Fused tricyclic benzimidazoles derivatives as modulators of TNF activity

Abstract

A series of tricyclic benzimidazole derivatives, in particular dihydro-1H-imidazo [1,2-a]benzimidazole, dihydro-1H-pyrrolo [1,2-a]benzimidazole, dihydro-1H-pyrazino[1,2-a]benzimidazole, dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole and dihydrothiazolo[3,4-a]benzimidazolem, and analogs thereof, 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.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable thereof, ##STR00287## wherein n represents an integer equal to 0 or 1; X and Z independently represent a covalent bond; an heteroatom; S(O), S(O).sub.2, S(O)(NR.sup.d), NC(O)R.sup.d, N(CO)OR.sup.d, NS(O).sub.2R.sup.d, N(R.sup.d); or a straight or branched C.sub.1-4 alkylene chain; Y represents aryl or heteroaryl, either of which groups may be optionally substituted by one, two or three substituents selected from halogen, cyano, C.sub.1-6 alkyl, trifluoromethyl, C.sub.1-6 alkoxy, difluoromethoxy, trifluoromethoxy, and C.sub.1-6 alkylsulfonyl; R.sup.1 represents aryl, (C.sub.3-7)heterocycloalkenyl-, heteroaryl, (C.sub.3-7)heterocycloalkyl-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 selected from halogen, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylcarbonyl, (hydroxy)C.sub.1-6 alkyl, (C.sub.3-7)cycloalkyl, C.sub.1-6 alkylsulphonyl, (C.sub.1-6)alkylsulphonyl(C.sub.1-6)alkyl, (C.sub.1-6)alkylsulphoximinyl, heteroaryl, oxo, carboxy, (cyano)C.sub.1-6 alkyl, (halo)C.sub.1-6 alkyl, aminosulphonyl, (C.sub.3-7)cycloalkylsulphonyl and hydroxy(C.sub.1-6)alkylaminosulphonyl; R.sup.2 represents hydrogen, halogen, cyano, trifluoromethyl; or a C.sub.1-6 alkyl which group may be optionally substituted by alkoxycarbonyl; R.sup.3 and R.sup.4 independently represents hydrogen, halogen, or C.sub.1-6 alkyl; R.sup.5a and R.sup.5b independently represent hydrogen, hydroxy, halogen, or trifluoromethyl; or NR.sup.bR.sup.c, S(O).sub.2R.sup.a, OR.sup.a, O(CO)R.sup.d or C.sub.1-6 alkyl; R.sup.6 represents hydrogen, hydroxy, halogen or trifluoromethyl; and R.sup.a represents C.sub.1-6 alkyl which group may be optionally substituted by one or more substituents selected from hydroxy, methoxy, oxo, and 2-oxo-1-pyrrolidinyl; R.sup.b represents hydrogen or C.sub.1-6 alkyl; R.sup.c represents hydrogen, C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; and R.sup.d represents hydrogen or C.sub.1-6 alkyl.

2. The compound as claimed in claim 1 wherein R.sup.1 represents aryl, heteroaryl, or (C.sub.3-7)heterocycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents selected from halogen, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylcarbonyl, (hydroxy)C.sub.1-6 alkyl, (C.sub.3-7)cycloalkyl, C.sub.1-6 alkylsulphonyl, (C.sub.1-6)alkylsulphonyl(C.sub.1-6)alkyl, (C.sub.1-6)alkylsulphoximinyl, heteroaryl, oxo, carboxy, (cyano)C.sub.1-6 alkyl, (halo)C.sub.1-6 alkyl, aminosulphonyl, (C.sub.3-7)cycloalkylsulphonyl and hydroxy(C.sub.1-6)alkylaminosulphonyl.

3. The compound as claimed in claim 1 wherein Y represents phenyl optionally substituted by one or more substituents selected from chloro, fluoro, cyano, methoxy, methylsulphonyl, trifluoromethoxy and difluoromethoxy.

4. The compound as claimed in claim 1 represented by formula (IIC), or a pharmaceutically acceptable salt, ##STR00288## wherein V represents CR.sup.12 or N; R.sup.9 represents hydrogen, hydroxy, oxo or carboxy; C.sub.1-6 alkyl, (hydroxy)C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkylcarbonyl, C.sub.1-6 alkylsulphonyl, (C.sub.1-6)alkylsulphonyl(C.sub.1-6)alkyl, (C.sub.1-6)alkylsulphoximinyl, (C.sub.3-7)cycloalkyl, (C.sub.3-7)heterocycloalkyl, (C.sub.4-9)heterobicycloalkyl, cyano(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkylsulphonyl or (C.sub.1-6)alkylaminosulphonyl, any of which groups may be optionally substituted by one or more substitutents independently selected from halogen, C.sub.1-6 alkyl, C.sub.1-6 alkylsulphonyl, C.sub.1-6 alkylcarbonyl, oxo and carboxy; R.sup.10 and R.sup.11 independently represents hydrogen, halogen, cyano, trifluoromethyl, hydroxyl, NR.sup.bR.sup.c, OR.sup.a, C.sub.1-6 alkyl, or C.sub.1-6 alkylsulphonyl; R.sup.12 represents hydrogen, halogen or C.sub.1-6 alkyl; X is methylene, S(O), oxygen atom or sulphur atom; Y represents phenyl optionally substituted by one or more substituents selected from chloro, fluoro, cyano, methoxy, methylsulphonyl, trifluoromethoxy and difluoromethoxy; R.sup.2 represents hydrogen, halogen, cyano, trifluoromethyl; or a C.sub.1-6 alkyl which group may be optionally substituted by alkoxycarbonyl; R.sup.5a and R.sup.5b independently represent hydrogen, hydroxy, halogen, or trifluoromethyl; or NR.sup.bR.sup.c, S(O).sub.2R.sup.a, OR.sup.a, O(CO)R.sup.d or C.sub.1-6 alkyl; R.sup.a represents C.sub.1-6 alkyl which group may be optionally substituted by one or more substituents selected from hydroxy, methoxy, oxo, and 2-oxo-1-pyrrolidinyl; R.sup.b represents hydrogen or C.sub.1-6 alkyl; R.sup.c represents hydrogen, C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; and R.sup.d represents hydrogen or C.sub.1-6 alkyl.

5. The compound as claimed in claim 2, wherein X represents methylene.

6. The compound as claimed in claim 1, wherein R.sup.5a represents hydrogen or hydroxy.

7. The compound as claimed in claim 1, wherein R.sup.5b represents hydrogen or methyl.

8. The compound as claimed in claim 1, wherein Y represents (difluoromethoxy)phenyl, (difluoromethoxy)(fluoro)phenyl, (chloro)(difluoromethoxy)phenyl or (difluoromethoxy)(cyano)phenyl.

9. The compound as claimed in claim 2, wherein R.sup.9 represents fluorotetrahydropyranyl, fluorooxetanyl, tetrahydropyranyl, isopropyl, methylsulphonyl, hydroxyisopropyl, morpholinyl, cyclopropyl, carboxy-3-azabicyclo[3.2.1]octanyl, piperazinyl, methylpiperazinyl, acetylpiperazinyl, oxodiazepanyl, and (methyl)(carboxy)piperidinyl, hydroxyoxetanyl, methylsulphoximinyl, 2-oxa-7-aza-spiro[3,5]nonanyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, -azabicyclo[3.2.1]octanyl, cyanoisopropyl, fluoroisopropyl, methylsulphoximinyl, cyclopropylsulphonyl, aminosulphonyl, isopropylsulphonyl, and (hydroxy)ethylaminosulphonyl.

10. The compound as claimed in claim 1 represented by formula (IIP) or a pharmaceutically acceptable salt thereof, ##STR00289## wherein X is methylene, S(O), oxygen atom or sulphur atom; Y represents phenyl optionally substituted by one or more substituents selected from chloro, fluoro, cyano, methoxy, methylsulphonyl, trifluoromethoxy and difluoromethoxy; R.sup.2 represents hydrogen, halogen, cyano, trifluoromethyl; or a C.sub.1-6 alkyl which group may be optionally substituted by alkoxycarbonyl; R.sup.5a and R.sup.5b independently represent hydrogen, hydroxy, halogen, or trifluoromethyl; or NR.sup.bR.sup.c, S(O).sub.2R.sup.a, OR.sup.a, O(CO)R.sup.d or C.sub.1-6 alkyl; R.sup.9 represents hydrogen, hydroxy, oxo or carboxy; C.sub.1-6 alkyl, (hydroxy)C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkylcarbonyl, C.sub.1-6 alkylsulphonyl, (C.sub.1-6)alkylsulphonyl(C.sub.1-6)alkyl, (C.sub.1-6)alkylsulphoximinyl, (C.sub.3-7)cycloalkyl, (C.sub.3-7)heterocycloalkyl, (C.sub.4-9)heterobicycloalkyl, cyano(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkylsulphonyl or (C.sub.1-6)alkylaminosulphonyl, any of which groups may be optionally substituted by one or more substitutents independently selected from halogen, C.sub.1-6 alkyl, C.sub.1-6 alkylsulphonyl, C.sub.1-6 alkylcarbonyl, oxo and carboxy; and R.sup.10 and R.sup.11 independently represents hydrogen, halogen, cyano, trifluoromethyl, hydroxy, NR.sup.bR.sup.c, OR.sup.a, C.sub.1-6 alkyl, or C.sub.1-6 alkylsulphonyl.

11. The compound as claimed in claim 1 represented by formula (IIR) or a pharmaceutically acceptable salt thereof, ##STR00290## wherein Z represents an heteroatom; NC(O)R.sup.d, N(CO)OR.sup.d, NS(O).sub.2R.sup.d, or N(R.sup.d); R.sup.1 represents aryl, (C.sub.3-7)heterocycloalkenyl-, heteroaryl, (C.sub.3-7)heterocycloalkyl-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 selected from halogen, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.-6 alkylcarbonyl, (hydroxy)C.sub.1-6 alkyl, (C.sub.3-7)cycloalkyl, C.sub.1-6 alkylsulphonyl, (C.sub.1-6)alkylsulphonyl(C.sub.1-6)alkyl, (C.sub.1-6)alkylsulphoximinyl, heteroaryl, oxo, carboxy (cyano)C.sub.1-6 alkyl, (halo)C.sub.1-6 alkyl, aminosulphonyl, (C.sub.3-7)cycloalkylsulphonyl and hydroxy(C.sub.1-6)alkylaminosulphonyl; R.sup.2 represents hydrogen, halogen, cyano, trifluoromethyl; or a C.sub.1-6 alkyl which group may be optionally substituted by alkoxycarbonyl; and Y represents phenyl optionally substituted by one or more substituents selected from chloro, fluoro, cyano, methoxy, methylsulphonyl, trifluoromethoxy and difluoromethoxy.

12. The compound as claimed in claim 1 represented by formula (IIS) or a pharmaceutically acceptable salt thereof ##STR00291## wherein Z represents an heteroatom; NC(O)R.sup.d, N(CO)OR.sup.d, NS(O).sub.2R.sup.d, or N(R.sup.d); Y represents phenyl optionally substituted by one or more substituents selected from chloro, fluoro, cyano, methoxy, methylsulphonyl, trifluoromethoxy and difluoromethoxy; R.sup.2 represents hydrogen, halogen, cyano, trifluoromethyl; or a C.sub.1-6 alkyl which group may be optionally substituted by alkoxycarbonyl; V represents CR.sup.12 or N; R.sup.9 represents hydrogen, hydroxy, oxo or carboxy; C.sub.1-6 alkyl, (hydroxy)C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkylcarbonyl, C.sub.1-6 alkylsulphonyl, (C.sub.1-6)alkylsulphonyl(C.sub.1-6)alkyl, (C.sub.1-6)alkylsulphoximinyl, (C.sub.3-7)cycloalkyl, (C.sub.3-7)heterocycloalkyl, (C.sub.4-9)heterobicycloalkyl, cyano(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkylsulphonyl or (C.sub.1-6)alkylaminosulphonyl, any of which groups may be optionally substituted by one or more substitutents independently selected from halogen, C.sub.1-6 alkyl, C.sub.1-6 alkylsulphonyl, C.sub.1-6 alkylcarbonyl, oxo and carboxy; R.sup.10 and R.sup.11 independently represents hydrogen, halogen, cyano, trifluoromethyl, hydroxyl, NR.sup.bR.sup.c, OR.sup.a, C.sub.1-6 alkyl, or C.sub.1-6 alkylsulphonyl; and R.sup.12 represents hydrogen, halogen or C.sub.1-6 alkyl.

13. The compound as claimed in claim 1 represented by formula (IIQ), or a pharmaceutically acceptable salt thereof, ##STR00292## wherein Z represents NR.sup.d; R.sup.d represents hydrogen; Y represents phenyl optionally substituted by one or more substituents selected from chloro, fluoro, cyano, methoxy, methylsulphonyl, trifluoromethoxy and difluoromethoxy; R.sup.1 represents aryl, (C.sub.3-7)heterocycloalkenyl-, heteroaryl, (C.sub.3-7)heterocycloalkyl-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 selected from halogen, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.-6 alkylcarbonyl, (hydroxy)C.sub.1-6 alkyl, (C.sub.3-7)cycloalkyl, C.sub.1-6 alkylsulphonyl, (C.sub.1-6)alkylsulphonyl(C.sub.1-6)alkyl, (C.sub.1-6)alkylsulphoximinyl, heteroaryl, oxo, carboxy, (cyano)C.sub.1-6 alkyl, (halo)C.sub.1-6 alkyl, aminosulphonyl, (C.sub.3-7)cycloalkylsulphonyl and hydroxy(C.sub.1-6)alkylaminosulphonyl; and R.sup.2 represents hydrogen, halogen, cyano, trifluoromethyl; or a C.sub.1-6 alkyl which group may be optionally substituted by alkoxycarbonyl.

14. A compound selected from the group consisting of 1-(2,5-dimethylphenyl)-7-(6-methoxy-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-7-(6-methoxy-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 4-[5-[(1S or R)-1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]morpholine; 7-(6-methoxypyridin-3-yl)-1-(2-methylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 1-(2-methylphenyl)-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 7-(6-methoxypyridin-3-yl)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 7-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 1-[2-(difluoromethoxy)phenyl]-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(6-methoxy-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(3-methylsulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(2-methylsulfonyl-4-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(6-methylsulfonyl-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-7-(2,5-dimethyl-3-pyridyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(5-methylsulfonyl-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-(6-methylsulfonyl-3-pyridyl)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-(6-cyclopropyl-3-pyridyl)-1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-7-(3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-7-(6-methylsulfonyl-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-7-(1-methylpyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (4R or S)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-(4-methylsulfonylphenyl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole; (4R or S)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-(6-methylsulfonyl-3-pyridyl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole; (4S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-[4-(methylsulfonylmethyl)phenyl]-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole; tert-butyl (4 S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-(3-methylsulfonylphenyl)-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazole-2-carboxylate; (1S or R)-6-fluoro-1-(4-fluorophenyl)-7-[2-morpholin-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-6-fluoro-1-(2-methoxyphenyl)-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 2-(5-1{(1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)propan-2-ol, (1R or S)-6-fluoro-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1S or R)-6-fluoro-1-[2-(methylsulfonyl)phenyl]-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-methoxy-7-[6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol, (1R or S)-1-(2-chlorophenyl)-6-fluoro-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S,3R or S)-7-(6-cyclopropylpyridin-3-yl)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; 2-(5-1{(1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)propan-2-ol; (1R or S)-7-(6-cyclopropylpyridin-3-yl)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-(6-cyclopropylpyridin-3-yl)-6-fluoro-1-[2-(methylsulfonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-(6-cyclopropylpyridin-3-yl)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 2-(5-1{(1R or S)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)propan-2-ol; (1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R or S,3S or R)-1-2-(difluoromethoxy)phenyl]-3,6-difluoro-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-7-[2-(morpholin-4-yl)pyrimidin-5-yl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 2-(5-{(1R or S,3S or R)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)propan-2-ol; 2(5-{(1R or S,3R or S)-1-2-(difluoromethoxy)phenyl]-3,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)propan-2-ol; (1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-{6-[(methylsulfonyl)methyl]pyridin-3-yl}-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(propan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol, (1R or S,3R or S)-1-[2(difluoromethoxy)phenyl]-6-fluoro-7-[2-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine, 1-(5-{1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)-1,4-diazepan-5-one; 1-[2-(difluoromethoxy)phenyl]-7-[4-(methyl sulfonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 1-[5-[(1S or R)-1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]-1,4-diazepan-5-one; 5-[1-(2-methylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyridin-2(1H)-one; 5-(1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl)pyridin-2(1H)-one; (1S or R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole; (1S or R)-1-[2-(difluoromethoxy)phenyl]-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(6-piperazin-1-yl-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 5-[(1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]-1H-pyridin-2-one; 1-[4-[5-[(1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]-2-pyridyl]piperazin-1-yl]ethenone; (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[6-(4-methylpiperazin-1-yl)-3-pyridyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[6-(4-methylsulfonylpiperazin-1-yl)-3-pyridyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-[6-(methyl sulfonylmethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S, 3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methyl sulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R or S,3S or R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methyl sulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol, (1R or S,3S or R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R or S)-1-[2-(difluoromethoxy)phenyl]-7-(6-piperazin-1-yl-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (4R or S)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-(6-piperazin-1-yl-3-pyridyl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole; (4S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-(4-methylsulfonylphenyl)-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole; (4S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-(2-methylsulfonyl-4-pyridyl)-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole; (4S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-(6-methylsulfonyl-3-pyridyl)-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole; 4-[2-(difluoromethoxy)phenyl]-7-(4-methylsulfonylphenyl)-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole; (4R or S)-4-[2-(difluoromethoxy)phenyl]-7-(6-methylsulfonyl-3-pyridyl)-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole; (4S or R)-4-[2-(difluoromethoxy)phenyl]-7-(2-methylsulfonyl-4-pyridyl)-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole; (4S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-[3-(methylsulfonyl)phenyl]-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole; 1-[(4S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-(4-methyl sulfonylphenyl)-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazol-2-yl]ethenone; (4S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-2-methylsulfonyl-7-(4-methylsulfonylphenyl)-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazole; (4S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-2-methyl-7-(4-methylsulfonylphenyl)-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazole; (4S or R)-4-[2-(difluoromethoxy)phenyl]-7-(4-methylsulfonylphenyl)-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole; (1R or S,3R or S)-6-fluoro-7-[6-(methylsulfonyl)pyridin-3-yl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; 2-(5-{(1S or R,3S or R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyridin-2-yl)propan-2-ol; 2-(5-{(1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyridin-2-yl)propan-2-ol; (1R or S)-7-bromo-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 2-(5-{(1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyridin-2-yl)propan-2-ol hydrochloride; 1-(5-{1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)-4-methylpiperidine-4-carboxylic acid; 1-(5-{3-[2-(difluoromethoxy)phenyl]-7-fluoro-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-6-yl}pyrimidin-2-yl)-4-methylpiperidine-4-carboxylic acid; (1S,5R)-3-[5-[1-1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylic acid; (1S,5R)-3-[5-[(1R or S)-1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylic acid; (1S,5R)-3-[5-[(4S or R)-4-[2-(Difluoromethoxy)phenyl]-8-fluoro-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylic acid dihydrochloride; 3-[2-(difluoromethoxy)phenyl]-7-fluoro-1-methyl-6-[2-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole; (1R,3R)-1-[2-chloro-6-(difluoromethoxy)phenyl]-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R,3S)-1-[2-chloro-6-(difluoromethoxy)phenyl]-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-7-[2-(2-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 2-(5-{(1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)propan-2-ol; 2-(5-{(1R,3S)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)propan-2-ol; 2-(5-{(1R)-1-[2-(difluoromethoxy)phenyl]-3,8-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)propan-2-ol; 2-(5-{(1R)-1-[2-(difluoromethoxy)phenyl]-8-fluoro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)-2-methylpropanenitrile; (1R)-1-[2-(difluoromethoxy)phenyl]-8-fluoro-7-[2-(4-fluorotetrahydro-2H-pyran-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R)-1-[2-(difluoromethoxy)phenyl]-8-fluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R,3R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(4-fluorotetrahydropyran-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-7-[2-(4-fluorotetrahydro-2H-pyran-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R,3R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R,3R)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R,3S)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R,3R)-1-[2-(difluoromethoxy)phenyl]-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R,3S)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 2-(5-{(1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)-2-methylpropanenitrile; (1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-7-[2-(4-fluorotetrahydropyran-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 3-[5-[(1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]oxetan-3-ol; (1R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[6-(1-fluoro-1-methyl-ethyl)-3-pyridyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 9-[5-[(1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]-3,7-dioxa-9-azabicyclo[3.3.1]nonane; 3-(difluoromethoxy)-2-{(1R,3R)-3-hydroxy-7-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl}benzonitrile; 3-(difluoromethoxy)-2-{(1R,3S)-3-hydroxy-7-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl}benzonitrile; (1R,3R)-1-(5-chloro-2-(difluoromethoxy)phenyl)-7-(4-((R)S-methylsulfonimidoyl)phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol, (1R,3R)-1-(5-chloro-2-(difluoromethoxy)phenyl)-7-(4-((S)S-methylsulfonimidoyl)phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol; (1R,3R)-1-(2-(difluoromethoxy)phenyl)-7-(4-((R)S-methylsulfonimidoyl)phenyl)-2,3-dihydro-1-H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol; (1R,3R)-1-(2-(difluoromethoxy)phenyl)-7-(4-((S)S-methylsulfonimidoyl)phenyl)-2,3-dihydro-1-H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol; 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-1H-pyridin-2-one; 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-(2-hydroxy-ethoxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-1H-pyridin-2-one; 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-(3-hydroxy-propoxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-1H-pyridin-2-one; 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-1H-pyridin-2-one; 5-{(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl}-1H-pyridin-2-one; 5-[(1R,3R)-1-(5-Chloro-2-difluoromethoxy-phenyl)-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-1H-pyridin-2-one; 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-6-methyl-1H-pyridin-2-one; 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-4-methyl-1H-pyridin-2-one; 2-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-7-(4-methylsulfonimidoyl-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yloxy]-ethanol; 2-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-7-(4 methanesulfonyl-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yloxy]-ethanol; (1R,3R)-1-(2-Difluoromethoxy-phenyl)-7-(4 methanesulfonyl-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol; (1R,3R)-7-(4-Cyclopropanesulfonyl-phenyl)-1-(2-difluoromethoxy-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol; (1R,3R)-1-(5-Chloro-2-difluoromethoxy-phenyl)-7-(4-methanesulfonyl-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol; (1R,3R)-1-(5-Chloro-2-difluoromethoxy-phenyl)-7-(4-cyclopropanesulfonyl-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol; 2-[(1R,3R)-7-(4-Cyclopropanesulfonyl-phenyl)-1-(2-difluoromethoxy-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yloxy]-ethanol; 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-1-methyl-1H-pyridin-2-one; 4-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-benzenesulfonamide; 2-[(1R,3R)-1-(5-Chloro-2-difluoromethoxy-phenyl)-7-(4-methanesulfonyl-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yloxy]-ethanol; 2-[(1R,3R)-1-(5-Chloro-2-difluoromethoxy-phenyl)-7-(4-cyclopropanesulfonyl-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yloxy]-ethanol; (1R,3R)-1-(2-Difluoromethoxy-phenyl)-7-[4-(propane-2-sulfonyl)-phenyl]-2,3-dihydro-1H-benzo[d]pyrrolo[1,2a]imidazol-3-ol; 4-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide; 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-1,3-dimethyl-1H-pyridin-2-one; 3-Cyclopropyl-5-[(1R,3R)-1-(2-difluoromethoxy-phenyl)-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-1H-pyridin-2-one; (8-anti)-3-(5-{(1R,3R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid; (1R,3R or S)-1-[2-(difluoromethoxy)phenyl]-8-fluoro-7-[4-(methyl sulfonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R,3R or S)-1-[2-(difluoromethoxy)phenyl]-8-fluoro-7-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; (1R,3R or S)-7-[4-(cyclopropylsulfonyl)phenyl]-1-[2-(difluoromethoxy)phenyl]-8-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; and (1R,3R or S)-1-[2-(difluoromethoxy)phenyl]-8-fluoro-7-(6-methoxy-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol.

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

16. A method of treating an inflammatory or autoimmune disorder, which method comprises administering to a patient in need of such a treatment an effective amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

Nomenclature

(1) Compounds were named with the aid of ACD/Name Batch (Network) ver. 12.0 or Accelyrs Draw 4.0

Abbreviations

(2) DCM: Dichloromethane

(3) DMF: N,N-Dimethylformamide

(4) DMSO: Dimethylsulfoxide

(5) Et.sub.2O: Diethyl ether

(6) THF: Tetrahydrofuran

(7) r.t.: Room temperature

(8) br.: Broad

(9) M: Mass

(10) Brine: Saturated aqueous sodium chloride solution

(11) HPLC: High Performance Liquid Chromatography

(12) LCMS: Liquid Chromatography Mass Spectrometry

(13) ES+: Electrospray Positive Ionisation

(14) TEA: Triethylamine

(15) DIPEA: N,N-di-iso-propylethylamine

(16) DIAD: Diisopropyl (E)-1,2-diazenedicarboxylate

(17) CDI: Carbonyl diimidazole

(18) bs.: Broad singlet

(19) Boc.sub.2O: Di-tert butyl dicarbonate

(20) DME dimethoxy ethane

(21) EtOAc: Ethyl acetate

(22) MeOH: Methanol

(23) SiO.sub.2: Silica

(24) h: Hour

(25) AcOH: Acetic acid

(26) RT: retention time

(27) TLC thin layer chromatography

(28) sat. Saturated

(29) Hex hexane

(30) aq. Aqueous

(31) TMSCN: trimethylsilyl cyanide

(32) DAST: diethylaminosulphur trifluoride

(33) The methanolic ammonia solution is made by mixing 100 mL of an aq. solution of 37% w/w of NH.sub.4OH in 900 mL of MeOH.

Analytical Conditions

(34) All NMRs were obtained either at 300 MHz or 400 MHz.

(35) All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware.

(36) All compound GCMS data were determined by using the method below:

(37) Method 1:

(38) ITQ 900 Ion Trap Finnigan mass spectrometer is used for GC-MS analysis. This spectrometer is equipped with a gas chromatograph model Trace GC ultra (Finnigan) fitted with a split/splitless injector. The separation is carried on a FactorFOUR fused-silica column (VF-5MS 15 m?0.25 33 I.D., 1 ?m) from Varian. Helium (purity 99.999%) is used as carried gas. Sample (1 ?L) is injected in splitless mode and the oven temperature is programmed as follows: 50? C. for 5 min, increasing to 280? C. (23? C./min) and holding for 10 min. The ITQ 900 spectrometer operates in electron impact (EI) or chemical ionization (ClCH4). The source temperature is set at 150? C.
All compound LCMS data were determined by using the method below.
Method 2:
Waters Acquity-SQD, Waters Acquity UPLC BEH C18, 2.1?50 mm, 1.7 ?m column
Mobile phase A: 10 mM Ammonium Formate+0.1% Ammonia
Mobile phase B: 95% MeCN+5% H2O+0.1% Ammonia
Gradient program (Flow Rate 1.0 mL/min, Column Temperature 40? C.):

(39) TABLE-US-00001 Time A % B % 0.00 95 5 0.50 95 5 1.75 5 95 2.00 5 95 2.25 95 5
Method 1b:
Waters Acquity-SDS, Waters Acquity BEH C18, 2.1?50 mm, 1.7 ?m column
Mobile phase A: water+0.5% formic acid
Mobile phase B: MeCN+0.035% formic acid
Gradient program (Flow Rate 0.9 mL/min, column temperature 55? C.):

(40) TABLE-US-00002 Time A % B % 0.00 95 5 2.00 5 95 2.60 5 95 2.70 95 5 3.00 95 5
Preparative HPLC
Method 2b:
Column: Merck Purosphere? STAR-RP18; 25 mm?250 mm, 10? at ambient temperature
Eluent: MeCN:H.sub.2O+0.05% TFA (flow rate 25 ml/min)
Gradient: 5:95 (0 min).fwdarw.95:5 (45 min),
Method 2d:
Column: Agilent Prep C-18, 30 mm?250 mm, 10 g at ambient temperature
Eluent: MeCN:H.sub.2O (flow rate 75 ml/min)
Gradient: 10:90 (0 min).fwdarw.90:10 (12.5 min).fwdarw.90:10 (15 min)
It will be apparent to the one skilled in the art that different retention times (RT) may be obtained for GCMS and LCMS data may be obtained id different analytical conditions are used.

Intermediate 1

Ethyl 4-(2,5-dimethylphenyl)-4-hydroxy-butanoate

(41) To a solution of 2,5-dimethylbenzaldehyde (5.00 g, 37.27 mmol) in DCM (75 mL) at ?78? C. was added TiCl.sub.4 (41.0 mL, 40.99 mmol, 1 M in DCM). A solution of (1-ethoxycyclopropoxy)-trimethyl-silane (7.79 g, 44.72 mmol) in DCM (30 mL) was added and the reaction was stirred at ?78? C. for 30 min and warmed to r.t. for 18 h. The reaction was treated with a sat. aq. solution of NH.sub.4Cl (100 mL) and extracted with DCM (100 mL). The organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (8.25 g, 94%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.31 (m, 1H), 7.06 (m, 2H), 5.26 (m, 1H), 4.15 (m, 3H), 2.57 (m, 2H), 2.39 (m, 8H), 1.28 (m, 3H). GC-MS m/z 218.1 (M-18).

