, 0.03 mmol) was dissolved in DCM (0.6 mL). The solution was cooled at −60° C. before successive addition of triethylamine (8.34 μL, 0.06 mmol) and a solution of methanesulfonyl chloride (2.31 μL, 0.03 mmol) in DCM (20 μL). The solution was slowly warmed to room temperature overnight. The reaction was quenched by addition of a saturated aqueous solution of NH.sub.4Cl (1 mL) and diluted by DCM (2 mL). The organic layer was washed with successively a saturated solution of NH.sub.4Cl (2×1 mL) and a saturated solution of NaHCO.sub.3 (2×1 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reverse phase basic preparative HPLC-MS yielding to 11 mg (66%) of the title compound as an off white solid.

[1394] LCMS Method 3 (ES+) RT 4.07 min., 560.13 (M+H).sup.+.

[1395] LCMS Method 4 (ES+) RT 4.24 min., 560.13 (M+H).sup.+.

Example 81

[1396] ##STR00265##

2-{5-[(7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6, 7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1397] To a solution of Intermediate 130 (7 mg, 0.011 mmol) in methanol (0.5 mL) was added p-toluenesulfonic acid monohydrate (10 mg, 0.053 mmol) and the resulting slurry was stirred overnight. The reaction mixture was then diluted with dichloromethane and aqueous saturated solution of NaHCO.sub.3. The two phases were separated and the aqueous layer further extracted with dichloromethane. The combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by basic reverse phase HPLC-MS, yielding to 2.8 mg (49%) of the title compound in a 83/17 ratio of diastereoisomers.

[1398] LCMS Method 3 (ES+) RT 4.1 min., 532.2 (M+H).sup.+.

[1399] LCMS Method 4 (ES+) RT 2.66 min., 532.2 (M+H).sup.+.

Example 82

[1400] ##STR00266##

2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1401] or

2-{5-[(5S,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1402] To a solution of Intermediate 131 (4.8 mg, 0.0074 mmol) in methanol (0.5 mL) was added p-toluenesulfonic acid monohydrate (7.1 mg, 0.037 mmol). The reaction mixture was stirred overnight. The methanol was evaporated at room temperature in vacuo. The crude material was purified by basic reverse phase HPLC-MS, yielding 3.9 mg (99%) of the title compound as a pale yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.72 (m, 2H), 7.17 (s, 1H), 7.03 (m, 4H), 6.86 (m, 2H), 6.38 (m, 1H), 5.32 (m, 1H), 4.61 (m, 1H), 4.51 (m, 1H), 3.48 (m, 1H), 2.83 (m, 1H), 2.41 (m, 1H), 1.62 (m, 6H). LCMS Method 3 (ES+) RT 2.33 min., 532.2 (M+H).sup.+. LCMS Method 4 (ES+) RT 2.35 min., 532.2 (M+H).sup.+.

Example 83

[1403] ##STR00267##

2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1404] or

2-{5-[(5S ,7R ,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1405] To a solution of Intermediate 132 (23 mg) in methanol (1 mL) was added p-toluenesulfonic acid monohydrate (34 mg). The reaction mixture was stirred overnight. The methanol was evaporated at room temperature in vacuo. The crude material was purified by basic reverse phase HPLC-MS, yielding 15 mg (80%) of the title compound as a pale yellow oil.

[1406] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.93 (m, 2H), 7.97 (m, 1H), 7.51 (m, 2H), 7.33 (m, 2 H), 7.23 (m, 1H), 6.77 (m, 1H), 6.32 (m, 1H), 4.91 (m, 1H), 4.68 (m, 1H), 3.39 (m, 1H), 3.21 (m, 1H), 2.67 (m, 1H), 2.54 (m, 1H), 1.63 (m, 6H). LCMS Method 4 (ES+) RT 2.33 min., 532.2 (M+H).sup.+. LCMS Method 3 (ES+) RT 2.59 min., 532.2 (M+H).sup.+.

EXAMPLE 84

[1407] ##STR00268##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-1-oxidopyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14h)-one

[1408] To a solution of Example 1 (10 mg, 0.02 mmol) in DCM (0.5 mL) were added m-chloroperbenzoic acid (57 mg, 0.33 mmol) and NaHCO.sub.3 (14 mg; 0.16 mmol). The reaction mixture was stirred at ambient temperature for 24 hours. The mixture was diluted with DCM (1 mL) and washed with a saturated aqueous solution of NaHCO.sub.3 (1 mL) and brine (1 mL), and concentrated in vacuo. The crude material was purified by LC-2D MS chromatography in acidic mode (formic acid) to give 0.5 mg (5%) of the title compound. LCMS Method 4 (ES+) RT 5.30 minutes, 512.2 (M+H).sup.+.

[1409] Analytical Method Used for the Separation :

[1410] semi preparative HPLC column: Sunfire prep C18 5 μm 10×150 mm column Gradient: 98% Solvent A (Water, acetonitrile, Formic acid (95/5/0.5, v/v/v)) to 90% Solvent B (Acetonitrile, Formic acid (99.3/0.7, v/v)) in 9 minutes with a hold at 90% B of 4 minutes.

[1411] Flow rate: 7 ml/min

Example 85

[1412] ##STR00269##

(7R,14R)-1-(difluoromethoxy)-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methylpyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1413] Example 11 (350 mg, 0.93 mmol) and crude Intermediate 133 (1.00 g, 2.8 mmol) were dissolved in dioxane (10 mL) and K.sub.3PO.sub.4 (592 mg, 2.79 mmol) in water (1 mL) was added, degassed and placed under nitrogen before adding tris(dibenzylideneacetone)dipalladium(0) (44 mg, 0.047 mmol) and tricyclohexylphosphonium tetrafluoroborate (42 mg, 0.11 mmol). The mixture was heated to 105° C. under nitrogen for 18 hours. The mixture was partitioned between EtOAc and water (50 mL each), separated and the organic phase dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by chromatography (silica 25 g, 0-15% gradient of methanol in dichloromethane) to give the title compound as an off-white solid (240 mg, 45% yield). LC/MS Method 3: RT 1.90 mins, m/z 573. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.13 (d, J=6.8 Hz, 1H), 8.31-8.13 (m, 2H), 7.89-7.24 (m, 6H), 7.18 (dd, J=8.4, 1.7 Hz, 1H), 6.30 (d, J=7.0 Hz, 1H), 4.88 (t, J=6.7 Hz, 1H), 4.31 (d, J=10.5 Hz, 2H), 4.08 (d, J=10.2 Hz, 2H), 3.48 (dt, J=13.6, 7.0 Hz, 1H), 2.73 (d, J=13.4 Hz, 1H), 2.29 (s, 3H).

Example 86

[1414] ##STR00270##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methylpyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1415] The title compound was prepared from Example 10 and Intermediate 133 in accordance with the synthetic procedure described for Example 85 to afford an off white solid. .sup.1H NMR (500 MHz, Chloroform-d) δ 8.44 (d, J=7.9 Hz, 1H), 8.09 (br s, 1H), 7.53-7.41 (m, 2H), 7.40-7.33 (m, 1H), 7.16 (br s, 1H), 6.77 (t, J=72.6 Hz, 1H), 6.32 (d, J=7.0 Hz, 1H), 4.97 (s, 1H), 4.52 (d, J=10.1 Hz, 2H), 4.24 (d, J=10.2 Hz, 2H), 3.57-3.40 (m, 1H), 2.87 (d, J=13.3 Hz, 1H), 2.26 (s, 3H). LCMS; Method 8, RT=2.78 min, m/z=591.0.

Example 87

[1416] ##STR00271##

(7R,14R)-1-(difluoromethoxy)-11-{6-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-2-methylpyridin-3-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1417] Intermediate 135 (500 mg, 1.39 mmol) and Example 11 (300 mg, 0.80 mmol) were treated in accordance with the synthetic procedure described for Example 86. After purification by preparative HPLC, the title compound was obtained as a white solid (30 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.14 (d, J=6.8 Hz, 1H), 8.24 (dd, J=5.9, 3.5 Hz, 1H), 7.76-7.24 (m, 7H), 7.13 (dd, J=8.4, 1.7 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 6.29 (d, J=7.1 Hz, 1H), 4.88 (t, J=6.7 Hz, 1H), 4.24 (d, J=9.6 Hz, 2H), 3.98 (d, J=9.6 Hz, 2H), 3.48 (dt, J=13.5, 6.9 Hz, 1H), 2.73 (d, J=13.3 Hz, 1H), 2.28 (s, 3H). LC/MS

[1418] Method 3: RT 2.02 minutes, m/z 572.

Example 88

[1419] ##STR00272##

(6R,12R)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine

[1420] Intermediate 136, (1.90 g, 3.35 mmol) was dissolved in dry THF (20 mL), cooled to 0° C. under nitrogen and N,N-diisopropylethylamine (0.76 mL, 4.4 mmol) and then methanesulfonyl chloride (0.31 mL, 4.0 mmol) were added and the mixture stirred for 1 hour until TLC analysis shows conversion to the faster running mesylate. Sodium ethoxide 21% wt solution in ethanol (2.5 mL, 6.7 mmol) was added and the mixture allowed to warm to ambient temperature with stirring overnight. A further portion of the sodium ethoxide solution (2.5 mL) was added and stirred for another 48 hours. The mixture was concentrated in vacuo, then partitioned between dichloromethane and aqueous sodium bicarbonate solution (75 mL each). The organic phase was dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, isohexane/DCM 0-100% gradient, then 0-10% ethyl acetate in DCM) afforded the title compound as a pink solid (670 mg, 55% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.77-7.46 (m, 2H), 7.49 (t, 1H, JILF =73.4 Hz), 7.35 (d, J=2.1 Hz, 1H), 7.31-7.11 (m, 2H), 7.01-6.89 (m, 1H), 6.01 (d, J=5.3 Hz, 1H), 4.97 (d, J=5.0 Hz, 1H), 3.50-3.34 (m, 1H), 2.66 (d, J=12.2 Hz, 1H). LC/MS Method 3: RT 2.16 minutes, m/z 365/367.

Example 89

[1421] ##STR00273##

2-{5-[(6R,12R)-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1422] Example 88 (100 mg, 0.25 mmol) and tris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.014 mmol), tricyclohexylphosphonium tetrafluoroborate (13 mg, 0.033 mmol) and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (116 mg, 0.44 mmol) were added to a microwave tube, dioxane (3 mL) added followed by K.sub.3PO.sub.4 (174 mg, 0.82 mmol) dissolved in water (300 μL) was added and the vessel placed under nitrogen. The mixture was heated to 140° C. under nitrogen in the microwave (3 bar pressure) until LCMS shows reaction to be complete (typically 1 hour). Purification by chromatography (silica, 0 to 10% methanol gradient in dichloromethane) followed by additional column chromatography (silica, EtOAc, 0 to 7% gradient of methanol) gave the title compound as an off white solid (105 mg, 82% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.07 (s, 2H), 7.82-7.35 (m, 4H), 7.26 (t, J=8.1 Hz, 1H), 6.96 (dd,J=8.1, 4.2 Hz, 2H), 6.08 (d, J=5.3 Hz, 1H), 5.13 (s, 1H), 5.06-4.97 (m, 1H), 3.47 (dt,J=12.2, 5.4 Hz, 1H), 2.71 (d, J=12.3 Hz, 1H), 1.55 (s, 6H). LC/MS Method 3: RT 2.02 minutes, m/z 467.0.

Example 90 and Example 91

[1423] ##STR00274##

Example 90

(6R,7R,12S)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine 7-oxide

Example 91

(6R,7S,125)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine 7-oxide

[1424] Example 88 (1.00 g, 2.741 mmol) was dissolved in dichloromethane (15 mL), saturated aqueous sodium bicarbonate solution (5 mL) was added and stirred vigorously, 3-meta-chloroperoxybenzoic acid (645 mg, 2.88 mmol, 77%) was added and the mixture stirred for 2 hours. The layers were separated and the organic phase dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, dichloromethane 0 to 5% methanol) gave the title compounds. The major diastereoisomer, Example 90, eluting first (771 mg, 74%) and then the minor diastereoisomer, Example 91 (44 mg, 4%).

[1425] Example 90, Major diastereoisomer: .sup.1H NMR (300 MHz, Chloroform-d) δ 7.61 (d, J=8.7 Hz, 1H), 7.54-7.42 (m, 2H), 7.37 (d, J=2.0 Hz, 1H), 7.32-7.15 (m, 2H), 6.77 (dd, J=72.7, 71.8 Hz, 1H), 5.98 (d, J=5.4 Hz, 1H), 4.90 (d, J=5.3 Hz, 1H), 3.70 (d, J =13.0 Hz, 1H), 3.43 (dt, J=13.1, 5.4 Hz, 1H). LC/MS Method 3: RT 1.93 minutes, m/z 381.0/383.0.

[1426] Example 91, Minor diastereoisomer: .sup.1H NMR (300 MHz, Chloroform-d) δ 7.73-7.60 (m, 2H), 7.47 (t, J=8.1 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.25-7.15 (m, 2H), 6.77 (dd, J=72.7, 71.8 Hz, 1H), 5.95 (d, J=5.6 Hz, 1H), 5.08 (d, J=6.3 Hz, 1H), 3.44 (dt, J =13.6, 6.0 Hz, 1H), 2.85 (d, J=13.5 Hz, 1H). LC/MS Method 3: RT 1.80 minutes, m/z 381.0/383.0.

Example 92

[1427] ##STR00275##

2-{5-[(6R,7R,12S)-11-(difluoromethoxy)-7-oxido-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1428] Example 90 (56 mg, 0.147 mmol) and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester were treated in accordance with the synthetic procedure described for Example 89. Flash column chromatography (silica, 0 to 5% gradient of methanol in dichloromethane) afforded the title compound as a pale brown solid (12 mg, 17% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.98 (s, 2H), 7.79-7.60 (m, 2H), 7.58-7.44 (m, 4H), 7.34 (q, J=4.3 Hz, 1H), 6.10 (d, J=4.7 Hz, 1H), 5.22 (d, J=4.5 Hz, 1H), 5.05 (s, 1H), 3.51-3.30 (m, 2H), 1.47 (s, 6H). LC/MS Method 3: RT 1.59 minutes, m/z 483.0

Example 93

[1429] ##STR00276##

2-{5-[(6R,7S,12S)-11-(difluoromethoxy)-7-oxido-6H,12H-6,12-methanobenzimidazo[2,1-c1[1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1430] Example 91 (44 mg, 0.15 mmol) and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester were treated in accordance with the synthetic procedure described for Example 89. Flash column chromatography (silica, 0 to 5% gradient of methanol in dichloromethane) afforded the title compound as a pale brown solid (15 mg, 27% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.08 (s, 2H), 7.89-7.49 (m, 6H), 7.40-7.23 (m, 1H), 6.08 (d, J=5.5 Hz, 1H), 5.46 (d, J=6.2 Hz, 1H), 5.12 (s, 1H), 3.44 (dt, J=13.6, 6.0 Hz, 1H), 2.93 (d, J=13.8 Hz, 1H), 1.55 (s, 6H). LC/MS Method 3: RT 1.56 minutes, m/z 483.0.

Example 94

[1431] ##STR00277##

(6R,12R)-2-chloro-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepine 7,7-dioxide

[1432] Example 88 (240 mg, 0.66 mmol) treated in accordance with the synthetic procedure described for Example 90/91 with 2 eq of mCPBA. The title compound was obtained after chromatography as a white solid (196 mg, 76% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.75-7.60 (m, 3H), 7.56 (t, 1H, J.sub.H-F=72.7 Hz), 7.53-7.45 (m, 1H), 7.41 (dd, J=2.1, 0.5 Hz, 1H), 7.26 (dd, J=8.7, 2.1 Hz, 1H), 6.12 (d, J=5.4 Hz, 1H), 5.61 (d, J=5.7 Hz, 1H), 3.75 (dt, J=13.6, 5.8 Hz, 1H), 3.52 (d, J=13.6 Hz, 1H). LC/MS Method 3: RT 1.86 minutes, m/z 397.0/399.0.

Example 95

[1433] ##STR00278##

2-{5-[(6R,12R)-11-(difluoromethoxy)-7,7-dioxido-6H,12H-6,12-methanobenzimidazo[2,1-c1[1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1434] Example 94 (198 mg, 0.50 mmol) and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester were treated in accordance with the synthetic procedure described for Example 89 to give the title compound after chromatography as an off-white solid (90 mg, 36% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.08 (s, 2H), 7.91-7.79 (m, 1H), 7.74-7.58 (m, 5H), 7.54-7.41 (m, 1H), 6.17 (d, J=5.4 Hz, 1H), 5.63 (d, J=5.7 Hz, 1H), 5.13 (s, 1H), 3.87-3.70 (m, 1H), 3.56 (d, J=13.5 Hz, 1H), 1.55 (s, 6H). LC/MS Method 3: RT 1.72 minutes, m/z 499.0.

Example 96

[1435] ##STR00279##

1-R5R,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b]1[2,5]benzodiazocin-6(7H)-yl]ethanone

[1436] or

1-[(5S,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b]1[2,5]benzodiazocin-6(7H)-yl]ethanone

[1437] To a solution of Example 76 (22 mg, 0.046 mmol) and pyridine (5 μL, 0.06 mmol) in dichloromethane (0.5 mL), cooled at 0° C., was added acetic anhydride (460 μL; 4.6 mmol). The reaction was allowed to reach ambient temperature and stirred overnight. The crude reaction mixture was poured into ice water (2 mL), before neutralisation by solid NaHCO.sub.3. The aqueous layer was extracted by ethyl acetate (2×2 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was taken up in di-isopropyl ether and concentrated in vacuum. The resulting solid was dissolved in 1-4 dioxane/water (1:1 mixture, total volume 5 mL) before freeze drying to yield 21 mg (90%) of the title compound as a white solid. LCMS Method 3 (ES.sup.+): RT 2.18 min, [M+H].sup.+=520.2

Example 97

[1438] ##STR00280##

1-[(5R,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone

[1439] Or

1-[(5S,7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-5-methyl-5,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-6(7H)-yl]ethanone

[1440] The title compound was prepared from Example 75 (2.3 mg, 4.8 μmol) by the method of Example 96. The crude material was purified by basic reverse phase preparative HPLC-MS, yielding 2.1 mg (90%) of the title compound as a colorless oil. LCMS Method 3 (ES+): RT 2.20 min, [M+H].sup.+=520.2.

Example 98

[1441] ##STR00281##

(7R,14R)-10-fluoro-1-hydroxy-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1442] Example 1 (300 mg, 0.61 mmol) was dissolved in dry tetrahydrofuran (10 mL/mmol). The solution was cooled to 0° C. and sodiumbis(trimethylsilyl)amide (5 eq, 3.03 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and overnight at room temperature. The reaction mixture was cooled to 0° C. and quenched with water (5 mL). Tetrahydrofuran was evaporated; the aqueous layer was brought to pH 6-7 by addition of 0.1N HCl and extracted with ethyl acetate (3×10 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified over silica gel (5-10% MeOH in DCM), yielding 85 mg (31%) of the title compound as a white solid. LCMS Method 3 (ES+): RT 1.64 min., [M+H].sup.+=446.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10,56 (s, 1H), 8,97 (d, J=1,5 Hz, 2H), 8,93 (d, J=7,0 Hz, 1H), 7,79 (dd, J1=8,0 Hz, J2=1,0 Hz, 1H), 7,71 (d, J=7,0 Hz, 1H), 7,63 (d, J=11,5 Hz, 1H), 7,20 (t, J=8,0 Hz, 1H), 7,10 (dd, J1=8,0 Hz, J2=1,2 Hz, 1H), 6,41 (d, J=7,0 Hz, 1H), 5,14 (s, 1 H), 4,87 (t, J=6,9 Hz, 1H), 3,42 (m, 1H), 2,68 (d, J=13,2 Hz, 1H), 1,56 (s, 6H).

Example 99

[1443] ##STR00282##

2-{5-[(7R,14R)-1-(difluoromethoxy)-5-methyl-5-oxido-7,14-dihydro-7,14-methano-5λ-4-benzimidazo[2,1-d][1,2,5]benzothiadiazo cin-11-yl]pyrimidin-2-yl}propan-2-ol

[1444] To a solution of Intermediate 142 (8 mg) in MeOH (5 mL) was added p-toluene sulfonic acid monohydrate (18.6 mg, 0.1 mmol). The reaction mixture was stirred at ambient temperature overnight. The methanol was evaporated and the residue was taken up in DCM (5 mL). The organic layer was washed with a mixture of saturated aqueous sodium bicarbonate solution and water ˜50/50 (3 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative LCMS yielding 3.7 mg (57%) of the title compound as a pale yellow solid. LCMS Method 3 (ES+): RT 2.02 minutes, [M+H]+=512.1. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ 9,04 (s, 2H), 7,99 (d, J=8,7 Hz, 1H), 7,94 (d, J=8,6 Hz, 1H), 7,84 (dd, J1=6,4 Hz, J2=2,4 Hz, 1H), 7,75 (s, 1H), 7,69 (d, J=6,4 Hz, 1H), 7,68 (s, 1H), 7,36 (t, J=72,6 Hz, 1H), 6,87 (d, J=7,9 Hz, 1H), 5,34 (d, J=5,1 Hz, 2H), 3,61 (m, 1H), 3,56 (s, 3 H), 2,95 (d, J=13,2 Hz, 1H), 1,65 (s, 6H).

Example 100

[1445] ##STR00283##

(7R,14R)-1-(difluoromethoxy)-11-{6-[1-(methylsulfonyl)cyclopropyl]pyridin-3-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1446] Example 11 (30 mg, 0.08 mmol), bis(pinacolato)diboron (25 mg, 0.096 mmol), potassium acetate (24 mg, 0.24 mmol), tricyclohexylphosphonium tetrafluoroborate (7 mg, 0.019 mmol) and tris(dibenzenylideneacetone)dipaladium(0) (7 mg, 0.008 mmol) were mixed in degassed dioxane (1 mL). The reaction mixture was stirred at 80° C. for 24 hours. Intermediate 143 (29 mg, 0.08 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4 mg, 0.006 mmol), cesium carbonate (52 mg, 0.16 mmol) and water (0.11 mL) were added and the reaction mixture was stirred at 95° C. for 2 hours. The reaction mixture was concentrated in vacuum and the crude was purified by reverse phase basic preparative LCMS yielding 8 mg (19%) of the title compound as an white solid. LCMS Method 3 (ES+): RT 1,19 min, [M+H]+=537.1. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ 8,90 (s, 1H), 8,36 (dd, J=7,0, 1,3 Hz, 1H), 8,23 (dd, J=8,2, 1,7 Hz, 1H), 8,02 (s, 1H), 7,88 (m, 3H), 7,55 (m, 2H), 7,35 (t, J=72,8 Hz, 1H), 6,74 (d, J=7,2 Hz, 1H), 5,27 (d, J=6,7 Hz, 1H), 3,67 (m, 1H), 3,04 (s, 3H), 3,01 (d, J=13,6 Hz, 1H), 1,87 (s, 2H), 1,58 (m, 2H).

Example 101

[1447] ##STR00284##

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dimethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1448] Intermediate 149 (55 mg, 0.14 mmol), 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (75 mg, 0.27 mmol), tricyclohexylphosphonium tetrafluoroborate (12 mg, 0.033 mmol), tris(dibenzenylideneacetone)dipaladium(0) (12 mg, 0.014 mmol), potassium triphosphate (60 mg, 0.27 mmol) and water (0,22 mL) were mixed in degassed 1,4-dioxane (2.2 mL). The reaction mixture was stirred at 130° C. under nitrogen for 3 hours. The crude reaction mixture was partially concentrated and purified over silica gel (Heptane : EtOAc 75 to 100%), yielding 63 mg (93%) of the title compound as a white solid. LCMS Method 3 (ES+): RT 2.19 min, [M+H].sup.+=506.2. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8,96 (s, 2H), 8,55 (d, J=8,0 Hz, 1H), 7,93 (d, J=7,7 Hz, 1H), 7,82 (s, 1H), 7,54 (d, J=7,8 Hz, 1H), 7,49 (t, J=8,5 Hz, 1H), 7,35 (d, J=7,8 Hz, 1H), 6,90 (t, J=72,7 Hz, 1H), 6,23 (d, J=6,0 Hz, 1H), 4,70 (bs, 1H), 3,46 (m, 4H), 3,14 (d, J=13,5 Hz, 1H), 2,22 (s, 3H), 1,68 (s, 6H).

Example 102

[1449] ##STR00285##

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1450] The title compound was prepared from Intermediate 148 (29 mg, 0.08 mmol) and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (41 mg, 0.15 mmol) following the procedure used for Example 101. The crude material was purified by reverse phase basic preparative HPLC, yielding 6 mg (13%) of the title compound as a white solid. LCMS Method 3 (ES+): RT 2.05 minutes, [M+H].sup.+=492. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8,95 (s, 2H), 8,48 (d, J=8,0 Hz, 1H), 8,04 (d, J=8,2 Hz, 1H), 7,79 (s, 1H), 7,66 (d, J=8,3 Hz, 1H), 7,55 (t, J=8,3 Hz, 1H), 7,45 (d, J=7,7 Hz, 1H), 6,93 (t, J=72,8 Hz, 1H), 6,52 (d, J=4,3 Hz, 1H), 3,67 (s, 1H), 3,50 (m, 1H), 3,09 (d, J=13,3 Hz, 1H), 2,31 (s, 3H), 1,68 (s, 6H).

Example 103

[1451] ##STR00286##

(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-6,7-dimethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1452] To a solution of Intermediate 150 (13 mg, 0.022 mmol) in DMF (0.5 mL), at 0° C., was added sodium hydride (60% mineral oil) (0,88 mg, 0.022 mmol) at 0° C. and stirred at room temperature for 30 minutes. Iodomethane (3 mg, 0.022 mmol) was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by reverse phase basic preparative HPLC-MS to yield 7 mg (0.012 mmol , 53%) of a white solid. The intermediate was added to a solution of DCM/trifluoroacetic acid (1:1, 0,25 mL). The reaction mixture was stirred at ambient temperature for 1 hour before addition of a saturated aqueous solution of NaHCO.sub.3 (1 mL). The aqueous layer was extracted by DCM (2×2 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by reverse phase basic preparative HPLC-MS, yielding 2.2 mg (38%) of the title compound as a beige solid. LCMS Method 3 (ES+): RT 1.99 minutes, [M+H].sup.+=505.

Example 104

[1453] ##STR00287##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4,6-dimethylpyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1454] Example 1 (25 mg, 0.052 mmol) was dissolved in a 1:1 mixture of TFA/MeCN (0.53 mL) in a 4 mL glass vial. [Ir{dF(CF.sub.3)ppy}.sub.2(dtbpy)]PF.sub.6 (1.175 mg, 0.00105 mmol, Aldrich) and tert-butyl peroxyacetate (41.5 mg, 0.16 mmol, 50% solution in mineral spirits, 3.0 eq., Aldrich) were then added. The mixture was degassed with argon for 5 minutes then irradiated with blue light emitting diodes (460 nm visible light, OSRAM Oslon SSL 80 royal-blue on Star, 1000 mA, ˜1 W) until UPLC-MS analysis indicates complete consumption of starting material (12 hours). The solvents were removed by evaporation to give an orange oil. Purification by reverse phase preparative chromatography (acidic mode, gradient from 30% MeCN in 0.1% TFA in water up to 95% MeCN) yielded the title compound as a colorless oil (5.8 mg, 21% yield). LCMS Method 4 (ES+): RT: 2.41 min, [M+H]+=524.2. LCMS Method 3 (ES+): RT: 2.21 min, [M+H]+=524.2. .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 8,26 (t, J=4,7 Hz, 1H), 7,52 (d, J=9,9 Hz, 1H), 7,42 (m, 3H), 7,05 (dd, J=73,6, 72,1 Hz, 1H), 6,43 (d, J=7,1 Hz, 1H), 4,97 (d, J=6,7 Hz, 2H), 3,54 (s, 1H), 3,49 (m, 1H), 2,80 (d, J=13,6 Hz, 1H), 2,37 (s, 3H), 2,17 (s, 3H), 1,59 (s, 6 H).

Example 105 and Example 106

[1455] ##STR00288##

2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,14-dihydro-7H-7,14-methanobenzimidazo[2,1-d][2,5Thenzoxazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1456] and

2-{5-[(5S,7R,14R)-1-(difluoromethoxy)-5-(trifluoromethyl)-5,14-dihydro-7H-7,14-methanobenzimidazo[2,1-d][2,5Thenzoxazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1457] Intermediate 155 (50 mg, 0.091 mmol) was dissolved in toluene (1 mL), cyanomethylenetributylphosphorane (100 μL, 0.1 mmol) was added. The slurry was stirred overnight at 100° C. Additional cyanomethylenetributylphosphorane (100 μL, 0.1 mmol) was added and the reaction mixture stirred overnight at 100° C. to complete the reaction. The solvent was evaporated and the crude partitioned into EtOAc (2 mL) and water (1 mL). The aqueous layer was extracted with EtOAc (2×1 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase basic HPLC-MS followed by reverse phase acid HPLC-MS purification. Each diastereoisomer was taken up in EtOAc (1 mL) and neutralized by a saturated solution of NaHCO.sub.3 (1 mL). The aqueous layer was extracted with EtOAc (2×1 mL). The organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give the following diastereoisomers. 3 mg (6%) of Diastereomer A was isolated as white solid. LCMS Method 3 (ES+): RT 2.39 min., 533 (M+H)+. LCMS Method 4 (ES+): RT 2.54 min., 533 (M+H)+. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.95 (s, 2H), 7.91 (m, 1H), 7.67 (m, 1H), 7.48 (m, 1H), 7.38 (m, 1H), 7.28 (s, 1H), 7.23 (d, J=7.8 Hz, 1H), 6.85 (m, 1H), 6.23 (m, 1H), 5.60 (d, J=4.4 Hz, 1H), 5.49 (m, 1H), 4.70 (m, 1H), 3.20 (m, 1H), 3.00 (m, 1H), 1.66 (s, 6H). 9 mg (19%) of Diastereomer B was isolated as off white solid. LCMS Method 3 (ES+): RT 2.59 min., 533 (M+H)+. LCMS Method 4 (ES+): RT 2.76 min., 533 (M+H)+. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.93 (m, 2H), 8.02 (m, 1H), 7.54 (m, 2H), 7.35 (d, J=5.3 Hz, 2H), 7.29 (m, 1H), 6.79 (m, 1H), 6.40 (m, 1H), 5.71 (m, 1H), 4.68 (m, 1H), 3.84 (m, 1H), 3.12 (m, 1H), 2.78 (m, 1H), 1.65 (s, 6H).

General Procedure for the Late Stage Trifluoromethylation

[1458] To a solution of Example 1 (600 mg, 1.211 mmol) in degassed acetonitrile (1 ml) and TFA (1 ml) was added trifluoromethanesulfonyl chloride (65 μL, 0.6045 mmol) followed by [Ir[DF(CF.sub.3)PPY].sub.2(DTBPY)]PF.sub.6 (4.5 mg, 0.0040 mmol) under argon . The slurry was stirred overnight under blue light emitting diodes (460 nm visible light, OSRAM Oslon SSL 80 royal-blue on Star, 1000 mA, ˜1 W). The reaction was performed in 6 vials of 100 mg portions of Example 1. The six crude mixtures were gathered and diluted with EtOAc (10 mL) and washed by a saturated solution of NaHCO.sub.3 (2×5 mL). The aqueous layer was back extracted by EtOAc (5 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced. The residue was purified by reverse phase basic LCMS to afford a mixture of the desired isomers as an yellow solid (218 mg, 33% yield).

Example 107

[1459] ##STR00289##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-12-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one 1.1 mg (0.5%) of the title compound as an off white solid was isolated from the above described mixture of diastereomers by LC-2D MS chromatography in acidic mode (formic acid) Method 14. LCMS Method 15 (ES+) RT 5.82 min., 564 (M+H).SUP.+.. .SUP.1.H NMR (400 MHz, DMSO-d.SUB.6.) δ 8.99 (d, J=6.2 Hz, 1H), 8.86 (s, 1H), 8.75 (s, 1H), 8.10 (d, J=8.10, 1H) 8.06 (d, J=8.06 Hz, 1H), 7.51 (t, J=7.51 Hz, 1H), 7.44 (d, J=7.44 Hz, 1H), 7.14 (dd, J=73.9, 72.3 Hz, 1H), 6.46 (d, J=7.3 Hz, 1H), 5.14 (s, 1H), 4.92 (t, J=6.3 Hz, 1H), 3.51 (m, 1H), 2.67 (d, J=13.6 Hz, 1H), 1.54 (s, 6H).

Example 108

[1460] ##STR00290##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-4-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1461] 77.1 mg (35%) of the title compound as an off white solid was isolated from the above described mixture of diastereomers by LC-2D MS chromatography in acidic mode (formic acid) Method 14 . LCMS Method 15 (ES+) RT 5.90 min., 564 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.97 (d, J=1.5 Hz, 2H), 8.85 (d, J=5.3 Hz, 1H), 7.90 (m, 1H), 7.71 (m, 2H), 7.54 (m, 2H), 6.29 (d, J=7.2 Hz, 1H), 5.16 (m, 1H), 4.90 (t, J=5.8 Hz, 1H), 3.49 (m, 1H), 2.77 (m, 1H), 1.56 (s, 6H).

Example 109

[1462] ##STR00291##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-9-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1463] 16.6 mg (7.6%) of the title compound as an off white solid was isolated from the above described mixture of diastereomers by LC-2D MS chromatography in acidic mode (formic acid) Method 14. LCMS Method 15 (ES+) RT 5.95 min., 564 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J=6.8 Hz, 1H), 8.99 (m, 2H), 8.25 (m, 1H), 7.81 (m, 1H), 7.52 (m, 3H), 6.42 (m, 1H), 5.23 (m, 1H), 4.99 (m, 1H), 3.53 (d, J=6.7 Hz, 1H), 2.80 (m, 1H), 1.56 (s, 6H).

Example 110

[1464] ##STR00292##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1465] 28.6 mg (13%) of the title compound as an off white solid was isolated from the above described mixture of diastereomers by LC-2D MS chromatography in acidic mode (formic acid) Method 14. LCMS Method 15 (ES+) RT 5.96 min., 564 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d6) δ 9.42 (m, 1H), 8.89 (m, 2H), 8.44 (m, 1H), 7.93 (m, 1H), 7.68 (m, 1H), 7.38 (m, 2H), 6.39 (m, 1H), 5.17 (m, 1H), 4.97 (m, 1H), 3.59 (m, 1H), 2.87 (m, 1H), 1.55 (s, 6H).