Intermediate 2

5-(2,5-dimethylphenyl)-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one

(42) To a solution of Intermediate 1 (2.00 g, 8.46 mmol) in toluene (35 mL) was added (4-methoxyphenyl)methanamine (11.61 g, 84.6 mmol) and the reaction was heated to 150? C. in a sealed tube for 4 h. The reaction was cooled and treated with water (50 mL) and DCM (50 mL), the organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-3% methanolic ammonia/DCM), yielding the title compound (1.20 g, 40%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.04 (m, 4H), 6.92 (s, 1H), 6.82 (d, J 8.6 Hz, 2H), 5.12 (m, 1H), 4.62 (m, 1H), 3.79 (m, 3H), 3.48 (m, 1H), 2.62 (m, 1H), 2.49 (m, 1H), 2.37 (m, 5H), 2.10 (m, 3H). LCMS (ES.sup.+) 310.3 (M+H).sup.+.

Intermediate 3

5-(2,5-dimethylphenyl)pyrrolidin-2-one

(43) Intermediate 2 (1.00 g, 3.23 mmol) and molecular sieves (4 ?, 1.5 g) were suspended in a solution of TFA (4 mL) and anisole (2 mL). The reaction mixture was heated at 110? C. for 18 h in a sealed tube. The reaction mixture was cooled and extracted with DCM (20 mL), washed with water (20 mL), brine (20 mL) and the organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-3% methanolic ammonia/DCM), yielding the title compound (0.12 g, 20%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.28 (m, 1H), 7.19 (m, 1H), 7.11 (m, 1H), 6.55 (m, 1H), 5.04 (m, 1H), 2.75 (m, 1H), 2.57 (m, 2H), 2.46 (s, 3H), 2.43 (s, 3H), 1.99 (m, 1H). LCMS (ES.sup.+) 190.2 (M+H).sup.+.

Intermediate 4 (Method A)

1-(5-bromo-2-nitro-phenyl)-5-(2,5-dimethylphenyl)pyrrolidin-2-one

(44) To a solution of Intermediate 3 (0.14 g, 0.74 mmol) in dry DMF (6 mL), was added sodium hydride (0.04 g, 0.89 mmol) and the reaction mixture was stirred at r.t. for 10 min. A solution of 2-fluoro-4-bromo-nitrobenzene (0.18 g, 0.81 mmol) in DMF (2 mL) was then added and the reaction stirred at r.t. for 18 h. The reaction mixture was diluted with DCM (20 mL), washed with water (20 mL), brine (20 mL) and the organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. The residue was triturated with Et.sub.2O yielding the title compound (0.11 g, 38%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.80 (m, 1H), 7.46 (m, 1H), 7.33 (m, 1H), 7.06 (m, 4H), 5.47 (m, 1H), 2.72 (m, 3H), 2.35 (m, 3H), 2.28 (m, 3H). LCMS (ES.sup.+) 389.2/391.2 (M+H).sup.+.

Intermediate 5

2-bromo-1-[2-(difluoromethoxy)phenyl]ethanone

(45) To a solution of 2-(difluoromethoxy)acetophenone (2.00 g, 10.74 mmol) in MeOH (40 mL) was added, dropwise, bromine (1.72 g, 10.74 mmol) in MeOH (5 mL). The mixture was stirred at 70? C. for 30 min. The reaction was concentrated in vacuo and the residue was washed with water (10 mL) and extracted with DCM (20 mL), dried (MgSO.sub.4) and concentrated in vacuo yielding the title compound (2.58 g, 88%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.86 (m, 1H), 7.62 (m, 1H), 7.38 (m, 1H), 7.21 (m, 1H), 6.67 (m, 1H), 4.54 (m, 2H). GC-MS m/z 265.0/267.0 (M+H).sup.+.

Intermediate 6

Diethyl 2-[2-[2-(difluoromethoxy)phenyl]-2-oxo-ethyl]propanedioate

(46) To a solution of Intermediate 5 (2.50 g, 9.41 mmol) in dry THF (50 mL) was added sodium hydride (0.56 g, 14.12 mmol), the reaction mixture was stirred at 0? C. for 1 h and a solution of diethylmalonate (1.81 g, 11.3 mmol) in THF (5 mL) was added drop wise. The reaction was stirred at r.t. for 18 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo, yielding the title compound (1.52 g, 46%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.77 (dd, J 7.8 Hz, J 1.7 Hz, 1H), 7.68 (m, 1H), 7.35 (m, 3H), 4.14 (m, 6H), 3.93 (t, J 7.1 Hz, 1H), 3.54 (d, J 7.1 Hz, 2H), 1.19 (m, 4H). LCMS (ES.sup.+) 345.2 (M+H).sup.+.

Intermediate 7

Diethyl 2-[2-[2-(difluoromethoxy)phenyl]-2-hydroxyimino-ethyl]propanedioate

(47) To a solution of Intermediate 6 (1.30 g, 3.78 mmol) in pyridine (10 mL) was added hydroxylamine hydrochloride (0.52 g, 7.55 mmol), the reaction mixture was stirred at 60? C. for 20 h and concentrated in vacuo, yielding the title compound (2.00 g, quantitative yield). LCMS (ES.sup.+) 360.3 (M+H).sup.+.

Intermediate 8

Ethyl 5-[2-(difluoromethoxy)phenyl]-2-oxo-pyrrolidine-3-carboxylate

(48) To a solution of Intermediate 7 (2.00 g, 3.78 mmol) in EtOH (50 mL), Ni Raney was added (10% mol). The autoclave was sealed and heated at 60? C., under 10 bar of hydrogen for 18 h. The reaction was filtered through celite and washed with EtOH (20 mL). The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-3% methanolic ammonia/DCM), yielding the title compound (0.36 g, 32%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.06 (m, 4H), 6.34 (m, 1H), 4.92 (m, 1H), 3.92 (m, 2H), 3.18 (m, 1H), 2.68 (m, 1H), 2.06 (m, 1H), 1.39 (m, 1H), 1.02 (m, 3H). LCMS (ES.sup.+) 300.2 (M+H).sup.+.

Intermediate 9

5-[2-(difluoromethoxy)phenyl]pyrrolidin-2-one

(49) To a solution of Intermediate 8 (4.0 g, 13.0 mmol) in EtOH (150 mL), 1 N sodium hydroxide (15 mL, 15 mmol) was added. The mixture was stirred at r.t. for 18 h. The reaction mixture was diluted with water (20 mL) and washed with DCM (50 mL). The organic layer was discarded, the aq. layer was treated with 1N HCl (15 mL, 15 mmol) and extracted with DCM (50 mL). The organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. The residue was dissolved in toluene (50 mL) and the mixture stirred at 110? C. for 18 h. The reaction was diluted with water (20 mL) and extracted with DCM (50 mL); the organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-3% methanolic ammonia/DCM), yielding the title compound (0.64 g, 21%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.44 (m, 1H), 7.35 (m, 1H), 7.24 (m, 1H), 7.14 (m, 1H), 6.59 (m, 1H), 6.18 (m, 1H), 5.15 (m, 1H), 2.67 (m, 1H), 2.46 (m, 2H), 1.97 (m, 1H). LCMS (ES.sup.+) 228.1 (M+H).sup.+.

Intermediate 10

1-(5-bromo-2-nitro-phenyl)-5-[2-(difluoromethoxy)phenyl]pyrrolidin-2-one

(50) The title compound was prepared from Intermediate 9 (0.13 g, 0.57 mmol) and 2-fluoro-4-bromo-nitrobenzene (0.14 g, 0.63 mmol) by the Method A, (0.09 g, 37%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.81 (m, 1H), 7.65 (m, 1H), 7.41 (m, 1H), 7.31 (m, 1H), 7.22 (m, 2H), 7.14 (m, 1H), 6.64 (m, 1H), 5.74 (m, 1H), 2.71 (m, 3H), 2.16 (m, 1H). LCMS (ES.sup.+) 427.2/429.2 (M+H).sup.+.

Intermediates 11 and 12

Enantiomer 1 (5 S or R)-5-[2-(difluoromethoxy)phenyl]pyrrolidin-2-one and enantiomer 2 (5R or S)-5-[2-(difluoromethoxy)phenyl]pyrrolidin-2-one

(51) The following title compounds were isolated from Intermediate 9 (0.47 g) by purification under SFC conditions on Chiralpak IA (50*226, 360 mL/min, 25? C., CO.sub.2+10% MeOH, con: 20 g/l), yielding Intermediate 11 (RT 3.9 min, 0.20 g) and Intermediate 12 (RT 5.4 min, 0.22 g) respectively.

Intermediate 13

Enantiomer 1 (5S or R)-1-(5-bromo-2-nitro-phenyl)-5-[2-(difluoromethoxy)phenyl]pyrrolidin-2-one

(52) The title compound was prepared from Intermediate 11 (0.20 g) and 2-fluoro-4-bromo-nitrobenzene by the Method A, (0.40 g, quantitative yield). LCMS (ES.sup.+) 427.2/429.2 (M+H).sup.+.

Intermediate 14

Enantiomer 2 (5R or S)-1-(5-bromo-2-nitro-phenyl)-5-[2-(difluoromethoxy)phenyl]pyrrolidin-2-one

(53) The title compound was prepared from Intermediate 12 (0.22 g) and 2-fluoro-4-bromo-nitrobenzene by the Method A, (0.40 g, 91%). LCMS (ES.sup.+) 427.2/429.2 (M+H).sup.+.

Intermediate 15

Ethyl 4-hydroxy-4-(o-tolyl)butanoate

(54) To a solution of 2-methylbenzaldehyde (3.0 g, 25.0 mmol) in DCM (60 mL) at ?78? C. was added TiCl.sub.4 (40.0 mL, 40 mmol, 1 M in DCM). A solution of (1-ethoxycyclopropoxy)-trimethyl-silane (8.70 g, 50.0 mmol) in DCM (20 mL) was added and the reaction was stirred at ?78? C. for 30 min and warmed to r.t. for 18 h. The reaction was treated with a sat. aq. solution of NH.sub.4Cl (100 mL) and extracted with DCM (100 mL). The organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-10% EtOAc/hexanes), yielding the title compound as a yellow oil (4.40 g, 79%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.50 (d, 1H), 7.20-7.10 (m, 3H), 5.22 (m, 1H), 4.15 (q, 2H), 2.50 (m, 2H), 2.30 (m, 2H), 2.35 (s, 3H), 1.25 (t, 3H).

Intermediate 16

1-[(4-methoxyphenyl)methyl]-5-(o-tolyl)pyrrolidin-2-one

(55) To a solution of Intermediate 15 (4.40 g, 19.8 mmol) in toluene (20 mL) was added (4-methoxyphenyl)methanamine (27.1 g, 198.0 mmol) and the reaction was heated to 150? C. in a sealed tube for 18 h. The reaction was cooled and treated with water (50 mL) and DCM (50 mL), the organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-35% EtOAc/hexanes), yielding the title compound as a white solid (3.20 g, 55%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.25-7.1 (m, 4H), 6.95 (d, 2H), 6.8 (d, 2H), 5.1 (d, 1H), 4.65 (m, 1H), 5.8 (s, 3H), 3.4 (d, 2H), 2.45-2.3 (m, 4H), 2.1 (s, 3H). LCMS (ES.sup.+) 296.0 (M+H).sup.+.

Intermediate 17

5-(o-tolyl)pyrrolidin-2-one

(56) A solution of Intermediate 16 (3.2 g, 10.0 mmol) in TFA (25 mL) was heated at 150? C. for 18 h in a sealed tube. The cooled reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-3% MeOH/DCM), yielding the title compound as a yellow solid (1.5 g, 79%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.20-7.10 (m, 4H), 4.85 (m, 1H), 3.50 (m, 2H), 2.25 (s, 3H), 2.20 (m, 2H). LCMS (ES.sup.+) 176.0 (M+H).sup.+.

Intermediate 18

1-(5-bromo-2-nitro-phenyl)-5-(o-tolyl)pyrrolidin-2-one

(57) The title compound was prepared from Intermediate 17 (0.75 g, 4.28 mmol) and 2-fluoro-4-bromo-nitrobenzene by the Method A, (0.50 g, 31%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.80 (d, 1H), 7.50 (d, 1H), 7.40 (d, 1H), 7.15 (m, 3H), 7.05 (s, 1H), 5.50 (m, 1H), 2.60-2.70 (m, 3H), 2.35 (s, 3H), 2.10 (m, 1H). LCMS (ES.sup.+) 375.0/377.0 (M+H).sup.+.

Intermediate 19

Ethyl 4-hydroxy-4-phenyl-butanoate

(58) The title compound was prepared in a similar manner to Intermediate 15. To a solution of benzaldehyde (1.00 g, 9.43 mmol) in DCM (30 mL) at ?78? C. was added TiCl.sub.4 (15.0 mL, 15.0 mmol, 1 M in DCM). A solution of (1-ethoxycyclopropoxy)-trimethyl-silane (2.90 g, 14.10 mmol) in DCM (20 mL) was added and the reaction was stirred at ?78? C. for 30 min and warmed to r.t. for 18 h. The reaction was treated with sat. aq. NH.sub.4Cl (20 mL) and extracted with DCM (20 mL). The organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-10% EtOAc/hexanes), yielding the title compound as a yellow oil (1.60 g, 84%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.30-7.20 (m, 5H), 4.95 (m, 1H), 4.10 (q, 2H), 2.45-2.30 (m, 4H), 1.25 (t, 3H).

Intermediate 20

1-[(4-methoxyphenyl)methyl]-5-phenyl-pyrrolidin-2-one

(59) To a solution of Intermediate 19 (2.00 g, 9.61 mmol) in toluene (20 mL) was added (4-methoxyphenyl)methanamine (13.20 g, 96.5 mmol) and the reaction was heated to 150? C. in a sealed tube for 18 h. The reaction was cooled and treated with water (50 mL) and DCM (50 mL), the organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-35% EtOAc/hexanes), yielding the title compound as a yellow solid (2.0 g, 74%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.30-7.40 (m, 3H), 7.15 (d, 2H), 7.00 (d, 2H), 6.80 (d, 2H), 5.05 (d, 1H), 4.40 (m, 1H), 3.80 (s, 3H), 3.40 (d, 1H), 2.50-2.35 (m, 3H), 1.9 (m, 1H). LCMS (ES.sup.+) 282.0 (M+H).sup.+.

Intermediate 21

5-phenylpyrrolidin-2-one

(60) A solution of Intermediate 20 (2.00 g, 7.11 mmol) in TFA (15 mL) was heated at 150? C. for 18 h in a sealed tube. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-3% MeOH/DCM), yielding the title compound as a yellow solid (0.80 g, 70%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.10 (br s, 1H), 7.30-7.40 (m, 5H), 4.65 (m, 1H), 2.50 (m, 1H), 2.20 (m, 2H), 1.75 (m, 1H). LCMS (ES.sup.+) 162.0 (M+H).sup.+.

Intermediate 22

1-(5-bromo-2-nitro-phenyl)-5-phenyl-pyrrolidin-2-one

(61) The title compound was prepared from Intermediate 21 (0.50 g, 3.10 mmol) and 2-fluoro-4-bromo-nitrobenzene by the Method A, (0.25 g, 23%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.80 (d, 1H), 7.30-7.40 (m, 6H), 7.10 (s, 1H), 5.15 (m, 1H), 2.60-2.70 (m, 3H), 2.20 (m, 1H). LCMS (ES.sup.+) 361.0/362.0 (M+H).sup.+.

Intermediate 23 (Method B)

7-bromo-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(62) ##STR00023##

(63) To a solution of Intermediate 22 (0.50 g, 1.38 mmol) in AcOH (5 mL) was added iron powder (0.39 g, 6.94 mmol). The reaction was heated to reflux for 18 h. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was treated with a sat. aq. solution of NaHCO.sub.3 and extracted with EtOAc (10 mL). The organics were washed with water (10 mL) and brine (10 mL), the organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sup.2, 0-3% methanolic ammonia/DCM), yielding the title compound (0.38 g, 87%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.60 (d, 1H), 7.45-7.40 (m, 4H), 7.35-7.30 (m, 2H), 6.90 (s, 1H), 5.40 (m, 1H), 3.20-3.05 (m, 3H), 2.50 (m, 1H). LCMS (ES.sup.+) 312.0/314.0 (M+H).sup.+.

Intermediate 24

(E/Z)-1-(difluoromethoxy)-2-(2-nitrovinyl) benzene

(64) To a solution of 2-(difluoromethoxy)benzaldehyde (10 g, 57.8 mmol) in AcOH (30 mL) was added nitromethane (7.05 g, 115.6 mmol) and ethylenediamine (1.73 g, 28.9 mmol) at 10? C. The reaction mixture was heated at 50? C. for 18 h. After completion of reaction, ice cold water was added and the mixture was stirred vigorously for 1 h. The precipitate was filtered, washed with water and dried in vacuo, yielding the title compound as a yellow solid (11 g, 92%). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.18 (d, J 13.6 Hz, 1H), 7.49-7.71 (m, 3H), 7.22-7.31 (m, 2H), 6.45-6.81 (t, 1H).

Intermediate 25

N-(1-(2-(difluoromethoxy)phenyl)-2-nitroethyl)hydroxylamine

(65) To a solution of Intermediate 24 (11.5 g, 53.48 mmol) in EtOH (40 mL), was added hydroxylamine hydrochloride (7.38 mg, 106.9 mmol) and triethylamine (14.61 mL, 106.9 mmol) at 0? C. The reaction mixture was stirred at r.t. for 18 h. Water was added, extracted with EtOAc and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-65% EtOAc/hexanes) yielding the title compound as a yellow oil (9 g, 77%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.36-7.41 (m, 2H), 7.16-7.25 (m, 2H), 6.41-6.77 (t, 1H), 5.12 (q, J 8.0 Hz, 1H), 4.99 (m, 1H), 4.71 (q, J 12.8 Hz, 1H).

Intermediate 26

1-(2-(difluoromethoxy) phenyl)ethane-1,2-diamine

(66) To a solution of Intermediate 25 (6 g, 24.19 mmol) in MeOH (150 mL), was added 10% palladium on carbon (1.5 g) at 0? C. The reaction mixture was stirred at r.t. under hydrogen atmosphere (100 psi pressure) for 18 h. The reaction mixture was filtered through a celite bed, the filter cake washed with MeOH and the filtrate concentrated in vacuo yielding the title compound as a pale yellow oil (4.7 g, 80%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.60 (d, J 6.8 Hz, 1H), 7.20-7.00 (m, 6H), 4.03 (q, J 11.2 Hz, 1H), 2.83 (dd, J 16.4 Hz, 1H), 2.44 (dd, J 12.4 Hz, 1H), 1.80 (bs, 2H). LCMS (ES.sup.+) RT 1.31 min, 203 (M+H).sup.+.

Intermediate 27

tert-butyl (2-amino-2-(2-(difluoromethoxy)phenyl)ethyl) carbamate

(67) To a solution of Intermediate 26 (4 g, 19.7 mmol) in dry DCM (50 mL), was added triethylamine (2.7 mL, 19.7 mmol) and di-tert-butyl dicarbonate (4.3 g, 19.7 mmol) at 0? C. The reaction mixture was stirred at r.t. for 3 h. Water was added and the mixture extracted with DCM. The organic layer was washed with water and brine, dried over (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in DCM) yielding the title compound as a white solid (3.1 g, 52%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.43 (d, J 7.6 Hz, 1H), 7.19-7.28 (m, 2H), 7.07 (d, J 7.6 Hz, 1H), 6.38-6.75 (t, 1H), 4.85 (bs, 1H), 4.35 (m, 1H), 3.36 (m, 2H), 1.80 (bs, 2H), 1.39 (s, 9H). LCMS (ES.sup.+) RT 2.09 min, 303 (M+H).sup.+.

Intermediate 28

tert-butyl 4-(2-(difluoromethoxy)phenyl)-2-oxoimidazolidine-1-carboxylate

(68) To a solution of Intermediate 27 (6 g, 19.8 mmol) in DCM (80 mL) was added 1,1-carbonyldiimidazole (3.8 g, 23.83 mmol) and the reaction mixture was stirred at r.t. for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO.sub.2, 0-50% EtOAc/hexanes), yielding the title compound as a yellow oil (4.2 g, 64%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.50 (t, J 7.2 Hz, 1H), 7.36-7.24 (m, 2H), 7.10 (d, J 8 Hz, 1H), 6.76-6.39 (t, 1H), 5.08 (dd, J 16 Hz, 1H), 4.27 (t, J 10 Hz, 1H), 3.58 (dd, J 10.8 Hz, 1H), 1.60 (s, 9H).

Intermediate 29

tert-butyl-3-(5-bromo-4-fluoro-2-nitrophenyl)-4-(2-(difluoromethoxy)phenyl)-2-oxoimidazolidine-1-carboxylate

(69) The title compound was prepared in a method similar to Method A. To a solution of Intermediate 28 (2.1 g, 6.4 mmol) in DMF (15 mL) was added Cs.sub.2CO.sub.3 (6.2 g, 19.2 mmol) and 2,5-difluoro-4-bromonitrobenzene (1.7 g, 7.04 mmol). The contents were heated in a sealed tube at 60? C. for 3 h. The reaction mixture was quenched with ice water and the aq. layer was extracted with EtOAc. The organic layer was dried over (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by column (SiO.sub.2, 0-30% EtOAc/hexanes) yielding the title compound as a yellow solid (2.6 g, 74%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.77 (d, J 8 Hz, 1H), 7.63 (d, J 7.6 Hz, 1H), 7.24-7.38 (m, 3H), 7.14 (d, J 8 Hz, 1H), 6.76-6.39 (t, 1H), 5.61 (t, J 16.8 Hz, 1H), 4.38 (t, J 20 Hz, 1H), 3.79 (dd, J 10 Hz, 1H), 1.60 (s, 9H).

Intermediate 30

1-(2-amino-5-bromo-4-fluoro-phenyl)-5-[2-difluoromethoxy)phenyl]imidazolidin-2-one

(70) To a solution of Intermediate 29 (500 mg, 0.91 mmol) in AcOH (6 mL) was added iron powder (252 mg, 4.58 mmol) and at 100? C. for 18 h. The reaction was filtered through a celite bed and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-5% MeOH/DCM), yielding the title compound as an off white solid (210 mg, 55%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.77 (d, J 10 Hz, 1H), 7.54 (d, J 7.6 Hz, 1H), 7.26-7.10 (m, 3H), 7.08 (t, J 16 Hz, 1H), 6.69-6.32 (t, 1H), 5.76 (q, J 17 Hz, 1H), 5.00 (bs, 2H), 4.08 (t, J 18 Hz, 1H), 3.44 (t, J 16.8 Hz, 1H). LCMS (ES.sup.+) RT 2.17 min, 416.1 (M+H).sup.+.

Intermediate 31

6-bromo-3-(2-(difluoromethoxy)phenyl)-7-fluoro-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazole

(71) ##STR00024##

(72) The title compound was prepared by a variation of Method B. To a solution of Intermediate 30 (150 mg, 0.36 mmol) in toluene (5 mL) was added P.sub.2S.sub.5 (160 mg, 0.72 mmol). The reaction mixture was refluxed for 4 h. The reaction mixture was quenched with sat. aq. NaHCO.sub.3 and the aq. layer was extracted with EtOAc. The combined organic layers were washed with water, brine and dried over (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH 95/5) yielding the title compound as an off white solid (50 mg, 35%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.40 (t, J 14.4 Hz, 1H), 7.26-7.10 (m, 4H), 6.84-6.46 (t, 1H), 5.86 (t, J 15 Hz, 1H), 5.60 (bs, 1H), 4.58 (t, J 18 Hz, 1H), 3.89 (dd, J 9.6 Hz, 1H). LCMS (ES.sup.+) RT 2.06 min, 398/400.0 (M+H).sup.+.

Intermediate 32

tert-butyl 3-(5-bromo-2-nitrophenyl)-4-(2-(difluoromethoxy)phenyl)-2-oxoimidazolidine-1-carboxylate

(73) The title compound was prepared in a method similar to Method A. To a solution of Intermediate 28 (200 mg, 0.6 mmol) in DMF (5 mL) were added Cs.sub.2CO.sub.3 (586 mg, 1.8 mmol) and 2-fluoro-4-bromonitrobenzene (147 mg, 0.67 mmol). The reaction mixture was heated in a sealed tube at 60? C. for 3 h. The reaction mixture was quenched by adding ice water and the aq. layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-30%, EtOAc/hexanes) yielding the title compound as a yellow solid (250 mg, 77%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.82 (d, J 8.4 Hz, 1H), 7.66 (d, J 7.6 Hz, 1H), 7.42-7.21 (m, 4H), 7.14 (d, J 8.4 Hz, 1H), 6.77-6.41 (t, 1H), 5.66 (t, J 17.2 Hz, 1H), 4.38 (t, J 20 Hz, 1H), 3.76 (t, J 10.4 Hz, 1H), 1.56 (s, 9H).

Intermediate 33

1-(2-amino-5-bromo-phenyl)-5-[2-(difluoromethoxy)phenyl]imidazolidin-2-one

(74) To a solution of Intermediate 32 (500 mg, 0.94 mmol) in AcOH (5 mL) was added iron powder (260 mg, 4.73 mmol) and the reaction mixture was heated at 100? C. for 4 h. The solvent was concentrated in vacuo, the residue diluted with water and the pH was adjusted to 7 by using sat. aq. NaHCO.sub.3. The mixture was filtered through a celite bed and the filtrate was extracted with EtOAc. The combined organic layers were washed with water, brine and dried over (Na.sub.2SO.sub.4), and concentrated in-vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-5% MeOH/DCM), yielding the title compound as an off white solid (300 mg, 80%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.70 (d, J 8.4 Hz, 1H), 7.54 (d, J 18 Hz, 1H), 7.42-7.11 (m, 4H), 6.90 (m, 1H), 6.62 (d, J 8.8 Hz, 1H), 5.71 (t, J 15.6 Hz, 1H), 3.86 (t, J 16.4 Hz, 1H), 3.15 (t, J 15.2 Hz, 1H). LCMS (ES.sup.+) RT 2.12 min, 398.2 (M+H).sup.+.

Intermediate 34

6-bromo-3-(2-(difluoromethoxy)phenyl)-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazole

(75) ##STR00025##

(76) The title compound was prepared by a variation of Method B. To a solution of Intermediate 33 (500 mg, 1.25 mmol) in toluene (5 mL) was added P.sub.2S.sub.5 (279 mg, 1.25 mmol). The reaction mixture was refluxed for 4 h. The reaction mixture was quenched with a sat. aq. solution of NaHCO.sub.3 and the aq. layer extracted with EtOAc. The combined organic layers were dried over (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-2% MeOH/DCM), yielding the title compound as an off white solid (55 mg, 11%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.40 (t, J 14.4 Hz, 1H), 7.30-7.15 (m, 5H), 7.09 (t, J 7.2 Hz, 1H), 6.86-6.45 (t, 1H), 5.86 (t, J 14.8 Hz, 1H), 5.10 (bs, 1H), 4.56 (t, J 18 Hz, 1H), 3.87 (t, J 14.8 Hz, 1H). LCMS (ES.sup.+) RT 2.48 min, 380.0/382.0 (M+H).sup.+.

Intermediate 35

(5R or S)-1-(5-bromo-4-fluoro-2-nitro-phenyl)-5-[2-(difluoromethoxy)phenyl]pyrrolidin-2-one

(77) The title compound was prepared in a method similar to Method A. To a solution of Intermediate 12 (5.0 g, 22.0 mmol) in MeCN (48 mL) was added 4-bromo-2,5-difluoronitrobenzene (5.76 g, 23.2 mmol) and Cs.sub.2CO.sub.3 (15.77 g, 47.93 mmol). The mixture was stirred at 40? C. for 18 h, and concentrated in vacuo. The residue was treated with brine and partitioned with EtOAc. The aq. layer was extracted with EtOAc, the combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was used in the next step without any further purification. LCMS (ES.sup.+) RT 5.0 min, 445.0/447.0 (M+H).sup.+.

Intermediate 36

1-(5-bromo-4-fluoro-2-nitro-phenyl)-5-[2-(difluoromethoxy)phenyl]pyrrolidin-2-one

(78) To a solution of Intermediate 9 (3.36 g, 14.8 mmol) and 4-bromo-2,5-difluoronitrobenzene (7.04 g, 29.6 mmol) by the Method A (3.31 g, 50%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) ?: 8.10 (d, J 8.3 Hz, 1H), 7.60 (m, 2H), 7.35 (m, 2H), 7.23 (m, 2H), 5.84 (m, 1H), 2.62 (m, 2H), 2.01 (m, 2H). LCMS (ES.sup.+) RT 1.52 min, 445.0/447.0 (M+H).sup.+.