Example 111

[1466] ##STR00293##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1467] 9.8 mg (5%) of the title compound as an off white solid was isolated from the above described mixture of diastereomers by LC-2D MS chromatography in acidic mode (formic acid) Method 14 . LCMS Method 15 (ES+) RT 5.91 min., 564 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d6) δ 9.19 (m, 1H), 9.10 (m, 1H), 8.25 (m, 1H), 7.67 (m, 1H), 7.49 (m, 4H), 6.32 (s, 1H), 5.40 (m, 1H), 4.92 (m, 1H), 3.53 (m, 1H), 2.75 (m, 1H), 1.60 (s, 6H)

Example 112

[1468] ##STR00294##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-3-(trifluoromethyl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1469] 9.8 mg (5%) of the title compound as an off white solid was isolated from the above described mixture of diastereomers by LC-2D MS chromatography in acidic mode (formic acid) Method 14. LCMS Method 15 (ES+) RT 6.07 min., 564 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d6) δ 9.45 (d, J=6.8 Hz, 1H), 8.98 (m, 2H), 8.52 (m, 1H), 7.88 (m, 2H), 7.70 (m, 1H), 7.57 (d, J=6.8 Hz, 1H), 6.42 (m, 1H), 5.17 (m, 1H), 4.97 (m, 1H), 3.52 (m, 1H), 2.86 (m, 1H), 1.56 (s, 6H).

Example 113

[1470] ##STR00295##

2-{5-[(6R,12R)-11-(difluoromethoxy)-3-fluoro-7,12-dihydro-6H-6,12-methanopyrido[1′,2′:1,2]imidazo[4,5-c][1]benzazepin-2-yl]pyrimidin-2-yl}propan-2-ol

[1471] To a solution of Intermediate 157 (69 mg, 0.12 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (0.25 mL, 0.25 mmol) and reaction stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (30 mL) and the organic phase washed with water (2×30 mL), brine (30 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. Crude material was purified by column chromatography (SiO.sub.2, 0-20% MeOH in DCM) and further purified by preparative HPLC-MS to give the title compound as a yellow solid (2 mg, 3.6%).

[1472] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.97 (s, 2H), 8.38 (d, J=7.1 Hz, 1H), 7.38 (d, J=11.0 Hz, 1H), 6.96 (t, J=74.3 Hz, 1H), 6.88 (t,J=8.2 Hz, 1H), 6.33 (dd, J=13.6, 8.3 Hz, 2H), 4.85-4.72 (m, 2H), 2.97-2.88 (m, 1H), 2.21 (d,J=10.3 Hz, 1H), 1.66 (s, 6H)

[1473] LCMS Method 3 (ES+) 468 (M+H).sup.+, RT 1.94 minutes.

[1474] LCMS Method 4 (ES+) 468 (M+H).sup.+, RT 1.76 minutes.

Example 114

[1475] ##STR00296##

(7R,14R)-1-(difluoromethoxy)-11-[2-(cis-1,3-dihydroxy-3-methylcyclobutyl)pyrimidin-5-yl]-6-trideutero-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1476] To a solution of Intermediate 160 (220 mg, 0.34 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (1 mL, 1.0M in THF) and the reaction stirred for 18 hours. Reaction mixture was diluted with DCM (25 mL) and washed with water (3×25 mL), the aqueous was extracted with DCM (3×25 mL), combined organics washed with brine and dried (by passage through a phase separator cartridge) and concentrated in vacuo. The crude material was purified by column chromatography (SiO.sub.2, gradient elution with DCM/MeOH/0.88 aqueous NH.sub.3: 97.5%: 2.25%: 0.25% to 87.5%: 11.25%: 1.25%), to give the title compound (134 mg, 74%) as an off-white solid.

[1477] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.08 (s, 2H), 8.28 (dd, J=5.6, 3.8 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.76 (d, J=1.3 Hz, 1H), 7.69 (t, J=73.6 Hz, 1H), 7.65 (dd, J=8.5, 1.7 Hz, 1H), 7.52-7.48 (m, 2H), 6.32 (d, J=7.1 Hz, 1H), 5.62 (s, 1H), 5.26 (d, J=7.2 Hz, 1H), 4.96 (s, 1H), 3.53 (dt, J=14.2, 7.3 Hz, 1H), 2.95-2.87 (m, 2H), 2.85 (d, J=13.8 Hz, 1H), 2.42 (d, J=13.2 Hz, 2H), 1.09 (s, 3H).

[1478] LCMS: Method 3 (ES+) 537 (M+H).sup.+, RT 1.53 minutes.

[1479] LCMS: Method 4 (ES+) 537 (M+H).sup.+, RT 1.54 minutes.

Example 115

[1480] ##STR00297##

Ethyl (7R,14S)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate

[1481] To a solution of Intermediate 188 (1.57 g, 2.87 mmol) in THF (30 mL) at 0° C. was added potassium bis(trimethylsilyl)amide (4.4 mL, 4.4 mmol) and reaction stirred at 0° C. for 1 hour. The reaction was quenched with water (50 mL) and extracted with EtOAc (4 x 100 mL), the combined organics dried (MgSO.sub.4), filtered and concentrated in vacuo to give an orange oil. Purification by column chromatography (SiO.sub.2, 11-22% EtOAc in DCM) and freeze drying from acetonitrile/water gave the title compound (607 mg, 47%) as an orange solid.

[1482] LCMS: Method 3 (ES+) 451 (M+H).sup.+, RT 2.51 minutes.

[1483] LCMS: Method 4 (ES+) 451 (M+H).sup.+, RT 2.49 minutes.

Example 118

[1484] ##STR00298##

Ethyl (7R,14S)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate

[1485] The title compound was prepared in accordance with the Method described for Example 88 from. Example 115 (200 mg, 0.44 mmol), tris(dibenzylideneacetone)dipalladium(0) (21 mg, 0.022 mmol), tricyclohexylphosphonium tetrafluoroborate (21 mg, 0.055 mmol) and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (190 mg, 0.72 mmol) and K.sub.3PO.sub.4 (282 mg, 1.33 mmol). The crude material was purified by column chromatography (SiO.sub.2, 0-20% MeOH in DCM) and further purified by preparative HPLC to give Example 118 (3 mg, 1.2%) as a white solid.

Example 118

Ethyl (7R,14S)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocine-6-carboxylate

[1486] LCMS: Method 3 (ES+) 553 (M+H).sup.+, RT 2.18 minutes

[1487] LCMS: Method 4 (ES+) 553 (M+H).sup.+, RT 2.18 minutes

Example 119

[1488] ##STR00299##

2-{5-[(5R,7R,14R)-1-(difluoromethoxy)-5-oxido-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1489] The title compound was prepared from Intermediate 163 (45 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (6 mg, 0.0064 mmol), tricyclohexylphosphonium tetrafluoroborate (6 mg, 0.016 mmol) and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (43 mg, 0.16 mmol), K.sub.3PO.sub.4 (64 mg, 0.30 mmol) dissolved in water (40 μL) and 1,4-dioxane (1 mL) by the method of Example 89. The reaction mixture was diluted with water (15 mL) and DCM (50 mL), acidified to pH 4 using acetic acid, layers separated and the aqueous phase extracted with DCM (4×15 mL). The combined organic phases were dried (phase separator) and concentrated in vacuo. The crude material was then dissolved in DMSO (450 μL) and water (50 μL) and lithium chloride (20 mg, 0.47 mmol) added and the reaction mixture heated at 130° C. in a sealed microwave vial for 1.5 hours. The material was purified by preparative HPLC to give the title compound (9 mg, 19%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.03 (s, 2H), 7.82 (d, J=8.5 Hz, 1H), 7.71-7.65 (m, 1H), 7.65-7.58 (m, 2H), 7.57-7.51 (m, 2H), 7.48 (t, J=73.2 Hz, 1H), 6.21 (d, J=8.3 Hz, 1H), 5.07 (s, 1H), 4.01 (t, J=6.7 Hz, 1H), 3.96-3.86 (m, 1H), 3.78 (d, J=12.3 Hz, 1H), 3.41-3.30 (m, 1H), 2.51 (d, J=1.8 Hz, 1H), 1.51 (s, 6H). LCMS: Method 3 (ES+) 497 (M+H).sup.+, RT 1.63 minutes.

[1490] LCMS: Method 4 (ES+) 497 (M+H).sup.+, RT 1.60 minutes

Example 120

[1491] ##STR00300##

2-{5-[(7R,14R)-1-(difluoromethoxy)-5,5-dioxido-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1492] The title compound can be prepared from Intermediate 162, and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester by the Method of Example 89 to provide, after purification by column chromatography (SiO2, 80-100% EtOAc in DCM, followed by 0-10% MeOH in EtOAc), the title compound as a white solid. Note: The ester is observed to decarboxylate during the reaction conditions to provide the desired product. If decarboxylation is not complete it can be further enabled by hydrolysis of the ester to the carboxylic acid followed by acid catalysed decarboxylation. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.05 (s, 2H), 7.94 (dd, J=6.6, 2.5 Hz, 1H), 7.72 (q, J=8.5 Hz, 2H), 7.63 (t, J=72 Hz, 1H), 7.59 (dd, J=8.4, 1.8 Hz, 1H), 7.51 (d, J=1.2 Hz, 2H), 6.34 (d, J=8.5 Hz, 1H), 5.09 (s, 1H), 4.37 (dd, J=14.6, 2.0 Hz, 1H), 4.18-3.95 (m, 2H), 3.56-3.43 (m, 1H), 2.77 (d, J=13.2 Hz, 1H), 1.53 (s, 6H). LCMS: Method 3 (ES+) 513 (M+H).sup.+, RT 1.65 minutes. LCMS: Method 4 (ES+) 513 (M+H).sup.+, RT 1.62 minutes

Example 121

[1493] ##STR00301##

2-{5-[(6R,7R,14S)-1-(difluoromethoxy)-6-(2-hydroxypropan-2-yl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol The title compound was prepared from Intermediate 164 (27 mg, 0.062 mmol), tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.0032 mmol), tricyclohexylphosphonium tetrafluoroborate (2.8 mg, 0.007 mmol) and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (27 mg, 0.10 mmol), K.SUB.3.PO.SUB.4 .(40 mg, 0.19 mmol) suspended in a mixture of water (40 μL) and 1,4-dioxane (220 μL) in accordance with the method of Example 89. The reaction mixture was partitioned between DCM (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL), layers separated and the aqueous phase extracted with DCM (3×10 mL). The combined organic phases were dried (phase separator) and concentrated in vacuo. The crude material was purified by preparative HPLC-MS to give the title compound (2 mg, 6%) as an off-white solid.

[1494] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.96 (s, 2H), 7.80 (d, J=8.5 Hz, 1H), 7.56 (dd, J=8.4, 1.7 Hz, 1H), 7.37 (dd, J=8.9, 1.8 Hz, 2H), 7.32-7.22 (m, 2H), 7.15 (t, J=73.0 Hz, 1H), 6.40 (d, J=8.3 Hz, 1H), 4.36 (d, J=7.4 Hz, 1H), 3.60 (s, 1H), 3.51 (dt, J=12.4, 7.8 Hz, 1H), 3.32 (m, 1H), 2.32 (d, J=12.9 Hz, 1H), 1.62 (s, 6H), 1.52 (s, 3H), 1.50 (s, 3H).

[1495] LCMS: Method 3 (ES+) 539 (M+H).sup.+, RT 2.07 minutes.

[1496] LCMS: Method 4 (ES+) 539 (M+H).sup.+, RT 1.99 minutes.

Example 122

[1497] ##STR00302##

2-{5-[(6S,7R,14S)-1-(difluoromethoxy)-6-(hydroxymethyl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

Example 123

[1498] ##STR00303##

2-{5-[(6R,7R,14S)-1-(difluoromethoxy)-6-(hydroxymethyl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1499] Intermediate 165 (30 mg, 0.07 mmol), 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (33 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium(0) (4 mg, 0.01 mmol), tricyclohexylphosphonium tetrafluoroborate (4 mg, 0.01 mmol) and 1,4-dioxane (0.25 mL) were added to a microwave tube, degassed, then K.sub.3PO.sub.4 (50 mg, 0.23 mmol) dissolved in water (40 μL) was added the mixture deagassed and then heated at 130° C. under nitrogen in the microwave for 2 hours. The reaction mixture was partitioned between water (10 mL) and DCM (10 mL), the layers separated and the aqueous phase extracted with DCM (3×10 mL). The combined organics phases were dried (phase separator) and concentrated in vacuo. Purification by column chromatography (SiO.sub.2, 50-100% EtOAc in hexane, followed by 0-20% MeOH in EtOAc) gave Example 122 (7 mg, 19%) as a white solid and Example 123 (3 mg, 8%) as a white solid.

Example 122

2-{5-[(6S,7R,14S)-1-(difluoromethoxy)-6-(hydroxymethyl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1500] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.00 (s, 2H), 7.77 (d, J=8.4 Hz, 1H), 7.58 (dd, J=8.4, 1.8 Hz, 1H), 7.50 (t, J=73.6 Hz, 1H), 7.40 (d, J=1.3 Hz, 1H), 7.27-7.19 (m, 3H), 6.23 (d, J=8.5 Hz, 1H), 5.29-5.22 (m, 1H), 5.07 (s, 1H), 4.01 (dd, J=7.6, 4.6 Hz, 1H), 3.81 (d, J=5.3 Hz, 1H), 3.66-3.54 (m, 1H), 3.45 (dt, J=9.7, 5.4 Hz, 1H), 3.26-3.13 (m, 1H), 2.53 (d, J=9.6 Hz, 1H), 1.52 (s, 6H).

[1501] LCMS: Method 3 (ES+) 511 (M+H).sup.+, RT 1.81 minutes.

[1502] LCMS: Method 4 (ES+) 511 (M+H).sup.+, RT 1.75 minutes.

Example 123

2-{5-[(6R,7R,14S)-1-(difluoromethoxy)-6-(hydroxymethyl)-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,5]benzothiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1503] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.99 (s, 2H), 7.77 (d, J=8.4 Hz, 1H), 7.57 (dd, J=8.4, 1.8 Hz, 1H), 7.50 (t, J=73.5 Hz, 1H) 7.38 (s, 1H), 7.26 (d, J=4.2 Hz, 3H), 6.26 (d, J=8.5 Hz, 1H), 5.34 (s, 1H), 5.07 (s, 1H), 4.01 (d, J=6.5 Hz, 1H), 3.95-3.86 (m, 1H), 3.87-3.71 (m, 1H), 3.66-3.51 (m, 1H), 3.53-3.39 (m, 1H), 2.35 (d, J=13.2 Hz, 1H), 1.52 (s, 6H).

[1504] LCMS: Method 3 (ES+) 511 (M+H).sup.+, RT 1.84 minutes.

[1505] LCMS: Method 4 (ES+) 511 (M+H).sup.+, RT 1.77 minutes.

Example 124

[1506] ##STR00304##

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1507] Intermediate 166 (750 mg, 1.37 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and cooled to −78° C. under nitrogen. Potassium bis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1 mol/L) was added drop wise at −78° C. and stirred for 30 minutes before the addition of iodotrideuteromethane (0.13 mL, 2.1 mmol). The reaction mixture was stirred for 2 hours with warming to room temperature. 2M HCl (aq) (10 mL) was added and the mixture stirred for 2 hours to remove the trimethylsilyl protecting group. The mixture was treated with 2M NaOH (15 mL) and extracted with EtOAc (50 mL). The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 0 to 10% MeOH in dichloromethane) gave the title compound as a white solid after drying under vacuum (500 mg, 74% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.74 (dd, J=2.4, 0.8 Hz, 1H), 8.34-8.20 (m, 1H), 7.99 (dd, J=8.3, 2.4 Hz, 1H), 7.80-7.68 (m, 3H), 7.67 (t, 1H, JH-F 75 Hz), 7.60-7.46 (m, 3H), 6.29 (d, J=7.0 Hz, 1H), 5.24 (d, J=6.9 Hz, 2H), 3.52 (dt, J=14.1, 7.2 Hz, 1H), 2.83 (d, J=13.8 Hz, 1H), 1.48 (s, 6H). LC/MS Method 3: RT 1.77 minutes, m/z 494.

Example 125

[1508] ##STR00305##

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)-1-oxidopyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1509] Intermediate 166 (240 mg, 0.437 mmol) was dissolved in THF (20 mL) and 2 mL of 2M aqueous HCl added and the mixture was stirred at room temperature for 30 minutes. LCMS shows complete removal of TMS group. The mixture was partitioned between DCM and saturated aqueous sodium carbonate solution and concentrated in vacuo. The residue was redissolved in DCM (10 mL) and mCPBA (103 mg, 0.46 mmol) was added and the mixture stirred for 2 hours. The reaction was washed with 2M sodium hydroxide (10 mL) and the organic layer concentrated in vacuo. The residual solid was purified by chromatography (silica 10 g, 0 to 15% MeOH in DCM gradient) to give the title compound as an off-white solid, (100 mg, 46% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.14 (d, J=6.8 Hz, 1H), 8.54 (t, J=1.1 Hz, 1H), 8.23 (dd, J=6.1, 3.3 Hz, 1H), 7.77-7.68 (m, 4H), 7.66 (t, 1H, JH-F 73.5 Hz) 7.56-7.45 (m, 2H), 7.00 (s, 1H), 6.36 (d, J=7.1 Hz, 1H), 4.89 (m, 1H) 3.49 (dt, J=13.7, 7.0 Hz, 1H), 2.75 (d, J=13.3 Hz, 1H), 1.61 (s, 6H). LC/MS Method 3: RT 1.57 minutes, m/z 493.

Example 126

[1510] ##STR00306##

(7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)-1-oxidopyridin-3-yl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1511] Example 124 (276 mg, 0.56 mmol) was dissolved in dichloromethane (15 mL) and 3-chloroperoxybenzoic acid (1.05 equiv., 0.59 mmol, 77%) was added and the mixture was stirred for 18 hours at room temperature. The mixture was then diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL), and concentrated in vacuo. The residue was purified by chromatography (silica, 0 to 15% methanol gradient in dichloromethane). The product fractions were concentrated in vacuo and the residues freeze dried from acetonitrile/water to give the title compound as a white solid, (165 mg, 58% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.54 (t, J=1.1 Hz, 1H), 8.34-8.18 (m, 1H), 7.97-7.34 (m, 8H), 6.99 (s, 1H), 6.30 (d,J=7.1 Hz, 1H), 5.25 (d, J=7.1 Hz, 1H), 3.52 (dt, J=14.2, 7.3 Hz, 1H), 2.83 (d,J=13.8 Hz, 1H), 1.61 (s, 6H). LC/MS Method 3: RT 1.67 minutes, m/z 510.

Example 127

[1512] ##STR00307##

2-{5-[(6R,12R)-11-(difluoromethoxy)-6H,12H-6,12-methanobenzimidazo[2,1-c][1,4]benzothiazepin-2-yl]pyrimidin-2-yl}propan-2-amine, dihydrochloride salt

[1513] Intermediate 114 (300 mg, 0.95 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.05 equiv., 0.0474 mmol), potassium acetate (4 equiv., 3.80 mmol) and bis(pinacolato)diboron (292 mg, 1.14 mmol) were dissolved in dry dioxane (10 ml) and the mixture heated to reflux for 2 hours. The mixture was partitioned between dichloromethane and water and the organic layer was concentrated in vacuo to give the crude boronate. The intermediate was dissolved in 1,4-dioxane (2.5 ml) and added to a microwave tube containing Example 88 (300 mg, 0.822 mmol), tris(dibenzylideneacetone)-dipalladium(0) (39 mg, 0.041 mmol), tricyclohexylphosphonium tetrafluoroborate (38 mg, 0.1 mmol) and a solution of potassium phosphate (523 mg, 2.47 mmol) in water (0.5 ml). The mixture was degassed and refilled with nitrogen twice then heated to 140° C. in the microwave for 2 hours. After cooling the mixture was partitioned between dichloromethane (50 mL) and water (50 mL) and the organic layer dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, 0 to 100% EtOAc gradient in DCM) to give the BOC protected amine of the title compound as a pale brown solid. The solid was dissolved in 1,4-dioxane (2 mL) and 4.0M HCl in 1,4-dioxane (10 mL) added and the mixture stirred for 2 hours. The solvent was removed in vacuo and the residue partitioned between DCM and water. The aqueous layer was washed with DCM (5 mL) and the aqueous phase was freeze dried to give the title compound as an off-white solid, (330 mg,75% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.20 (s, 2H), 8.89-8.54 (br m, 3H, R-NH.sub.3.sup.+), 7.95-7.66 (m, 3H), 7.58 (dt, JILF =75Hz, 1.8 Hz, 1H), 7.39-7.21 (m, 1H), 6.98 (dd, J=8.1, 2.6 Hz, 2H), 6.14 (d, J=5.2 Hz, 1H), 5.11 (d, J=5.0 Hz, 1H), 3.55-3.43 (m, 1H), 2.73 (d, J=12.3 Hz, 1H), 1.71 (s, 6H). LC/MS Method 3: RT 1.62 minutes, m/z 466.

Example 128

[1514] ##STR00308##

tert-Butyl 3-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyridin-2-yl}-3-hydroxypyrrolidine-1-carboxylate

[1515] To a mixture of Intermediate 159 (200 mg, 0.41 mmol), tris(dibenzylideneacetone) dipalladium(0) (19 mg, 0.021 mmol), tricyclohexylphosphonium tetrafluoroborate (16 mg, 0.041 mmol) and Intermediate 167 (170 mg, 0.50 mmol) in 1,4-dioxane (1.5 mL) was added a solution of potassium phosphate tribasic (271 mg, 1.24 mmol) in water (0.15 mL). The reaction mixture was heated at 110° C. in the microwave for 3 hours. cooled, partitioned between EtOAc (100 mL) and water (100 mL) and the organic layer dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, 100% EtOAc then to 7% MeOH in EtOAc gradient) to give the title compound as a white solid (128 mg, 50% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.79 (s, 1H), 8.27 (dd, J=5.8, 3.6 Hz, 1H), 8.05 (dd, J=8.2, 2.4 Hz, 1H), 7.85-7.68 (m, 3H), 7.67 (t, JILF=73.4Hz, 1H), 7.60-7.45 (m, 3H), 6.30 (d, J=7.0 Hz, 1H), 5.71 (s, 1H), 5.24 (d, J=7.1 Hz, 1H), 3.72 (t, J=10.6 Hz, 1H), 3.64-3.38 (m, 2H), 2.83 (d, J=13.7 Hz, 1H), 1.76 (s, 2H), 1.40 (9H, s), 1.33-1.06 (m, 2H). LC/MS Method 3: RT 2.18 minutes, m/z 621.

Example 129

[1516] ##STR00309##

(7R,14R)-1-(difluoromethoxy)-11-[6-(3-hydroxypyrrolidin-3-yppyridin-3-yl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one, dihydrochloride salt

[1517] Example 128 (120 mg, 0.193 mmol) was dissolved in 1,4-dioxane (5 mL) and 4M HCl in 1,4-dioxane (5 mL) added and the mixture stirred at room temperature for 1 hour. After removing the solvent in vacuo the residue was treated with diethyl ether (5 mL) and isohexanes (5 mL). The resultant solid was filtered off, washed with diethyl ether (10 mL) and dried under high vacuum for 1 hour to give the title compound as an off-white solid (88 mg, 72%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.56 (s, 1H), 9.41 (s, 1H), 8.88-8.76 (m, 1H), 8.28 (dd, J=6.0, 3.4 Hz, 1H), 8.21-8.04 (m, 1H), 7.98-7.32 (m, 4H), 7.68 (t, J.sub.H-F=73.5 Hz, 1H) 6.34 (d, J=7.0 Hz, 1H), 5.31 (d, J=7.1 Hz, 1H), 3.76-3.27 (m, 4H), 2.87 (d, J=13.8 Hz, 1H), 2.40 (t, J=11.1 Hz, 1H), 2.28-2.22 (m, 1H), 1.89-1.83 (m, 1H). LC/MS Method 3: RT 1.32 minutes, m/z 521.

Example 130

[1518] ##STR00310##

Methyl (2-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl)carbamate

[1519] Intermediate 168 (226 mg, 0.826 mmol) and Intermediate 159 (200 mg, 0.4130 mmol) were coupled in accordance with the method of Example 128. Purification by chromatography (silica, 0 to 10% MeOH in DCM) and freeze drying of the residue gave the title compound as a white solid (197 mg, 87% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.01 (s, 2H), 8.37-8.19 (m, 1H), 7.81-7.71 (m, 2H), 7.68 (dd, J.sub.H-F=72.6, 73.8 Hz, 1H), 7.62 (dd, J=8.5, 1.8 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J=4.9 Hz, 2H), 6.31 (d, J=7.1 Hz, 1H), 5.25 (d, J=7.1 Hz, 1H), 3.56-3.47 (m, 1H), 3.44 (s, 3H), 2.84 (d, J=13.8 Hz, 1H), 1.61 (s, 6H). LC/MS Method 3: RT 1.95 minutes, m/z 552.

Example 131

[1520] ##STR00311##

(7R,14R)-1-(difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)-4-methylpyrimidin-5-yl]-6-trideutero-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1521] The title compound was synthesised from Intermediate 110 (400 mg, 1.018 mmol) and Intermediate 62 (1.2 equivalents) in accordance with the Method described for Example 128. Purification by column chromatography (silica, DCM/EtOAc gradient) gave the desired product as a white solid.

[1522] .sup.1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.28 (dt, J=8.3, 4.2 Hz, 1H), 7.86-7.24 (m, 6H), 6.27 (d, J=7.1 Hz, 1H), 5.25 (d, J=7.1 Hz, 1H), 5.06 (s, 1H), 3.61-3.40 (m, 1H), 2.83 (d, J=13.8 Hz, 1H), 2.45 (s, 3H), 1.53 (s, 6H). LC/MS: Method 3 ESI MH.sup.+ 509, retention time 1.85 minutes.

Example 132

[1523] ##STR00312##

(7R,14R)-11-chloro-1-(difluoromethoxy)-5-methylidene-5,14-dihydro-7H-7,14-methanobenzimidazo[2,1-d][2,5]benzoxazo eine

[1524] Intermediate 169 (37.0 mg, 0.08 mmol) was dissolved in THF (2 mL), and sodium hydride (20.0 mg, 0.83 mmol) was added at 0° C. and the mixture was stirred for 1 hour. Water was added to quench the reaction and the mixture was partitioned between water and DCM (2×10 mL). The organics were combined, dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by preparative HPLC-MS to give the O-alkylated product (3.5 mg, 12%).

[1525] .sup.1H NMR (300 MHz, DMSO-d6) δ 7.78-7.65 (m, 2H), 7.53-7.14 (m, 5H), 6.19 (d, J=7.1 Hz, 1H), 5.68 (d, J=4.1 Hz, 1H), 4.73 (dd, J=13.8, 0.9 Hz, 2H), 3.27-3.13 (m, 1H), 2.79 (d, J=13.7 Hz, 1H). LC/MS: Method 3 ESI MH.sup.-1 375, retention time 2.36 minutes.

Example 133

[1526] ##STR00313##

(7R,14R)-1-(difluoromethoxy)-11-{2-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]-4-methyl pyrimidin-5-yl}-6-trideutero-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(1411)-one

[1527] A mixture of Intermediate 133 (600 mg, 0.84 mmol), Intermediate 110 (314 mg, 0.80 mmol), K.sub.3PO.sub.4 (594 mg, 2.80 mmol), tricyclohexylphosphonium tetrafluoroborate (37 mg, 0.1 mmol) and tris(dibenzylideneacetone)dipalladium(0) (90 mg, 0.1 mmol) were suspended in a mixture of 1,4-dioxane (5 mL) and water (0.4 mL). The mixture was degassed and purged with N.sub.2 before heating in a microwave at 140° C. for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc (3×10 mL). The combined organic phases were dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-10% MeOH in DCM) to give the title compound (200 mg, 42%). .sup.1H NMR (400 MHz, DMSO-d6) δ 8.28 (dd, J=7.5, 2.0 Hz, 1H), 8.21 (s, 1H), 7.80-7.31 (m, 6H), 7.20 (dd, J=8.4, 1.7 Hz, 1H), 6.25 (d, J=7.1 Hz, 1H), 5.24 (d, J=7.1 Hz, 1H), 4.31 (d, J=10.1 Hz, 2H), 4.09 (d, J=10.1 Hz, 2H), 3.52 (dt, J=14.1, 7.3 Hz, 1H), 2.82 (d, J=13.7 Hz, 1H), 2.29 (s, 3H).

[1528] LC/MS: Method 3 ESI MH.sup.-1590, retention time 1.97 minutes.

Example 134

[1529] ##STR00314##

(7R,14R)-1-(difluoromethoxy)-11-[6-(piperazin-1-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1530] A mixture of 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (277 mg, 0.96 mmol), Example 11 (300 mg, 0.79 mmol), K.sub.3PO.sub.4 (600 mg, 2.83 mmol), tricyclohexylphosphonium tetrafluoroborate (37 mg, 0.1 mmol) were suspended in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL). The mixture was degassed and purged with N.sub.2 before the addition of tris(dibenzylideneacetone) dipalladium(0) (75 mg, 0.08 mmol). The mixture was degassed for 10 minutes before heating in a microwave at 105° C. for 1 hour. The reaction mixture was quenched with water and extracted with EtOAc (3×10 mL). The aqueous phase was basified with saturated aqueous NaHCO.sub.3 solution and extracted with DCM (3×10 mL). The organics were combined, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-30% MeOH in DCM) to give the title compound (57 mg, 14%). The HCl salt was prepared by addition of 2 equivalents of HCl followed by freeze-drying. .sup.1H NMR (300 MHz, Deuterium Oxide) δ 8.13 (dd, J=7.2, 2.3 Hz, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.85 (dd, J=9.2, 2.4 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.48-7.27 (m, 3H), 7.00 (d, J=9.4 Hz, 2H), 6.54 (d, J=7.1 Hz, 1H), 5.17 (d, J=6.6 Hz, 1H), 3.82 (t, J=5.4 Hz, 4H), 3.56-3.34 (m, 5H), 2.90 (d, J=13.8 Hz, 1H). LC/MS: Method 3 ESI MH.sup.+503, retention time 1.41 minutes.

Example 135

[1531] ##STR00315##

(7R,14R)-1-(difluoromethoxy)-6-trideutero-methyl-11-[6-(piperazin-1-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1532] A mixture of 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (277 mg, 0.96 mmol), Intermediate 110 (300 mg, 0.80 mmol), K.sub.3PO.sub.4 (600 mg, 2.83 mmol), tricyclohexylphosphonium tetrafluoroborate (37.0 mg, 0.1 mmol) were suspended in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL). The mixture was degassed and purged with N.sub.2 before the addition of tris(dibenzylideneacetone) dipalladium(0) (75 mg, 0.08 mmol). The mixture was degassed for 10 min before heating in a microwave at 105° C. for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted with EtOAc (3×10 mL). The combined organic phases were acidified with aqueous HCl (2N), extracted with water (3×10 mL), and the aqueous phase neutralised with NaOH solution (10%) and extracted with DCM (3×10 mL). The organics were combined, dried (MgSO.sub.4), filtered and concentrated in vacuo to give the title compound (170 mg, 43%). .sup.1H NMR (300 MHz, DMSO-d6) 6 8.38 (d, J=2.6 Hz, 1H), 8.33-8.22 (m, 1H), 7.94-7.36 (m, 7H), 6.88 (d, J=8.7 Hz, 1H), 6.27 (d, J=7.0 Hz, 1H), 5.21 (d, J=7.1 Hz, 1H), 3.60-3.39 (m, 5H), 2.88-2.68 (m, 5H). LC/MS: Method 3 ESI MH.sup.+520, retention time 1.45 minutes.

Example 136

[1533] ##STR00316##

(7R,14R)-1-(difluoromethoxy)-6-trideutero-methyl-11-{6-[4-(methylsulfonyl)piperazin-1 yl]pyridine-3-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1534] Example 135 (80 mg, 0.15 mmol) was dissolved in DCM (5 mL) and N,N-diisopropylethylamine (55 μL, 0.31 mmol) was added to the mixture at 0° C. The mixture was stirred for 5 minutes before the addition of methanesulfonyl chloride (18 μL, 0.23 mmol). The mixture was stirred at 0° C. for 1 hour before the completion of the reaction. The mixture was quenched with saturated NH.sub.4Cl solution and extracted with DCM (3×10 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC-MS to give the title compound (30 mg, 32%). .sup.1H NMR (300 MHz, DMSO-d6) δ 8.42 (d, J=2.5 Hz, 1H), 8.27 (dd, J=6.0, 3.5 Hz, 1H), 7.97-7.39 (m, 7H), 7.01 (d, J=8.9 Hz, 1H), 6.27 (d, J=7.0 Hz, 1H), 5.22 (d, J=7.1 Hz, 1H), 3.69 (t, J=5.1 Hz, 4H), 3.50 (dt, J=14.2, 7.3 Hz, 1H), 3.21 (t, J=5.1 Hz, 4H), 2.91 (s, 3H), 2.81 (d, J=13.8 Hz, 1H). LC/MS: Method 3 ESI MH.sup.+598, retention time 1.95 minutes.

Example 137

[1535] ##STR00317##

(7R,14R)-1-(difluoromethoxy)-11-{2-2-(dimethylamino)propan-2-yl]pyrimidin-5-yl}-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1536] A solution of Intermediate 171 (175 mg, 0.37 mmol) in 1,4-dioxane (2 mL) was added to a mixture of Intermediate 170 (120 mg, 0.49 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane complex (16.0 mg, 0.0196 mmol), potassium phosphate tribasic (240 mg, 1.11 mmol) in 1,4-dioxane (2 mL) and water (0.3 mL). The mixture was degassed and purged with N.sub.2 before heating at 110° C. for 2 hours. The reaction mixture was quenched with saturated aqueous NaHCO.sub.3 solution and extracted with EtOAc (3×10 mL). The organics were combined, dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product purified by column chromatography (0-40% MeOH in DCM (1% Et.sub.3N)) to give the title compound (18 mg, 9%). .sup.1H NMR (300 MHz, DMSO-d6) δ 9.16 (d, J=6.9 Hz, 1H), 9.05 (s, 2H), 8.23 (dd, J=6.3, 3.1 Hz, 1H), 8.03-7.37 (m, 6H), 6.37 (d, J=7.0 Hz, 1H), 4.90 (t, J=6.7 Hz, 1H), 3.59-3.39 (m, 1H), 2.75 (d, J=13.5 Hz, 1H), 2.13 (s, 6H), 1.51 (s, 6H). LC/MS: Method 3 ESI MH.sup.+505, retention time 1.44 minutes.