Intermediate 37

1-tert-butyl-4-ethyl 4-methylpiperidine-1,4-dicarboxylate

(79) Ethyl N-Boc-piperidine-4-carboxylate (10.00 g, 36.92 mmol) was dissolved in THF (100 mL) and cooled to ?78? C. LDA (47 mmol, 23 mL) was added and the reaction stirred for 1 h. Iodomethane (81.25 mmol, 5.08 mL) was then added and the reaction stirred for a further 1 h before removing the cold bath and allowing the reaction to warm to r.t. for 30 min. The reaction was quenched with sat. aq. NH.sub.4Cl and partitioned with EtOAc, the organics were extracted and dried (MgSO.sub.4) and concentrated in vacuo, (quantitative yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ?: 4.11 (q, J 7.1 Hz, 2H), 3.61 (dt, J 13.4 Hz, J 4.5 Hz, 2H), 2.95 (d, J 0.3 Hz, 2H), 1.91 (d, J 13.6 Hz, 2H), 1.39 (s, 9H), 1.31 (m, 2H), 1.19 (m, 3H), 1.15 (s, 3H).

Intermediate 38

ethyl 4-methylpiperidine-4-carboxylate; hydrochloride

(80) To a solution of Intermediate 37 (11.0 g, 40.5 mmol) dissolved in 1,4-dioxane (30.0 mL) at 0-5? C. was added HCl (15.2 mL, 4 M in 1,4-dioxane). The mixture was allowed to warm to r.t. and stirred for 18 h. The reaction mixture was concentrated in vacuo and residue washed with diethyl ether, yielding the title compound as an orange solid (5.02 g, 59.6%). .sup.1H NMR (DMSO-d.sub.6) ?: 9.00 (m, 1H), 4.14 (q, J 6.8 Hz, 2H), 3.16 (m, 2H), 2.82 (m, 2H), 2.08 (d, J 14.4 Hz, 2H), 1.65 (m, 2H), 1.22 (m, 6H).

Intermediate 39

[2-(4-ethoxycarbonyl-4-methyl-1-piperidyl)pyrimidin-5-yl]boronic acid

(81) A mixture of 2-chloropyrimidine-5-boronic acid (3.95 g, 24.2 mmol), Intermediate 38 (5.03 g, 24.2 mmol) and triethylamine (60.6 mmol, 8.50 mL) in EtOH (50 mL) was heated at 70? C. for 5 h. The reaction was cooled and partitioned between water (100 mL) and EtOAc (100 mL). The aq. layer was separated and re-extracted with further EtOAc (2?100 mL). The organic layers were combined and washed with brine (100 mL) before separating, drying (MgSO.sub.4), filtering under reduced pressure and concentrating in vacuo, yielding the title compound as a brown foam (quantitative yield). LCMS (ES.sup.+) RT 1.23 min 294.0 (M+H).sup.+.

Intermediate 40

[2-[(1R,5S)-8-methoxycarbonyl-3-azabicyclo[3.2.1]octan-3-yl]pyrimidin-5-yl]boronic acid

(82) (1R,5S)-3-tert-butoxycarbonyl-3-azabicyclo[3.2.1]octane-8-carboxylic acid (9.0 g, 35.3 mmol) was suspended in HCl solution (2.25 M in MeOH) and the reaction heated to reflux for 4 h. The reaction was allowed to cool to r.t. and then concentrated in vacuo to give a white solid. (2-chloropyrimidin-5-yl)boronic acid (5.58 g, 35.2 mmol) was added and the mixture suspended in EtOH (130 mL). Triethylamine (9.90 mL, 70.5 mmol) was added and the reaction heated at 80? C. for 5 h. The reaction was allowed to cool to r.t. and then water was added (30 mL). The reaction mixture was concentrated to around ? volume and then more water added (100 mL). An off-white solid precipitated out, which was filtered and washed with water (2?30 mL) to afford the title compound (8.9 g, 86% yield) as an off-white powder. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? ppm 8.59 (2H, s), 8.02 (2H, s), 4.45 (2H, dd, J 13.1, 3.4 Hz), 3.62 (3H, s), 2.98 (2H, br d, J 12.4 Hz), 2.77 (1H, s), 2.59 (2H, br s), 1.66-1.63 (2H, m), 1.38-1.33 (2H, m). LCMS (ES.sup.+) RT 0.97 min 292.0 (M+H).sup.+.

Intermediates 41 and 42

Enantiomer 1: (5R or S)-5-phenylpyrrolidin-2-one and enantiomer 2: (5S)-5-phenylpyrrolidin-2-one

(83) The title compounds were isolated by purification of Intermediate 20 under SFC conditions on Chiralpak IC (50*264 mm*mm, flow 360 mL/min, 25? C., CO.sub.2+20% EtOH, injection of 7.6 mL, solution at a concentration of 100 g/L. The first eluting enantiomer (RT 6.2 min) was collected and the fractions were evaporated to yield enantiomer 1 (5R or S)-5-phenylpyrrolidin-2-one (arbitrarily attributed as the (5R) enantiomer, 5.34 g). The second eluting enantiomer (RT 9.0 min) was collected and the fractions were evaporated to yield enantiomer 2 (5S or R)-5-phenylpyrrolidin-2-one (arbitrarily attributed as the (5S) enantiomer, 5.58 g). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.33 (m, 5H), 6.34 (m, 1H), 4.75 (t, 1H, J 7.0 Hz), 2.49 (m, 3H), 1.97 (m, 1H). LCMS (ES.sup.+) RT 3.14 min, 162.2 (M+H).

Intermediate 43

Enantiomer 1: (5R or S)-1-(5-bromo-2-nitro-phenyl)-5-phenyl-pyrrolidin-2-one

(84) The title compound was prepared in a method similar to Method A. To a solution of Intermediate 42 (5.34 g, 33.1 mmol) in MeCN (400 mL) was added, 4-bromo-2-fluoro-1-nitro-benzene (8.75 g, 39.8 mmol) and Cs.sub.2CO.sub.3 (23.7 g, 72.9 mmol) and the reaction was heated at 75? C. for 20 h. Water was added and the mixture was extracted three times with EtOAc. The combined organic phases were dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (11.9 g, 100%) which was used in the next step without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.02 (s, 1H), 7.78 (d, 1H, J 8.7 Hz), 7.41 (m, 5H), 7.13 (d, 1H, J 1.6 Hz), 5.16 (t, 1H, J 7.4 Hz), 2.68 (m, 3H), 2.22 (m, 1H). LCMS (ES.sup.+) RT 4.74 min, 361/363 (M+H).

Intermediate 44

Enantiomer 1: (1R or S)-7-bromo-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(85) ##STR00026##

(86) The title compound was prepared from Intermediate 43 (33.1 mmol) by the -Method B (8.2 g, 84%). LCMS (ES.sup.+) RT 4.84 min, 313.0/315.0 (M+H).sup.+.

Intermediate 45

2-[2-(difluoromethoxy)phenyl]thiazolidin-4-one

(87) To a solution of 2-(difluoromethoxy)benzaldehyde (9.87 g, 57.4 mmol) dissolved in toluene (30 mL) were added 2-sulfanylacetic acid (6.87 g, 74.6 mmol) and (NH.sub.4).sub.2CO.sub.3 (28.66 g, 298.3 mmol). The mixture was stirred at 110? C. for 18 h and concentrated in vacuo. The residue was triturated with EtOAc. The obtained precipitate was filtered to yield the title compound as a white solid (8.07 g, 57%). LCMS (ES.sup.+) RT 3.34 min, 246.1 (M+H).

Intermediates 46 and 47

Enantiomer 1: (2R or S)-2-[2-(difluoromethoxy)phenyl]thiazolidin-4-one; enantiomer 2 (2S or R)-2-[2-(difluoromethoxy)phenyl]thiazolidin-4-one

(88) The title compounds were isolated by purification of Intermediate 45 under SFC conditions on Chiralpak AD (50*216 mm*mm, flow 360 mL/min, 25? C., CO.sub.2+20% EtOH for 1.7 min then 40% EtOH for 3 min, injection of 4.45 mL solution at a concentration of 100 g/L). The first eluting enantiomer (RT 1.7 min) was collected and the fractions were evaporated to yield the compound (arbitrarily attributed as the (2R) enantiomer). The second eluting enantiomer (RT 2.7 min) was collected and the fractions were evaporated to yield the compound (arbitrarily attributed as the (2S) enantiomer).

Intermediate 48

3-(5-bromo-2-nitro-phenyl)-2-[2-(difluoromethoxy)phenyl]thiazolidin-4-one

(89) The title compound was prepared from Intermediate 45 (3.03 g, 12.3 mmol) and 4-bromo-2-fluoro-1-nitro-benzene (5.44 g, 24.7 mmol) by the Method A (3.76 g, 68.0%). LCMS (ES.sup.+) RT 4.5 min, 445.0/447.0 (M+H).sup.+.

Intermediate 49

7-bromo-1-[2-(difluoromethoxy)phenyl]-1,3-dihydrothiazolo[3,4-a]benzimidazole

(90) ##STR00027##

(91) The title compound was prepared from Intermediate 48 (3.01 g, 6.76 mmol) and iron (1.89 g, 33.8 mmol) by the Method B. The residue was used in the next step without any further purification. LCMS (ES.sup.+) RT 4.54 min, 397.1/399.1 (M+H).sup.+.

Intermediate 50

5-Ethoxypyrrolidin-2-one

(92) To a solution of succinimide (50 g, 0.50 mol) in EtOH (1.2 L) was added sodium borohydride (48 g, 1.3 mol) at 0? C., and 1M H.sub.2SO.sub.4 solution (100 mL) in EtOH was slowly added over a period of 3 h. Then the reaction mixture was cooled to ?50? C. and acidified to pH 2 by using 6M solution of H.sub.2SO.sub.4. Reaction mixture was stirred at r.t. for 3 h and neutralized by using 2M KOH solution in EtOH. The reaction was concentrated in vacuo. The residue was stirred in chloroform (1.0 L) for 30 min, and filtered through a celite bed. The filtrate was concentrated in-vacuo and the residue was purified by column chromatography (SiO.sub.2, 0-2% MeOH/DCM), yielding the title compound as a white solid (25 g, 38%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.8 (bs, 1H), 4.9 (d, 1H), 3.5-3.6 (m, 1H), 3.3-3.4 (m, 1H), 2.4-2.5 (m, 1H), 2.2-2.3 (m, 2H), 2-2.1 (m, 1H), 1.2 (t, 3H). LCMS (ES.sup.+) (M+H).sup.+ 130.

Intermediate 51

[2-(Morpholin-4-yl)pyrimidin-5-yl]boronic acid

(93) A solution of (2-chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol), morpholine (2.19 mL, 25.26 mmol) and triethylamine (0.9 mL, 6.32 mmol) in ethanol (25 mL) was stirred at 20? C. for 1 h. Water (50 mL) was slowly added to the reaction mixture to form a precipitate that was collected by filtration, to afford the title compound as a cream solid (950 mg, 70%). ?H (250 MHz, DMSO-d.sub.6) 8.63 (s, 2H), 8.05 (s, 2H), 3.68 (ddd, J 23.4, 5.7, 3.9 Hz, 8H). LCMS (ES.sup.+) 210 (M+H).sup.+.

Intermediate 52

5-(2-methoxyphenyl)pyrrolidin-2-one

(94) Under inert atmosphere, dry magnesium metal (540 mg, 23.25 mmol) was suspended in dry THF (15 mL). At 70? C. 1,2-dibromoethane (0.1 mL) and 2-bromo anisole (2.9 mL, 23.25 mmol) were added in succession. The reaction was stirred at 70? C. for 1 h before cooling to 0? C. A solution of Intermediate 50 (1 g, 7.75 mmol) in THF (10 mL) was added. The reaction mixture was stirred at 70? C. for 5 h, before careful addition of water (10 mL) and AcOH (5 mL). The stirring was continued for 30 min at r.t. and extracted in EtOAc (3?50 mL). The organic layer was dried (Na.sub.2SO.sub.4), concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-2% MeOH/DCM), yielding 5-(2-methoxyphenyl)pyrrolidin-2-one as a white solid (600 mg, 40%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.30 (m, 2H), 7.00-6.90 (m, 2H), 5.90 (bs, 1H), 5.10 (t, 1H), 3.90 (s, 3H), 2.70-2.32 (m, 3H), 2 (m, 1H).

Intermediate 53

1-(5-bromo-4-fluoro-2-nitrophenyl)-5-(2-methoxyphenyl)pyrrolidin-2-one

(95) The title compound was prepared in a method similar to Method A. To a solution of Intermediate 52 (600 mg, 3.14 mmol) in DMF (10 mL) was added cesium carbonate (3.06 g, 9.42 mmol), 4-bromo-2,5-difluoro nitrobenzene (747 mg, 3.14 mmol, 1 eq) and heated at 90? C. for 18 h. At r.t., the slurry was poured in ice cold water and extracted with EtOAc (3?70 mL). The organic layer was washed with ice cold water and brine, dried (Na.sub.2SO.sub.4), concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-30% EtOAc/hexanes), yielding 1-(5-bromo-4-fluoro-2-nitrophenyl)-5-(2-methoxyphenyl)pyrrolidin-2-one as a yellow solid (600 g, 46%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.70 (d, 1H), 7.40-7.22 (m, 3H), 7.00-6.90 (m, 2H), 5.60 (t, 1H), 3.90 (s, 3H), 2.80-2.60 (m, 2H), 2.30-2.20 (m, 2H). LCMS (ES.sup.+) 409.0/411.0 (M+H).sup.+.

Intermediate 54

7-bromo-6-fluoro-1-(2-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(96) ##STR00028##

(97) The title compound was prepared from Intermediate 53 (3 g, 7.3 mmol) and Iron powder (1.3 g, 22 mmol) by the Method B (1.5 g, 57%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.50 (d, 1H), 7.30 (t, 1H), 7.10 (d, 1H), 6.90 (d, 1H), 6.82 (t, 1H), 6.90 (d, 1H), 5.90 (t, 1H), 3.90 (s, 3H), 3.20-3.00 (m, 3H), 2.60-2.50 (m, 1H). LCMS (ES.sup.+) 361.0/363.0 (M+H).sup.+.

Intermediates 55 and 56

Enantiomer 1 (1R or S)-7-bromo-6-fluoro-1-(2-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; enantiomer 2 (1S or R)-7-bromo-6-fluoro-1-(2-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(98) ##STR00029##

(99) The title compounds were isolated by chiral purification of 2 g of Intermediate 54 under SFC conditions on Chiralpak AD (50*216 mm*mm, flow 360 mL/min, 25? C., CO2+25% MeOH, injection of 25 mL solution at a concentration of 10 g/L). The first eluting enantiomer (RT 3.4 min) was collected and the fractions were evaporated to yield 863 mg of Intermediate 55. The second eluting enantiomer (RT 5.3 min) was collected and the fractions were evaporated to yield 834 mg of Intermediate 56.

Intermediate 57

Ethyl 4-(2-chlorophenyl)-4-hydroxybutanoate

(100) The title compound was prepared by a similar method to Intermediate 1. To a solution of 2-chlorobenzaldehyde (1.5 g, 10.71 mmol) in DCM (12 mL), was added drop wise TiCl.sub.4 (11.8 mL, 1M in DCM) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane (2.6 mL, 12.8 mmol) at ?78? C. After stirring at ?78? C. for 30 min, the reaction was warmed r.t for 18 h. The reaction was quenched by addition of sat. aq. NH.sub.4Cl (5 mL). The aq. layer was extracted by DCM (2?10 mL) and dried (Na.sub.2SO.sub.4), concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-10% EtOAc/hexanes), yielding the title compound as a yellow oil (1.4 g, 60%). LCMS (ES.sup.+) 243.0 (M+H).sup.+.

Intermediate 58

5-bromo-4-fluoro-2-nitroaniline

(101) A solution of 1-bromo-2,5-difluoro-4-nitrobenzene (2 g, 8.43 mmol) in methanolic ammonia (25 mL) was heated at 60? C. in a sealed tube, for 18 h. The reaction was concentrated in vacuo, and the residue purified by column chromatography (SiO.sub.2, 0-30% EtOAc/hexanes), yielding the title compound as a yellow solid (1.4 g, 73%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.90 (d, 1H), 7.10 (d, 1H), 5.98 (bs, 2H).

Intermediate 59

1-(5-bromo-4-fluoro-2-nitrophenyl)-5-(2-chlorophenyl)pyrrolidin-2-one

(102) In a sealed tube, Intermediate 57 (200 mg, 0.82 mmol), Intermediate 58 (287 mg, 1.23 mmol) and 3 drops of conc. H.sub.2SO.sub.4 in toluene were heated at 160? C. for 10 h. The reaction was cooled to r.t and water (10 mL) was added. The aq. layer was extracted with EtOAc (2?10 mL), and the combined organic layer was washed with water, brine, dried (Na.sub.2SO.sub.4), concentrated in vacuo. The residue purified by column chromatography (SiO.sub.2, 0-40% EtOAc/hexanes), the title compound as a yellow solid (75 mg, 22%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.78 (d, 1H), 7.60 (d, 1H), 7.40-7.25 (m, 4), 5.78 (m, 1H), 2.80-2.65 (m, 3H), 2.15 (m, 1H). LCMS (ES.sup.+) 412.0/414.0 (M+H).sup.+.

Intermediate 60

7-bromo-1-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(103) ##STR00030##

(104) The title compound was prepared from Intermediate 59 (500 mg, 1.21 mmol) and Iron powder (203 mg, 3.64 mmol) by the Method B (300 mg, 68%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.50 (d, 2H), 7.30-7.20 (m, 2H), 7.10 (d, 1H), 6.65 (d, 1H), 5.92 (m, 1H), 3.25-3.15 (m, 3H), 2.56 (m, 1H). LCMS (ES.sup.+) 366.0/368.0 (M+H).sup.+.

Intermediates 61 and 62

Enantiomer 1: (1R or S)-7-bromo-1-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; enantiomer 2 (1S or R)-7-bromo-1-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(105) ##STR00031##

(106) The title compounds were isolated by chiral purification of 478 mg of Intermediate 60 under SFC conditions on Chiralpak IA (50*266 mm*mm, flow 360 mL/min, 25? C., CO.sub.2+20% MeOH, injection of 5.33 mL solution at a concentration of 30 g/L). The first eluting enantiomer 1 (RT 6.3 min) was collected and the fractions were evaporated to yield. Intermediate 61. The second eluting enantiomer 2 (RT 8.2 min) was collected and the fractions were evaporated to yield Intermediate 62.

Intermediate 63

5-(4-fluorophenyl)pyrrolidin-2-one

(107) The title compound was prepared by a method similar to the provided procedure for Intermediate 52. To a solution of magnesium metal (1.1 g, 46.5 mmol) in dry THF (20 mL) was added catalytic 1,2-dibromoethane and 4-fluoro bromobenzene (5.1 mL, 46.5 mmol) in THF (5 mL) over a period of 15 min at 60? C. The reaction mixture was refluxed for 1 h. The reaction was cooled to 0? C. and a solution of Intermediate 50 was added drop wise (2 g, 15.5 mmol) in dry THF (10 mL). The reaction mixture was stirred r.t. for 1 h at 0? C. and then refluxed for 5 h. The reaction mixture was cooled and water (4 mL) was added carefully, followed by AcOH (6 mL). The stirring was continued for 30 min at r.t. and extracted in EtOAc (3?50 mL). The organic layer was dried over Na.sub.2SO.sub.4, concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-2% MeOH/DCM), yielding 5-(4-fluorophenyl)pyrrolidin-2-one as a white solid (1.3 g, 47%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.27 (dd, J 8.7, 4.9 Hz, 2H), 7.05 (t, J 8.5 Hz, 2H), 6.21 (s, 1H), 4.74 (t, J 7.0 Hz, 1H), 2.68-2.33 (m, 3H), 1.94 (dq, J 11.9, 8.1 Hz, 1H). LCMS (ES.sup.+) (M+H).sup.+ 180.

Intermediate 64

1-(5-bromo-4-fluoro-2-nitrophenyl)-5-(4-fluorophenyl)pyrrolidin-2-one

(108) The title compound was prepared in a method similar to Method A. To a solution of Intermediate 63 (2.2 g, 12.2 mmol) in dry DMF (15 mL) was added cesium carbonate (9.98 g, 30.7 mmol) and 4-bromo-2,5-difluoro nitrobenzene (3.1 g, 13.5 mmol). The reaction mixture was stirred at r.t. for 18 h. The reaction mixture was treated with the addition of water (30 mL), and extracted with EtOAc (4?20 mL). The organic layer was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-50% EtOAc/hexanes), yielding the title compound as a yellow solid (2.3 g, 47%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.73 (dd, J=7.6, 2.4 Hz, 1H), 7.35 (ddd, J 8.7, 5.1, 2.4 Hz, 2H), 7.19 (dd, J 6.2, 2.4 Hz, 1H), 7.04 (tt, J 9.7, 2.9 Hz, 2H), 5.17-5.00 (m, 1H), 2.88-2.54 (m, 3H), 2.30-2.10 (m, 1H).

Intermediate 65

7-bromo-6-fluoro-1-(4-fluorophenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(109) ##STR00032##

(110) The title compound was prepared from Intermediate 64 (2.3 g, 5.8 mmol) and Iron powder (975 mg, 17.4 mmol) by the Method B (1.5 g, 74%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.47 (d, J 9.2 Hz, 1H), 7.22-7.02 (m, 4H), 6.93 (d, J 6.0 Hz, 1H), 5.40 (t, J 6.8 Hz, 1H), 3.38-3.01 (m, 3H), 2.54 (ddt, J 14.4, 11.7, 5.1 Hz, 1H). LCMS (ES.sup.+) 349.0/351.0 (M+H).sup.+.

Intermediates 66 and 67

Enantiomer 1: (1S or R)-7-bromo-6-fluoro-1-(4-fluorophenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; enantiomer 2 (1R or S)-7-bromo-6-fluoro-1-(4-fluorophenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(111) ##STR00033##

(112) The title compounds were isolated by chiral purification of 2 g of Intermediate 65 under SFC conditions on Chiralpak AD (50*216 mm*mm, flow 360 mL/min, 25? C., CO2+40% EtOH, injection of 10 mL solution at a concentration of 50 g/L). The first eluting enantiomer 1 (RT 1.9 min) was collected and the fractions were evaporated to yield 1.23 g of Intermediate 66. The second eluting enantiomer 2 (RT 3 min) was collected and the fractions were evaporated to yield 1.19 Intermediate 67.

Intermediate 68

1-bromo-2-(methylsulfanyl)benzene

(113) To a solution of NaOH (1.7 g, 42.50 mmol) in EtOH (15 mL) was added 2-bromo thiophenol (5 g, 26.45 mmol). The reaction mixture was stirred at r.t. for 30 min before cooling to 0? C., and methyl iodide (2.4 mL, 39 mmol) was added. The reaction mixture was stirred at r.t. for 10 h. The reaction mixture was treated with iced water, and extracted with DCM (2?20 mL). The organic layer was washed with water and brine, dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO.sub.2, 0-5% EtOAc/hexanes), yielding the title compound as a yellow oil (4.6 g, 86%). LCMS (ES.sup.+) 203.0/205.0 (M+H).sup.+.

Intermediate 69

5-[2-(methylsulfanyl)phenyl]pyrrolidin-2-one

(114) To a solution of magnesium metal (223 mg, 9.30 mmol) in dry THF (10 mL) was added catalytic 1,2-dibromoethane and Intermediate 68 (1.87 g, 9.30 mmol) in THF (5 mL) over a period of 15 min at 60-65? C. The reaction mixture was refluxed for 1 h. The reaction was cooled to 0? C. and a solution of Intermediate 50 was added drop wise (400 mg, 3.10 mmol) in dry THF (5 mL). The reaction mixture was stirred r.t. for 1 h at 0? C. and then refluxed for 5 h. The reaction mixture was cooled and water (1 mL) was added carefully, followed by AcOH (1 mL). The stirring was continued for 30 min at r.t. and extracted in EtOAc (3?50 mL). The organic layer was dried (Na.sub.2SO.sub.4), concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-2% MeOH/DCM), yielding the title compound as white solid (300 mg, 46%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.35-7.20 (m, 4H), 5.95 (bs, 1H), 5.20 (m, 1H), 2.70 (m, 1H), 2.44 (s, 3H), 2.40 (m, 2H), 1.95 (m, 1H). LCMS (ES.sup.+) (M+H).sup.+ 208.0.

Intermediate 70

1-(5-bromo-4-fluoro-2-nitrophenyl)-5-[2-(methylsulfanyl)phenyl]pyrrolidin-2-one

(115) The title compound was prepared by a similar variation of Method A. To a solution of Intermediate 69 (300 mg, 1.44 mmol) in dry DMF (6 mL) was added cesium carbonate (1.4 g, 4.32 mmol) and 4-bromo-2,5-difluoro nitrobenzene (376 mg, 1.59 mmol). The reaction mixture was stirred at r.t. for 14 h. The reaction mixture was treated with water (5 mL), and extracted with EtOAc (4?10 mL). The organic layer was washed with water, brine and dried (Na.sub.2SO.sub.4), concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-65% EtOAc/hexanes), yielding the title compound as a yellow solid (305 mg, 49%). LCMS (ES.sup.+) 425.0/427.0 (M+H).sup.+.

Intermediate 71

7-bromo-6-fluoro-1-[2-(methylsulfanyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(116) ##STR00034##

(117) The title compound was prepared from Intermediate 70 (300 mg, 0.707 mmol) and Iron powder (118 mg, 2.12 mmol) by the Method B (205 mg, 77%). LCMS (ES.sup.+) 377.0/379.0 (M+H).sup.+.

Intermediate 72

7-bromo-6-fluoro-1-[2-(methylsulfonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(118) ##STR00035##

(119) To a solution of Intermediate 71 (1.9 g, 5.03 mmol) in DCM (25 mL) was added m-CPBA (2.58 g, 15.09 mmol) at 0? C., portion wise. The reaction mixture was stirred at r.t. for 2 h. 5 mL sat. aq. NaHCO.sub.3 was added, and the aq. layer was extracted with DCM (2?10 mL). The organic layer was washed with water, brine and dried (Na.sub.2SO.sub.4), concentrated in vacuo. The residue was purified by flash chromatography (SiO.sub.2, 0-100% EtOAc/hexanes), yielding the title compound as a yellow solid (1.25 g, 60%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.2 (d, 1H), 7.55-7.60 (m, 3H), 6.82-6.9 (m, 2H), 6.4 (m, 1H), 3.4 (m, 1H), 3.25 (s, 3H), 3.15-3.21 (m, 2H), 2.5 (m, 1H). LCMS (ES.sup.+) 409.0/411.0 (M+H).sup.+.

Intermediates 73 and 74

Enantiomer 1: (1S or R)-7-bromo-6-fluoro-1-(2-methylsulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; enantiomer 2 (1R or S)-7-bromo-6-fluoro-1-(2-methylsulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(120) ##STR00036##

(121) The title compounds were isolated by chiral purification of 2.35 g of Intermediate 72 under LC conditions on Chiralpak AD (100*500 mm*mm, flow 300 mL/min, 30? C., CO2+heptane-i-PrOH (1:1), injection of 972 mL solution at a concentration of 1 g/L). The first eluting enantiomer 1 (RT 25 min) was collected and the fractions were evaporated to yield Intermediate 73. The second eluting enantiomer 2 (RT 47 min) was collected and the fractions were evaporated to yield Intermediate 74.

Intermediate 75

5-[2-(trifluoromethyl)phenyl]pyrrolidin-2-one

(122) The title compound was prepared by a method similar to that previously described for Intermediate 52. To a solution of magnesium metal (2.78 g, 116 mmol) in dry THF (80 mL) was added catalytic 1,2-dibromoethane and 2-bromobenzotrifluoride (26 g, 116 mmol) in THF (10 mL) over a period of 20 min at 60-65? C. The reaction mixture was refluxed for 1 h. The reaction was cooled to 0? C. and a solution of Intermediate 50 was added drop wise (5 g, 38.7 mmol) in dry THF (10 mL). The reaction mixture was stirred r.t. for 1 h at 0? C. and then refluxed for 5 h. The reaction mixture was cooled and water (10 mL) was added carefully, followed by AcOH (20 mL). The stirring was continued for 30 min at r.t. and extracted in EtOAc (3?50 mL). The organic layer was dried (Na.sub.2SO.sub.4), concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-2% MeOH/DCM), yielding the title compound as a yellow solid (1.1 g, 13%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.70-7.60 (m, 3H), 7.42 (m, 1H), 5.94 (bs, 1H), 5.18 (m, 1H), 2.70-2.40 (m, 3H), 1.95 (m, 1H). LCMS (ES.sup.+) 230.0 (M+H).sup.+.

Intermediate 76

1-(5-bromo-4-fluoro-2-nitrophenyl)-5-[2-(trifluoromethyl)phenyl]pyrrolidin-2-one

(123) The title compound was prepared by a similar variation of Method A. To a solution of Intermediate 75 (2.7 g, 11.7 mmol) in dry DMF (30 mL) was added cesium carbonate (9.57 g, 29.4 mmol) and 4-bromo-2,5-difluoro nitrobenzene (3 g, 12.9 mmol). The reaction mixture was stirred at r.t. for 18 h. The reaction mixture was treated with the addition of water (5 mL), and extracted with EtOAc (4?10 mL). The organic layer was washed with water and brine, dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-50% EtOAc/hexanes), yielding the title compound as a yellow solid (2.5 g, 47%). LCMS (ES.sup.+) 447.0/449.0 (M+H).sup.+.