Example 138

[1537] ##STR00318##

(7R,14R)-1-(difluoromethoxy)-11-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1538] A mixture of [2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]boronic acid (310 mg, 1.40 mmol), Example 11 (350 mg, 0.93 mmol), K.sub.3PO.sub.4 (592 mg, 2.80 mmol), tricyclohexylphosphonium tetrafluoroborate (36 mg, 0.1 mmol) and tris(dibenzylideneacetone) dipalladium(0) (85 mg, 0.1 mmol) were suspended in a mixture of 1,4-dioxane (10 mL) and water (0.5 mL). The mixture was degassed and purged with N.sub.2 before heating in an oil bath at 105° C. for 16 hours. The reaction mixture was quenched with water and extracted with EtOAc (3×10 mL), and the combined organics were dried (MgSO.sub.4), filtered and concentrated in vacuo. Purification by column chromatography (0%-10% MeOH in DCM) afforded the title compound (130 mg, 27%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.12 (d, J=6.8 Hz, 1H), 8.69 (s, 2H), 8.29-8.16 (m, 1H), 8.11 (s, 1H), 7.74-7.63 (m, 2H), 7.60 (dd, J=1.8, 0.7 Hz, 1H), 7.55-7.39 (m, 3H), 6.33 (d, J=7.0 Hz, 1H), 4.87 (t, J=6.7 Hz, 2H), 4.23 (s, 2H), 3.96 (t, J=5.4 Hz, 2H), 3.47 (dt, J=13.5, 6.9 Hz, 2H), 2.73 (d, J=13.3 Hz, 1H).LC/MS: Method 3 ESI MH.sup.+518, retention time 1.54 minutes.

Example 139

[1539] ##STR00319##

1-[(6R,12R)-11-(difluoromethoxy)-2-(1-methyl-1H-pyrazol-4-yl)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]-2-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)ethanone

[1540] The title compound was prepared from 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and Preparative Example 40 in accordance with the Method described for Example 20 to give, following purification by preparative HPLC a white solid (2 mg, 4% yield). LC/MS: Method 3 RT 1.72 mins, [M+H].sup.+=563. .sup.1H NMR (300 MHz, Methanol-d4) δ 8.19 (d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.70-7.55 (m, 2H), 7.49-7.42 (m, 1H), 7.25 (t, J=8.5 Hz, 1H), 7.13 (t, J=73.5 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.35 (d, J=4.0 Hz, 1H), 6.14 (d, J=4.4 Hz, 1H), 4.37 (s, 2H), 4.24 (d, J=11.6 Hz, 2H), 4.11 (d, J=11.5 Hz, 2H), 3.95 (s, 3H), 3.86 (dd, J=11.5, 6.7 Hz, 4H), 3.29-3.20 (m, 1H), 2.76-2.62 (m, 3H).

Example 140

[1541] ##STR00320##

(6R,12R)-2-chloro-11-(difluoromethoxy)-7-[(6-methoxypyridin-3-yl)sulfonyl]-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine

[1542] To Intermediate 172 (630 mg, 1.050 mmol) was added anhydrous cesium acetate (2000 mg, 10.41 mmol), cuprous iodide (510 mg, 2.62 mmol) and dimethyl sulfoxide (1.0 mL). The mixture was sealed and purged 3 times with nitrogen. The reaction mixture was stirred for 45 minutes at 160° C. The reaction mixture was cooled at room temperature the solid was filtered and the filtrate was evaporated under vacuum. The crude material was purified by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) as eluent, yielding 133 mg (25% yield) of the title compound as a brown solid. LCMS Method 3: RT 2.07 min, [M+H.sup.+=519.6 δ .sup.1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J=2.5 Hz, 1H), 8.39 (dd, J=8.9, 2.7 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.49-7.41 (m, 2H), 7.40 (t, J=73.3 Hz, 1H). 7.27 (t, J=8.5 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H). 6.99-6.92 (m, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.28 (d, J=3.7 Hz, 1H), 6.04 (d, J=4.5 Hz, 1H), 3.89 (s, 3H), 3.23-3.13 (m, 1H), 2.54 (d, J=11.9 Hz, 1H).

Example 141

[1543] ##STR00321##

5-{[(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepin-7(12H)-yl]sulfonyl}pyridin-2(1H)-one

[1544] To a solution of Example 140 (120 mg, 0.23 mmol) in acetonitrile (3.4 mL) was added chloromethyltrimethylsilane (0.15 mL, 1.2 mmol) in acetonitrile (3.4 mL) and potassium iodide (195 mg, 1.17 mmol) and the reaction mixture heated at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue diluted with EtOAc, washed with water and Na.sub.2S.sub.2O.sub.3 10% aq. solution. The combined organic layers were washed with brine and filtered through a phase separator and evaporated under vacuum. The crude material was purified by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) as eluent, yielding 106 mg (91% yield) of the title compound as a pale brown solid. LCMS Method 3: RT 2.06 min, [M−H].sup.+=503/505. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (300 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.72-7.62 (m, 1H), 7.50-7.37 (m, 2H), 7.41 (t, J=73.3 Hz, 1H), 7.33-7.13 (m, 2H), 6.89 (d, J=8.0 Hz, 1H), 6.28 (d, J=9.7 Hz, 1H), 6.16 (d, J=3.7 Hz, 1H), 6.03 (d, J=4.3 Hz, 1H), 3.17 (d, J=12.4 Hz, 1H), 2.56 (d, J=12.4 Hz, 1H).

Example 142

[1545] ##STR00322##

2-{5-[(7R,14R)-1-(difluoromethoxy)-5,5-dioxido-6,7-dihydro-14H-7,14-methanobenzimidazo[2,1-d][1,2,5]benzothiadiazocin-11-yl]pyrimidin-2-yl}propan-2-ol

[1546] To a solution of Intermediate 175 (10 mg, 0.024 mmol) in 1,4-dioxane (0.1 mL), 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (9.6 mg, 0.036 mmol), potassium phosphate, (13 mg, 0.061 mmol), tris(dibenzylideneacetone)dipalladium (O) (1.2 mg, 0.0013 mmol), tricyclohexylphosphonium trifluoroborate (1.1 mg, 0.003 mmol) and water (10 μL) were added. The reaction mixture was de-gassed and stirred at 140° C. for 5 hours in the microwave. The reaction mixture was filtered through a pad of Celite and the residue washed successively with EtOAc, and 20% MeOH in DCM. The filtrate was evaporated under vacuum and the crude material was purified by preparative HPLC-MS (pH 10) yielding 1.2 mg (16% yield) of the title compound as a white solid. LCMS Method 3: RT 1.42 min, [M−H].sup.+=514. .sup.1H NMR (400 MHz, Methanol-d4) δ 9.03 (s, 2H), 7.89 (dd, J=6.9, 2.2 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.67-7.55 (m, 3H), 7.30 (t, J=72.8 Hz, 1H), 6.60 (d, J=7.8 Hz, 1H), 5.02 (d, J=4.9 Hz, 1H), 3.44 (ddd, J=13.2, 7.8, 5.0 Hz, 1H), 3.07 (d, J=13.6 Hz, 1H), 1.64 (s, 6H). (OH and NH signals are missing).

Example 143

[1547] ##STR00323##

(7R,14R)-1-(difluoromethoxy)-11-[2-methyl-4-(methylsulfanyl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1548] To a solution of 4-bromo-3-methylthioanisole (500 mg, 2.23 mmol), in 1,4-dioxane (8 mL), bis(pinacolato)diboron (1.2 g, 4.46 mmol) potassium acetate (885 mg, 8.92 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethanecomplex (92 mg, 0.11 mmol) were added and the solution was degassed and heated at 100° C., using a preheated oil bath, for 1 hour. The reaction was quenched by the addition of water and the mixture extracted with EtOAc (×3). The combined organic layers were filtered through a phase separator and the solvent was evaporated to give 590 mg (99%) of 4,4,5,5-tetramethyl-2-(2-methyl-4-methylsulfanyl-phenyl)-1,3,2-dioxaborolane which was used in the next step without further purification. LCMS (ES+) Method 3: 265 (M+H).sup.+, RT 1.70 minutes.

[1549] To a solution of 4,4,5,5-tetramethyl-2-(2-methyl-4-methylsulfanyl-phenyl)-1,3,2-dioxaborolane (590 mg, 2.23 mmol) in 1,4-dioxane (3.8 mL) were added Example 11 (400 mg, 1.06 mmol), potassium phosphate (567 mg, 2.67 mmol), tricyclohexylphosphonium tetrafluoroborate (52 mg, 0.138 mmol) and tris(dibenzylideneacetone)dipalladium (0) (108 mg, 0.114 mmol). The reaction mixture was degassed for 10 mins before heating to 140° C. degree in a microwave for 2 hours. The reaction was quenched with water and extracted with EtOAc (×3). The combined organic layers were filtered through a phase separator and the solvent was evaporated to give a crude residue. Purification by column chromatography on silica eluting with EtOAc: MeOH (0 to 20%) gave the title compound (80 mg) as a white solid. LCMS (ES+) Method 3: 478 (M+H).sup.+, RT 2.42 minutes. .sup.1H NMR (300 MHz, DMSO-d6) δ 9.14 (d, J=6.8 Hz, 1H), 8.24 (dd, J=5.8, 3.6 Hz, 1H), 7.63 (dd, J=8.4, 0.7 Hz, 1H), 7.55-7.49 (m, 2H), 7.48 (t, J=83.2 Hz, 1H).7.37 (dd, J=1.7, 0.7 Hz, 1H), 7.23-7.08 (m, 4H), 6.29 (d, J=7.0 Hz, 1H), 4.87 (t, J=6.7 Hz, 1H), 3.48 (dt, J=13.5, 7.0 Hz, 1H), 2.72 (d, J=13.3 Hz, 1H), 2.5 (s, 3H), 2.19 (d, J=0.6 Hz, 3H).

Example 144

[1550] ##STR00324##

(7R,14R)-1-(difluoromethoxy)-11-[2-(morpholin-4-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1551] The title compound was prepared from Example 11 (450 mg, 1.20 mmol) and 2-morpholinopyrimidin-5-yl)boronic acid (380 mg, 1.82 mmol) in accordance with the Method described for Example 20 to give, following purification by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) then DCM:MeOH (0 to 20%) as eluent, the title compound (300 mg, 50% yield) as a pale yellow solid. LCMS (ES+) Method 3: 505 (M+H).sup.+, RT 1.89 minutes. .sup.1H NMR (300 MHz, DMSO-d6) δ 9.12 (d, J=6.7 Hz, 1H), 8.66 (s, 2H), 8.22 (t, J=4.7 Hz, 1H), 7.68 (d, J=2.7 Hz, 1H), 7.65 (t, J=79.0 Hz, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.54-7.40 (m, 3H), 6.33 (d, J=7.1 Hz, 1H), 4.87 (t, J=6.7 Hz, 1H), 3.80-3.65 (m, 8H), 3.58-3.39 (m, 1H), 2.73 (d, J=13.3 Hz, 1H).

Example 145

[1552] ##STR00325##

(6R,12R)-2-chloro-11-(difluoromethoxy)-7-(pyrimidin-2-yl)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiaz epine

[1553] To Intermediate 176 (200 mg, 0.39 mmol) was added cesium acetate anhydrous (600 mg, 3.12 mmol), cuprous iodide (192 mg, 1.0 mmol) and dimethyl sulfoxide (0.4 mL). The mixture was sealed and purged 3 times with nitrogen. The reaction mixture was stirred for 45 minutes at 160° C. The reaction mixture was cooled to room temperature the solid was filtered and the filtrate was evaporated under vacuum. The crude material was purified by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) as eluent, followed by a second purification by preparative HPLC, yielding 2 mg (1% yield) of the title compound as a white solid. LCMS Method 3: RT 2.37 min, [M+H].sup.+=426. .sup.1H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J=4.8 Hz, 2H), 8.00 (d, J=8.7 Hz, 1H), 7.59-7.43 (m, 2H), 7.42 (t, J=73.7 Hz, 1H), 7.28-7.11 (m, 3H), 6.82 (d, J=8.3 Hz, 1H), 6.66 (s, 1H), 6.08 (d, J=4.3 Hz, 1H), 3.17 (d, J=11.9 Hz, 1H), 2.60 (d, J=12.0 Hz, 1H).

Example 146

[1554] ##STR00326##

Ethyl-(6R,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine-7(12H)-carboxylate

[1555] To Intermediate 177 (260 mg, 0.52 mmol) was added sodium acetate (167 mg, 2.04 mmol), cuprous iodide (101 mg, 0.52 mmol) and dimethyl sulfoxide (6.4 mL). The mixture was sealed and purged 3 times with nitrogen. The reaction mixture was stirred overnight at 100° C. Additional sodium acetate (167 mg, 2.03 mmol) and cuprous iodide (101 mg, 0.52 mmol) were added and the reaction was stirred at 160° C. for 1 hour. The reaction mixture was cooled to room temperature, the solid was filtered and the filtrate was evaporated under vacuum. The crude material was purified by column chromatography over silica gel using hexane/ethyl acetate (0 to 100%) as eluent, followed by a second purification by preparative HPLC, yielding 12 mg (6% yield) of the title compound as a white solid. LCMS Method 3: RT 2.47 min, [M+H].sup.+=420/422. .sup.1H NMR (300 MHz, DMSO-d6) δ 8.02 (d, J=8.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.42 (t, J=73.5 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 7.19 (dd, J=8.7, 2.1 Hz, 1H), 6.90 (dd, J=8.4, 1.0 Hz, 1H), 6.04 (m, 2H), 4.38-4.23 (m, 2H), 3.10 (dt, J=12.1, 4.4 Hz, 1H), 2.56 (d, J=12.1 Hz, 1H), 1.38 (t, J=7.1 Hz, 3H).

Example 147

[1556] ##STR00327##

Ethyl-(6R,12R)-11-(difluoromethoxy)-2-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine-7(12H)-carboxylate

[1557] The title compound was prepared from 2-(1-hydroxy-1-methtylethyl) pyrimidine-5-boronic acid pinacol ester, and Example 146 in accordance with the Method for Example 20 to give, following purification by preparative HPLC a white solid (1.2 mg, 8% yield).

[1558] LC/MS Method 3: RT 2.18 mins, [M+H].sup.+=522

[1559] .sup.1H NMR (300 MHz, Methanol-d4) δ 9.05 (s, 2H), 8.17 (d, J=8.7 Hz, 1H), 7.87-7.73 (m, 2H), 7.58 (dd, J=8.5, 1.7 Hz, 1H), 7.25 (t, J=8.5 Hz, 1H), 7.14 (t, J=73.3 Hz, 1H), 6.93-6.84 (m, 1H), 6.20 (d, J=4.3 Hz, 2H), 4.43 (m, 2H), 3.20 (dt, J=12.1, 4.4 Hz, 1H), 2.65 (d, J=12.0 Hz, 1H), 1.65 (s, 6H), 1.49 (t, J=7.1 Hz, 3H).

Example 148

[1560] ##STR00328##

N-(1-{5-[(7 R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyridin-2-yl}cyclobutyl)-2-methylpropane-2-sulfinamide

[1561] The title compound was prepared from Intermediate 178 (300 mg, 0.91 mmol) and Intermediate 159 (751 mg, 1.09 mmol) in accordance with the Method described for Example 20 to give, following purification by column chromatography in silica gel (Hexane: EtOAc (from 0 to 100%) then DCM :MeOH(from 0 to 15%) a yellow solid (600 mg, 98% yield). LC/MS Method 3: RT 2.03 minutes, [M+H].sup.+=609.

[1562] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.32-8.25 (m, 1H), 8.01 (d, J=6.3 Hz, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.76 (t, J=73.6 Hz, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 1H), 7.53-7.44 (m, 2H), 6.31 (d, J=6.9 Hz, 1H), 5.91 (s, 1H), 3.56-3.50 (m, 1H), 2.84 (d, J=13.9 Hz, 1H), 2.41-2.45 (m, 2H), 1.75-1.8 (m, 2H), 1.97-2.03 (m, 2H), 1.15 (s, 9H).

Example 149

[1563] ##STR00329##

(7R,14R)-11-[6-(1-aminocyclobutyl)pyridin-3-yl]-1-(difluoromethoxy)-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1564] Example 148 (600 mg, 0.89 mmol) was dissolved in methanol (4.5 mL) and HCl 4N in dioxane (0.50 mL, 2.0 mmol) was added at room temperature, the reaction was stirred for 5 hours. The solvent was evaporated and the crude mixture was dissolved in water and DCM. The aqueous layer was extracted with dichloromethane (×2) and then freeze dried to give the title compound as an HCl salt and a white solid (460 mg, 99% yield). LC/MS Method 3: RT 1.65 minutes, [M+H].sup.+=505..sup.1H NMR (300 MHz, DMSO-d.sup.6) δ 8.91 (dd, J=2.4, 0.8 Hz, 1H), 8.89 (bs, 3H, NH.sub.3.sup.+), 8.34-8.15 (m, 2H), 7.96-7.76 (m, 3H), 7.73-7.63 (m, 1H), 7.69 (t, J=73.3 Hz, 1H), 7.53-7.49 (m, 2H), 6.36 (d, J=7.1 Hz, 1H), 5.34 (d, J=7.1 Hz, 1H), 3.56 (dt, J=14.2, 7.3 Hz, 1H), 2.88 (d, J=13.8 Hz, 1H), 2.63 (q, J=7.3 Hz, 2H), 2.35-2.12 (m, 2H), 2.11-1.93 (m, 2H).

Example 150

[1565] ##STR00330##

N-(3-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyridin-2-yl}oxetan-3-yl)-2-methylpropane-2-sulfinamide

[1566] The title compound was prepared from Intermediate 159 (890 mg, 1.65 mmol), and Intermediate 179 (500 mg, 1.5 mmol) in accordance with the method described for Example 20 to give, following purification by column chromatography in silica gel (hexanes: EtOAc from 0 to 100% then DCM :MeOH from 0 to 15%), a yellow solid (750 mg, 82%). LC/MS Method 3: RT 1.82 minutes, [M+H].sup.+=611. .sup.1H NMR (300 MHz, DMSO-d.sup.6) δ 8.88 (d, J=2.3 Hz, 1H), 8.34-8.22 (m, 1H), 8.08 (dd, J=8.3, 2.4 Hz, 1H), 7.76 (dd, J=5.1, 3.3 Hz, 2H), 7.70-7.63 (m, 1H), 7.67 (t, J=73.3 Hz, 1H), 7.59 (dd, J=8.6, 1.7 Hz, 1H), 7.49 (d, J=5.0 Hz, 2H), 6.48 (s, 1H), 6.31 (d, J=7.1 Hz, 1H), 5.24 (d, J=7.1 Hz, 1H), 5.17 (d, J=6.1 Hz, 1H), 5.04-4.75 (m, 3H), 3.53 (dt, J=14.3, 7.4 Hz, 1H), 2.83 (d, J=13.8 Hz, 1H), 1.17 (d, J=1.2 Hz, 9H).

Example 151

[1567] ##STR00331##

(7R,14R)-11-[6-(3-aminooxetan-3-yl)pyridin-3-yl]-1-(difluoromethoxy)-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1568] Example 150 (249 mg, 0.4077 mmol) was dissolved in methanol (8 mL) and HCl 4N in dioxane (0.2 mL, 0.8 mmol) was added at 0° C. and the reaction was kept in the fridge overnight. A saturated aqueous solution of NaHCO.sub.3 was added at 0° C. and the reaction mixture was extracted with EtOAc. The combined organic layers were filtered through a phase separator and the solvent was evaporated to give the title compound (120 mg, 58%) as a pale brown solid. LC/MS Method 3: RT 1.49 mins, [M+H].sup.+=507. .sup.1H 1H NMR (300 MHz, DMSO-d6) δ 8.85 (dd, J=2.4, 0.8 Hz, 1H), 8.34-8.21 (m, 1H), 8.05 (dd, J=8.3, 2.5 Hz, 1H), 7.80-7.71 (m, 3H), 7.67 (t, J=73.3 Hz, 1H), 7.61-7.44 (m, 3H), 6.30 (d, J=7.1 Hz, 1H), 5.24 (d, J=7.0 Hz, 1H), 4.93 (d, J=5.6 Hz, 2H), 4.59 (d, J=5.6 Hz, 2H), 3.60-3.44 (m, 1H), 2.83 (d, J=13.8 Hz, 1H).

Example 152

[1569] ##STR00332##

N-(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]pyridin-2-yl}oxetan-3-yl)-2-methylpropane-2-sulfinamide

[1570] The title compound was obtained as a by-product of the preparation of Example 150.

[1571] LC/MS: RT 1.75 mins (pH 10), [M+H].sup.+=594.

[1572] .sup.1H NMR 1H NMR (300 MHz, DMSO-d6) δ 9.14 (d, J=6.9 Hz, 1H), 8.88 (s, 1H), 8.22 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.78-7.63 (m, 2H), 7.69 (t, J=73.3 Hz, 1H), 7.62-7.40 (m, 2H), 6.47 (s, 1H), 6.37 (d, J=6.9 Hz, 1H), 5.17 (d, J=6.3 Hz, 1H), 4.93-4.81 (m, 4H), 3.28 (s, 2H), 3.56 (m, 1H), 2.75 (d, J=13.2 Hz, 1H), 1.17 (s, 9H).

Example 153

[1573] ##STR00333##

N-(3-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]-1-oxidopyridin-2-yl}oxetan-3-yl)-2-methylpropane-2-sulfonamide

[1574] To a solution of Example 152 (18 mg, 0.03 mmol) in dichloromethane (0.3 mL), 3-chloroperoxybenzoic acid (5.2 mg, 0.03 mmol) was added and the reaction was stirred overnight. More 3-chloroperoxybenzoic acid (10.4 mg, 0.060 mmol) was added and the reaction mixture was stirred for 48 hours. The reaction mixture was directly purified by column chromatography on silica gel (hexanes: EtOAc from 0 to 100% then DCM :MeOH from 0 to 15% to give the title compound as a white solid (12 mg, 63% yield). LC/MS Method 3: RT 1.78 mins, [M+H].sup.+=626. .sup.1H NMR (300 MHz, DMSO-d6) δ 9.16 (d, J=6.8 Hz, 1H), 8.57 (s, 1H), 8.27-8.18 (m, 1H), 7.89 (d, J=13.7 Hz, 1H), 7.77-7.64 (m, 3H), 7.67 (t, J=73.3 Hz, 1H), 7.63-7.46 (m, 2H), 6.36 (d, J=7.0 Hz, 1H), 5.02-4.88 (m, 2H), 4.87 (d, J=7.8 Hz, 3H), 3.56 (m, 1H), 2.77 (s, 1H), 1.14 (s, 9H).

Example 154

[1575] ##STR00334##

(7R,14R)-1-(difluoromethoxy)-11-[4-(2,4-dimethyl-1H-imidazol-5-yl)phenyl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1576] The title compound was prepared from Intermediate 159 (600 mg, 1.24 mmol), and 5-bromo-2-pyrrolidin-2-yl-pyridine (352 mg, 1.55 mmol) in accordance with the Method described for Example 20 to give, following purification by column chromatography in silica gel (Hex: EtOAc from 0 to 100% then DCM :MeOH with 2% of NH.sub.3 from 0 to 20%) and subsequent SCF purification, a white solid (20 mg, 3.2% yield). LC/MS Method 3: RT 1.62 minutes, [M+H].sup.+=505. .sup.1H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J=2.4 Hz, 1H), 8.27 (dd, J=5.9, 3.6 Hz, 1H), 8.01-7.93 (m, 1H), 7.78-7.58 (m, 2H), 7.67 (t, J=73.3 Hz, 1H), 7.58-7.44 (m, 4H), 6.29 (d, J=7.2 Hz, 1H), 5.24 (d, J=7.2 Hz, 1H), 4.24 (d, J=7.9 Hz, 1H), 3.52 (dt, J=14.0, 7.3 Hz, 1H), 3.11-2.87 (m, 2H), 2.83 (d, J=13.7 Hz, 1H), 2.18 (m, 2H), 1.74 (m, 2H).

Example 155

[1577] ##STR00335##

(7R,14R)-1-(difluoromethoxy)-11-[4-(2,4-dimethyl-1H-imidazol-5-yl)phenyl]-6-trideuteromethyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1578] The title compound was prepared from Intermediate 159 (466 mg, 0.9622 mmol), and Intermediate 180 (200 mg, 0.789 mmol) in accordance with the Method described for Example 20. The reaction mixture was filtered and the solid was washed with dicholoromethane and water to give the title compound (110 mg, 27% yield) as a white solid. LC/MS Method 3: RT 1.72 mins, [M+H].sup.+=529. Free base: .sup.1H NMR (300 MHz, DMSO-d6) δ 8.32-8.23 (m, 1H), 7.75-7.64 (m, 2H), 7.68 (t, J=73.3 Hz, 1H), 7.63 (s, 4H), 7.57-7.46 (m, 3H), 6.29 (d, J=7.1 Hz, 1H), 5.23 (d, J=7.1 Hz, 1H), 3.58-3.46 (m, 1H), 2.82 (d, J=13.8 Hz, 1H), 2.36 (s, 3H), 2.27 (s, 3H).

Example 156

[1579] ##STR00336##

(7R,14R)-1-(difluoromethoxy)-11-[4-(2,4-dimethyl-1H-imidazol-5-yl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1580] The title compound was prepared from Intermediate 171 (114 mg, 0.2196 mmol), and Intermediate 180 (50 mg, 0.2 mmol) in accordance with the Method described for Example 20. The reaction mixture was diluted in dicholoromethane:MeOH (10%) and extracted with water. The aqueous layer was extracted with dichloromethane:MeOH (10%) five times and the combined organic layer was filtered through a phase separator and the solvent was evaporated in vacuo. The solid obtained was triturated in dichloromethane and water to give the title compound (75 mg, 73% yield) as a yellow solid. HCl in methanol was added and the solid was freeze dried to give the HCl salt of the title compound. LC/MS Method 3: RT 1.65 mins, [M+H].sup.+=512.

[1581] .sup.1H NMR (300 MHz, DMSO-d.sup.6) 1H NMR (300 MHz, DMSO-d6) δ 14.24 (s, 1H), 14.13 (s, 1H), 9.15 (d, J=6.8 Hz, 1H), 8.24 (t, J=4.7 Hz, 1H), 7.85-7.64 (m, 5H), 7.68 (t, J=73.3 Hz, 1H), 7.62-7.47 (m, 3H), 6.37 (d, J=6.9 Hz, 1H), 4.91 (t, J=6.6 Hz, 1H), 3.50-3.45 (m, 1H), 2.78 (m, 1H), 2.61 (s, 3H), 2.46 (s, 3H).

Example 157

[1582] ##STR00337##

[(6R,7E,12R)-2-chloro-11-(difluoromethoxy)-6H-6,12-methano-7λ-4-benzimidazo[2,1-c][1,4]benzothiazepin-7(12H)-ylidene]cyanamide

[1583] To a solution of Example 88 (200 mg, 0.55 mmol) and cyanamide (34 mg, 0.81 mmol) in acetonitrile (5 mL) at 0° C., was added iodobenzene diacetate (388 mg, 1.21 mmol). The reaction was stirred for 3 hours at 0° C. The solvent was evaporated and the crude mixture was purified by column chromatography on silica gel, hexane : EtOAc (0 to 100%) to give the title compound (145 mg) as a yellow solid. LC/MS Method 3: RT 1.98 mins, [M+H].sup.+=405. .sup.1H NMR (300 MHz, DMSO-d.sup.6) δ 7.75-7.62 (m, 3H), 7.57 (t, J=73.1 Hz, 1H), 7.68-7.50 (m, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.27 (dd, J=8.7, 2.1 Hz, 1H), 6.24 (t, J=2.9 Hz, 1H), 5.85 (dd, J=3.2, 2.1 Hz, 1H), 3.60 (t, J=3.5 Hz, 2H).

Example 158

[1584] ##STR00338##

N-(2-{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}propan-2-yl)methanesulfonamide

[1585] To a solution of Example 62 (350 mg, 0.66 mmol) cooled to 0° C. in DCM (5 mL) was added sequentially, 4-dimethylaminopyridine (0.1 equiv., 0.066 mmol), di-isopropylethylamine (2.2 equiv., 1.45 mmol) followed by drop wise addition of methane sulphonyl chloride (1.1 equiv., 0.73 mmol) and the mixture allowed to stir at ambient temperature for 2 hours. The reaction mixture was quenched by addition of water (20 mL), the organic phase separated, dried over sodium sulphate, filtered and the solvents removed in vacuo. The crude residue was purified by preparative HPLC to afford the title compound as an off white solid (200 mg). .sup.1H NMR (300 MHz, DMSO-d.sup.6) δ 9.08 (s, 2H), 8.27 (t, J=4.7 Hz, 1H), 8.01-7.72 (m, 2H), 7.71-7.59 (m, 1H), 7.57-7.35 (m, 3H), 6.31 (d, J=7.1 Hz, 1H), 5.25 (d, J=7.1 Hz, 1H), 3.53 (dt, J=14.1, 7.3 Hz, 1H), 2.86 (m, 4H), 1.70 (s, 6H). LCMS Method 3 RT=1.85 minutes (M+H).sup.+572, LCMS Method 4 RT=1.79 minutes (M+H).sup.+572.

Example 159

[1586] ##STR00339##

N-(2-{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}propan-2-yl)acetamide

[1587] The title compound was synthesised from Example 62 (350 mg, 0.66 mmol) and acetyl chloride (1.1 eq, 0.73 mmol) in accordance with the Method described for Example 158. Purification by preparative HPLC gave an off white solid (50 mg). .sup.1H NMR (300 MHz, DMSO-d.sup.6) δ 8.99 (s, 2H), 8.39-8.13 (m, 2H), 8.01-7.66 (m, 3H), 7.61 (dd, J=8.5, 1.8 Hz, 1H), 7.53-7.41 (m, 2H), 6.30 (d, J=7.1 Hz, 1H), 5.25 (d, J=7.1 Hz, 1H), 3.53 (dt, J=14.1, 7.3 Hz, 1H), 2.84 (d, J=13.8 Hz, 1H), 1.80 (s, 3H), 1.60 (s, 6H). LCMS Method 4 RT=1.62 minutes 536 (M+H).sup.+1. LCMS Method 3 RT=1.68 minutes 536 (M+H).sup.+

Example 160

[1588] ##STR00340##

(7R,14R)-1-(difluoromethoxy)-11-[4-(pyrrolidin-2-yl)phenyl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1589] Intermediate 182 (275 mg, 0.42 mmol) was dissolved in HCl/dioxane (4M) (10 mL) and stirred for 3 hrs at room temperature. After this time the solution was evaporated in vacuo. The mixture was separated between DCM (20 mL) and aqueous HCl (0.5M) (20 mL) and the DCM layer was discarded. The aqueous layer was then made basic with sodium carbonate solution and then extracted into DCM (2×50 mL) and the combined organics were dried (phase separator) and evaporated in vacuo. to provide the title compound as the HCl salt (90 mg, 44%). .sup.1H NMR (300 MHz, DMSO-d6) δ 9.13 (d, J=6.8 Hz, 1H), 8.23 (dd, J=5.9, 3.6 Hz, 1H), 7.70-7.61 (m, 2H), 7.60-7.37 (m, 7H), 6.33 (d, J=7.0 Hz, 1H), 4.87 (t, J=6.7 Hz, 1H), 4.06 (t, J=7.6 Hz, 1H), 3.48 (dt, J=13.5, 7.2 Hz, 1H), 3.11-2.82 (m, 1H), 2.73 (d, J=13.4 Hz, 1H), 2.14 (dtd, J=12.1, 7.5, 4.8 Hz, 1H), 1.77 (dq, J=13.2, 7.8, 7.4 Hz, 1H), 1.60-1.41 (m, 1H), 0.91-0.76 (m, 1H).

[1590] LC/MS Method 3: RT 1.76 minutes, m/z 487.2

Example 161

[1591] ##STR00341##

(7R,14R)-1-(difluoromethoxy)-6-trideutero-methyl-11-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1592] The title compound was prepared from Intermediate 110 (350 mg, 0.89 mmol) and [2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]boronic acid (296 mg, 1.33 mmol) in accordance with the Method described for Example 20. The product was purified by crystallisation from EtOAc to afford the title compound (245 mg, 51%). .sup.1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 2H), 8.26 (dd, J=6.2, 3.2 Hz, 1H), 8.14 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.60 (d, J=1.7 Hz, 1H), 7.56-7.41 (m, 3H), 6.28 (d, J=7.1 Hz, 1H), 5.23 (d, J=7.1 Hz, 1H), 4.22 (s, 2H), 3.96 (t, J=5.4 Hz, 2H), 3.60-3.42 (m, 2H), 3.30 (s, 1H), 2.82 (d, J=13.7 Hz, 1H). LC/MS Method 3: RT 1.50 minutes, m/z 535.2

Example 162

[1593] ##STR00342##

(7R,14R)-1-(difluoromethoxy)-6-methyl-11-[2-(5-oxo-1,4-diazepan-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1594] The title compound was prepared from Intermediate 110 (350 mg, 0.89 mmol) and [2-(5-oxo-1,4-diazepan-1-yl)pyrimidin-5-yl]boronic acid (315 mg, 1.33 mmol) in accordance with the Method described for Example 20. Purification by flash chromatography on silica gel (0 to 10% gradient of MeOH in DCM) and then crystallisation from EtOAc afforded the title compound (245 mg, 51%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.67 (s, 2H), 8.27 (dd, J=5.9, 3.5 Hz, 1H), 7.76-7.65 (m, 2H), 7.60 (d, J=1.7 Hz, 1H), 7.56-7.40 (m, 3H), 6.27 (d, J=7.1 Hz, 1H), 5.22 (d, J=7.1 Hz, 1H), 3.97 (q, J=4.3, 3.8 Hz, 4H), 3.50 (dt, J=14.1, 7.2 Hz, 1H), 3.24 (d, J=6.9 Hz, 2H), 2.82 (d, J=13.8 Hz, 1H), 2.54 (s, 2H). LC/MS Method 3: RT 1.63 minutes, m/z 549.2

Example 163

[1595] ##STR00343##

(7R,14R)-11-[4-(2-aminopropan-2-yl)phenyl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1596] Intermediate 182(a) (0.10 g, 0.13 mmol) (75% pure) was dissolved in HCl dioxane (4M, 10 mL) and stirred for 18 hrs at r.t. and before being evaporated in vacuo. The mixture was separated between DCM (20 mL) and sodium carbonate (20 mL) and the organic layer was then dried (phase separator) and evaporated in vacuo. Purification by flash chromatography on silica gel (0 to 10% gradient of MeOH in DCM) and freeze drying from HCl (0.5M) to obtain the HCl salt of the title compound as a white powder. (36 mg, 58%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.13 (d, J=6.8 Hz, 1H), 8.23 (dd, J=6.0, 3.5 Hz, 1H), 7.72-7.54 (m, 5H), 7.59-7.32 (m,7H), 6.34 (d, J=7.1 Hz, 1H), 4.87 (t, J=6.7 Hz, 1H), 3.60-3.43 (m, 1H), 2.73 (d, J=13.2 Hz, 1H), 1.44 (s, 6H), 1.24 (s, 1H).