Intermediate 77

7-bromo-6-fluoro-1-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(124) ##STR00037##

(125) The title compound was prepared from Intermediate 76 (2.5 g, 5.6 mmol) and iron powder (941 mg, 16.8 mmol) by the Method B (2 g, 89%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.80 (m, 1H), 7.50 (m, 3H), 6.90 (d, 1H), 6.80 (m, 1H), 5.88 (m, 1H), 3.30-3.15 (m, 3H), 2.50 (m, 1H). LCMS (ES.sup.+) 399.0/401.0 (M+H).sup.+.

Intermediates 78 and 79

Enantiomer 1: (1R or S)-7-bromo-6-fluoro-1-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; enantiomer 2 (1S or R)-7-bromo-6-fluoro-1-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(126) ##STR00038##

(127) The title compounds were isolated by chiral purification of 1.95 g of Intermediate 77 under LC conditions on Chiralpak AD (100*500 mm*mm, flow 300 mL/min, 30? C., CO.sub.2+MeOH 100%, injection of 12.5 mL solution at a concentration of 65 g/L). The first eluting enantiomer 1 (RT 12 min) was collected and the fractions were evaporated to yield 880 mg of Intermediate 78. The second eluting enantiomer 2 (RT 21 min) was collected and the fractions were evaporated to yield 880 mg of Intermediate 79.

Intermediate 80

7-bromo-1-(o-tolyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(128) ##STR00039##

(129) The title compound was prepared from Intermediate 18 (0.33 g, 0.88 mmol) and iron powder (0.24 g, 4.4 mmol) by the Method B, (0.20 g, 69%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.60 (d, 1H), 7.30-7.25 (m, 3H), 7.10 (m, 1H), 7.00 (s, 1H), 6.80 (d, 1H), 5.70 (m, 1H), 3.15-3.05 (m, 3H), 2.50 (m, 1H), 2.45 (s, 3H). LCMS (ES.sup.+) 327.0/329.0 (M+H).sup.+.

Intermediate 81

methyl 5-(2,5-dimethylphenyl)-5-oxo-pentanoate

(130) To a solution of p-xylene (21 mL, 170 mmol) and methyl 5-chloro-5-oxo-pentanoate (23.5 mL, 170 mmol), aluminium chloride (24.9 g, 187 mmol) was added slowly portion wise. The reaction was exothermic. After 1 h, p-xylene (40 mL) was added to avoid solidification of the reaction mixture. The reaction was stirred at r.t. for 2 h. DCM (200 mL) was added and the resulting solution was poured on ice and sat. aq. Na.sub.2CO.sub.3. The aluminium salts were filtered and the filtrate was decanted. The aq. layer was extracted with DCM, the organics were washed with 0.1 M NaOH, dried (MgSO.sub.4) and concentrated in vacuo. The residue (27.8 g, 70%) was used without any purification. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.43 (m, 1H), 7.21 (m, 1H), 7.07 (m, 1H), 3.67 (m, 3H), 2.95 (m, 2H), 2.46 (m, 5H), 2.39 (m, 3H), 2.06 (m, 2H). GC-MS(CI) MH+ 235.18.

Intermediate 82

methyl (5Z)-5-(2,5-dimethylphenyl)-5-hydroxyimino-pentanoate

(131) To a solution of Intermediate 81 (1.50 g, 6.40 mmol) in pyridine (5 mL), hydroxylamine hydrochloride (0.89 g, 12.8 mmol) was added. The reaction mixture was heated to 60? C. for 20 h in a sealed tube. The reaction mixture was cooled and concentrated in vacuo. The residue was diluted with EtOH (2?10 mL) and concentrated in vacuo, yielding the title compound in quantitative yield (2.0 g). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.42 (m, 1H), 6.96 (m, 2H), 3.66 (m, 3H), 2.73 (m, 1H), 2.48 (m, 1H), 2.38 (m, 2H), 2.30 (m, 3H), 2.21 (m, 3H), 1.84 (m, 2H). LC-MS: MH+ 250.3.

Intermediate 83

6-(2,5-dimethylphenyl)piperidin-2-one

(132) Intermediate 82 (2.0 g, 8.02 mmol) was dissolved in EtOH (50 mL) and placed in an autoclave. Ni Raney (1.0 g) was added to the mixture. The autoclave was charged with hydrogen (10 bar) and heated at 60? C. for 48 h. The reaction mixture was filtered over celite and concentrated in vacuo. DCM was added, the organic layer was washed with water, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by prep HPLC, yielding 0.25 g of the title compound (19% for the 2 steps) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.16 (m, 1H), 7.00 (m, 2H), 6.04 (m, 1H), 4.75 (m, 1H), 2.47 (m, 2H), 2.27 (m, 6H), 2.09 (m, 1H), 1.94 (m, 1H), 1.79 (m, 1H), 1.59 (m, 1H). LC-MS MH+ 204.2.

Intermediate 84

1-(5-bromo-2-nitro-phenyl)-6-(2,5-dimethylphenyl)piperidin-2-one

(133) The title compound was prepared from Intermediate 83 (0.25 gr, 1.2 mmol) and 4-bromo-2-fluoro-1-nitro-benzene (0.54 g, 2.5 mmol) by the Method A. LCMS (ES.sup.+) 403.2/405.2 (M+H).sup.+.

Intermediate 85

2-(2-(difluoromethoxy)phenyl)oxirane

(134) A mixture of 2-(difluoromethoxy)benzaldehyde (110 g, 639 mmol), tetrabutylammonium iodide (2.360 g, 6.39 mmol) and trimethylsulfonium iodide (156 g, 767 mmol) in DCM (900 ml) and aq. NaOH (50%, 600 ml) was vigorously stirred for 6 days. The reaction mixture was diluted with DCM and water and the layers were separated. The water layer was extracted three times with DCM. The organic layers were combined and washed with water and concentrated in vacuo. The residue was diluted with diethylether, washed with aq. Na.sub.2S.sub.2O.sub.3 (1 M, ?2), water (?2) and brine, and dried (Na.sub.2SO.sub.4) to give the title compound as a yellow oil (135.8 g, 96%). .sup.1H NMR (300 MHz, CDCl.sub.3-d) ? 7.31 (ddd, J 8.0, 6.4, 2.8 Hz, 1H), 7.27-7.17 (m, 2H), 7.13 (d, J 8.0 Hz, 1H), 6.56 (t, J 73.8 Hz, 1H), 4.18 (dd, J 4.1, 2.6 Hz, 1H), 3.17 (dd, J 5.6, 4.2 Hz, 1H), 2.72 (dd, J 5.7, 2.6 Hz, 1H).

Intermediate 86

tert-butyl (1-(2-(difluoromethoxy)phenyl)-2-hydroxyethyl)carbamate

(135) Sodium azide (13.97 g, 215 mmol) and NH.sub.4Cl (11.49 g, 215 mmol) were added to a solution of Intermediate 85 (40 g, 215 mmol) in a mixture of water (80 ml) and MeOH (320 ml). The flask was sealed and the reaction mixture stirred at 50? C. for 18 h. After cooling to r.t. the reaction mixture was flushed with argon and palladium (10 wt % on activated charcoal, 2.287 g, 2.149 mmol) was added. The resulting mixture was stirred under hydrogen atmosphere for 5 hours, purged with argon, filtered over kieselguhr, and rinsed with methanol. To the filtrate, di-tert-butyl dicarbonate (46.9 g, 215 mmol) was added and the mixture was stirred overnight. The mixture was diluted with water and the MeOH was evaporated in vacuo. The formed precipitate was filtered, washed successively with water, taken up in EtOAc, dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was triturated with diethylether to give the title compound as a white solid. (27.2 g, 40%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 7.47-7.39 (m, 1H), 7.34-7.20 (m, 3H), 7.19 (t, J 74.0 Hz, 1 Hz), 7.12 (dd, J 7.9, 1.3 Hz, 1H), 4.99-4.80 (m, 2H), 3.53-3.34 (m, 2H), 1.45-1.10 (m, 9H). LCMS (ES.sup.+) RT1.962 min, 248 [M-tBuOCO+H].sup.+.

Intermediate 87

2-amino-2-(2-(difluoromethoxy)phenyl)ethanol hydrochloride

(136) Intermediate 86 (84.7 g, 279 mmol) was dissolved in 1,4-dioxane (extra dry, 500 ml) and hydrochloric acid in 1,4-dioxane (4 M, 880 mmol, 220 ml) was added. The mixture was stirred overnight. The formed precipitate was filtered, washed with DCM, and dried in vacuo to give the title compound as a white solid (55.8 g, 79%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 8.67 (s, 3H), 7.73 (dd, J 7.7, 1.4 Hz, 1H), 7.47 (td, J 8.1, 1.6 Hz, 1H), 7.39-7.22 (m, 2H), 7.29 (t, J 73.6 Hz, 1H), 5.59 (t, J 5.2 Hz, 1H), 4.51 (t, J 6.0 Hz, 1H), 3.78-3.62 (m, 2H). LCMS (ES.sup.+): RT 2.33 min, 204 [M-Cl].sup.+.

Intermediate 88

(R)-5-(2-difluoromethoxy-phenyl)-morpholin-3-one

(137) To a suspension of sodium hydride (6.67 g, 167 mmol, 60% dispersion in mineral oil, 4.0 eq.) in THF (200 mL) was added Intermediate 87 (10 g, 41.72 mmol, 10 g) and ethyl chloroacetate (1.2 eq., 50.07 mmol, 6.14 g). The reaction mixture was heated at 75? C. for 14 h and then cooled to r.t. The reaction mixture was taken up in Et.sub.2O, washed three times with water and brine, then dried (MgSO.sub.4) and concentrated in vacuo. The residue was washed with iso-Hexane, to give the title compound as a yellow solid (8.4 g) used in the next step without any further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.41 (d, J 7.7 Hz, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 7.06 (m, 1H), 6.51 (m, 1H), 5.05 (m, 1H), 4.02 (m, 1H), 3.67 (m, 1H), 3.59 (dd, J 11.8 Hz, J 6.3 Hz, 1H), 3.40 (q, J 7.0 Hz, 1H). LCMS (ES.sup.+) 244.0 (M+H).sup.+.

Intermediate 89

4-(5-bromo-4-fluoro-2-nitro-phenyl)-5-(2-difluoromethoxy-phenyl)-morpholin-3-one

(138) The title compound was prepared by Intermediate 88 (10.14 g, 41.69 mmol), DMF (35 mL), sodium hydride (1.2 eq., 50.0 mmol, 2.00 g, 60% dispersion in mineral oil) and 4-bromo-2,5-difluoronitrobenzene (1.0 eq, 41.69 mmol, 9.92 g) by the Method A (5.62 g, 29%). .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.67 (m, 1H), 7.30 (m, 3H), 7.00 (m, 2H), 6.35 (m, 1H), 4.37 (m, 4H), 3.96 (m, 1H). LCMS (ES.sup.+) 461/463 (M+H).sup.+.

Intermediate 90

6-(2-(difluoromethoxy)phenyl)piperazin-2-one

(139) To a solution of Intermediate 26 (7.3 g, 36.13 mmol, 1 eq.) in MeCN (30 mL), K.sub.2CO.sub.3 (4.98 g, 36.13 mmol, 1 eq.) and ethyl chloroacetate (4.40 g, 36.13 mmol, 1 eq.) were added at 0? C. The reaction mixture was stirred at r.t. for 18 h. Water was added and the reaction mixture extracted with EtOAc. The organic layer was washed with water and brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-4% MeOH/DCM), yielding the title compound as a white solid (3.2 mg, 36%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.42 (d, J 6.8 Hz, 1H), 7.35-7.23 (m, 2H), 7.10 (d, J 8 Hz, 1H), 6.75-6.38 (t, 1H), 5.01 (m, 1H), 3.56 (s, 2H), 3.30 (d, J 17.6 Hz, 1H), 2.86 (d, J 19.6 Hz, 1H). LCMS (ES.sup.+) RT 1.29 min, 243.1 (M+H).sup.+.

Intermediate 91

tert-butyl 3-(2-(difluoromethoxy)phenyl)-5-oxopiperazine-1-carboxylate

(140) To a solution of Intermediate 90 (3.2 g, 13.22 mmol, 1 eq.) in dry DCM (25 mL), triethylamine (1.6 g, 15.86 mmol, 1.2 eq.) and di-tertbutyl dicarbonate (3.45 g, 15.86 mmol, 1.2 eq.) was added at 0? C. The reaction mixture was stirred at r.t. for 6 h. Water was added and the mixture was extracted with DCM. The organic layer was washed with water and brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-2% MeOH/DCM), yielding the title compound as a white solid (3.2 mg, 71%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.36 (bs, 1H), 7.38 (m, 2H), 7.24 (d, J 6.8 Hz, 1H), 7.17 (d, J 6.8 Hz, 1H), 4.78 (m, 1H), 4.42 (d, J 17.6 Hz, 1H), 3.84 (d, J 12.4 Hz, 1H), 3.77 (d, J 18 Hz, 1H), 3.63 (d, J 11.2 Hz, 1H), 1.10-1.29 (s, 9H). LCMS (ES.sup.+) RT 2.19 min, 287.1 (M+H-.sup.tBu).sup.+.

Intermediate 92

tert-butyl 4-(5-bromo-4-fluoro-2-nitrophenyl)-3-(2-(difluoromethoxy) phenyl)-5-oxopiperazine-1-carboxylate

(141) The title compound was prepared by a variation of Method A. To a solution of Intermediate 91 (5 g, 14.61 mmol, 1 eq.) in dry MeCN (25 mL), K.sub.2CO.sub.3 (6.05 g, 43.5 mmol, 3 eq.) and 4-bromo-2,5-difluoro nitrobenzene (3.4 g, 14.61 mmol, 1 eq.) was added. The mixture was heated at 90? C. for 20 h in a sealed tube. The reaction mixture was cooled, water was added and the mixture was extracted with DCM. The organic layer was washed with water and brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-30% EtOAc/hexanes), yielding the title compound as a yellow solid (1.5 g, 18%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.30 (s, 1H), 7.66 (d, J 6.8 Hz, 1H), 7.27-7.45 (m, 5H), 5.14 (m, 1H), 4.56 (d, J 16.4 Hz, 1H), 4.03 (d, J 15.2 Hz, 2H), 3.18 (d, J 16 Hz, 1H), 1.08-1.34 (s, 9H).

Intermediate 93

tert-butyl 4-(5-bromo-2-nitrophenyl)-3-(2-(difluoromethoxy)phenyl)-5-oxopiperazine-1-carboxylate

(142) The title compound was prepared by a variation of Method A. To a solution of Intermediate 91 (2.92 mmol, 1 eq.) in dry MeCN (15 mL) were added K.sub.2CO.sub.3 (1.2 g, 8.76 mmol, 3 eq.) and 4-bromo-2-fluoro nitrobenzene (511 mg, 3.21 mmol, 1.1 eq.). The mixture was heated at 90? C. in a sealed tube. After 26 h, the reaction mixture was cooled to r.t., water was added and extracted with EtOAc, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-30% EtOAc/hexanes), yielding the title compound as a yellow solid (225 mg, 15%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.05 (d, J 8.4 Hz, 1H), 7.93 (s, 1H), 7.27-7.63 (m, 6H), 5.43 (m, 1H), 4.29-4.38 (m, 3H), 4.03 (d, J 6.8 Hz, 1H), 1.07-1.23 (s, 9H).

Intermediate 94

2-[2-(difluoromethoxy)phenyl]-2-morpholino-acetonitrile

(143) 2-(difluoromethoxy)benzaldehyde (44 g, 255.6 mmol) was added drop wise (temperature kept below 25? C.) to cold (0? C.) morpholine (200 g, 2.3 moles). KCN (20 g, 307.1 mmol, 1.2 eq.) dissolved in 25 mL of water was added and the reaction mixture was stirred for 2.5 h at 80? C. After cooling, the solidified reaction mixture was dissolved in EtOAc (250 mL) and the organic phase was washed with water (250 mL). The aq. layers were extracted 3? with 150 mL of EtOAc. The combined organic layers were washed with water (2?), brine (1?), dried (MgSO.sub.4) and concentrated in vacuo to give the title compound as a pale yellowish oil (65 g) that was used in the next step without any further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ?: 7.60 (dd, J 7.6 Hz, J 1.0 Hz, 1H), 7.45 (m, 1H), 7.29 (m, 2H), 6.50 (dd, J 79.0 Hz, J 70.2 Hz, 1H), 3.68 (m, 5H), 2.62 (m, 4H).

Intermediate 95

2-[2-(difluoromethoxy)phenyl]-2-morpholino-pentanedinitrile

(144) A methanolic KOH solution (30%, 3 mL) was added to a stirred solution of Intermediate 94 (67 g, 249.7 mmol) in 500 mL of THF. Acrylonitrile (20 g, 373.2 mmol, 1.5 eq.) was then added to the mixture and the resulting solution was stirred at r.t. for 3 h. The mixture was concentrated in vacuo, water was added (50 mL) and the mixture was extracted with EtOAc. The extract was washed with water (150 mL), dried (MgSO.sub.4) and concentrated in vacuo to give the title compound as an orange oil (61 g) used in the next step without any further purification. .sup.1H NMR (CDCl.sub.3) ?: 7.68 (dd, J 7.7 Hz, J 1.1 Hz, 1 H), 7.47 (td, J 7.9 Hz, J 1.4 Hz, 1H), 7.30 (m, 2H), 6.54 (dd, J 76.0 Hz, J 71.3 Hz, 1H), 3.74 (t, J 4.5 Hz, 4H), 2.80 (ddd, J 13.7 Hz, J 10.5 Hz, J 6.1 Hz, 1H), 2.71 (m, 2H), 2.55 (ddd, J 13.8 Hz, J 10.2 Hz, J 5.3 Hz, 1H), 2.47 (m, 2H), 2.27 (ddd, J 17.0 Hz, J 10.3 Hz, J 5.3 Hz, 1H), 2.05 (ddd, J 17.1 Hz, J 10.3 Hz, J 6.0 Hz, 1H).

Intermediate 96

4-[2-(difluoromethoxy)phenyl]-4-oxo-butanenitrile

(145) Intermediate 95 (82 g, 255 mmol) was dissolved in a mixture of AcOH (300 mL), water (150 mL) and THF (600 mL) and stirred at r.t. for 24 h. The mixture was then concentrated in vacuo, the orange residue was taken up in EtOAc (800 mL), washed with a 1 N aq. solution of NaOH until pH 8, washed with water, brine, dried (MgSO.sub.4) and concentrated in vacuo to give an orange oil. Purification by chromatography (SiO.sub.2, 0-20% EtOAc/heptane), yield the title compound as a pale yellow oil (45 g, 80%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ?: 7.83 (dd, J 7.8 Hz, J 1.4 Hz, 1H), 7.57 (m, 1H), 7.32 (m, 1H), 7.20 (d, J 8.2 Hz, 1H), 6.65 (t, J 72.9 Hz, 1H), 3.37 (t, J 7.0 Hz, 2H), 2.75 (t, J 7.0 Hz, 2H).

Intermediate 97

5-[2-(difluoromethoxy)phenyl]-3,4-dihydro-2H-pyrrole

(146) Intermediate 96 (20 g, 88.8 mmol) was dissolved in 200 mL of EtOH. 12 g of Ni Raney (washed 1? with EtOH) was added and the resulting mixture was hydrogenated at 1 bar at r.t. for 5.5 h. The mixture was degassed with Argon and filtered on a bed of celite. The greenish filtrates were then concentrated in vacuo to yield the title compound as a light green oil (18.5 g, 98%) used without further purification in the next step. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ?: 7.82 (m, 1H), 7.40 (m, 1H), 7.20 (m, 2H), 6.55 (m, 1H), 4.00 (m, 2H), 2.98 (m, 2H), 2.02 (m, 2H). LCMS (ES.sup.+) RT 2.3 min, 212.0 (M+H).sup.+.

Intermediate 98

2-[2-(difluoromethoxy)phenyl]pyrrolidine

(147) Sodium borohydride (3.71 g, 97.1 mmol, 1 eq.) was added portion wise to a solution of Intermediate 97 (20.5 g, 97.1 mmol) in 200 mL of MeOH. After 1 h of reaction, an additional portion of sodium borohydride (1.85 g, 0.5 eq., 48 mmol) was added and the resulting reaction mixture was stirred at r.t. for 5 h. Water was added to the reaction mixture, and extracted with EtOAc (3?). The combined organics were washed with water (1?), then with brine (1?), dried (MgSO.sub.4), concentrated in vacuo to yield the title compound as a light orange oil used in the next step without any further purification (19.4 g). LCMS (ES.sup.+) RT 2.5 min, 214.0 (M+H).sup.+.

Intermediate 99

1-(5-bromo-4-fluoro-2-nitro-phenyl)-2-[2-(difluoromethoxy)phenyl]pyrrolidine

(148) Intermediate 98 (19.41 g, 91.0 mmol) was added to a solution of 1-bromo-2,5-difluoro-4-nitro-benzene (21.66 g, 91.0 mmol, 1.0 eq.) in MeCN (180 mL). K.sub.2CO.sub.3 (15.25 g, 109.2 mmol, 1.2 eq.) was then added and the resulting reaction mixture was stirred at 80? C. for 14 h. The reaction mixture was filtered and the solvent was concentrated in vacuo to yield orange oil. This residue was taken up in EtOAc and washed with water (1?), dried (MgSO.sub.4), concentrated in vacuo to yield the title compound as an orange oil (37 g, 94%) that was used in the next step without any further purification. LCMS (ES.sup.+) RT 5.7 min, 431.0/433.0 (M+H).sup.+.

Intermediate 100

1-(5-bromo-2-nitro-phenyl)-2-phenyl-pyrrolidine

(149) The title compound was prepared from 2-phenylpyrrolidine and 4-bromo-2-fluoro-1-nitro-benzene following the method described for Intermediate 99. LCMS (ES.sup.+) RT 5.68 min, 347.1/349.2 (M+H).sup.+.

Intermediate 101

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

(150) To a solution of 2-(difluoromethoxy)benzaldehyde (4.7 g, 0.027 mol) in THF (3.44 mL) was added (S)-2-methyl-2-propanesulfinamide (5.62 g, 0.029 mol). Potassium diphosphate dibasic (0.2 eq.) and K.sub.3PO.sub.4 (0.8 eq.) were added and the reaction mixture was stirred at r.t. for 4 h. DCM was added, the reaction mixture was washed with water, dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound as a yellow oil (7 g, 96%) which was used in the next step without purification.

Intermediate 102

ethyl (3R)-3-[[(S)-tert-butylsulfinyl]amino]-3-[2-(difluoromethoxy)phenyl]propanoate

(151) Activated zinc powder (356.4 g, 10 eq.) and dry copper chloride (53.95 g, 1 eq.) in THF (1 L) were heated at reflux for 30 min. A solution of ethyl bromoacetate (227.5 g, 2.5 eq.) in THF (250 mL) was added while keeping a slight and constant reflux. After complete addition, the mixture was heated for 1 h at reflux. At 0? C., a solution of Intermediate 101 (150 g, 1 eq.) in THF (200 mL) was added, the reaction mixture was stirred for 1 h and filtered on celite. Water (300 mL) was added, a solid precipitates, and 1M HCl (1 L) was added until complete dissolution of the precipitate. The mixture was decanted by adding NaCl. The organic phase was washed with brine and concentrated in vacuo. The residue was taken up by DCM (1500 mL), washed with sat. aq. NaHCO.sub.3, dried (MgSO.sub.4) and concentrated in vacuo to yield ethyl 3-(tert-butylsulfinylamino)-3-[2-(difluoromethoxy)phenyl]propanoate (192 g, 97%) which was used in the next step without further purification.

Intermediate 103

ethyl (3R)-3-amino-3-[2-(difluoromethoxy)phenyl]propanoate

(152) To a solution of Intermediate 102 (1.2 g, 3.30 mmol) in Et.sub.2O (10 mL), HCl (4 M in 1,4-dioxane, 6.60 mmol) was added and the mixture was stirred at r.t. for 10 min. Water was added to the reaction mixture and extracted with Et.sub.2O. The aq. phase was brought to basic pH with Na.sub.2CO.sub.3, extracted with EtOAc, dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound, 0.8 g (90%). LCMS (ES.sup.+) 2.83 min, 260 (M+H).sup.+. The absolute configuration of ethyl (3R)-3-amino-3-[2-(difluoromethoxy)phenyl]propanoate confirmed by derivatization with Mosher's reagents (R)-(+)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid & (S)-(?)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid followed by NMR spectroscopy.

Intermediate 104

(3R)-3-amino-3-[2-(difluoromethoxy)phenyl]propan-1-ol

(153) LiBH.sub.4 (1.9 g, 2.2 equiv.) was suspended in THF (150 mL) and the mixture was heated at 55-60? C. A solution of Intermediate 103 (10.28 g, 1 eq.) in THF (40 mL) was added drop wise. The reaction mixture was stirred at 65? C. for 1.5 h, an additional amount of LiBH.sub.4 (2 eq) was added and heating was continued for 3 h. The reaction mixture was then cooled to 0? C. and HCl 5N was added until pH 4. The mixture was washed with DCM and the aq. phase was brought to basic pH with 50% NaOH at 0? C., extracted with a (8.5:1.5) mixture of DCM:MeOH, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by UV directed preparative reverse chromatography, yielding the title compound, (1.79 g, 21%). LCMS (ES.sup.+) 3.34 min 218 (M+H).sup.+.

Intermediate 105

(3R)-3-(5-bromo-4-fluoro-2-nitro-anilino)-3-[2-(difluoromethoxy)phenyl]propan-1-ol

(154) To a solution of 1-bromo-2,5-difluoro-4-nitro-benzene (10.41 g.), Intermediate 104 (1 eq.) in MeCN (200 mL), was added and K.sub.2CO.sub.3 (2 eq.). The reaction mixture was stirred at 70? C. for 16 h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in (1:1) mixture of EtOAc/water and brought to neutral pH with 1N HCl. The organic phase was dried over (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 100% DCM) yielding the title compound (11.6 g, 61%).

Intermediate 106

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

(155) Intermediate 105 (8.865 g, 1.0 eq.) was dissolved in DCM (400 mL). TEMPO (0.01 eq.) was added, and the mixture was cooled to 0? C. and a solution of KBr (0.1 eq.) in 1 mL of water was added, followed by a solution of NaHCO.sub.3 (0.4 eq.) in 8 mL of water. NaOCl (2 eq.) was added drop wise to the reaction mixture. 0.1N NaOH was added, the mixture was extracted twice by DCM, the combined organic phases were washed with 0.1N HCl, and brine, dried over (MgSO.sub.4) and concentrated in vacuo to afford the title compound (8.57 g, 97%).

Intermediate 107

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

(156) Intermediate 106 (35.92 g, 1.0 eq.) and triethylamine (0.1 eq.) are dissolved in DCM (500 mL). Trimethylsilylcyanide (1.2 eq.) was added and the reaction mixture was stirred at rt for 6 h. Water was added, the mixture was extracted twice with DCM, the organic phases are washed with brine, dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound as an oil (40.05 g, 91%).

Intermediate 108

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

(157) ##STR00040##

(158) Intermediate 107 (40.5 g, 1.0 eq.) and iron powder (3 eq.) are dissolved AcOH (70 mL) and the reaction mixture was stirred at 100? C. for 1 h. At r.t., water was added, the mixture was extracted with DCM, the combined organic phases were washed with sat. aq. NaHCO.sub.3, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by chiral chromatography using SFC conditions on Lux-Cell-4 (50*261 mm*mm, flow 360 mL/min, 25? C., CO.sub.2+20% MeOH, injection of 3.66 mL solution at a concentration of 30 g/L). The first eluting diastereomer (RT 5.15 min) was collected and the fractions were evaporated to yield the 1R,3R or S diastereisomer (550 mg, 64.4%). The second eluting diastereomer (RT 7.95 min) was collected and the fractions were evaporated to yield the title compound (90 mg, 10.5%). LCMS (ES.sup.+) RT 4.49 min, 413.0/415.0 (M+H).sup.+.

Intermediate 109

7-bromo-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-methyl-1,2-dihydroimidazo[1,2-a]benzimidazole

(159) ##STR00041##

(160) Intermediate 31 (13 mg, 0.033 mmol) was solubilized in 500 ?L of DMF. At 0? C., sodium hydride (4 mg, 0.100 mmol, 60 mass %) was added. The reaction was continued for 2 h before addition of iodomethane (10 ?L, 0.161 mmol). The reaction was continued at r.t. for 2 h before addition of water (2 mL) and EtOAc (2 mL). The organic layer was washed with brine (2 mL), dried over MgSO.sub.4 and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 50-100% EtOAc in Heptane) yielding the title compound (6 mg, 44%). LCMS (ES.sup.+) RT 4.96 min, 412.0/414.0 (M+H).sup.+.

Intermediate 110

(1R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-8-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(161) ##STR00042##

(162) To Intermediate 103 (5 g, 16.8 mmol) in dry MeCN (40 mL) was added K.sub.2CO.sub.3 (6.9 g, 50 mmol) and 4-bromo-2,3-difluoro nitrobenzene (4.8 g, 20.2 mmol). The reaction mixture was stirred at 80? C. for 18 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2?150 mL). The combined organic layer was washed with water (300 mL), brine (250 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 10% EtOAc in Heptane) yielding a yellow solid (6.2 g, 77%).

(163) To a solution of the intermediate (6.2 g, 13.02 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 the reaction (monitored by TLC), the reaction mixture was quenched with an aqueous solution of ammonium chloride (200 mL). The reaction mixture was diluted with EtOAc (200 mL) and filtered through celite. The filtrate was washed with water (200 mL) and the organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford 3 g (57% yield) of a yellow oil, which was used in the next step without purification.

(164) To a solution of the previous intermediate (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 Na.sub.2SO.sub.4 and concentrated in vacuo to afford 3.25 g of crude material which was used for the next step without purification.

(165) To a solution of the previous intermediate (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 EtOAc (100 mL) and filtered through celite. The organic layer was washed with water (100 mL), brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 0-70% EtOAc in hexane) to afford the title compound as a pale brown solid (0.85 g, 36%). LCMS (ES+) RT 2.42 min, 413.0/415.1 (M+H).sup.+.

Intermediate 111 and 112

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

(166) ##STR00043##

(167) (1R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol was prepared following the procedure described for preparing the intermediate 110 but using 4-bromo-2-fluoro-1-nitro-benzene as reagent in the first step.

(168) To compound (1R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol (100 mg, 0.25 mmol) in DCM (5 mL) was added DAST (0.04 mL, 0.32 mmol) at 0? C. Reaction mixture was stirred for 30 min at the same temperature. After completion of reaction (monitored by TLC), the reaction mixture was quenched with sat. NaHCO.sub.3 solution and extracted with DCM, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 0-20% EtOAc in hexane) to afford a brown oil (30 mg, 30%). LCMS (ES.sup.+) 397 (M+H).sup.+.

(169) The title intermediate was obtained by chiral purification of the above intermediate by chiral purification under SFC conditions on Chiralpak AD (50*216 mm*mm, flow 360 mL/min, 25? C., CO.sub.2+30% i-PrOH, injection of 11 mL solution at a concentration of 45 g/L). The first eluting diastereoisomer (RT 6.00 min) was collected and the fractions were evaporated to yield the title compound, Intermediate 111 (150 mg, 33%). The second eluting diastereoisomer (RT 9.77 min) was collected and the fractions were evaporated to yield the Intermediate 112 (240 mg, 53%).

(170) Single crystal X-Ray diffraction allowed the determination of the absolute configuration of both chiral centers.

Intermediate 113

4-(5-bromopyrimidin-2-yl)tetrahydropyran-4-ol

(171) 5-bromo-2-iodo-pyrimidine (20.02 g, 70.28 mmol) was dissolved in anhydrous toluene (12.5 mL). At ?78? C., n-buthyllitium 2.7 mol/L in hexane (28 mL, 76 mmol) was added, followed by a solution of tetrahydro-4H-pyran-4-one (7.39 g, 73.81 mmol) in anhydrous toluene (3.5 mL). The reaction mixture was stirred at ?78? C. for 1 h. At 0? C., the reaction mixture was quenched by addition of water (200 mL), extracted by 3?100 mL of EtOAc. Combined organic layers were washed with water (100 mL), a saturated solution of brine (2?100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 7-25% EtOAc in heptane) to afford the title compound as a yellow solid (5.2 g, 18%). LCMS basic (ES.sup.+) 241.27 (M+H).sup.+.

Intermediate 114

5-bromo-2-(4-fluorotetrahydropyran-4-yl)pyrimidine

(172) Under Argon atmosphere, Intermediate 113 (0.15 g, 0.58 mmol) was dissolved in dichloromethane (10 mL). At 0? C., diethylaminosulfur trifluoride (0.093 g, 0.58 mmol) was added and the mixture was stirred at 0? C. for 30 minutes. The reaction mixture was quenched by addition of water, extracted by DCM (3?20 mL). Combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 10-20% EtOAc in heptane) to afford the title compound as a white solid (83 mg, 56%). LCMS acid (ES.sup.+) 261.00 (M+H).sup.+

Intermediate 115

2-chloro-6-(difluoromethoxy)benzaldehyde

(173) 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 minutes. 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 minutes. 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 (SiO.sub.2, 5% EtOAc in hexane) yielding the title compound (13.9 g, 53%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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 116

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

(174) To a solution of Intermediate 115 (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%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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 117

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

(175) 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 minutes 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.

(176) 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 minutes. The reaction mixture was cooled to r.t. 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 116 (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%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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 118

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

(177) To a solution of Intermediate 117 (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%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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 119

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

(178) To a solution of Intermediate 118 (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%) as a yellow viscous liquid.

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

Intermediate 120

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

(180) To a solution of Intermediate 119 (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%) as a yellow oil, which was used in the next step without purification.

Intermediate 121

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

(181) To a solution of Intermediate 120 (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 122

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

(182) To a solution of Intermediate 121 (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. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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). LCMS (ES+) RT 2.39 min, 447.0/449.0/451.0 (M+H).sup.+

Intermediates 123 and 124

(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

(183) ##STR00044##

(184) The title compounds were isolated by chiral purification of Intermediate 122 (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 ?m, 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.

(185) (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.

(186) 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, 5 ?m, 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 124 (12.7 g, 50%). .sup.1H NMR (400 MHz, CDCl3) ? 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.+.

(187) 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 123 (6.6 g, 26%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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.+.

(188) Under preparative conditions the order of elution was reversed.

Intermediate 125

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

(189) ##STR00045##

(190) The title compound was also prepared by the following procedure: Intermediate 123 (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 ?L, 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 126

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

(191) Intermediate 126 was prepared from Intermediate 118 (9.3 g, 28.3 mmol) and 4-bromo-2-fluoro-nitrobenzene (7.4 g, 34 mmol), using the same procedure described for preparation of Intermediate 119. The reaction was stirred overnight at 80? C. and purified by chromatography (SiO.sub.2, 10% EtOAc in hexane). Intermediate 126 was obtained as a yellow oil (12.5 g, 90%).

(192) LCMS (ES.sup.+) 493.0/495.0 (M+H).sup.+

Intermediate 127

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

(193) Intermediate 127 was prepared from Intermediate 126 (12.5 g, 25.4 mmol) using the same procedure described for preparation of Intermediate 120. Following work-up the crude Intermediate 127 was purified by chromatography (SiO.sub.2, 15% EtOAc in hexane) yielding Intermediate 127 (9 g, 80%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 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 128

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

(194) Intermediate 128 was prepared from Intermediate 127 (9 g, 20 mmol) using the same procedure described for preparation of Intermediate 121. 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 129

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

(195) ##STR00046##

(196) Intermediate 129 was prepared from Intermediate 128 (9 g, 16.4 mmol) using the same procedure described for preparation of Intermediate 122. 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. LCMS (ES.sup.+) 429.0/431.0 (M+H).sup.+

Intermediates 130 and 131

(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

(197) ##STR00047##

(198) The title compounds were isolated by chiral purification of Intermediate 129 (12.5 g) by 2 successive chiral separation.

(199) First Chiral Separation:

(200) 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 130 (3.63 g, 29%). .sup.1H NMR (400 MHz, DMSO) ? 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.+.

(201) Second Chiral Separation:

(202) 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).

(203) 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.

(204) 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 131 (4.46 g, 36%). .sup.1H NMR (400 MHz, DMSO) ? 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, 0.4H), 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.+.

(205) Under preparative conditions the order of elution was reversed.

Intermediate 132

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

(206) ##STR00048##

(207) The title compound was prepared from the same procedure described for the preparation of Intermediate 125 starting from Intermediate 130 (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.

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

Intermediate 133

3-(5-bromopyrimidin-2-yl)oxetan-3-ol

(209) 5-bromo-2-iodo-pyrimidine (20.02 g, 70.28 mmol) was dissolved in anhydrous toluene (260 mL). At ?78? C., n-buthyllitium 1.6 mol/L in hexane (44 mL, 70.0 mmol) was added drop by drop and following a solution of oxetan-3-one (4.5 mL, 73.3 mmol) in anhydrous dry toluene (40 mL) was added drop by drop. The reaction mixture was stirred at ?78? C. for 1 h. At 0? C., the reaction mixture was quenched by addition on distilled water (500 mL), extracted by 4?200 mL of ethyl acetate. Combined organic layers were washed with solution 2.5M of ascorbic acid, saturated solution of NaCl (200 mL), dried over sodium sulfate and concentrated in vacuo to give crude product which was filtered on celite. The celite was washed with DCM, hot diisopropyl ether, and combined filtrates was concentrated in vacuo. The crude residue obtained was crystallised in mixture of isopropyl ether and toluene yielding the title compound as a yellow solid (1.8 g, 11%). LCMS (ES.sup.+) 231.03 (M+H).sup.+.

Intermediate 134

[3-(5-bromopyrimidin-2-yl)oxetan-3-yl]oxy-trimethyl-silane

(210) Intermediate 133 (2.7 g, 12.85 mmol) and imidazole (0.95 g, 13.9 mmol) were mixed in DCM (9 mL/mmol). Chlorotrimethylsilane (1.52 mL, 16.71, 1.3 eq) was added and the reaction mixture was stirred at r.t. for 1.5 h. Chlorotrimethylsilane (1 mL) was added and the stirring was continued for 3 h. Imidazole (0.450 mg) was then added and the reaction mixture was stirred for a additional 1.5 h. The reaction mixture was filtered, the residue washed with DCM (3?100 mL). The filtrate was washed with distilled water (2?100 mL), a saturated solution of NaCl (100 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow oil (3.7 g, 96%). LCMS (ES.sup.+) 303.17 (M+H).sup.+.

Intermediate 135

5-bromo-2-(3-fluorooxetan-3-yl)pyrimidine

(211) Intermediate 134 (3.53 g, 12.1 mmol) was dissolved in DCM (4.2 mL). At ?78? C., DAST (1.81 mL, 14.2 mmol) was added drop wise. The reaction mixture was stirred a ?78? C. for 0.5 h then stirred at r.t. for 1 h., DAST (0.5 mL, 14.2 mmol) was added and the mixture was stirred 3 h additional. Then DAST (1.0 mL, 7.82 mmol) was added and the mixture was again stirred for 1 h at r.t. A saturated solution of NaHCO.sub.3 was added and after decantation the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 0-20% DCM in heptane) yielding the title compound (0.801 g, 29%). LCMS (ES.sup.+) 233.0 (M+H).sup.+.

Intermediate 136

(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

(212) ##STR00049##

(213) Intermediate 136 was prepared from Intermediate 124 (4.61 g, 10.30 mmol), and 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), by the Method C (3.6 g, 69%). LCMS (ES.sup.+) RT 1.91 min. 505.15/507.15 (M+H).sup.+.

Intermediate 137 Method I

(1R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-3,8-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(214) ##STR00050##

(215) Intermediate 110 (1.0 g, 2.420 mmol) was dissolved in DCM (30 mL). At 0? C., DAST (0.384 mL, 2.904 mmol, 1.2 eq) was added drop wise. The reaction mixture was stirred a 0? C. for 0.5 h. A saturated solution of NaHCO.sub.3 was added and the mixture was extracted by DCM (2?100 mL) and combined organic layers were dried over sodium sulfate, concentrated in vacuo yielding the title compound (0.94 g, 83%). LCMS acid (ES.sup.+) 415.0/417.0 (M+H).sup.+.

Intermediates 138 and 139

(1R,3S or R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-3,8-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole and (1R,3R or S)-7-bromo-1-[2-(difluoromethoxy)phenyl]-3,8-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(216) ##STR00051##

(217) Intermediate 137 was purified by chiral chromatography and the title compounds were isolated under SFC conditions on Chiralpak IA (50*266 mm*mm, flow 360 mL/min, 25? C., CO2/2-PrOH 80/20, injection of 9 mL solution at a concentration of 66 g/L).

(218) The first eluting enantiomer (RT 6 min) was collected and the fractions were evaporated to yield (enantiomer 1) (Intermediate 138).

(219) The second eluting enantiomer (RT 12.19 min) was collected and the fractions were evaporated to yield (enantiomer 2) (Intermediate 139). LCMS (ES.sup.+) 417.19 (M+H).sup.+.

Intermediate 140

9-(5-bromopyrimidin-2-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane

(220) 3,7-dioxa-9-azabicyclo[3.3.1]nonane (0.39 g, 3.0 mmol) and 5-bromo-2-chloropyrimidine (0.61 g, 3.0 mmol) were dissolved in ethanol (5 mL). Triethylamine (0.47 mL, 3.3 mmol) was added and the reaction mixture was heated at 80? C. for 18 h. The reaction mixture was concentrated in vacuo, taken up in EtOAc and remaining starting material was filtered off. The residue was purified by chromatography (SiO.sub.2, 0-100% EtOAc in DCM) yielding the title compound (297 mg, 35%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 8.33 (s, 2H), 4.48 (s, 2H), 4.11 (d, J 11.2 Hz, 4H), 3.93 (d, J 11.8 Hz, 4H). LCMS (ES.sup.+) 286 MH.sup.+.

Intermediate 141

N-[(4-Bromophenyl)(methyl)oxo-?6-sulfanylidene]-2,2,2-trifluoroacetamide

(221) To a suspension of 1-bromo-4-methanesulfinylbenzene (5 g, 22.8 mmol), MgO (3.68 g, 91.3 mmol), tetrakis(acetato-?O)dirhodium(RhRh) (0.25 g, 0.57 mmol) and 2,2,2-trifluoroacetamide (5.16 g, 45.6 mmol) in anhydrous DCM (150 mL) was added bis(acetyloxy)(phenyl)-??3?-iodane (11.03 g, 34.2 mmol) at room temperature. The reaction was left to stir at r.t. for 18 h. The reaction mixture was filtered over celite and the filter cake washed with DCM (30 mL). The filtrate was concentrated in vacuo and purified by column chromatography (SiO2, 0-100% EtOAc in heptane) yielding the title compound as a light yellow oil (5.7 g, 97%). .sup.1H NMR (250 MHz, CDCl.sub.3) ? ppm 7.92-7.75 (m, 4H), 3.45 (s, 3H). LCMS (ES.sup.+) RT 1.27 min, 330.0/332.0 (M+H).sup.+.

Intermediate 142

(4-bromophenyl)-imino-methyl-oxo-?6-sulfane

(222) To a solution of Intermediate 141 (5.7 g, 17.1 mmol) in MeOH (100 mL) was added potassium carbonate (11.6 g, 83.7 mmol). The reaction was left to stir at r.t. for 2 h. The mixture was concentrated in vacuo then diluted with water (50 mL). The product was extracted with EtOAc (3?100 mL). The combined organic fraction was dried (MgSO.sub.4) and concentrated in vacuo to yield the title compound as a yellow oil (4.00 g, 96%). .sup.1H NMR (500 MHz, CDCl.sub.3) ? ppm 7.89-7.83 (m, 2H), 7.70-7.65 (m, 2H), 3.09 (s, 3H), 2.65 (s, 1H). LCMS (ES.sup.+) RT 0.81 min, 234.0/236.0 (M+H).sup.+.

Intermediate 143

Imino-methyl-oxo-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-?-6-sulfane

(223) A solution of Intermediate 142 (4 g, 15.4 mmol) in anhydrous 1,4-dioxane (80 mL) was treated with 4,4,4,4,5,5,5,5-octamethyl-2,2-bi-1,3,2-dioxaborolane (4.69 g, 18.5 mmol) and potassium acetate (4.53 g, 46.1 mmol). The mixture was degassed thoroughly under a stream of nitrogen for 10 minutes prior to the addition of bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; dichloropalladium (0.63 g, 0.77 mmol). The reaction was stirred at 80? C. for 75 min. The reaction was concentrated in vacuo, re-dissolved in EtOAc (200 mL) and washed with water (100 mL). The aqueous phase was re-extracted with EtOAc (50 mL) and the combined organic extracts washed with brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was triturated with heptane afforded the title compound as a brown solid (3.05 g, 60%). .sup.1H NMR (500 MHz, CDCl.sub.3) ? ppm 8.02-7.98 (m, 4H), 3.09 (s, 3H), 1.36 (s, 12H).

Intermediate 144

5-bromo-2-methanesulfinylpyridine

(224) NaIO.sub.4 (9.56 g, 44.69 mmol) was added as a slurry in water (10 mL) to a stirred solution of 5-bromo-2-(methylsulfanyl)pyridine (2.4 g, 11.76 mmol) in acetic acid (40 mL) at r.t. The mixture was stirred at r.t. for 2 h. After this time, a colourless precipitate had formed. The mixture was treated with water (50 mL) upon which the precipitate dissolved. The aqueous acidic mixture was basified through addition of saturated aqueous potassium carbonate solution and the product extracted with EtOAc (3?50 mL). The combined organic phase was washed with 10% aqueous sodium thiosulfate solution (50 mL), dried (Na.sub.2SO.sub.4) and reduced in vacuo to give the crude product as an amber glass (2.52 g) which solidified on standing. Purification by chromatography (SiO.sub.2, 0-100% EtOAc in heptane) afforded the title compound as a pale yellow oil (2.04 g, 79%). ?H (500 MHz, CDCl.sub.3) 8.68 (d, J 2.0 Hz, 1H), 8.08 (dd, J 8.3, 2.2 Hz, 1H), 7.93 (d, J 8.3 Hz, 1H), 2.84 (s, 3H).

Intermediates 145-147

(225) The following intermediates were prepared from the intermediates listed or from commercially available starting materials using methods analogous to the methods described.

(226) TABLE-US-00003 Intermediate Number Name used Method 145 N-[(5-bromopyridin-2-yl)(methyl)oxo- 144 Int141 ?6-sulfanylidene]-2,2,2- trifluoroacetamide ?H (500 MHz, CDCl.sub.3) 8.79 (d, J 1.4 Hz, 1H), 8.22-8.19 (m, 1H), 8.18 (dd, J 8.4, 2.0 Hz, 1H), 3.56 (s, 3H). 146 (5-bromopyridin-2-yl)(imino)methyl-?.sup.6- 145 Int 142 sulfanone ?H (500 MHz, DMSO-d6) 8.88 (d, J 2.2 Hz, 1H), 8.37 (dd, J 8.4, 2.3 Hz, 1H), 8.01 (d, J 8.4 Hz, 1H), 4.54 (s, 1H), 3.17 (s, 3H). 147 Imino(methyl)[5-(tetramethyl-1,3,2- 146 Int 143 dioxaborolan-2-yl)pyridin-2-yl]-?.sup.6- sulfanone ?H (250 MHz, CDCl.sub.3) 8.77 (s, 1H), 8.30 (d, J 6.5 Hz, 1H), 8.04 (d, J 5.3 Hz, 1H), 3.25 (s, 3H), 1.36 (s, 12H).

Intermediates 148 and 149

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

(227) ##STR00052##

(228) (1R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol was prepared following the procedure described for the intermediate 110 using 4-bromo-2-fluoro-1-nitro-benzene as reagent in the first step.

(229) The title compounds were isolated by purification of (1R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol under SFC conditions on Lux-Cell-4 (50*291 mm*mm, flow 360 mL/min, 25? C., CO2/EtOH 75/25, injection of 9.1 mL solution at a concentration of 33 g/L).

(230) The first eluting enantiomer (RT 3 min) was collected and the fractions were evaporated to yield (distereoisomer 1) (Intermediate 148).

(231) The second eluting enantiomer (RT 5 min) was collected and the fractions were evaporated to yield (distereoisomer 1) (Intermediate 149).

Intermediate 150

2-[(1R,3R)-7-Bromo-1-(2-difluoromethoxy-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yloxy]-ethanol

(232) ##STR00053##

(233) NaH (53 mg, 1.33 mmol, 60% in mineral oil) was added to a solution of Intermediate 148 (500 mg, 1.27 mmol) in DMF (1 mL) and the reaction mixture was stirred at r.t. for 30 minutes. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (279 mg, 1.27 mmol) was added and the reaction mixture was stirred for 3 h and distributed between EtOAc (4 mL) and water (4 mL). The phases were separated and the organic phase washed with water (3?2 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was dissolved in MeCN (50 mL), 2N HCl (10 mL) was added and the mixture stirred at r.t. for 45 minutes. Evaporation, lyophilisation and purification via preparative HPLC chromatography (Prep-C18 silica gel, MeCN/water: Gradient from 30/70 to 70/30) yielded the title compound (420 mg, 75.6%); LCMS (ES.sup.+) RT 1.71 min, 438.99 (M+H).sup.+.

Intermediate 151

3-[(1R,3R)-7-Bromo-1-(2-difluoromethoxy-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yloxy]-propan-1-ol

(234) ##STR00054##

(235) The title compound was prepared from Intermediate 148 (600 mg, 1.52 mmol) and 2-(3-bromopropoxy) tetrahydro-2-H-pyran (339 mg, 1.52 mmol) by the analogous method described for the synthesis of Intermediate 150 (420 mg, 61%). LCMS (ES.sup.+) RT 1.73 min, 453.02 (M+H).sup.+.

Intermediate 152

2-[[(1R,3R)-7-bromo-1-[5-chloro-2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]oxy]ethano 1

(236) ##STR00055##

(237) The title compound was prepared from Intermediate 161 (350 mg, 0.81 mmol) as described for the synthesis of intermediate 150 (300 mg, 77.7%). LCMS (ES.sup.+) RT 1.77 min, 473.04 (M+H).sup.+.

Intermediate 153

1-{2-[(1R,3R)-7-Bromo-1-(2-difluoromethoxy-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yloxy]-ethyl}-pyrrolidin-2-one

(238) ##STR00056##

(239) To a solution of Intermediate 148 (300 mg, 0.76 mmol) in DMF (2 mL), NaH (32 mg, 0.80 mmol; 60% in mineral oil) was added at 0? C. The mixture was stirred at 0? C. for 30 minutes. 1-(2-bromomethyl)pyrrolidin-2-one (153 mg, 0.76 mmol) was added and the mixture stirred for another 30 minutes. NaH (32 mg, 0.80 mmol; 60% in mineral oil) was added at 0? C. The mixture was stirred at 0? C. for 30 minutes and 1-(2-bromomethyl)pyrrolidin-2-one (153 mg, 0.76 mmol) was added and the mixture again stirred for 30 minutes. This procedure was repeated 5 times. The reaction mixture was distributed between EtOAc (4 mL) and water (4 mL), the phases were separated and the organic phase washed with water (3?2 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 5% MeOH in DCM) yielding the desired product (100 mg, 26%). LCMS (ES.sup.+) RT 0.816 min, 506.05 (M+H).sup.+.

Intermediate 154

N-[[5-chloro-2-(difluoromethoxy)phenyl]methylene]-2-methyl-propane-2-sulfinamide

(240) The title compound was prepared from 5-chloro-2-difluoromethoxy-benzaldehyde and (S)-(?)-t-butyl sulfinamide following the method described for the preparation of Intermediate 116.

Intermediate 155

Ethyl (3R)-3-[[(S)-tert-butylsulfinyl]amino]-3-[5-chloro-2-(difluoromethoxy)phenyl]propanoate

(241) The title compound was prepared from Intermediate 154 following the method described for the preparation of Intermediate 117.

Intermediate 156

Ethyl (3R)-3-amino-3-[5-chloro-2-(difluoromethoxy)phenyl]propanoate hydrochloride

(242) The title compound was prepared from Intermediate 155 following the method described for the preparation of Intermediate 118.

Intermediate 157

(R)-ethyl-3-((5-bromo-2-nitrophenyl)amino)-3-(5-chloro-2-(difluoromethoxy)phenyl)propanoate

(243) The title compound was prepared from Intermediate 156 and 4-bromo-2-fluoro-1-nitro-benzene following the method described for the preparation of Intermediate 119.

Intermediate 158

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

(244) To a solution of Intermediate 157 (10 g, 20.3 mmol) in anhydrous THF (50 mL) at ?78? C. was added DIBAL-H (40.5 mmol, 1M in toluene) drop wise and the mixture was stirred at ?78? C. After 3 h at ?78? C. further DIBAL-H (40.5 mmol, 1M in toluene) was added. After stirring another 1 h at ?78? C., the reaction mixture was quenched with an aqueous solution of ammonium chloride and allowed to warm up to r.t. After further dilution with an aqueous solution of ammonium chloride, DCM was added. After addition of NaCl to the aqueous phase, the organic phase was separated, washed with NaCl solution and dried over Na.sub.2SO.sub.4 and concentrated in vacuo yielding the title product (9.99 g, quantitative) which was used for the next step without purification.

Intermediate 159

(4R)-4-((5-bromo-2-nitrophenyl)amino)-4-(5-chloro-2-(difluoromethoxy)phenyl)-2-((trimethylsilyl)oxy)butanenitrile

(245) To a solution of Intermediate 158 (9.99 g, 22.22 mmol) in DCM (50 mL) was added ZnI.sub.2 (723 mg, 2.22 mmol), TEA (0.313 mL, 2.22 mmol) and TMSCN (6.08 ml, 44.44 mmol). The reaction mixture was stirred at r.t. for 1 h, diluted with water and the organic phase was separated. The organic layer was washed with NaCl solution and dried over Na.sub.2SO.sub.4 and concentrated in vacuo to yield the title product (11 g, 90%).

Intermediate 160

(R)-7-Bromo-1-(5-chloro-2-difluoromethoxy-phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol

(246) ##STR00057##

(247) To a solution of Intermediate 159 (11 g, 20.04 mmol) in EtOH (80 ml) SnCl.sub.2 (19.39 g, 100.21 mmol) was added and the reaction mixture was heated at 80? C. for 3 h. The reaction mixture was quenched with water (80 mL) and basified to pH 8 using 2 M KOH. The mixture was diluted with EtOAc. After filtration the organic phase was separated, washed with NaCl solution, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 30% EtOAc in heptane) yielding the title compound (4.5 g, 52% yield over 3 steps).

Intermediates 161 and 162

(1R,3R)-7-bromo-1-[5-chloro-2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol and (1R,3S)-7-bromo-1-[5-chloro-2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(248) ##STR00058##

(249) Intermediate 160 was separated by chiral chromatography (Chiralpak AD, 400?100 mm, 20 ?M, heptane/ethanol=3/1, flow=300 ml/min). First eluting distereoisomer 1 (9 min): Intermediate 161 (1.75 g, 20%). LCMS (ES.sup.+) RT 1.75 min, 429 (M+H).sup.+.

(250) Second eluting distereoisomer (16.3 min): Intermediate 162, (1.98 g, 23%). LCMS (ES.sup.+) RT 1.74 min, 428.96 (M+H).sup.+.

Intermediate 163

Methyl (1R,5S)-3-[5-[(1R,3R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylate

(251) ##STR00059##

(252) The title compound was prepared from Example 160 (500 mg, 1.21 mmol) and Intermediate 40 (493 mg, 1.69 mmol) by the Method C (501 mg, 71%). LCMS (ES+) RT 1.49 min, 580.0 (M+H).sup.+

Intermediate 164

(1R,3R or S)-7-bromo-1-[2-(difluoromethoxy)phenyl]-8-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(253) ##STR00060##

(254) Intermediate 107 (40.5 g, 1.0 eq.) and iron powder (3 eq.) are dissolved AcOH (70 mL) and the reaction mixture was stirred at 100? C. for 1 h. At r.t., water was added, the mixture was extracted with DCM, the combined organic phases were washed with sat. aq. NaHCO.sub.3, dried (MgSO.sub.4), and concentrated in vacuo. The residue was purified by chiral chromatography using SFC conditions on Lux-Cell-4 (50*261 mm*mm, flow 360 mL/min, 25? C., CO.sub.2+20% MeOH, injection of 3.66 mL solution at a concentration of 30 g/L). The first eluting diastereomer (RT 5.15 min) was collected and the fractions were evaporated to yield the title compound 1R,3R or S diastereoisomer (550 mg, 64.4%).

Intermediate 165 Method K

tert-butyl 4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazole-2-carboxylate

(255) ##STR00061##

(256) In a microwave vessel (20 ml) Example 12 (300 mg, 586 ?mol) was dissolved in 1,4-dioxane (8 mL) and the solution purged with argon. Then sodium carbonate (124 mg, 1.17 mmol), 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propan-2-ol (186 mg, 703 ?mol) and water (2 mL) were added. This mixture was again purged with argon before tris(dibenzylideneacetone)dipalladium(0) complex (54 mg, 59 ?mol) and tri-tert-butylphosphonium tetrafluoroborate (5 mg, 18 ?mol) were added. After heating for 15 minutes at 100? C. in a microwave oven and cooling to r.t. brine and EtOAc were added and after phase separation the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (M2d) yielding the title compound (211 mg, 63%). LCMS [M 1b](ES.sup.+) RT 1.82 min, 570.3 (M+H).sup.+.

Example 1

7-bromo-1-(2,5-dimethylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(257) ##STR00062##

(258) The title compound was prepared from a solution of Intermediate 4 (0.09 g, 0.23 mmol) in AcOH (1 mL) with iron powder (0.06 g, 1.15 mmol) by Method B (0.09 g, 38%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.63 (m, 1H), 7.35 (dd, J 8.5, 1.5 Hz, 1H), 7.17 (m, 1H), 7.04 (m, 2H), 6.48 (m, 1H), 5.65 (m, 1H), 3.21 (m, 3H), 2.53 (m, 1H), 2.39 (m, 3H), 2.22 (m, 3H). LCMS (ES.sup.+) RT 1.65 min, 341.0/343.0 (M+H).sup.+.