[1597] LC/MS Method 3: RT 1.80 minutes, m/z 475.2

Example 164

[1598] ##STR00344##

(7R,14R)-1-(difluoromethoxy)-11-[2-(3-hydroxy-3-methylazetidin-1-yl)-4-methylpyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1599] The title compound can be prepared from Intermediate 171 (0.35 g, 0.93 mmol, leg) and 1-(5-bromo-4-methyl-pyrimidin-2-yl)-3-methyl-azetidin-3-ol(leq) in accordance with the Method described for Example 137. The product was purified by column chromatography on silica gel (EtOAc in DCM (0 to 100% gradient) and then MeOH in EtOAc (0 to15% gradient)) to afford the free base of the title compound as a brown solid. The solid could be further purified by dissolving into aqueous 0.5M HCl (20 mL) and then washing the aqueous solution with DCM (2×25 mL). Sodium carbonate solution was then added until precipitation was observed and the mixture extracted into DCM (3×50 mL). The organics were dried (phase separator) and evaporated in vacuo before being again dissolved into aqueous 0.5M HCl and freeze dried to afford the HCl salt of the title compound (215 mg, 42%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.14 (d, J=6.9 Hz, 1H), 8.23 (dd, J=5.8, 3.6 Hz, 1H), 8.15 (s, 1H), 7.71-7.45 (m, 4H), 7.41-7.27 (m, 1H), 7.17 (dd, J=8.4, 1.7 Hz, 1H), 6.31 (d, J=7.1 Hz, 1H), 4.90 (t, J=6.7 Hz, 1H), 3.93 (d, J=1.9 Hz, 4H), 3.60-3.32 (m, 1H), 2.74 (d, J=13.3 Hz, 1H), 2.26 (s, 3H), 1.45 (s, 3H). LC/MS Method 3: RT 1.58 minutes, m/z 519.2.

Example 165

[1600] ##STR00345##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-trideutero-methyl -11-[2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1601] Intermediate 187 (120 mg, 0.18 mmol) was suspended in 2-propanol (20 mL) and treated with hydrochloric acid (5 ml, 20 mmol, 4M in 1,4-dioxane) and stirred for 3 hours at ambient temperature. The solvent was removed in vacuo and the residual solid used without further purification.

[1602] The residue was suspended in acetonitrile (10 ml), cooled to 0° C. and 4-methylmorpholine (0.1 mL, 0.9 mmol) added followed by COMU (87 mg, 0.197 mmol) and the mixture allowed to stir and reach ambient temperature. After 1 hour the mixture was diluted with water (25 mL) and extracted into EtOAc (3×20 mL). Combined organics were washed with water (20 mL) and dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give a crude beige solid. Purification by column chromatography eluting with 0 to 100% DCM/EtOAc and then a gradient of DCM/MeOH 1 to 10% before freeze drying afforded the title compound as a white solid (46 mg, 47%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.56 (t, J=1.7 Hz, 2H), 8.27 (dd, J=7.0, 2.5 Hz, 1H), 8.15 (s, 1H), 7.66-7.56 (m, 2H), 7.56-7.35 (m, 3H), 6.27 (d, J=7.0 Hz, 1H), 5.24 (d, J=7.1 Hz, 1H), 4.23 (s, 2H), 3.96 (t, J=5.4 Hz, 2H), 3.50 (d, J=7.2 Hz, 1H), 3.31 (s, 2H), 2.82 (d, J=13.8 Hz, 1H). LC/MS Method 3: RT 1.52 minutes, m/z 553.2

General Method A: Suzuki Coupling between Intermediate 171 and Aryl Bromides

[1603] ##STR00346##

[1604] To a degassed suspension of Intermediate 171 (0.08 mmol), Pd.sub.2dba.sub.3 (5%mol), tricyclohexylphosphonium tetrafluoroborate (12% mol) and K.sub.3PO.sub.4(2.5eq) in 1,4-dioxane/water (2 ml/0.1 mL)was added the appropriate aryl bromide (1.5 eq). The resultant mixture was stirred in an Anton Paar microwave at 110° C. for 2 hours and then concentrated in vacuo. The residue was dissolved into EtOAc, washed with water, concentrated in vacuo and subsequently purified by preparative HPLC in basic mode to afford the title compounds described in Table 1.

TABLE-US-00007 TABLE 1 EXAMPLES 166 to 173 LCMS Method 4 RT Example Structure IUPAC_NAME Mass (mins) 166 [00347] (7R,14R)-1-(difluoromethoxy)-11-[2- (1-oxidothiomorpholin-4-yl)pyrimidin- 5-yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 537.1 3.6  167 [00348] (7R,14R)-11-[2-(4,4-difluoro-1- hydroxycyclohexyl)pyrimidin-5-yl]-1- (difluoromethoxy)-6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 554.1 4.67 168 [00349] (7R,14R)-1-(difluoromethoxy)-11-[2- (3-hydroxy-1,1- dioxidotetrahydrothiophen-3- yl)pyrimidin-5-yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 554.1 3.66 169 [00350] (3R)-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}-3- hydroxytetrahydrothiophenium-1-olate 538.1 3.35 170 [00351] (3S)-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}-3- hydroxytetrahydrothiophenium-1-olate 538.1 3.33 171 [00352] (7R,14R)-1-(difluoromethoxy)-11-[2- (3-hydroxyoxetan-3-yl)pyrimidin-5- yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 492.1 3.58 172 [00353] (7R,14R)-1-(difluoromethoxy)-11-{1- [1-(methylsulfonyl)azetidin-3-yl]-1H- pyrazol-4-yl}-6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 541.1 3.8  173 [00354] (7R,14R)-1-(difluoromethoxy)-11-(2- hydroxypyrimidin-5-yl)-6,7-dihydro- 7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 436.1 3.06

[1605] General Method B: Suzuki Coupling between Example 11 and Aryl Boronic Acids

##STR00355##

[1606] To a degassed suspension of Example 11 (0 .1 mmol), Pd.sub.2dba.sub.3 (5% mol), tricyclohexylphosphonium tetrafluoroborate (12% mol) and K.sub.3PO.sub.4(2.5eq) in 1,4-dioxane/water (2 ml/0.1 mL)was added the appropriate aryl boronic acid or pinacalato ester (1.5 eq). The resultant mixture was stirred in an Anton Paar microwave at 110° C. for 2 hours and then concentrated in vacuo. The residue was dissolved into EtOAc, washed with water, concentrated in vacuo and subsequently purified by preparative HPLC in basic mode to afford the title compounds described in Table 2.

TABLE-US-00008 TABLE 2 EXAMPLES 174 to 185 LCMS Method 4 RT Example Structure IUPAC NAME Mass (mins) 174 [00356] (7R,14R)-1-(difluoromethoxy)-11-[2- (1,4-dihydroxy-4- methylcyclohexyl)pyrimidin-5-yl]-6,7- dihydro-7,14-methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 548.2 3.88 175 [00357] 2-{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}-2-methylpropanenitrile 487.2 4.49 176 [00358] 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-methylazetidine-3-carbonitrile 514.2 4.18 177 [00359] (7R,14R)-1-(difluoromethoxy)-11-{2- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept- 5-yl]pyrimidin-5-yl}-6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 517.1 3.94 178 [00360] (7R,14R)-1-(difluoromethoxy)-11-[2- (thiomorpholin-4-yl)pyrimidin-5-yl]- 6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 521.1 4.86 179 [00361] (7R,14R)-1-(difluoromethoxy)-11-{2- [3-(2-hydroxypropan-2-yl)azetidin-1- yl]pyrimidin-5-yl}-6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 533.2 3.86 180 [00362] (7R,14R)-11-[2-(3,3-difluoroazetidin-1- yl)pyrimidin-5-yl]-1-(difluoromethoxy)- 6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 511.1 4.47 181 [00363] (7R,14R)-1-(difluoromethoxy)-11-[2- (3-oxa-8-azabicyclo[3.2.1]oct-8- yl)pyrimidin-5-yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 531.2 4.39 182 [00364] (7R,14R)-1-(difluoromethoxy)-11-[2- (7-oxo-3,6-diazabicyclo[3.2.2]non-3- yl)pyrimidin-5-yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 558.2 3.73 183 [00365] (7R,14R)-1-(difluoromethoxy)-11-[2- (1,1-dioxidothiomorpholin-4- yl)pyrimidin-5-yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 553.1 4.02 184 [00366] (7R,14R)-1-(difluoromethoxy)-11-(1- methyl-6-oxo-1,6-dihydropyridin-3-yl)- 6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 449.1 3.48 185 [00367] (7R,14R)-1-(difluoromethoxy)-11-[2- (tetrahydro-2H-pyran-4-yl)pyrimidin-5- yl]-6,7-dihydro-7,14- methanobenzimidazo[1,2- b][2,5]benzodiazocin-5(14H)-one 504.1 4.05

Example 186

[1607] ##STR00368##

(7R ,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-10-fluoro-6-trideutero methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1608] Intermediate 191 (420 mg, 0.70 mmol) was dissolved in HCl (4M in 1,4-dioxane) 10 mL and stirred for 3 hours at room temperature. After 3 hours the solution was concentrated in vacuo.

[1609] The mixture was separated between DCM and aqueous HCl (0.5M) and the DCM layer was discarded. The aqueous layer was then made basic with sodium carbonate solution and then extracted with DCM (3×50 mL) and the combined organics were dried (MgSO.sub.4), filtered and evaporated in vacuo. The product was purified by column chromatography on silica eluting with 0 to 15% MeOH in DCM to afford an off-white solid. The compound was freeze dried with an equivalent of hydrochloric acid to afford the title compound as an HCl salt (275 mg, 72%).

[1610] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.10 (d, J=1.6 Hz, 2H), 8.61 (bs, 3H, NH.sub.3.sup.+), 8.29 (dd, J=7.5, 1.9 Hz, 1H), 7.82-7.70 (m, 1H), 7.60 (d, J=6.7 Hz, 2H), 7.57-7.45 (m, 2H), 6.29 (d, J=7.1 Hz, 1H), 5.29 (d, J=7.2 Hz, 1H), 3.54 (dt, J=14.0, 7.5 Hz, 1H), 2.86 (d, J=13.8 Hz, 1H), 1.70 (s, 6H). LC/MS Method 3: RT 1.67 minutes, m/z 512.2

Example 187

[1611] ##STR00369##

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl phosphate, disodium salt

[1612] To a solution of Intermediate 192 (31.0 g, 41.0 mmol) in a mixture of ethanol (450 mL) and sodium hydroxide (410 mL, 82.0 mmol, 0.200 mol/L) was added 10% Pd/C (3.10 g). The reaction mixture was degassed under vacuum and placed under a hydrogen atmosphere using a balloon. The reaction mixture was stirred vigorously until LCMS analysis showed the reaction was complete. It was necessary to add a further portion of Pd/C catalyst (775 mg, 2.5%w/w) after 1 hour and the mixture stirred under hydrogen for a further 30 minutes. The reaction mixture was degassed with nitrogen, filtered through a pad of celite which was washed with EtOH/H.sub.2O (1/1, 1000 mL), collecting the colourless eluent. The ethanol was removed in vacuo and the aqueous reduced to 400 mL volume in vacuo. The aqueous was washed with dichloromethane (3×250 mL) which was discarded, before further concentrating the aqueous solution in vacuo to a 200 mL volume. The aqueous layer was stirred with phosphonics MTU resin (15 g) for 2.5 hours to remove palladium residues. After filtration to remove the resin, the aqueous was concentrated down to ˜100 mL in vacuo and then freeze dried to give the title compound as a white solid (23.15 g, 91%). .sup.1H NMR: (D20 , 300 MHz) 1.76 (s, 6H), 2.61 (d, 1H, J=13.6 Hz), 3.16 (m, 1H), 4.83 (d, 1H, J=6.5 Hz), 6.19 (d, 1H, J=7.0 Hz), 6.84 (m, 1H), 7.05 (t, 1H, J=73.3 Hz) 7.12 (m, 1H), 7.30 (m, 2H), 7.93 (dd, 1H, J=8.2, 0.9 Hz), 8.56 (d, 2H, J=1.2Hz). LC/MS Method 3: RT 1.00 minutes, m/z 576.

Example 188

[1613] ##STR00370##

2-{5-[(7R,14R)-1-(difluoromethoxy)-10-fluoro-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}propan-2-yl phosphate, disodium salt

[1614] To a solution of Intermediate 193 (3.2 g, 4.2 mmol) in a mixture of ethanol (60 mL) and sodium hydroxide solution (330 mg in 42 mL of water) was added 10% Pd/C (480 mg). The reaction was degassed and placed under a hydrogen atmosphere, and stirred vigorously for 40 minutes before the reaction completed. The reaction mixture was filtered through a pad of celite, washed with EtOH/H.sub.2O (1:1, 200 mL), and most of the EtOH was removed in vacuo. The aqueous was washed with DCM (5×50 mL) before being further concentrated in vacuo, and treated with MTU resin (1.5 g) to remove palladium impurities and stirred for 1.5 hours before filtration through a pad of celite. The water was removed in vacuo and further dried on freezer-drier to give the desired product as the disodium salt (2.43 g, 92%). .sup.1H NMR (D20, 400 MHz) δ 8.65 (s, 2H), 8.01 (d, J=8.1 Hz, 1H), 7.43 (d, J=6.7 Hz, 1H), 7.3-6.9 (m, 4H), 6.16 (d, J=7.1 Hz, 1H), 5.04 (d, J=7.2 Hz, 1H), 3.34 (s, 3H), 3.27 (m, 1H), 2.67 (d, J=14.0 Hz, 1H), 1.76 (s, 6H). LC/MS Method 3: ES.sup.+(M+H).sup.+590, retention time 0.91 minutes.

Example 189

[1615] ##STR00371##

(7R,14R)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-1-(trifluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1616] A 0.6M solution of phenol in anhydrous DMSO (1.15 ml, 0.69 mmol) was added to a solution of Intermediate 206 (0.300 g, 0.57 mmol) in anhydrous DMSO (5 ml). Potassium carbonate (0.120 g, 0.86 mmol), dried 4A molecular sieves (0.360 g), dichloro-[bis(dicyclohexylphosphino)propane]palladium(II) (0.035 g, 0.057 mmol) were added and the reaction mixture was heated to 100° C. under 3 bars of carbon monoxide for 48 hours.

[1617] Water (50 ml) was added and the resulting mixture was extracted with EtOAc (1×150 ml). The organic phase was then washed with brine (2×300 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by SiO.sub.2 flash chromatography with DCM/MeOH (100/0 to 95/5) as eluent to give a brown solid. The solid was treated with iPr.sub.2O (10 ml), filtered, and dried under reduced pressure at 45° C. to give the title compound (0.110 g, 37% yield).

[1618] LCMS (Method 20, ES+) RT 1.02 min., 514 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 1.55 (s, 6H), 2.82 (d, J=13.5 Hz, 1H), 3.51 (m, 1H), 4.95 (t, J=6.9 Hz, 1H), 5.15 (s, 1H), 6.32 (d, J=7.2 Hz, 1H), 7.42 (d, J=6.8 Hz, 1H), 7.58 (t, J=8.3 Hz, 1H), 7.69 (d, J=11.5 Hz, 1H), 7.72 (m, 1H), 8.38 (dd, J=1.3 and 8.3 Hz, 1H), 8.92 (d, J=1.8 Hz, 2H), 9.21 (d, J=6.9 Hz, 1H).

Example 190

[1619] ##STR00372##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1620] The title compound was prepared from Intermediate 208 (0.265 g, 0.55 mmol)in accordance with the synthetic procedure described for Example191. Purification by SiO.sub.2 flash chromatography with DCM/MeOH (100/0 to 95/5) as eluent to give a pink solid. This solid was treated with iPr.sub.2O (10 ml) and the resulting suspension was filtered, and before being dried under reduced pressure at 45° C., the isolated solid was washed with iPr.sub.2O (2×10 ml) and with pentane (3×10 ml) to give the title compound (0.082 g, 36% yield).

[1621] LCMS (Method 20, ES+) RT 0.88 min., 473 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 1.05 (s, 6H), 2.66 (d, J=13.5 Hz, 1H), 2.69 (m, 1H), 3.40 (m, 1H), 3.71-3.85 (m, 4H), 4.38 (s, 1H), 4.77 (t, J=6.9 Hz, 1H), 6.18 (d, J=7.2 Hz, 1H), 6.49 (d, J=8.3 Hz, 1H), 7.27 (d, J=13.2 Hz, 1H), 7.49 (m, 2H), 7.63 (t, J=74.3 Hz, 1H), 8.21 (m, 1H), 9.05 (d, J=6.9 Hz, 1H).

Example 191

[1622] ##STR00373##

(7R,14R)-11-((2-aminopropan-2-yl)phenyl)-10-fluoro-1-(trifluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1623] The title compound was prepared from Intermediate 210 (0.195 g, 0.38 mmol) in accordance with the synthetic procedure described for Example 189 to give after purification by SiO.sub.2 flash chromatography with DCM/MeOH/NH.sub.4OH (100/0/0 to 94.5/5/0.5) as eluent followed flash chromatography on amino modified silica eluting with DCM/MeOH (100/0 to 98/8) as eluent and subsequent trituration with iPr.sub.2O to give (0.055 g, 26% yield).

[1624] LCMS (Method 20, ES+) RT 0.65 min., 511 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) 1.42 (s, 6H), 2.25 (broad m, 2H), 2.81 (d, J=13.5 Hz, 1H), 3.50 (m, 1H), 4.91 (t, J=6.9 Hz, 1H), 6.30 (d, J=7.2 Hz, 1H), 7.32 (d, J=7.0 Hz, 1H), 7.40 (broad d, J=8.5 Hz, 2H), 7.54 (d, J=12.0 Hz, 1H), 7.57 (t, J=8.3 Hz, 1H), 7.63 (d, J=8.5 Hz, 2H), 7.70 (broad d, J=8.3 Hz, 1H), 8.49 (dd, J=1.2 and 8.3 Hz, 1H), 9.20 (d, J=6.9 Hz, 1H).

Example 192

[1625] ##STR00374##

(7R,14R)-11-((2-aminopropan-2-yl)phenyl)-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1626] The title compound was prepared from Intermediate 212 (0.240 g, 0.48 mmol) in accordance with the synthetic procedure described for Example191. Purification by SiO.sub.2 flash chromatography with DCM/MeOH/NH.sub.4OH (100/0/0 to 94.5/5/0.5) as eluent gave a pink solid. This solid was purified with preparative HPLC using C18 Nucleodur gravity 250x 4.6 mm Macherey-Nagel column and a gradient of acetonitrile (B) in water (A) containing 0.1% TFA (B/A 5/95 to 1/1 in 23 min, 1 ml/min) to afford the title compound (0.041 g, 17% yield).

[1627] LCMS (Method 20, ES+) RT 0.60 min., 493 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.68 (s, 6H), 2,74 (d, J=13.5 Hz, 1H), 3,48 (m, 1H), 4,90 (t, J=6.9 Hz, 1H), 6,31 (d, J=7.2 Hz, 1H), 7.47-7.54 (m, 3H), 7.58 (t, J=73.4 Hz, 1H), 7.59 (m, 3H), 7,65 (d, J=8.5 Hz, 2H), 8,24 (m, 1H), 9.15 (d, J=6.9 Hz, 1H).

Example 193

[1628] ##STR00375##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[2-(2-hydroxypropan-2-yl)-4-(tetrahydrofuran-3-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(1411)-one

[1629] The title compound was prepared from Example 1 (100 mg, 0,202 mmol), tetrahydrofuran-3-sulfonyl chloride (106 mg, 0,6026 mmol) and [Ir[DF(CF.sub.3)PPY].sub.2(DTBPY)]PF.sub.6 (4,5 mg, 0,0040 mmol) in acetonitrile/TFA (1/1) (2 mL), following the General procedure for the late stage trifluoromethylation described for Example 107. The crude reaction was purified by LC-2D MS chromatography in acidic mode (formic acid) Method 14 yielding to 6,6 mg (6%) of the title compound as a white solid. LCMS Method 15 (ES+) RT 5.23 min., 566 (M+H)+..sup.1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J=6.8 Hz, 1H), 8.62 (s, 1H), 8.26 (dd, J=6.3, 3.1 Hz, 1H), 7.62 (d, J=10.6 Hz, 1H), 7.53-7.47 (m, 2H), 7.46 (t, J=73.6 Hz, 1H), 7.36 (t, J=5.9 Hz, 1H), 6.34 (d, J=7.1 Hz, 1H), 5.04-4.77 (m, 2H), 4.02-3.80 (m, 2H), 3.80-3.60 (m, 2H), 3.52 (dd, J=13.8, 6.9 Hz, 1H), 3.42-3.27 (m, 1H), 2.75 (d, J=13.5 Hz, 1H), 2.28-2.08 (m, 1H), 2.07-1.90 (m, 1H), 1.57 (s, 6H).

Example 194

[1630] ##STR00376##

(7R,14R)-1-(difluoromethoxy)-11-[4-(difluoromethyl)-2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1631] The title compound was prepared from Example 1 (100 mg, 0,202 mmol), difluoromethanesulfonyl chloride (54 μL, 0,61 mmol) and [IR[DF(CF.sub.3)PPY].sub.2(DTBPY)]PF.sub.6 (4,5 mg, 0,0040 mmol) in acetonitrile/TFA (1/1) (2 mL), following the General procedure for the late stage trifluoromethylation described for Example 107. The crude reaction was taken up in methanol (4 mL) before addition of potassium carbonate (170 mg, 1,218 mmol) and stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by LC-2D MS chromatography Method 14 yielding to 13.7 mg (13%) of the title compound as a white solid. LCMS Method 15 (ES+) RT 5.40 min., 546 (M+H).sup.+..sup.1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J=6.8 Hz, 1H), 8.98 (s, 1H), 8.25 (dd, J=6.6, 2.1 Hz, 1H), 7.67 (d, J=10.3 Hz, 1H), 7.55-7.49 (m, 2H), 7.48 (t, J=73.1 Hz, 1H), 7.44 (d, J=6.5 Hz, 1H), 6.83 (t, J=53.0 Hz, 1H), 6.33 (d, J=7.0 Hz, 1H), 5.28 (s, 1H), 4.93 (t, J=6.6 Hz, 1H), 3.51 (dd, J=13.6, 7.0 Hz, 1H), 2.76 (d, J=13.4 Hz, 1H), 1.60 (s, 6H).

Example 195

[1632] ##STR00377##

(7R,14R)-1-(difluoromethoxy)-6-ethyl-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1633] The title compound was prepared from Intermediate 194 (5 mg, 0,012 mmol) and 2-(1-hydroxy-1-methylethyl)pyrimidine-5-boronic acid pinacol ester (6.58 mg, 0,024 mmol), following the synthetic protocol described for Example 101. TPutification over silica gel (heptane/ethyl acetate 25/75 to 0/100) to afforded 3 mg (48%) of the title compound as an off-white solid. LCMS Method 3 (ES+): RT 2.32 min, [M+H].sup.+=520.2.

Example 196

[1634] ##STR00378##

(7R,14R)-11-[2-(2-aminopropan-2-yl)pyrimidin-5-yl]-1-(difluoromethoxy)-7-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1635] Intermediate 150 (7 mg, 0.012 mmol) was added to a solution of DCM/trifluoroacetic acid (1:1, 0.17 mL). The reaction mixture was stirred at ambient temperature for 1 hour before addition of a saturated aqueous solution of NaHCO.sub.3 (1 mL). The aqueous layer was extracted with DCM (2×2 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuo, yielding 6 mg (100%) of the title compound as a white solid. LCMS Method 3 (ES+): RT 3.04 minutes, [M+H]+=491.

Example 197

[1636] ##STR00379##

(7R,14R)-1-(difluoromethoxy)-11-(2-{2-[di(prop-2-en-1-yl)amino]propan-2-yl}pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1637] The title compound was prepared from [2-(3-oxopiperazin-1-yl)pyrimidin-5-yl]boronic acid pinacol ester, and Example 23 in accordance with General Method B to give, following purification by preparative HPLC, a white solid (30 mg, 15% yield). LC/MS Method 3: RT 1.84 mins (pH 10), [M+H]+=568. .sup.1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 2H), 8.12 (s, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.65-7.25 (m, 4H), 7.33 (t, J=8.5 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.10 (d, J=4.3 Hz, 1H), 5.93 (d, J=3.9 Hz, 1H), 4.23 (s, 2H), 3.96 (t, J=5.4 Hz, 2H), 3.35-3.28 (m, 2H), 3.32-3.15 (m, 1H), 3.06 (s, 3H), 2.66 (d, J=12.2 Hz, 1H).

Example 198

[1638] ##STR00380##

(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-11-[6-(S-methylsulfonimidoyl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1639] The title compound was prepared from Intermediate 159 (0.5 g, 1.03 mmol) in 1,4-dioxane (10 mL, 116 mmol) and N-[(5-bromopyridin-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (0.42 g, 1.29 mmol) in accordance with General Method A. Purification by flash chromatography on silica in ethyl acetate/DCM (gradient from 0 to 100%) and then methanol in ethyl acetate (0 to 15%) gave the title compound as a white solid (50 mg, 9%). .sup.1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J=2.2 Hz, 1H), 8.30 (m, 2H), 8.15 (d, J=8.2 Hz, 1H), 7.79 (m, 2H), 7.71-7.59 (m, 2H), 7.59-7.46 (m, 2H), 6.32 (d, J=7.1 Hz, 1H), 5.26 (d, J=7.2 Hz, 1H), 4.47 (s, 1H), 3.54 (dt, J=14.1, 7.2 Hz, 1H), 3.22 (d, J=1.1 Hz, 3H), 2.85 (d, J=13.8 Hz, 1H). LC/MS Method 3: RT 1.45 mins (pH 10), [M+H]+=513.2

Example 199

[1640] ##STR00381##

(7R,14R)-1-(difluoromethoxy)-11-[6-(S-methylsulfonimidoyl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1641] The title compound was prepared from Intermediate 171 (250 mg, 0.43 mmol) and, N-[(5-bromopyridin-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (216 mg, 0.652 mmol), in accordance with General Method A. Purification by preparative HPLC gave the title compound (66 mg, 31%) as a white solid. LC/MS Method 3: ESI MH+496, retention time 0.76 minutes (pH 10). .sup.1H NMR (300 MHz, DMSO-d.sup.6) δ 9.15 (d, J=6.8 Hz, 1H), 8.96 (dd, J=2.3, 0.8 Hz, 1H), 8.31 (dd, J=8.3, 2.3 Hz, 1H), 8.23 (dd, J=5.8, 3.6 Hz, 1H), 8.14 (dd, J=8.3, 0.8 Hz, 1H), 7.95-7.66 (m, 3H), 7.61 (dd, J=8.6, 1.7 Hz, 1H), 7.55-7.47 (m, 2H), 6.38 (d, J=7.0 Hz, 1H), 4.91 (t, J=6.8 Hz, 1H), 4.47 (s, 1H), 3.50 (dt, J=13.6, 7.0 Hz, 1H), 3.21 (d, J=1.1 Hz, 3H), 2.76 (d, J=13.4 Hz, 1H).

Example 200

[1642] ##STR00382##

(7R,14R)-1-(difluoromethoxy)-11-(2-{2-[di(prop-2-en-1-yl)amino]propan-2-yl}pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one

[1643] Intermediate 171 (400 mg, 0.86 mmol), Intermediate 213 (254 mg, 0.86 mmol), tris(dibenzylideneacetone)-dipalladium(0) (39.2 mg,0.043 mmol) and tricyclohexylphosphonium tetrafluoroborate (32.5 mg, 0.086 mmol) were added to a microwave tube and dioxane (2.5 ml) was added, followed by potassium phosphate tribasic (562 mg, 2.57 mmol) dissolved in water (0.5 ml). The mixture was degassed and refilled with nitrogen then heated to 105° C. for 2 hours. The mixture was partitioned between ethyl acetate and water (50 ml) each. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. Purification by flash chromatography (silica, 0 to 10% methanol in dichloromethane) afforded the title compound as an off-white solid (200 mg, 42% yield). LCMS Method 3 (ES+) RT 2.62 minutes, 557.2 (M+H).sup.+. .sup.1H NMR (300 MHz, DMSO-d.sup.6) δ 9.14 (d, J=6.8 Hz, 1H), 9.03 (s, 2H), 8.23 (dd, J=6.4, 3.1 Hz, 1H), 7.83-7.70 (m, 2H), 7.68 (t, JH-F =73.4 Hz, 1H), 7.60 (dd, J=8.5, 1.8 Hz, 1H), 7.55-7.45 (m, 2H), 6.37 (d, J=7.1 Hz, 1H), 5.87-5.60 (m, 2H), 5.05 (dt, J=17.1, 1.8 Hz, 2H), 4.95-4.82 (m, 3H), 3.61-3.41 (m, 1H), 3.22 (dt, J=6.0, 1.6 Hz, 4H), 2.75 (d, J=13.4 Hz, 1H), 1.57 (s, 6H).

Example 201

[1644] ##STR00383##

Ammonium 2-(5-((7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo [f]benzo [4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)propan-2-yl sulfate.

[1645] A 4 mL reaction vial was charged with Example 1 (100 mg, 0.202 mmol), sulfur trioxide trimethylamine complex (56.2 mg, 0.404 mmol) and pyridine (1 mL). The vial was closed and heated at 130° C. for 20 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (Reveleris Prep; Detection: UV (220 nm), Column: XSelect™ CSH C18, 145×25 mm, Flow: 40 mL/min, Gradient: t.sub.0=5% B, t.sub.1min=5% B, t.sub.2min=20% B, t.sub.17min=60% B, t.sub.18min=100% B, Post time: 5 min 100% B, Eluent A: 10 mM ammoniumbicarbonate in water (pH=9.0), Eluent B: 99% acetonitrile +1% 10 mM ammoniumbicarbonate in water in acetonitrile) to afford the title compound (71 mg, 61%) as a white solid after lyophilisation of the product fractions.

[1646] LCMS (Method 9): RT=1.69 minutes; [M-NH4.sup.+].sup.−=574.

[1647] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.15 (d, J=6.9 Hz, 1H), 8.88 (d, J=1.5 Hz, 2H), 8.23 (dd, J=7.7, 1.5 Hz, 1H), 7.66 (d, J=11.5 Hz, 1H), 7.63 (dd, J=72.2, J=1.6 Hz, 1H), 7.57-7.46 (m, 3H), 7.07 (bs, 4H), 6.36 (d, J=7.1 Hz, 1H), 4.91 (t, J=6.8 Hz, 1H), 3.54--3.44 (m, 1H), 2.75 (d, J=13.4 Hz, 1H), 1.75 (s, 6H).

Example 202

[1648] ##STR00384##

4-((2-(5-((7R,14R)-1-(difluoromethoxy)-10-fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo [f]benzo [4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)propan-2-yl)oxy)-4-oxobutanoic acid.

[1649] A mixture of Example 1(1.5 g, 3.03 mmol), succinic anhydride (1.82 g, 18.2 mmol) and 4-dimethylaminopyridine (555 mg, 4.54 mmol) in acetonitrile (20 mL) was heated to reflux temperature for 6 days. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between aqueous HCl solution (1M) and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with aqueous HCl solution (1M) and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford a brown residue. The material was purified by flash column chromatography (silica (80 g); 5-10% MeOH in DCM) to afford the title compound (515 mg, 28%) as a white solid after trituration with Et.sub.2O.

[1650] LCMS (Method 10): RT=3.09 minutes; [M+H].sup.+=596.

[1651] .sup.1H NMR (400 MHz, DMSO-d6) δ 12.20 (bs, 1H), 9.16 (d, J=6.8 Hz, 1H), 8.92 (d, J=1.6 Hz, 2H), 8.23 (dd, J=6.8, 2.6 Hz, 1H), 7.67 (d, J=11.5 Hz, 1H), 7.62 (t, J=72.5 Hz, 1H), 7.57-7.47 (m, 3H), 6.35 (d, J=7.1 Hz, 1H), 4.91 (t, J=6.8 Hz, 1H), 3.54-3.44 (m, 1H), 2.75 (d, J=13.4 Hz, 1H), 2.58-2.47 (m, 2H, coincides with DMSO), 2.42 (t, J=6.7 Hz, 2H), 1.74 (s, 6H).

Example 203 and Example 204

[1652] ##STR00385##

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-(2-((2R *)-hydroxybutan-2-yl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo [f]benzo [4,5]imidazo[1,2-a[1,4]diazocin-5(14H)-one

(7R,14R)-1-(difluoromethoxy)-10-fluoro-11-(2-((2S*)-hydroxybutan-2-yl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f[benzo[4,5]imidazo[1,2-a[1,4]diazocin-5(14H)-one

[1653] 1M Tetrabutylammonium fluoride (8.46 ml, 8.46 mmol) was added to a solution of Intermediate 216 (0.176 g, 0.28 mmol). The reaction mixture was stirred at room temperature over 15 days.

[1654] Water (50 ml) was added and the resulting mixture was extracted with EtOAc (3×50 ml). The organic phase was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by SiO.sub.2 flash chromatography with DCM/MeOH (98/2) as eluent to afford the expected product as a mixture of diastereoisomers.

[1655] The mixture was purified by preparative chiral HPLC using Chiralcel OD 10 μm 250×30 mm with EtOH/MeOH/Triethylamine (50/50/0.1) as eluent and with 45 ml/min flow in 18 min to afford each pure diastereoisomer.

[1656] Diastereomer A Example 203:

[1657] 12.8 mg: Analytical Chrial HPLC Chiralcel OD 10 μm 250×4.6 mm with EtOH/MeOH/Triethylamine (50/50/0.1) as eluant and with 1 ml/min flow over 15 minutes with RT=7.7 min.

[1658] LCMS (Method 20, ES+) RT 1.04 min., 510 [M+H].sup.+.

[1659] .sup.1H NMR (400 MHz, DMSO-d6) 0.75 (t, J=7 Hz, 3H),1.50 (s, 3H),1.80-2.00 (m, 2 H),2.75 (d, J=13 Hz, 1H),3.49 (m, 1H),4.90 (t, J=7 Hz, 1H),5.00 (s, 1H),6.35 (d, J=7 Hz, 1H),7.50 (m, 2H),7.56 (d, J=6 Hz, 1H),7.62 (t, J=73 Hz, 1H),7.68 (d, J=9 Hz, 1 H),8.23 (m, 1H),8.97 (d, J=2 Hz, 1H),9.15 (d, J=6 Hz, 1H).

[1660] Diastereomer B Example 204:

[1661] 10.7 mg: Analytical Chiral HPLC Chiralcel OD 10 μm 250×4.6 mm with EtOH/MeOH/Triethylamine (50/50/0.1) as eluent and with a 1 ml/min flow rate over 15 minutes with RT=12.9 minutes.

[1662] LCMS (Method 20, ES+) RT 1.04 min., 510 [M+H].sup.+.

[1663] .sup.1H NMR (400 MHz, DMSO-d6) 0.75 (t, J=7 Hz, 3H) ; 1.50 (s, 3H) ; 1.80 à2.00 (m, 2 H) ; 2.75 (d, J=13 Hz, 1H) ; 3.49 (m, 1H) ; 4.90 (t, J=7 Hz, 1H) ; 5.00 (s, 1H) ; 6.35 (d, J=7 Hz, 1H) ; 7.50 (m, 2H) ; 7.56 (d, J=6 Hz, 1H) ; 7.62 (t, J=73 Hz, 1H) ; 7.68 (d, J=9 Hz, 1H) ; 8.23 (m, 1H) ; 8.97 (d, J=2 Hz, 1H) ; 9.15 (d, J=6 Hz, 1H).