Example 2 Method C

1-(2,5-dimethylphenyl)-7-(6-methoxy-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(259) ##STR00063##

(260) To a solution of Example 1 (0.08 g, 0.23 mmol) and 6-methoxy pyridine 3-yl boronic acid (0.04 g, 0.26 mmol) in 1,4-dioxane/water (6 mL, 10:1) was added K.sub.2CO.sub.3 (0.10 g, 0.70 mmol). The reaction mixture was degassed for 10 minutes and then Pd(PPh.sub.3).sub.4 (0.003 g, 0.01 mmol) was added. The reaction mixture was heated at 100? C. for 20 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water (10 mL), brine (10 mL) and the organic layer was separated, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by prep-HPLC yielding the title compound (0.01 g, 15%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.26 (d, J 2.3 Hz, 1H), 7.84 (m, 1H), 7.70 (m, 1H), 7.43 (dd, J 8.4, 1.5 Hz, 1H), 7.17 (m, 1H), 7.06 (m, 1H), 6.99 (s, 1H), 6.80 (m, 1H), 6.61 (m, 1H), 5.72 (m, 1H), 3.97 (m, 3H), 3.26 (m, 3H), 2.55 (m, 1H), 2.43 (m, 3H), 2.18 (s, 3H). LCMS (ES.sup.+) RT 1.62 min, 370.0 (M+H).sup.+.

Examples 3-13

(261) The following Examples were prepared from the assigned precursor by the Method B.

(262) TABLE-US-00004 Ex- ample Pre- No. cursor Compound Name LCMS 3 Int 10 LCMS (ES.sup.+) RT 1.58 min, 379.0/381.0 (M + H).sup.+. 4 Int 13 LCMS (ES.sup.+) RT 1.58 min, 379.0/381.0 (M + H).sup.+. 5 Int 14 LCMS (ES.sup.+) RT 1.58 min, 379.0/381.0 (M + H).sup.+. 6 Int 35 LCMS (ES.sup.+) RT 4.8 min, 397.0/399.0 (M + H).sup.+. 9 Int 84 LCMS (ES.sup.+) RT 5.1 min, 355.1/357.1 (M + H).sup.+. 10 Int 89 LCMS (ES.sup.+) RT 4.8 min, 413.0/415.0 (M + H).sup.+ 11 Int 36 0 LCMS (ES.sup.+) RT 1.53 min, 397.0/399.0 (M + H).sup.+. 12 Int 92 LCMS (ES.sup.+) RT 2.85 min, 512.0/514.0 (M + H).sup.+. 13 Int 93 LCMS (ES.sup.+) RT 2.73 min, 494.0/496.0 (M + H).sup.+.

Examples 14-102

(263) The following Examples were prepared using Method C from the assigned precursor using the appropriate boronate ester or boronic acid, either available commercially or prepared as set out in the Intermediates above.

(264) TABLE-US-00005 Example No. Precursor Compound Name LCMS 14 Ex 4 LCMS (ES.sup.+) RT 1.55 min, 408.0 (M + H).sup.+. 15 Ex 5 LCMS (ES.sup.+) RT 1.55 min, 408.0 (M + H).sup.+. 16 Ex 4 LCMS (ES.sup.+) RT 1.5 min, 464.0 (M + H).sup.+. 17 Ex. 5 LCMS (ES.sup.+) RT 1.5 min, 464.0 (M + H).sup.+. 18 Int 80 LCMS (ES.sup.+) RT 1.58 min, 356.0 (M + H).sup.+. 19 Int 80 LCMS (ES.sup.+) RT 1.52 min, 412.0 (M + H).sup.+. 20 Int 23 LCMS (ES.sup.+) RT 1.53 min, 342.0 (M + H).sup.+. 21 Int 23 0 LCMS (ES.sup.+) RT 1.47 min, 398.0 (M + H).sup.+. 22 Int 31 LCMS (ES.sup.+) RT 1.39 min, 474.0 (M + H).sup.+. 23 Int 34 LCMS (ES.sup.+) RT 1.36 min, 456.0 (M ' H).sup.+. 24 Ex 6 LCMS (ES.sup.+) RT 4.66 min, 580.44 (M + H).sup.+. 25 Ex 6 LCMS (ES.sup.+) RT 1.54 min, 426.0 (M + H).sup.+. 26 Ex 6 LCMS (ES.sup.+) RT 1.40 min, 396.0 (M + H).sup.+. 27 Ex 6 LCMS (ES.sup.+) RT 1.45 min, 473.0 (M + H).sup.+. 28 Ex 6 LCMS (ES.sup.+) RT 1.41 min, 474.0 (M + H).sup.+. 29 Ex 6 LCMS (ES.sup.+) RT 1.41 min, 474.0 (M + H).sup.+. 30 Ex 6 LCMS (ES.sup.+) RT 1.48 min, 424.0 (M + H).sup.+. 31 Ex 6 0 LCMS (ES.sup.+) RT 1.41 min, 474.0 (M + H).sup.+. 32 Int 44 LCMS (ES.sup.+) RT 1.34 min, 390.0 (M + H).sup.+. 33 Int 44 LCMS (ES.sup.+) RT 1.32 min, 342.0 (M + H).sup.+. 34 Ex 116 LCMS (ES.sup.+) RT 4.4 min, 531.2 (M + H).sup.+. 35 Ex 5 LCMS (ES.sup.+) RT 4.08 min, 562.51 (M + H).sup.+. 36 Ex 5 LCMS (ES.sup.+) RT 2.29 min, 418.0 (M + H).sup.+. 37 Ex 5 LCMS (ES.sup.+) RT 1.39 min, 378.0 (M + H).sup.+. 38 Ex 5 LCMS (ES.sup.+) RT 1.38 min, 456.0 (M + H).sup.+. 39 Ex. 5 LCMS (ES.sup.+) RT 1.35 min, 381.0 (M + H).sup.+. 40 Ex 6 LCMS (ES.sup.+) RT 1.48 min, 414.0 (M + H).sup.+. 41 Ex 6 00 LCMS (ES.sup.+) RT 1.50 min, 410.0 (M + H).sup.+. 42 Int 44 01 LCMS (ES.sup.+) RT 4.66 min, 496.0 (M + H).sup.+. 43 Ex 133 02 LCMS (ES.sup.+) RT 1.39 min, 489.0 (M + H).sup.+. 44 Ex 132 03 LCMS (ES.sup.+) RT 1.39 min, 489.0 (M + H).sup.+. 45 Ex 133 04 LCMS (ES.sup.+) RT 1.37 min, 490.0 (M + H).sup.+. 46 Ex 132 05 LCMS (ES.sup.+) RT 1.37 min, 490.0 (M + H).sup.+. 47 Ex 133 06 LCMS (ES.sup.+) RT 1.50 min, 596.0 (M + H).sup.+. 48 Ex 132 07 LCMS (ES.sup.+) RT 1.50 min, 596.0 (M + H).sup.+. 49 Ex 132 08 LCMS (ES.sup.+) RT 1.34 min, 503.0 (M + H).sup.+. 50 Ex 145 09 LCMS (ES.sup.+) RT 1.53 min, 588.0 (M + H).sup.+. 51 Ex 145 0 LCMS (ES.sup.+) RT 1.53 min, 588.0 (M + H).sup.+. 52 Ex 145 LCMS (ES.sup.+) RT 1.50 min, 589.0 (M + H).sup.+. 53 Ex 145 LCMS (ES.sup.+) RT 1.50 min, 589.0 (M + H).sup.+. 54 Ex 146 LCMS (ES.sup.+) RT 1.50 min, 589.0 (M + H).sup.+. 55 Ex 13 LCMS (ES.sup.+) RT 1.53 min, 570.0 (M + H).sup.+. 56 Ex 148 LCMS (ES.sup.+) RT 1.41 min, 571.0 (M + H).sup.+. 57 Ex 147 LCMS (ES.sup.+) RT 1.41 min, 571.0 (M + H).sup.+. 58 Ex 147 LCMS (ES.sup.+) RT 1.41 min, 571.0 (M + H).sup.+. 59 Ex 145 LCMS (ES.sup.+) RT 1.45 min, 588.0 (M + H).sup.+. 60 Ex 128 LCMS (ES.sup.+) RT 1.24 min, 424.0 (M + H).sup.+. 61 Int 66 0 LCMS (ES.sup.+) RT 1.47 min, 434.0 (M + H).sup.+. 62 Int 67 LCMS (ES.sup.+) RT 1.47 min, 434.0 (M + H).sup.+. 63 Int 55 LCMS (ES.sup.+) RT 1.51 min, 446.0 (M + H).sup.+. 64 Int 56 LCMS (ES.sup.+) RT 1.51 min, 446.0 (M + H).sup.+. 65 Ex 162 LCMS (ES.sup.+) RT 1.46 min, 485.0 (M + H).sup.+. 66 Int 78 LCMS (ES.sup.+) RT 1.59 min, 484.0 (M + H).sup.+. 67 Int 79 LCMS (ES.sup.+) RT 1.59 min, 484.0 (M + H).sup.+. 68 Int 73 LCMS (ES.sup.+) RT 1.37 min, 494.0 (M + H).sup.+. 69 Ex 165 LCMS (ES.sup.+) RT 1.46 min, 485.0 (M + H).sup.+. 70 Ex 165 LCMS (ES.sup.+) RT 1.60 min, 556.0 (M + H).sup.+. 71 Ex 162 0 LCMS (ES.sup.+) RT 1.60 min, 556.0 (M + H).sup.+. 72 Int 74 LCMS (ES.sup.+) RT 1.38 min, 494.0 (M + H).sup.+. 73 Ex 162 LCMS (ES.sup.+) RT 1.38 min, 510.0 (M + H).sup.+. 74 Ex 161 LCMS (ES.sup.+) RT 1.38 min, 496.0 (M + H).sup.+. 75 Int 61 LCMS (ES.sup.+) RT 1.55 min, 450.0 (M + H).sup.+. 76 Int 62 LCMS (ES.sup.+) RT 1.55 min, 450.0 (M + H).sup.+. 77 Ex 161 LCMS (ES.sup.+) RT 1.50 min, 452.0 (M + H).sup.+. 78 Ex 6 LCMS (ES.sup.+) RT 1.60 min, 526.0 (M + H).sup.+. 79 Ex 6 LCMS (ES.sup.+) RT 1.42 min, 455.0 (M + H).sup.+. 80 Ex 6 LCMS (ES.sup.+) RT 1.60 min, 436.0 (M + H).sup.+. 81 Int 74 0 LCMS (ES.sup.+) RT 1.45 min, 448.0 (M + H).sup.+. 82 Ex 168 LCMS (ES.sup.+) RT 1.62 min, 454.0 (M + H).sup.+. 83 Ex 168 LCMS (ES.sup.+) RT 1.45 min, 473.0 (M + H).sup.+. 84 Ex 161 LCMS (ES.sup.+) RT 1.34 min, 471.0 (M + H).sup.+. 85 Ex 171 LCMS (ES.sup.+) RT 1.62 min, 500.0 (M + H).sup.+. 86 Ex 170 LCMS (ES.sup.+) RT 1.62 min, 500.0 (M + H).sup.+. 87 Ex 171 LCMS (ES.sup.+) RT 1.45 min, 473.0 (M + H).sup.+. 88 Ex 170 LCMS (ES.sup.+) RT 1.45 min, 473.0 (M + H).sup.+. 89 Ex 161 LCMS (ES.sup.+) RT 1.26 min, 504.0 (M + H).sup.+. 90 Ex 161 LCMS (ES.sup.+) RT 1.46 min, 457.0 (M + H).sup.+. 91 Ex 161 0 LCMS (ES.sup.+) RT 1.48 min, 455.0 (M + H).sup.+. 92 Ex 161 LCMS (ES.sup.+) RT 1.37 min, 497.0 (M + H).sup.+. 93 Ex 173 LCMS (ES.sup.+) RT 1.34 min, 495.0 (M + H).sup.+. 94 Ex 11 LCMS (ES.sup.+) RT 1.57 min, 566.0 (M + H).sup.+. 95 Ex 3 LCMS (ES.sup.+) RT 1.30 min, 491.0 (M + H).sup.+. 96 Ex 3 LCMS (ES.sup.+) RT 1.43 min, 455.0 (M + H).sup.+. 97 Ex 4 LCMS (ES.sup.+) RT 1.32 min, 491.0 (M + H).sup.+. 98 Ex 5 LCMS (ES.sup.+) RT 1.32 min, 491.0 (M + H).sup.+. 99 Ex 145 LCMS (ES.sup.+) RT 1.60 min, 579.0 (M + H ? .sup.tBu).sup.+. 100 Int 31 LCMS (ES.sup.+) RT 1.59 min, 567.2 (M + H).sup.+. 101 Int 34 0 LCMS (ES.sup.+) RT 1.53 min, 547.0 (M + H).sup.+. 102 Ex 5 LCMS (ES.sup.+) RT 2.52 min, 546.8 (M + H).sup.+.

Example 103 Method D

5-[1-(2-methylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyridin-2(1H)-one

(265) ##STR00162##

(266) To a solution of Example 18 (0.10 g, 0.28 mmol) in EtOH (2 mL) was added aq. HBr (2 mL). The reaction was heated at 95? C. for 18 h. The reaction mixture concentrated in vacuo and the residue was diluted with EtOAc (10 mL), washed with sat. aq. NaHCO.sub.3 solution (10 mL), water (10 mL), brine (10 mL) and the organic layer was separated, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by preparative TLC yielding the title compound (0.06 g, 62%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 12.85 (s, 1H), 7.77 (d, J 8.4 Hz, 1H), 7.73-7.63 (m, 1H), 7.44 (d, J 2.7 Hz, 1H), 7.32-7.01 (m, 4H), 6.85 (d, J 1.8 Hz, 1H), 6.63 (dd, J 16.2, 8.6 Hz, 2H), 5.70 (dd, J 7.5, 4.9 Hz, 1H), 3.29-3.03 (m, 3H), 2.61-2.36 (m, 4H). LCMS (ES.sup.+) RT 1.35 min, 342.1 (M+H).sup.+.

Example 104

5-(1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl)pyridin-2(1H)-one

(267) ##STR00163##

(268) The title compound was prepared from Example 20 (0.10 g, 0.02 mmol) and aq. HBr by the Method D, (0.07 g, 71%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.75 (d, J 8.4 Hz, 1H), 7.64 (dd, J 9.5, 2.6 Hz, 1H), 7.51-7.28 (m, 4H), 7.33-7.06 (m, 3H), 6.82 (d, J 1.8 Hz, 1H), 6.61 (d, J 9.4 Hz, 1H), 5.48 (t, J 6.7 Hz, 1H), 3.30-3.06 (m, 3H), 2.70-2.51 (m, 1H). LCMS (ES.sup.+) RT 1.21 min, 328.1 (M+H).sup.+.

Example 105

Enantiomer 1: (1S or R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole

(269) ##STR00164##

(270) The title compound was isolated from Example 22 by chiral purification under SFC conditions on Chiralpak IA (50*266 mm*mm, flow 360 mL/min, 25? C., CO2+20% MeOH, injection of 5 mL solution at a concentration of 8 g/L). First eluting enantiomer (6.88 min).

Example 106

Enantiomer 2: (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole

(271) ##STR00165##

(272) The title compound was isolated from Example 22 by chiral purification under SFC conditions on Chiralpak IA (50*266 mm*mm, flow 360 mL/min, 25? C., CO.sub.2+20% MeOH, injection of 5 mL solution at a concentration of 8 g/L). Second eluting enantiomer (9.06 min).

Example 107

Enantiomer 1: (1S or R)-1-[2-(difluoromethoxy)phenyl]-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole

(273) ##STR00166##

(274) The title compound was prepared from Example 23 by chiral purification under LC conditions on Lux-Cell-2 (76*370 mm*mm, flow 200 mL/min, 30? C., EtOH 100%, injection of 10 mL solution at a concentration of 1.8 g/L) yielding the title compound (9 mg, 50%, first eluting enantiomer, RT 15 min) and the second eluting enantiomer (RT 24 min). LCMS (ES.sup.+) RT 3.4 min, 456.3 (M+H).sup.+.

Example 108 (Method F)

Enantiomer 2: (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(6-piperazin-1-yl-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(275) ##STR00167##

(276) Example 24 (1.0 g, 1.73 mmol, 1 eq.) was dissolved in 1,4-dioxane (25 mL/mmol and HCl/1,4-dioxane 4 M (0.436 mL, 1 eq.) was added, followed by water (2 mL). The mixture was stirred 4 h at r.t. The reaction was concentrated in vacuo and the residue was dissolved in DCM (100 mL) and water (50 mL). The organic layer was discarded and the aq. layer was basified with Na.sub.2CO.sub.3 and extracted with DCM (2?100 mL). The organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound as a foam (650 mg, 79%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.19 (s, 1H), 7.64 (dt, J 8.8 Hz, J 2.1 Hz, 1H), 7.49 (d, J 11.2 Hz, 1H), 7.35 (td, J 7.7 Hz, J 1.2 Hz, 1H), 7.21 (d, J 8.1 Hz, 1H), 7.13 (t, J 7.3 Hz, 1H), 6.84 (d, J 7.6 Hz, 1H), 6.80 (d, J 6.7 Hz, 1H), 6.66 (d, J 8.8 Hz, 1H), 6.61 (t, J 73.2 Hz, 1H), 5.84 (dd, J 7.5 Hz, J 4.8 Hz, 1H), 3.54 (m, 4H), 3.19 (m, 3H), 3.00 (m, 4H), 2.55 (m, 1H). LCMS (ES.sup.+) RT 2.99 min, 480 (M+H).sup.+.

Example 109

Enantiomer 2: 5-[(1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]-1H-pyridin-2-one

(277) ##STR00168##

(278) The title compound was prepared from Example 25 (26 mg, 0.064 mmol, 1.0 eq) by the Method D, yielding the title compound as a colorless glassy solid (17 mg, 65%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.61 (d, J 9.4 Hz, 1H), 7.49 (d, J 11.3 Hz, 1H), 7.45 (d, J 1.6 Hz, 1H), 7.37 (t, J 7.4 Hz, 1H), 7.24 (t, J 8.6 Hz, 1H), 7.14 (t, J 7.6 Hz, 1H), 6.78 (d, J 7.7 Hz, 1H), 6.75 (d, J 6.8 Hz, 1H), 6.65 (t, J 73.4 Hz, 1H), 6.60 (d, J 9.4 Hz, 1H), 5.84 (m, 1H), 3.21 (m, 3H), 2.56 (m, 1H). LCMS (condition #AC, ES.sup.+) RT 3.13 min, 412.3 (M+H).sup.+ , 96.3% purity. LCMS (ES.sup.+) RT 3.71 min, 412.1 (M+H).sup.+.

Example 110

Enantiomer 2: 1-[4-[5-[(1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1 H-pyrrolo[1,2-a]benzimidazol-7-yl]-2-pyridyl]piperazin-1-yl]ethanone

(279) ##STR00169##

(280) To a solution of Example 108 (0.03 g, 0.067 mmol) and PS-DIPEA (Argonaut No 800280, 3.53 mmol/g, 0.035 g, 0.125 mmol) in DCM (5 mL/g) was added a solution of acetyl chloride (5.4 mg, 0.068 mmol, 1.1 eq.) in DCM (0.1 mL). The reaction was stirred for 2 h at r.t. The reaction mixture was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-3% methanolic ammonia/DCM), yielding the title compound (12 mg, 36%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.21 (s, 1H), 7.66 (m, 1H), 7.50 (d, J 11.2 Hz, 1H), 7.35 (m, 1H), 7.21 (d, J 8.0 Hz, 1H), 7.13 (t, J 7.5 Hz, 1H), 6.64 (m, 4H), 5.85 (m, 1H), 3.74 (m, 2H), 3.65 (m, 2H), 3.58 (m, 2H), 3.53 (m, 2H), 3.20 (m, 3H), 2.55 (m, 1H), 2.15 (s, 3H). LCMS (ES.sup.+) RT 3.4 min, 522.2 (M+H).sup.+.

Example 111

Enantiomer 2: (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[6-(4-methylpiperazin-1-yl)-3-pyridyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(281) ##STR00170##

(282) A solution of Example 108 (0.03 g, 0.067 mmol) and formaldehyde (33 ?L, 0.43 mmol, 7 eq.) in MeOH (5 mL/g) was stirred for 4 h. MP-CNBH.sub.3 (Biotage, ref 800406, loading 2.49 mmol/g, 70.5 mg, 0.173 mmol, 2.7 eq.) was added. The reaction was stirred at r.t. for 20 h. Formaldehyde (0.1 mL, 1.23 mmol, 18 eq.) was added, followed by NaBH.sub.3CN (10 mg, 1.6 mmol, 23 eq.). The reaction was heated at 60? C. for 2 h. The mixture was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-5% methanolic ammonia/DCM), yielding the title compound (20 mg, 78%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.19 (s, 1H), 7.63 (dt, J 8.7, 2.0 Hz, 1H), 7.48 (d, J 11.2 Hz, 1H), 7.34 (m, 1H), 7.21 (d, J 8.2 Hz, 1H), 7.12 (t, J 7.6 Hz, 1H), 6.64 (m, 4H), 5.84 (m, 1H), 3.59 (m, 4H), 3.19 (m, 3H), 2.55 (m, 5H), 2.35 (s, 3H). LCMS (ES.sup.+) RT 2.9 min, 494.3 (M+H).sup.+.

Example 112

Enantiomer 2: (1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[6-(4-methylsulfonylpiperazin-1-yl)-3-pyridyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(283) ##STR00171##

(284) To a solution of Example 108 (0.03 g, 0.067 mmol) and PS-DIEA (Argonaut Technologies, No 800280, loading 3.53 mmol/g, 70 mg, 0.250 mmol, 4 eq.) in DCM (5 mL/g) was added a solution of methanesulfonyl chloride (16.2 mg, 0.125 mmol, 2.2 eq.) in DCM (0.1 mL). The reaction was stirred at r.t. for 2 h. The reaction was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-5% methanolic ammonia/DCM), yielding the title compound (20 mg, 57%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.21 (d, J 0.5 Hz, 1H), 7.67 (d, J 9.1 Hz, 1H), 7.49 (m, 1H), 7.35 (m, 1H), 7.22 (d, J 8.3 Hz, 1H), 7.13 (t, J 7.4 Hz, 1H), 6.66 (m, 4H), 5.90 (m, 1H), 3.70 (m, 4H), 3.26 (m, 7H), 2.80 (s, 3H), 2.55 (m, 1H). LCMS (ES.sup.+) RT 3.8 min, 558.3 (M+H).sup.+.

Example 113

Enantiomer 1: (1R or S)-7-[6-(chloromethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(285) ##STR00172##

(286) To a solution of Example 33 (20 mg, 0.059 mmol) in CHCl.sub.3 (0.2 mL) was added at 0? C. SOCl.sub.2 (0.021 mL, 35 mg, 0.29 mmol, 5.0 eq.). The mixture was then heated at 60? C. for 3 h. A sat. aq. solution of NaHCO.sub.3 was added, the mixture was extracted with DCM, dried (MgSO.sub.4) and concentrated in vacuo to yield to the title compound (12 mg) used in the next step without further purification. LCMS (ES.sup.+) RT 4.58 min, 360.2/362.1 (M+H).sup.+.

Example 114

Enantiomer 1: (1R or S)-7-[6-(methylsulfonylmethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(287) ##STR00173##

(288) Example 113 (22 mg, 0.06 mmol, 1.0 eq.), sodium methanesulfinate (26 mg, 0.25 mmol, 4 eq.), NaI (1 mg, 0.07 mmol, 0.1 eq.) were heated at 100? C. in EtOH (0.75 mL) under microwave irradiation (300 Watt) for 15 min. The reaction mixture was diluted with water and extracted with DCM. The organics were dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 2-5% methanolic ammonia/DCM), yielding the title compound as a white solid (14 mg, 56%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.67 (d, J 1.9 Hz, 1H), 7.82 (d, J 8.3 Hz, 1H), 7.80 (dd, J 7.9 Hz, J 1.9 Hz, 1H), 7.48 (d, J 8.0 Hz, 1H), 7.35-7.44 (m, 4H), 7.21 (d, J 2.0 Hz, 1H), 7.19 (t, J 1.4 Hz, 1H), 6.98 (s, 1H), 5.51 (t, J 6.4 Hz, 1H), 4.42 (s, 2H), 3.29 (ddd, J 14.3 Hz, J 8.1 Hz, 1H), 3.12-3.24 (m, 2H), 2.92 (s, 3H), 2.63 (m, 1H). LCMS (ES.sup.+) RT 3.7 min, 404.3 (M+H).sup.+.

Example 115

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

(289) ##STR00174##

(290) A solution A was prepared with Example 32 (1.07 mg, 0.00226 mmol, 1 eq) in 400 ?L of MeCN and was diluted with 1.6 mL of water to reach a 0.5 mg/mL. A solution B was prepared from a solution of D-Glucose 6-phosphate disodium salt hydrate (2.113 g, 100 mM), B-nicotinamide adenine dinucleotide phosphate (533.5 mg, 10 mM) and 700 ?L of MgCl.sub.2.6H.sub.2O (1 M) in 69 mL of phosphate buffer (100 mM, pH=7.4). In a glassware tube, 5.5 mL of phosphate buffer, 1 mL of mouse microsome (20 mg/mL Male CD1 pool of 1042, M1000), 1 mL of solution A, 2.5 mL of solution B, 12 ?L of glucose-6-phosphate dehydrogenase was incubated at 37? C. under swelling for 30 minutes. The incubation was stopped by addition of MeCN (5 mL) and the tube was centrifuged for 15 minutes at 3000 rpm. The title compound was purified from the supernatant by preparative 2D LCMS yielding the title compound as a white solid (116 ?g, 20%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ?. 8.81 (s, 1H), 8.19 (d, J 8.3 Hz, 1H), 8.09 (d, J 8.1 Hz, 1H), 7.72 (d, J 11.7 Hz, 1H), 7.40 (d, J 7.3 Hz, 1H), 7.36 (t, J 74.0 Hz, 1H), 7.30 (d, J 7.9 Hz, 1H), 7.19 (m, 2H), 6.96 (d, J 7.6 Hz, 1H), 6.21 (bs, 1H), 5.87 (dd, J 7.9 Hz, J 4.8 Hz, 1H), 5.27 (m, 1H), 3.49 (dt, J 13.6 Hz, J 7.8 Hz, 1H), 3.30 (s, 3H), 2.30 (dt, J 13.3 Hz, J.sub.2 4.3 Hz, 1H). LCMS (ES+) RT 3.83 min, 490.2 (M+H).sup.+.

Example 116

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

(291) ##STR00175##

(292) Intermediate 99 (37 g, 85.8 mmol) was dissolved in acetic anhydride (160 mL). ZnCl.sub.2 (11.7 g, 85.8 mmol, 1.0 eq.) was added and the mixture was stirred at r.t. for 2 min then heated at 90? C. for 45 min. The mixture was chilled to 0? C., then water (200 mL) and EtOAc (200 mL) were added. The mixture decanted slowly after the addition of 50 mL water. The aq. layer was extracted with EtOAc (50 mL 2?). The combined organic layers were washed with an aq. solution of NaOH (1 N, 2?100 mL), then brine and then dried (MgSO.sub.4), concentrated in vacuo to yield a black oil as a residue (52 g) which was purified by column chromatography (SiO.sub.2, 0-1% methanolic ammonia/DCM). The combined fractions containing the desired compounds were purified by column chromatography (SiO.sub.2, 0-35% EtOAc/heptane), to yield of the title compound (8.3 g, 21%, as a mixture of 4 isomers). LCMS (ES.sup.+) RT 4.9 min, 455.1/457.1.1 (M+H).sup.+.

Example 117

1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(293) ##STR00176##

(294) Example 34 (900 mg, 1.70 mmol) and K.sub.2CO.sub.3 (355 mg, 2.5 mmol, 1.5 eq.) were poured in MeOH (3.4 mL) and the mixture was stirred 2 h at r.t. The reaction mixture was concentrated in vacuo. Water (2 mL) and EtOAc (10 mL) were added. The mixture was decanted and the aq. layer was extracted with EtOAc. The combined organic layers were dried (MgSO.sub.4), concentrated in vacuo, to yield the title compound as a colorless oil (886 mg, 89%) used in the next step without any further purification. LCMS (ES.sup.+) RT 3.9 min, 489.2 (M+H).sup.+.

Examples 118, 119, 120 and 121

(1R or S,3R or S)(diastereoisomer 1)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol, (1R or S,3S or R) (diastereoisomer 2)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol, (1R or S,3S or R) (diastereoisomer 3)-1-[2-(difluoromethoxy) phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-H-pyrrolo[1,2-a]benzimidazol-3-ol and (1S or R, 3S or R) (diastereoisomer 4)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-H-pyrrolo[1,2-a]benzimidazol-3-ol

(295) ##STR00177##

(296) The title compounds were isolated by purification of Example 117 under LC conditions on Lux-Cell-4 (76*265 mm*mm, flow 200 mL/min, 30? C., EtOH/heptane 1/1, injection of 83 mL solution at a concentration of 1.8 g/L).

(297) The first eluting enantiomer (RT 12.89 min) was collected and the fractions were evaporated to yield (diastereoisomer 1) (1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol (115 mg, 14%, Example 118). .sup.1H NMR ?: 7.97 (d, J 8.4 Hz, 2H), 7.67 (m, 3H), 7.40 (m, 1H), 7.31 (m, 1H), 7.19 (m, 1H), 7.07 (d, J 6.9 Hz, 1H), 6.99 (d, J 7.7 Hz, 1H), 6.14 (d, J 4.8 Hz, 1H), 5.87 (dd, J 8.0 Hz, J 4.8 Hz, 1H), 5.27 (m, 1H), 3.49 (m, 1H), 3.24 (s, 3H), 2.30 (dt, J 13.5 Hz, J 4.4 Hz, 1H). LCMS (ES.sup.+) RT 3.9 min, 489.2 (M+H).sup.+.

(298) The second eluting enantiomer (RT 14.95 min) was collected and the fractions were evaporated to yield (diastereoisomer 2) (1R or S,3S or R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol (110 mg, 13%, Example 119). LCMS (ES.sup.+) RT 3.9 min, 489.2 (M+H).sup.+.

(299) The third eluting enantiomer (RT 21.61 min) was collected and the fractions were evaporated to yield (diastereoisomer 3) (1S or R,3S or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol (135 mg, 16%, Example 120). LCMS (ES.sup.+) RT 3.9 min, 489.2 (M+H).sup.+.

(300) The fourth eluting enantiomer (RT 29.56 min) was collected and the fractions were evaporated to yield (diastereoisomer 4) (1S or R,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-(4-methylsulfonylphenyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol (135 mg, 16%, Example 121). LCMS (ES.sup.+) RT 3.9 min, 489.2 (M+H).sup.+.

Example 122

Enantiomer 1: (1R or S)-7-bromo-1-[2-(difluoromethoxy)phenyl]-1,3-dihydrothiazolo[3,4-a]benzimidazole

(301) ##STR00178##

(302) The title compound was prepared following the methods described for Intermediate 48 and 49, starting from the Intermediate 46 (5 g) to yield the title compound (1.9 g, 43%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.49 (d, 1H, J 8.6 Hz), 7.28 (m, 2H), 7.13 (d, J 8.1 Hz, 1H), 7.06 (t, J 7.5 Hz, 1H), 6.91 (s, 1H), 6.85 (d, J 7.5 Hz, 1 H), 6.53 (m, 2H), 4.37 (m, 1H), 4.20 (m, 1H). LCMS (ES.sup.+) RT 4.8 min, 397.0/399.0 (M+H).sup.+.

Example 123

Enantiomer 2: (1S or R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-1,3-dihydrothiazolo[3,4-a]benzimidazole

(303) ##STR00179##

(304) The title compound was prepared following the methods described for Intermediate 48 and 49, starting from the Intermediate 47 (5 g) to yield the title compound (1.7 g, 38%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.58 (d, J 8.6 Hz, 1H), 7.36 (m, 2H), 7.22 (d, J 8.1 Hz, 1H), 7.15 (t, J 7.6 Hz, 1H), 7.00 (d, J 1.4 Hz, 1H), 6.93 (d, J 7.6 Hz, 1H), 6.62 (m, 2H), 4.45 (m, 1H), 4.29 (m, 1H). LCMS (ES.sup.+) RT 4.8 min, 397 (M+H).sup.+.

Example 124

Enantiomer 2: (1R or S)-1-[2-(difluoromethoxy)phenyl]-7-(6-piperazin-1-yl-3-pyridyl)-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(305) ##STR00180##

(306) The title compound was prepared from Example 35 (0.3 g, 36.2 mmol 1 eq.) and TFA (2 mL) by the Method F. (0.085 g, 34%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.31 (d, J 2.2 Hz, 1H), 7.76 (m, 1H), 7.63 (m, 1H), 7.35 (m, 2H), 7.22 (d, J 7.9 Hz, 1H), 7.12 (t, J 7.7 Hz, 1H), 6.98 (m, 1H), 6.86 (m, 1H), 6.63 (m, 2H), 5.86 (m, 1H), 3.51 (m, 4H), 3.20 (m, 3H), 3.00 (m, 4H), 2.55 (m, 1H). LCMS (ES.sup.+) RT 2.7 min, 462 (M+H).sup.+.

Example 125

Enantiomer 1: (1R or S)-7-bromo-1-[2-(difluoromethoxy)phenyl]-3H-[1,3]thiazolo[3,4-a]benzimidazole 2-oxide

(307) ##STR00181##

(308) Example 122 (1.0 g, 1.0 eq) was dissolved in AcOH (10 mL). Hydrogen peroxide (0.56 mL, 2.2 eq, 30-37% in water) was added and the mixture was stirred at r.t. for 18 h. The reaction mixture was concentrated in vacuo, and the mixture was diluted with DCM (10 mL) washed with water, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-2% methanolic ammonia/DCM), yielding the title compound as a beige solid (6 mg, 0.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.70 (m, 1H), 7.55 (m, 1H), 7.44 (m, 1H), 7.33 (m, 1H), 7.10 (m, 1H), 6.88 (m, 1H), 6.82 (m, 1H), 6.55 (m, 1H), 4.70 (m, 1H), 4.11 (m, 1H), 4.10 (m, 1H). LCMS (ES.sup.+) RT 5.85 min, 413.0/415.0 (M+H).sup.+.

Example 126

Enantiomer 2: (1S or R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-3H-[1,3]thiazolo[3,4-a]benzimidazole 2-oxide

(309) ##STR00182##

(310) The title compound was prepared from Example 123 (1.50 g, 1.0 eq) following the procedure described for Example 125. The title compound was obtained as a brown oil (21 mg, 1.4%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 0.70 (m, 1H), 7.55 (m, 1H), 7.44 (m, 1H), 7.33 (m, 1H), 7.10 (m, 1H), 6.88 (m, 1H), 6.82 (m, 1H), 6.55 (m, 1H), 4.70 (m, 1H), 4.11 (m, 1H), 4.10 (m, 1H). LCMS (ES.sup.+) RT 5.85 min, 413.0/415.0 (M+H).sup.+.

Example 127

7-bromo-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl) acetate

(311) ##STR00183##

(312) The title compound (as a mixture of 2 diastereoisomers) was prepared from Intermediate 100 following the method described for Example 116. LCMS (ES.sup.+) RT 4.82 and 4.77 min, 371.1/373.1 (M+H)+(ratio: 49/51).

Example 128

7-bromo-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(313) ##STR00184##

(314) The title compound (as a mixture of 2 diastereoisomers) was prepared from Example 127 following the method described for Example 117. LCMS (ES.sup.+) RT 4.06 and 4.12 min, 329.1/331.1 (M+H).sup.+ (ratio 27/72).

Example 129

7-bromo-1-phenyl-1,2-dihydro-3H-pyrrolo[1,2-a]benzimidazol-3-one

(315) ##STR00185##

(316) A solution of Example 128 (1.85 g, 5.62 mmol) in CHCl.sub.3 (25 mL) was heated at 60? C. in the presence of manganese dioxide (10 eq., 56.2 mmol) for 1 h. The reaction mixture was cooled, and filtered on a bed of celite, and the solid was washed with DCM (3?50 mL), then MeCN (2?25 mL). The filtrates were concentrated in vacuo, to yield brown oil (1.44 g). The residue was purified by column chromatography (SiO.sub.2, 25-100% DCM/hexanes), yielding the title compound (390 mg, 21%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.87 (d, J 8.8 Hz, 1H), 7.50 (dd, J 8.8 Hz, J 1.8 Hz, 1H), 7.41 (m, 5H), 7.26 (d, J 1.5 Hz, 1H), 6.02 (dd, J 7.3 Hz, J 3.6 Hz, 1H), 3.84 (dd, J 18.9 Hz, J 7.4 Hz, 1H), 3.19 (dd, J 18.9 Hz, J 3.6 Hz, 1H). LCMS (ES.sup.+) RT 4.62 min, 327.1/329.1 (M+H).sup.+.

Example 130

(3Z)-7-bromo-N-hydroxy-1-phenyl-1,2-dihydro-3H-pyrrolo[1,2-a]benzimidazol-3-imine

(317) ##STR00186##

(318) Hydroxylamine hydrochloride (0.198 g, 2.85 mmol) was added to a solution Example 129 (600 mg, 1.84 mmol) in EtOH (25 mL) and pyridine (2 mL). The resulting suspension was heated for 1 h at 65? C. The mixture was then cooled to r.t. and EtOAc (200 mL) was added and the mixture was washed with water (3?30 mL), then brine (2?50 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was triturated with a solution of Et.sub.2O/EtOAc (15:5) and the solid was filtered and dried in vacuo to yield an off white powder (220 mg, 35%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.67 (d, J 8.7 Hz, 1H), 7.39 (m, 6H), 7.24 (m, 3H), 7.16 (d, J 1.4 Hz, 1H), 5.86 (dd, J 8.3 Hz, J 3.5 Hz, 1H), 3.96 (dd, J 18.5 Hz, J 8.4 Hz, 1H), 3.16 (dd, J 18.6 Hz, J 3.6 Hz, 1H). LCMS (ES.sup.+) RT 4.45 min, 342.0/344.0 (M+H).sup.+.

Example 131

Enantiomer 1: (1R or S)-1-phenyl-7-[6-(piperazin-1-yl)pyridin-3-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(319) ##STR00187##
The title compound was prepared from Example 42 (250 mg, 1.0 eq.), and (1:1) mixture of DCM-TFA (2 mL) by the Method F (157 mg, 39.7%). LCMS (ES.sup.+) RT 2.5 min, 396 (M+H).sup.+.

Examples 132 and 133

Enantiomer 1: (4S or R)-7-bromo-4-[2-(difluoromethoxy)phenyl]-8-fluoro-3,4-dihydro-1 H-[1,4]oxazino[4,3-a]benzimidazole; enantiomer 2: (4R or S)-7-bromo-4-[2-(difluoromethoxy)phenyl]-8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole

(320) ##STR00188##

(321) The title compounds were isolated by chiral separation Example 10 under SFC conditions on Chiralpak AD (50*216 mm*mm, flow 360 mL/min, 25? C., CO.sub.2+20% MeOH for 2.1 min then 40% MeOH for 3.3 min, injection of 16 mL solution at a concentration of 15 g/L). The first eluting enantiomer (RT 2.1 min) was collected and the fractions were evaporated to yield (enantiomer 1) (4S or R)-7-bromo-4-[2-(difluoromethoxy)phenyl]-8-fluoro-3, 4-dihydro-1H-[1, 4]oxazino[4,3-a]benzimidazole (Example 132). The second eluting enantiomer (RT 3.4 min) was collected and the fractions were evaporated to yield (enantiomer 2) (4R or S)-7-bromo-4-[2-(difluoromethoxy)phenyl]-8-fluoro-3, 4-dihydro-1H-[1, 4]oxazino[4,3-a]benzimidazole (Example 133) .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.42 (d, J 8.9 Hz, 1H), 7.32 (m, 1H), 7.17 (m, 2H), 7.05 (t, J 7.6 Hz, 1H), 6.91 (d, J 5.8 Hz, 1H), 6.61 (m, 1H), 5.71 (t, J 3.9 Hz, 1H), 5.02 (m, 2H), 4.16 (m, 2H). LCMS (ES.sup.+) RT 4.76 min, 413.0/415.0 (M+H).sup.+.

Examples 134-144

(322) The following Examples were prepared from the assigned precursor by the Method F.

(323) TABLE-US-00006 Example No. Precursor Compound Name LCMS 134 Ex 47 Enantiomer 2: (4R or S)-4-[2- LCMS (difluoromethoxy)phenyl]-8-fluoro-7-(6- (ES.sup.+) RT piperazin-1-yl-3-pyridyl)-3,4-dihydro-1H- 1.32 min, [1,4]oxazino[4,3-a]benzimidazole 496.0 (M + H).sup.+. 135 Ex 48 Enantiomer 1: (4S or R)-4-[2- LCMS (difluoromethoxy)phenyl]-8-fluoro-7-(6- (ES.sup.+) RT piperazin-1-yl-3-pyridyl)-3,4-dihydro-1H- 1.32 min, [1,4]oxazino[4,3-a]benzimidazole 496.0 0 (M + H).sup.+. 136 Ex 50 Enantiomer 1: (4S or R)-4-[2- LCMS (difluoromethoxy)phenyl]-8-fluoro-7-(4- (ES.sup.+) RT methylsulfonylphenyl)-1,2,3,4- 1.31 min, tetrahydropyrazino[1,2-a]benzimidazole 488.0 (M + H).sup.+. 137 Ex 52 Enantiomer 1: (4S or R)-4-[2- LCMS (difluoromethoxy)phenyl)-8-fluoro-7-(2- (ES.sup.+) RT methylsulfonyl-4-pyridyl)-1,2,3,4- 1.30 min, tetrahydropyrazino[1,2-a]benzimidazole 489.0 (M + H).sup.+. 138 Ex 53 Enantiomer 1: (4S or R)-4-[2- LCMS (difluoromethoxy)phenyl)-8-fluoro-7-(6- (ES.sup.+) RT methylsulfonyl-3-pyridyl)-1,2,3,4- 1.29 min, tetrahydropyrazino[1,2-a]benzimidazole 489.0 (M + H).sup.+. 139 Ex 54 Enantiomer 2: (4R or S)-4-[2- LCMS (difluoromethoxy)phenyl)-8-fluoro-7-(6- (ES.sup.+) RT methylsulfonyl-3-pyridyl)-1,2,3,4- 1.29 min, tetrahydropyrazino[1,2-a]benzimidazole 489.0 (M + H).sup.+. 140 Ex 55 4[2-(difluoromethoxy)phenyl]-7-(4- LCMS methylsulfonylphenyl)-1,2,3,4- (ES.sup.+) RT tetrahydropyrazino[1,2-a]benzimidazole 1.30 min, 470.0 (M + H).sup.+. 141 Ex 56 Enantiomer 2: (4R or S)-4-[2- LCMS (difluoromethoxy)phenyl]-7-(6-methylsulfonyl- (ES.sup.+) RT 3-pyridyl)-1,2,3,4-tetrahydropyrazino[1,2- 1.26 min, a]benzimidazole 471.0 (M + H).sup.+. 142 Ex 57 Enantiomer 1: (4S or R)-4-[2- LCMS (difluoromethoxy)phenyl]-7-(6-methylsulfonyl- (ES.sup.+) RT 3-pyridyl)-1,2,3,4-tetrahydropyrazino[1,2- 1.26 min, a]benzimidazole 471.0 (M + H).sup.+. 143 Ex 58 Enantiomer 1: (4S or R)-4-[2- LCMS (difluoromethoxy)phenyl)-7-(2-methylsulfonyl- (ES.sup.+) RT 4-pyridyl)-1,2,3,4-tetrahydropyrazino[1,2- 1.26 min, a]benzimidazole 471.0 (M + H).sup.+. 144 Ex 59 Enantiomer 1: (4S or R)-4-[2- LCMS (difluoromethoxy)phenyl)-8-fluoro-7-[3- (ES.sup.+) RT (methylsulfonyl)phenyl]-1,2,3,4- 1.31 min, tetrahydropyrazino[1,2-a]benzimidazole 488.0 (M + H).sup.+.

Examples 145 and 146

Enantiomer 1: tert-butyl (4S or R)-7-bromo-4-[2-(difluoromethoxy)phenyl]-8-fluoro-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazole-2-carboxylate; enantiomer 2: tert-butyl (4R or S)-7-bromo-4-[2-(difluoromethoxy)phenyl]-8-fluoro-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazole-2-carboxylate

(324) ##STR00200##

(325) The title compounds were isolated by chiral purification of Example 12 under SFC conditions on Chiralpak AD (50*216 mm*mm, flow 360 mL/min, 15? C., CO.sub.2+20% i-PrOH, injection of 5 mL solution at a concentration of 20 g/L). The first eluting enantiomer (RT 3.9 min) was collected and the fractions were evaporated to yield Enantiomer 1: tert-butyl (4S or R)-7-bromo-4-[2-(difluoromethoxy)phenyl]-8-fluoro-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazole-2-carboxylate (Example 145). The second eluting enantiomer (RT 5.9 min) was collected and the fractions were evaporated to yield enantiomer 2: tert-butyl (4R or S)-7-bromo-4-[2-(difluoromethoxy)phenyl]-8-fluoro-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazole-2-carboxylate (Example 146).

Examples 147 and 148

Enantiomer 1: tert-butyl 7-bromo-(4S or R)-(2-(difluoromethoxy)phenyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate; enantiomer 2: tert-butyl 7-bromo-(4R)-(2-(difluoromethoxy)phenyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate

(326) ##STR00201##

(327) The title compounds were isolated by chiral purification of Example 13 under SFC conditions on Chiralpak IC (50*264 mm*mm, flow 360 mL/min, 25? C., CO.sub.2+20% i-PrOH, injection of 15.5 mL solution at a concentration of 20 g/L). The first eluting enantiomer (RT 6.6 min) was collected and the fractions were evaporated to yield enantiomer 1: tert-butyl 7-bromo-(4R or S)-(2-(difluoromethoxy)phenyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (Example 147). The second eluting enantiomer (RT 11.3 min) was collected and the fractions were evaporated to yield enantiomer 2: tert-butyl 7-bromo-(4S)-(2-(difluoromethoxy)phenyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (Example 148).

Example 149

Enantiomer 1: 1-[(4S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-7-(4-methylsulfonylphenyl)-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazol-2-yl]ethanone

(328) ##STR00202##

(329) To a solution of Example 136 (0.150 g, 1 eq.) in DCM (10 mL/g) were added sequentially PS-DIEA (Argonaut No 800280, 261 mg, 3.0 eq., 3.53 mmol/g), acetyl chloride (1.2 eq.) and N,N-diisopropylethylamine (0.1 eq.) and the mixture was stirred at r.t. After 20 h, DIPEA (2 drops) and acetyl chloride (0.5 eq.) were added to the mixture which was stirred at r.t. for an additional 3 h until disappearance of the starting material. Then the mixture was filtered, the filtrate was washed with sat. aq. NH.sub.4Cl, dried (MgSO.sub.4), concentrated in-vacuo, purified by column chromatography (SiO.sub.2, 0-100% EtOAc/hexanes), yielding the title compound as an off white solid (94 mg, 58%). LCMS (ES.sup.+) RT 3.9 min, 530.3 (M+H).sup.+.

Example 150

Enantiomer 1: (4S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-2-methylsulfonyl-7-(4-methylsulfonylphenyl)-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazole

(330) ##STR00203##

(331) To a solution of Example 136 (0.150 g, 1 eq.) in DCM (10 mL/g) were added sequentially PS-DIEA (Argonaut No 800280, 261 mg, 3.0 eq., 3.53 mmol/g), methanesulfonyl chloride (43 mg, 1.2 eq.) and N,N-diisopropylethylamine (4 mg, 0.1 eq.). The mixture was stirred at r.t. After 20 h DIPEA (2 drops) and methanesulfonyl chloride (0.5 eq.) were added to the mixture which was stirred at r.t. for 3 h until the disappearance of starting material. Then the mixture was filtered, the filtrate was washed with sat. aq. NH.sub.4Cl, dried (MgSO.sub.4), concentrated in-vacuo, purified by column chromatography (SiO.sub.2, 0-100% EtOAc/hexanes), yielding the title compound as an off white solid (51 mg, 29% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.94 (d, J 8.3 Hz, 2H), 7.56 (m, 3H), 7.41 (t, J 8.1 Hz, 1H), 7.26 (d, J 6.7 Hz, 1H), 7.13 (t, J 7.5 Hz, 1H), 6.85 (d, J 8.4 Hz, 1H), 6.67 (t, J 68.2 Hz, 1H), 6.66 (d, J 18.7 Hz, 1H), 5.97 (t, J 4.1 Hz, 1H), 5.03 (d, J 16.8 Hz, 1H), 4.78 (d, J 16.6 Hz, 1H), 4.06 (dd, J 13.5 Hz, J 4.2 Hz, 1H), 3.98 (dd, J 13.7 Hz, J 4.3 Hz, 1H), 2.78 (s, 3H), 3.07 (s, 3H). LCMS (ES.sup.+) RT 4.2 min, 566.3 (M+H).sup.+.

Example 151

Enantiomer 1: (4S or R)-4-[2-(difluoromethoxy)phenyl]-8-fluoro-2-methyl-7-(4-methylsulfonylphenyl)-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazole

(332) ##STR00204##

(333) To a solution of Example 136 (0.150 g, 0.308 mmol) in MeOH (0.673 g, 21.0 mmol) were added Et.sub.3N (0.029 g, 0.28 mmol), formaldehyde (0.0244 g, 0.301 mmol) and sodium cyanoborohydride (0.02 g, 0.317 mmol). The reaction mixture was stirred at r.t. for 14 h. The reaction mixture was taken up in EtOAc, washed with water and brine, dried (MgSO.sub.4), and concentrated in vacuo. The residue was purified by prep TLC (Eluent: 90 DCM/10 methanolic ammonia) yielding the title compound (12 mg, 8%). LCMS (ES.sup.+) RT 4 min, 502 (M+H).sup.+.

Examples 152 and 153

Enantiomer 1: ((4S or R)-4-[2-(difluoromethoxy)phenyl]-7-(4-methylsulfonylphenyl)-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole; enantiomer 2 (4R or S)-4-[2-(difluoromethoxy)phenyl]-7-(4-methylsulfonylphenyl)-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole

(334) ##STR00205##

(335) The title compounds were isolated by chiral purification of Example 140 under LC conditions on Lux-Cell-4 (76*265 mm*mm, flow 200 mL/min, 30? C., EtOH 100%, injection of 10 mL solution at a concentration of 5.7 g/L). The first eluting enantiomer (RT 13 min) was collected and the fractions were evaporated to yield the enantiomer 1 (Example 152). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.92 (d, J 8.4 Hz, 2H), 7.81 (d, J 8.4 Hz, 1H), 7.60 (d, J 8.4 Hz, 2H), 7.48 (dd, J 8.4 Hz, J 1.4 Hz, 1H), 7.36 (td, J 7.9 Hz, J 1.2 Hz, 1H), 7.25 (d, J 6.3 Hz, 1H), 7.09 (t, J 7.6 Hz, 1H), 7.00 (d, J 1.0 Hz, 1H), 6.72 (t, J 72.9 Hz, 1H), 6.66 (d, J 8.1 Hz, 1H), 5.88 (t, J 4.0 Hz, 1H), 4.44 (q, J 17.4 Hz, 2H), 3.68 (dd, J 13.9 Hz, J 4.6 Hz, 1H), 3.38 (dd, J 13.4 Hz, J 3.6 Hz, 1H), 3.06 (s, 3H). LCMS (ES.sup.+) RT 1.30 min, 470.0 (M+H).sup.+.

(336) The second eluting enantiomer (RT 18 min) was collected and the fractions were evaporated to yield enantiomer 2 (Example 153). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.92 (d, J 8.4 Hz, 2H), 7.82 (d, J 8.2 Hz, 1H), 7.60 (d, J 8.4 Hz, 2H), 7.48 (dd, J 8.5 Hz, J 1.2 Hz, 1H), 7.36 (t, J 7.0 Hz, 1H), 7.25 (d, J 5.9 Hz, 1H), 7.09 (t, J 6.9 Hz, 1H), 7.01 (d, J 0.3 Hz, 1H), 6.71 (t, J 73.0 Hz, 1H), 6.66 (d, J 7.2 Hz, 1H), 5.88 (t, J 4.0 Hz, 1H), 4.44 (q, J 17.0 Hz, 2H), 3.68 (dd, J 13.7 Hz, J 4.6 Hz, 1H), 3.38 (dd, J 13.7 Hz, J 3.6 Hz, 1H), 3.06 (s, 3H). LCMS (ES.sup.+) RT 1.30 min, 470.0 (M+H).sup.+.

Example 154

(7-bromo-6-fluoro-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl) acetate

(337) ##STR00206##

(338) The title compound (as a mixture of 2 diastereoisomers) was prepared from 1-(5-bromo-4-fluoro-2-nitro-phenyl)-2-phenyl-pyrrolidine following the method described for Example 116. LCMS (ES.sup.+) RT 4.85 and 4.90 min, 389.1/391.1 (M+H).sup.+.

Example 155

7-bromo-6-fluoro-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(339) ##STR00207##

(340) The title compound (as a mixture of 2 diastereoisomers 67/33 trans/cis) was prepared from Example 154 following the method described for Example 117 as a colorless oil (89%). The compound is used in the next step without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.51 (m, 1H), 7.40 (m, 4H), 7.18 (m, 2H), 7.00 (m, 1H), 5.69 (t, J 6.8 Hz, 1H), 5.53 (m, 1H), 3.19 (m, 1H), 2.91 (m, 1H), LCMS (ES+) RT 4.82 and 4.76 min, 347.1/349.1 (M+H).sup.+.

Example 156

7-bromo-6-fluoro-1-phenyl-1,2-dihydropyrrolo[1,2-a]benzimidazol-3-one

(341) ##STR00208##

(342) MnO.sub.2 (1.06 g, 12.2 mmol) was added to a solution of Example 155 (0.507 g, 1.46 mmol) in CHCl.sub.3 (20 mL) and the mixture was heated at 60? C. for 5 h. MnO.sub.2 (405 mg) and CHCl.sub.3 (20 mL) were added and the mixture heated for another 2 h. The residue is cooled to r.t., filtered on a bed of celite, and the solid is washed with DCM. The filtrates were washed with water (2?50 mL), a sat. aq. NaHCO.sub.3 (2?50 mL), a sat. solution of NH.sub.4Cl (2?50 mL), dried (MgSO.sub.4), concentrated in vacuo, to yield the title compound used in the next step without any purification (370 mg, 74%). LCMS (ES.sup.+) RT 4.67 min, 345/347 (M+H).sup.+.

Example 157

7-bromo-6-fluoro-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(343) ##STR00209##

(344) Lithium tri-sec-butylborohydride (1M, 1.7 mL, 1.5 eq.) was added drop wise to a cold (?78? C.) solution of Example 156 (307 mg, 1.1 mmol) in THF (10 mL). The resulting mixture was stirred 2 h, then the solution was allowed to reach 0? C. After 0.5 h at 0? C., MeOH (2 mL) was added. After 20 min, an aq. solution of NaOH (3 mL), followed by water (50 mL) were added and the resulting mixture was extracted with EtOAc (100 mL). The combined organic layers were washed with water (50 mL), with brine (2?50 mL), dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-10% methanolic ammonia/EtOAc) to yield the tile compound as a mixture of 2 cis diastereoisomers (270 mg, 72%). LCMS (ES.sup.+) RT 4.27 min, 347.08/349.07 (M+H).sup.+.

Examples 158 and 159

Diasteroisomer 1 (1S or R,3S or R)-6-fluoro-7-[6-(methylsulfonyl)pyridin-3-yl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol; diastereoisomer 2 (1R or S,3R or S)-6-fluoro-7-[6-(methylsulfonyl)pyridin-3-yl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(345) ##STR00210##

(346) The title compounds were isolated by chiral purification under SFC conditions on Chiralcel OD (50*266 mm*mm, flow 360 mL/min, 25? C., CO.sub.2+20% MeOH, injection of 17 mL solution at a concentration of 3.6 g/L). The first eluting enantiomer (RT 8.9 min) was collected and the fractions were evaporated to yield the title compound, diastereoisomer 1 (Example 158) as an off white solid (36 mg, 11%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.68 (s, 1H), 8.10 (m, 1H), 7.99 (m, 1H), 7.62 (m, 1H), 7.39 (m, 6H), 6.85 (s, 1H), 5.59 (m, 1H), 5.46 (m, 1H), 3.61 (m, 1H), 3.24 (s, 3H), 2.75 (m, 1H). LCMS (ES.sup.+) RT 1.24 min, 424.0 (M+H).sup.+. The second eluting enantiomer (RT 12.9 min) was collected to yield the second enantiomer diastereoisomer 2 (Example 159) as a white solid (6 mg, 11%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.68 (d, J 0.5 Hz, 1H), 8.10 (d, J 8.6 Hz, 1H), 7.99 (m, 1H), 7.40 (m, 7H), 6.87 (m, 1H), 5.58 (m, 1H), 5.46 (m, 1H), 3.61 (m, 1H), 3.24 (s, 3H), 2.75 (m, 1H). LCMS (ES.sup.+) RT 1.24 min, 424.0 (M+H).sup.+.

Example 160

Diastereoisomer 1 [(1R or S,3R or S)-7-bromo-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]acetate

(347) ##STR00211##

(348) The title intermediate was isolated by purification of the 4 diastereoisomers Example 116 by chiral purification under LC conditions on Chiralpak AD (100*500 mm*mm, flow 300 mL/min, 30? C., heptane-i-PrOH (1:1), injection of 10 mL solution at a concentration of 25 g/L). The first eluting peak (RT 13 min) contained 2 diastereoisomers (1R or S,3R or S) and (1S or R, 3R or S). The second peak (RT 22 min) contained the third diastereoisomer (1R or S, 3S or R) and the third pic (RT 30 min) contained the fourth diastereoisomer (1S or R, 3S or R).

(349) The mixture of the 2 diastereoisomers (1R or S,3R or S) and (1S or R, 3R or S) were separated by chiral purification under LC conditions on Lux-Cell-4 (78*265 mm*mm, flow 200 mL/min, 30? C., heptane-i-PrOH (7:3), injection of 2.5 mL solution at a concentration of 100 g/L). The first eluting enantiomer (RT 9 min) was collected and the fractions were evaporated to yield the title compound as colorless foam. The second eluting enantiomer (RT 12 min) was collected and the fractions were concentrated in-vacuo to yield the diastereoisomer (1S or R, 1R or S). .sup.1H NMR ?: 7.75 (d, J 9.6 Hz, 1H), 7.45 (m, 1H), 7.33 (m, 3H), 7.21 (t, J 7.6 Hz, 1H), 6.86 (d, J 7.0 Hz, 1H), 6.23 (dd, J 7.9 Hz, J 3.6 Hz, 1H), 5.92 (dd, J 8.2 Hz, J 4.3 Hz, 1H), 3.66 (m, 1H), 2.41 (dt, J 14.3 Hz, J 4.0 Hz, 1H), 2.03 (s, 3H).

Example 161

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

(350) ##STR00212##

(351) K.sub.2CO.sub.3 (172 mg, 1 eq.) was added to a solution of Example 160 (743 mg, 1.72 mmol) in MeOH (5.2 mL). The resulting mixture was stirred at r.t. for 4 h. The mixture was filtered, evaporated and the resulting residue was taken up in EtOAc, washed with brine (1?), dried (MgSO.sub.4) and concentrated in vacuo to yield the title intermediate as an off white solid (710 mg, 89%). LCMS (ES+) RT 1.50 min, 413.0/415.0 (M+H).sup.+.

Example 162

Diastereoisomer 1: (1R or S,3R or S)-7-bromo-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(352) ##STR00213##

(353) Sodium Hydride (50 mg, dispersed in mineral oil, 1.25 mmol, 80% w/w) was added portion wise to a solution of Example 161 (413 mg, 1.0 mmol) in anhydrous THF (5 mL). The mixture was sonicated 5 min, then stirred at r.t. for 30 min. Iodomethane (287 mg, 2 mmol) was added and the reaction mixture was stirred 2 h at 0? C., then at r.t. for 18 h. Purification by column chromatography (SiO.sub.2, 0-45% EtOAc/heptane), gave the title intermediate as a colorless oil (350 mg, 82%). LCMS (ES.sup.+) RT 5.24 min, 427.0/429.0 (M+H).sup.+.

Example 163

Diastereoisomer 4 [(1S or R,3S or R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]acetate

(354) ##STR00214##

(355) The title intermediate was isolated by the purification of a mixture of the 4 diastereoisomers of Example 116 described in Example 160 as the fourth diastereoisomer (RT 30 min). .sup.1H NMR (DMSO-d6) ?: 7.75 (d, J 9.6 Hz, 1H), 7.45 (m, 1H), 7.33 (m, 3H), 7.21 (t, J 7.6 Hz, 1H), 6.86 (d, J 7.6 Hz, 1H), 6.23 (dd, J 7.9 Hz, J 3.6 Hz, 1H), 5.92 (dd, J 8.3 Hz, J 4.3 Hz, 1H), 3.66 (m, 1H), 2.41 (dt, J 14.3 Hz, J 3.9 Hz, 1H), 2.03 (s, 3H).

Example 164

Distereoisomer 4: (1S or R, 3S or R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(356) ##STR00215##

(357) K.sub.2CO.sub.3 (172 mg, 1 eq.) was added to a solution of Example 163 (430 mg, 0.95 mmol) in MeOH (3.0 mL). The resulting mixture was stirred at r.t. for 4 h. The mixture was filtered, concentrated in vacuo, and the resulting residue was taken up in EtOAc, washed with brine (1?), dried (MgSO.sub.4) and concentrated in vacuo to yield the title compound as an off white solid (346 mg, 88%). LCMS (ES.sup.+) RT 4.62 min, 413.1/415.1 (M+H).sup.+.

Example 165

Diastereoisomer 4: (1S or R, 3S or R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(358) ##STR00216##

(359) Sodium hydride (50 mg, dispersed in mineral oil, 1.25 mmol, 80% w/w) was added portion wise to a solution of Example 164 (348 mg, 0.84 mmol) in anhydrous THF (4.2 mL). The mixture was sonicated 5 min, then stirred at r.t. for 30 min. Iodomethane (241 mg, 1.68 mmol) was added and the reaction mixture was stirred 2 h at 0? C., then at r.t. for 18 h. Purification by column chromatography (SiO.sub.2, 0-40% EtOAc/heptane), gave the title intermediate as a colorless oil (290 mg, 80%). LCMS (ES.sup.+) RT 5.24 min, 427.1/429.1 (M+H).sup.+.

Example 166

Diastereoisomer 4: 2-(5-{(1S or R,3S or R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyridin-2-yl)propan-2-ol

(360) ##STR00217##

(361) HCl (4 N in 1,4-dioxane, 0.2 mL) was added onto a solution of Example 78 (25 mg, 0.045 mmol) in DCM (0.5 mL) and the mixture was stirred at r.t. for 1 h. The solvent was concentrated in vacuo and the residue triturated in Et.sub.2O. The resulting powder was collected by filtration and concentrated in vacuo to yield the title compound as a pale orange powder (5 mg, 23%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.69 (s, 1H), 8.48 (d, J 8.1 Hz, 1H), 8.12 (d, J 8.4 Hz, 1H), 7.84 (d, J 11.4 Hz, 1H), 7.36 (m, 6H), 6.82 (d, J 7.5 Hz, 1H), 5.96 (dd, J 8.3 Hz, J 3.4 Hz, 1H), 5.04 (dd, J 7.4 Hz, J.sub.2 2.6 Hz, 1H), 3.58 (m, 4H), 2.42 (m, 1H), 1.59 (s, 6H). LCMS (ES.sup.+) RT 1.45 min, 484.0 (M+H).sup.+.

Example 167

Diastereoisomer 1: 2-(5-{(1R or S,3R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyridin-2-yl)propan-2-ol

(362) ##STR00218##

(363) HCl (4 N in 1,4-dioxane, 0.5 mL) was added onto a solution of Example 79 (168 mg) in DCM (0.5 mL) and the mixture was stirred at 0? C. for 3 h. The solvent was concentrated in vacuo and the residue triturated in Et.sub.2O, then in EtOAc. The resulting powder was collected by filtration and concentrated in vacuo to yield the title compound as an off white powder (135 mg, 100%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.69 (s, 1H), 8.48 (d, J 8.1 Hz, 1H), 8.12 (d, J 8.4 Hz, 1H), 7.84 (d, J 11.4 Hz, 1H), 7.36 (m, 6H), 6.82 (d, J 7.5 Hz, 1H), 5.96 (dd, J 8.3 Hz, J 3.4 Hz, 1H), 5.04 (dd, J 7.4 Hz, J.sub.2 2.6 Hz, 1H), 3.58 (m, 4H), 2.42 (m, 1H), 1.59 (s, 6H). LCMS (ES.sup.+) RT 1.45 min, 484.0 (M+H).sup.+.

Example 168

(1R or S)-7-bromo-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(364) ##STR00219##

(365) The title compound was prepared from a solution of Intermediate 161 (200 mg, 1.0 eq.), dissolved in DCM (2.5 mL). At 0? C., a solution of diethylaminosulfur trifluoride (1.2 eq.) in 0.5 mL of DCM was added. The mixture was stirred at 0? C. for 30 min. The reaction mixture was quenched with sat. aq. NaHCO.sub.3, extracted with DCM, dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, 0-6% MeOH/DCM), followed by purification by UV directed preparative reverse chromatography, yielding the title compound as a beige solid glass (102 mg, 51%). LCMS (ES+) RT1.60 min, 415.0/417.0 (M+H).sup.+.

Example 169

Enantiomer 2: 2-(5-{(1R or S)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyridin-2-yl)propan-2-ol hydrochloride

(366) ##STR00220##

(367) 4N HCl (0.5 mL) was added to a solution of Example 78 (0.38 g, 0.75 mmol) in DCM (5 mL) at 0? C. The reaction was stirred at r.t. for 30 min. The reaction mixture was concentrated in vacuo and triturated with EtOAc/iPr.sub.2O (1:1, 2 mL), yielding the title compound as a beige powder (355 mg, 96%). LCMS (ES.sup.+) RT 1.45 min, 454.0 (M+H).sup.+.

Examples 170 and 171

Diastereoisomer 1: (1R or S,3R or S)-7-bromo-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; diastereoisomer 2: (1R or S,3S or R)-7-bromo-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(368) ##STR00221##

(369) The title compounds were obtained by chiral purification Example 168 (diasteromeric ratio 60/40) by chiral purification under SFC conditions on Whelko-O1 (R,R) (50*227 mm*mm, flow 360 mL/min, 25? C., CO.sub.2+20% i-PrOH, injection of 22.5 mL solution at a concentration of 11.6 g/L). The first eluting diastereoisomer (RT 4.9 min) was collected and the fractions were evaporated to yield the title compound, diastereoisomer 1 (Example 170) (96 mg, 19%). The second eluting diastereoisomer (RT 7.9 min) was collected and the fractions were evaporated to yield the other diastereoisomer, diastereoisomer 2 (Example 171) (154 mg, 31%).

Example 172

(1R or S,3R or S)-3-azido-7-bromo-1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(370) ##STR00222##

(371) To a solution of Intermediate 108 (0.1 g, 1.0 eq.) in toluene (0.5 mL), diphenylphosphorylazide (1.3 eq.) is added drop wise at 0? C., followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 eq.). The reaction mixture was stirred at 0? C. for 1 h and at r.t. for 16 h. The reaction mixture was taken up by EtOAc and washed with water. The organic phase is dried (Na.sub.2SO.sub.4) and concentrated in vacuo to afford 110 mg (100%) of orange oil which was used in the next step without further purification. LCMS (ES.sup.+) RT 5.20 min, 438.0/440.0 (M+H).sup.+.

Example 173

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

(372) ##STR00223##

(373) Example 172 (0.110 g, 1.1 eq.) was dissolved in 1 mL of toluene. Triphenylphosphine (3 eq.) and 0.5 mL of water were added and the reaction mixture was stirred at r.t. for 16 h. The mixture was concentrated in vacuo and dissolved in EtOAc and extracted with HCl 1N. The aq. phase was neutralized with NaHCO.sub.3, extracted with DCM, dried (Na.sub.2SO.sub.4) and concentrated in vacuo to afford the title compound (87, 84%). LCMS (ES.sup.+) RT 3.51 min, 412.0/414.0 (M+H).sup.+.

Example 174 (Method G)

1-(5-{1-[2-(difluoromethoxy)phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)-4-methylpiperidine-4-carboxylic acid

(374) ##STR00224##

(375) Example 94 (0.384 g, 0.679 mmol) was dissolved in THF (8 mL) and 2 mL water. Lithium hydroxide monohydrate (0.102 g, 1.36 mmol) was added and the reaction was heated to 70? C. for 18 h. The reaction was concentrated in vacuo and the residue dissolved in a minimal amount of THF and diluted with water. The mixture was treated with EtOAc, and the organic layer extracted. The aq. was treated with AcOH, drop wise, to pH7, and the solution was stirred. The precipitate was filtered off and dried in vacuo. The solid was purified by prep-HPLC yielding the title compound as a cream solid (0.084 g, 23%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) ?: 8.38 (d, J 1.7 Hz, 2H), 7.55 (m, 1H), 7.41 (m, 1H), 7.31 (m, 2H), 7.18 (td, J 7.6 Hz, J 0.9 Hz, 1H), 6.98 (d, J 7.1 Hz, 1H), 6.85 (dd, J 7.7 Hz, J 1.4 Hz, 1H), 5.88 (m, 1H), 4.24 (m, 2H), 3.15 (m, 6H), 1.97 (m, 2H), 1.34 (m, 2H), 1.16 (s, 3H). LCMS (ES.sup.+) RT 1.57 min, 538.0 (M+H).sup.+.

Example 175

1-(5-{3-[2-(difluoromethoxy)phenyl]-7-fluoro-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-6-yl}pyrimidin-2-yl)-4-methylpiperidine-4-carboxylic acid

(376) ##STR00225##

(377) The title compound was prepared from Example 100 (0.21 g, 0.36 mmol) was and lithium hydroxide monohydrate (0.055 g, 0.74 mmol) by the Method G (0.041 g, 21%). 1H NMR (DMSO-d.sub.6, 300 MHz) ?: 8.36 (d, J 1.6 Hz, 2H), 7.42 (m, 2H), 7.31 (m, 2H), 7.21 (td, J 7.7 Hz, J 1.0 Hz, 1H), 7.14 (d, J 11.8 Hz, 1H), 6.96 (dd, J 7.8 Hz, J 1.5 Hz, 1H), 6.78 (d, J 7.1 Hz, 1H), 5.89 (dd, J 8.8 Hz, J 4.8 Hz, 1H), 4.47 (t, J 9.6 Hz, 1H), 4.22 (m, 1H), 3.76 (dd, J 9.8 Hz, .sub.25.2 Hz, 1H), 3.26 (m, 4H), 1.98 (m, 2H), 1.27 (m, 2H), 1.11 (s, 2H). LCMS (ES.sup.+) RT 1.96 min, 539.8 (M+H).sup.+.

Example 176

(1S,5R)-3-[5-[1-1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylic acid

(378) ##STR00226##

(379) The title compound was prepared from Example 101 (0.197 g, 0.36 mmol) and lithium hydroxide monohydrate (0.108 g, 1.44 mmol) by the Method G (0.077 g, 40%). 1H NMR (DMSO-d6) ?: 8.48 (s, 2H), 7.39 (m, 2H), 7.29 (m, 3H), 7.19 (m, 2H), 6.95 (m, 2H), 5.90 (dd, J.sub.1 8.8 Hz, J.sub.24.7 Hz, 1H), 4.47 (t, J 9.3 Hz, 1H), 4.37 (d, J 12.3 Hz, 2H), 3.75 (dd, J.sub.1 9.7 Hz, J.sub.2 4.9 Hz, 1H), 2.96 (d, J 12.0 Hz, 2H), 2.57 (s, 3H), 1.67 (m, 2H), 1.35 (d, J 7.5 Hz, 2H). LCMS (ES.sup.+) RT 1.55 min, 533.8 (M+H).sup.+.

Example 177

Enantiomer 2: (1S,5R)-3-[5-[(1R or S)-1-[2-(difluoromethoxy)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylic acid

(380) ##STR00227##

(381) The title compound was prepared from Example 102 (0.163 g, 0.30 mmol) and lithium hydroxide monohydrate (0.089 g, 1.19 mmol) by the Method G (0.083 g, 52%). .sup.1H NMR (DMSO-d.sub.6) ?: 12.29 (m, 1H), 8.50 (s, 2H), 7.65 (d, J 8.4 Hz, 1H), 7.40 (m, 3H), 7.31 (m, 1H), 7.18 (m, 1H), 7.10 (s, 1H), 6.85 (d, J 7.6 Hz, 1H), 5.89 (m, 1H), 4.40 (d, J 12.4 Hz, 2H), 3.14 (m, 3H), 2.99 (m, 2H), 2.62 (d, J 25.7 Hz, 3H), 1.68 (m, 2H), 1.37 (d, J 8.2 Hz, 2H). LCMS (ES+) RT 1.20 min, 532.2 (M+H).sup.+.

Example 178

Enantiomer 1: (1S,5R)-3-[5-[(4S or R)-2-tert-butoxycarbonyl-4-[2-(difluoromethoxy)phenyl]-8-fluoro-3,4-dihydro-1H-pyrazino[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylic acid

(382) ##STR00228##

(383) Example 99 (100 mg, 0.15 mmol) in THF (3 mL) was treated with NaOH (10% w/v aq. solution, 286 uL) and water (1 mL), and heated to 70? C. for 9 h then allowed to cool to r.t. The reaction mixture was diluted with EtOAc (25 mL), acidified by the addition of AcOH (2 mL) and washed with water (25 mL). The aq. layer was extracted with EtOAc (25 mL) and the combined organic extracts were washed with water (25 mL) and brine (25 mL) and dried (MgSO.sub.4) and concentrated in vacuo, yielding colourless gum. LCMS (ES+) RT 1.30 min, 665.0 (M+H).sup.+.

Example 179

Enantiomer 1: (1S,5R)-3-[5-[(4S or R)-4-[2-(Difluoromethoxy)phenyl]-8-fluoro-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylic acid dihydrochloride

(384) ##STR00229##

(385) Example 178 (200 mg, 0.30 mmol) was dissolved in 4 M HCl in 1,4-dioxane (4 mL) and stirred at rt for 1.5 h. The reaction mixture was diluted with 1,4-dioxane (10 mL), concentrated in vacuo, suspended in 1,4-dioxane (25 mL) and concentrated in vacuo. The crude residue was triturated in i-Pr.sub.2O to give the title compound (94 mg) as yellow solid (100%). ?.sub.H (400 MHz, DMSO-d.sub.6) 10.2 (brs, 1H), 8.20 (s, 2H), 7.63 (d, J 11.2 Hz, 1H), 7.56 (m, 1H), 7.40 (d, 1H), 7.38 (tr, J 74.4 Hz, 1H), 7.27 (m, 2H), 6.49 (d, J 6.9 Hz, 1H), 6.12 (dd, J 9.6, 4.9 Hz, 1H), 4.75 (s, 2H), 4.37 (dd, J 12.9, 3.3 Hz, 2H), 4.03 (m, 1H), 3.70-3.57 (m, 2H), 3.00 (d, J 11.9 Hz, 2H), 2.65 (s, 1H), 2.58 (s, 2H), 1.68 (m, 2H), 1.37 (d, J 7.8 Hz, 2H), 1.04 (d, J 6.1 Hz, 2H). LCMS (ES+) RT 0.90 min, 565.0 (M+H).sup.+.

Examples 180-186

(386) The following Examples were prepared using Method C from the assigned precursor using the appropriate boronate ester or boronic acid, either commercially available or prepared in the Intermediates above.

(387) TABLE-US-00007 Example No. Precursor Compound Name LCMS 180 Int 109 3-[2-(difluoromethoxy)phenyl]-7-fluoro-1-methyl- LCMS 6-12-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-yl]- (ES+) RT 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole 4.35 min, 0 496.3 (M + H).sup.+. 181 Int 130 (1R,3R or S)-1-[2-chloro-6- LCMS (difluoromethoxy)phenyl]-7-[2-(1-hydroxy-1- (ES.sup.+) RT methyl-ethyl)pyrimidin-5-yl]-2,3-dihydro-1H- 1.99 min. pyrrolo[1,2-a]benzimidazol-3-ol 487.0 (M + H).sup.+. 182 Int 131 (1R,3S or R)-1-[2-chloro-6- LCMS (difluoromethoxy)phenyl]-7-[2-(1-hydroxy-1- (ES.sup.+) RT methyl-ethyppyrimidin-5-yl]-2,3-dihydro-1H- 2.00 min. pyrrolo[1,2-a]benzimidazol-3-ol 487.0 (M + H).sup.+. 183 Int 111 (1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-7- LCMS [2-(2-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-5-yl]- (ES.sup.+) RT 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole 1.52 min. 522.0 (M + H).sup.+. 184 Int 111 2-(5-{(1R,3R)-1-[2-(difluoromethoxy)phenyl]-3- LCMS fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol- (ES.sup.+) RT 7-yl}pyrimidin-2-yl)propan-2-ol 1.41 min. 455.0 (M + H).sup.+. 185 Int 112 2-(5-{(1R,3S)-1-[2-(difluoromethoxy)phenyl]-3- LCMS fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol- (ES.sup.+) RT 7-yl}pyrimidin-2-yl)propan-2-ol 1.41 min. 455.0 (M + H).sup.+. 186 Int 137 2-(5-{(1R)-[2-(difluoromethoxy)phenyl]-3,8- LCMS difluoro-2,3-dihydro-1H-pyrrolo[1,2- (ES.sup.+) RT a]benzimidazol-7-yl}pyrimidin-2-yl)propan-2-ol 1.45 min. 473.0 (M + H).sup.+.

Example 187 Method H

2-(5-{(1R)-1-[2-(difluoromethoxy)phenyl]-8-fluoro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)-2-methylpropanenitrile

(388) ##STR00237##
2-(5-bromopyrimidin-2-yl)-2-methyl-propanenitrile (170 mg, 0.75 mmol), bis(pinacolato)diboron (0.235 g, 0.927 mmol), potassium acetate (0.153 g, 1.545 mmol) were suspended in 5 mL of degassed anhydrous dioxane before addition of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.028 g, 0.039 mmol). The reaction mixture was degassed for further 5 minutes and heated at 105? C. for 1 hour. The reaction was cooled to r.t. and Intermediate 110 (0.200 g, 0.484 mmol), cesium carbonate (0.187 g, 0.968 mmol), water (0.315 mL) were added and the mixture was heated at 100? C. for 18 h. The reaction mixture was filtered over Na.sub.2SO.sub.4 and 45 ?M filter washing with EtOAc, and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 80% EtOAc/5% MeOH in hexane) to afford the title compound as a brown solid (175 mg, 75%). LCMS (ES.sup.+) RT 4.39 min, 480.2 (M+H).sup.+

Example 188

(1R)-1-[2-(difluoromethoxy)phenyl]-8-fluoro-7-[2-(4-fluorotetrahydro-2H-pyran-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(389) ##STR00238##
The title compound was prepared following the Method H using the Intermediate 114 (200 mg, 0.766 mmol) and Intermediate 110 affording the compound as a brown solid (108 mg, 43%). LCMS (ES+) RT 4.15 min, 515.3 (M+H).sup.+.

Example 189

(1R)-1-[2-(difluoromethoxy)phenyl]-8-fluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(390) ##STR00239##
The title compound was prepared following the Method H, using Intermediate 135 (180 mg, 0.77 mmol) and Intermediate 110. LCMS (ES+) RT 1.32 min, 487.2 (M+H).sup.+.

Example 191

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

(391) ##STR00240##
A solution of Example 182 (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 EtOAc 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%). LCMS (ES.sup.+) RT 2.66 min. 571.25 (M+H).sup.+.

Example 192

(1R,3R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[2-(4-fluorotetrahydropyran-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(392) ##STR00241##
The title compound was prepared following the Method H using the Intermediate 114 (0.50 g, 1.92 mmol) and Example 161 (0.300 g, 0.75 mmol), affording the compound (195 mg, 52%). LCMS (ES.sup.+) RT 1.39 min, 515.0 (M+H).sup.+.

Example 193

(1R)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-7-[2-(4-fluorotetrahydro-2H-pyran-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(393) ##STR00242##
The title compound was prepared following the Method I using the Example 192 (0.050 g, 0.097 mmol) and DAST (0.017 mL, 0.117 mmol yielding the title compound as a white solid (20 mg, 42%). LCMS (ES.sup.+) RT 1.45 min. 517.0 (M+H).sup.+.

Example 194

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

(394) ##STR00243##
The title compound was prepared from Example 161 and Intermediate 135 by the Method H. LCMS (ES.sup.+) RT 1.36 min, 487.0 (M+H).sup.+.

Example 195

(1R)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(395) ##STR00244##
The title compound was prepared following the Method I using the Example 194 (0.170 g, 0.350 mmol) and DAST (0.061 mL, 0.419 mmol) yielding the title compound as a white solid (102 mg, 62%). LCMS (ES.sup.+) RT 1.46 min, 489.0 (M+H).sup.+.

Examples 196 and 197

(1R,3R or S)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole and (1R,3S or R)-1-[2-(difluoromethoxy)phenyl]-3,6-difluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(396) ##STR00245##
The title compounds were prepared from Example 170 and Example 171 respectively with Intermediate 135 by the Method H. LCMS (ES.sup.+) RT 1.46 min, 489.0 (M+H).sup.+.

Example 198

(1R,3R)-1-[2-(difluoromethoxy)phenyl]-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(397) ##STR00246##
The title compound was prepared from Intermediate 148 and Intermediate 135 by the Method H. LCMS (ES.sup.+) RT 1.33 min, 469.0 (M+H).sup.+.

Example 199

(1R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(398) ##STR00247##
The title compound was prepared following the Method I using the Example 198 (00.170 g, 0.363 mmol) and DAST (0.06 mL, 0.43 mmol) yielding the title compound as a white solid (50 mg, 29%). LCMS (ES.sup.+) RT 1.39 min, 471.0 (M+H).sup.+.

Examples 200 and 201

(1R,3R or S)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole and (1R,3S or R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-7-[2-(3-fluorooxetan-3-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(399) ##STR00248##
The title compounds were prepared from Intermediates 111 and 112 respectively with Intermediate 135 by the Method H. LCMS (ES.sup.+) RT 1.40 min, 471.0 (M+H).sup.+.

Example 202

2-(5-{(1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)-2-methylpropanenitrile

(400) ##STR00249##
The title compound was prepared following the Method H using the Intermediate 111 (0.068 g, 0.30216 mmol) and 2-(5-bromopyrimidin-2-yl)-2-methyl-propanenitrile (0.108 g, 92%). LCMS (ES+) RT 1.55 min, 464.0 (M+H).sup.+.

Example 203

(1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-7-[2-(4-fluorotetrahydropyran-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(401) ##STR00250##
The title compound was prepared following the Method H using the Intermediate 111 (122 mg, 0.30 mmol) and Intermediate 114 (100 mg, 0.38 mmol), (0.025 g, 13%). LCMS (ES+) RT 1.47 min, 499.0 (M+H).sup.+.

Example 204

3-[5-[(1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]oxetan-3-ol

(402) ##STR00251##
The title compound was prepared following the Method H using the Intermediate 111 (100 mg, 0.25 mmol) and Intermediate 133 (116 mg, 0.50 mmol) yielding a brown solid (0.072 g, 61%). LCMS (ES+) RT 1.32 min, 469.0 (M+H).sup.+.

Example 205

(1R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-7-[6-(1-fluoro-1-methyl-ethyl)-3-pyridyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole

(403) ##STR00252##
The title compound was prepared following the Method I from Example 169 (0.315 g, 0.695 mmol) and DAST (1.39 mmol) yielding a white solid (0.220 g, 66%). LCMS (ES+) RT 1.64 min, 456.0 (M+H).sup.+.

Example 206

9-[5-[(1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]pyrimidin-2-yl]-3,7-dioxa-9-azabicyclo[3.3.1]nonane

(404) ##STR00253##
The title compound was prepared following the Method H using the Intermediate 111 (216 mg, 0.54 mmol) and Intermediate 140 (195 mg, 0.68 mmol) yielding a brown solid (0.206 g, 58%). LCMS (ES+) RT 1.43 min, 524.0 (M+H).sup.+.

Example 207

3-(difluoromethoxy)-2-{(1R,3R)-3-hydroxy-7-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl}benzonitrile

(405) ##STR00254##
Example 181 (180 mg, 0.37 mmol) and zinc cyanide (87 mg, 0.74 mmol) were dissolved in anhydrous DMF (3 mL). Tetrakis(triphenylphosphine)palladium (0) (43.2 mg, 0.037 mmol) was added and the mixture was heated at 180? C. for 30 minutes under microwave irradiation. The reaction mixture was poured on ice, a saturated solution of NaHCO.sub.3 was added and the reaction mixture was extracted with EtOAc (3?10 mL) and a mixture of DCM/MeOH (9:1) (3?10 mL). The combined organic layers were dried over MgSO.sub.4 and concentrated in vacuo. The crude compound was purified by chromatography (SiO.sub.2, 0.5-1% MeOH in DCM) and recrystallized in Et.sub.2O to afford the title compound as a white solid (76 mg, 43%). LCMS (ES+) RT 1.22 min, 478.0 (M+H).sup.+.

Example 208

3-(difluoromethoxy)-2-{(1R,3S)-3-hydroxy-7-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-yl}benzonitrile

(406) ##STR00255##
The title compound was prepared from Example 182 (150 mg, 0.308 mmol), zinc cyanide (73 mg, 0.62 mmol), DMF (2 mL) and tetrakis(triphenylphosphine)palladium (0) (36 mg, 0.031 mmol) by the analogous procedure to the preparation of Example 210 (14 mg, 9.5%). LCMS (ES+) RT 1.76 min, 478.0 (M+H).sup.+.

Examples 209 and 210Method J

(1R,3R)-1-(5-chloro-2-(difluoromethoxy)phenyl)-7-(4-((R or S)S methylsulfonimidoyl)phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol and (1R,3R)-1-(5-chloro-2-(difluoromethoxy)phenyl)-7-(4-((S or R)S-methylsulfonimidoyl)phenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol

(407) ##STR00256##
To a mixture of Intermediate 161 (250 mg, 0.58 mmol) in degassed dioxane (4 mL), Intermediate 143 (164 mg, 0.58 mmol), Na.sub.2CO.sub.3 (123 mg, 1.16 mmol) and water (1 mL) was added and the mixture was flushed with Argon. Pd.sub.2(dba).sub.3 (11 mg, 0.12 mmol) and phosphonium tetrafluoroborate (17 mg, 0.58 mmol) was added and the mixture was stirred in a microwave apparatus (Biotage Initiator) at 100? C. for 15 minutes. The reaction mixture was distributed between NaCl solution (3 mL) and EtOAc (4 mL). The organic phase was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 5% MeOH in DCM) and by preparative HPLC on SiO.sub.2 (Prep-C18) with water/MeCN as eluent (gradient 30/70 up to 70/30). After concentration in vacuo and lyophilisation (147 mg, 50%) of the desired product was obtained as a mixture of 2 diastereoisomers which were separated by chiral chromatography (Chiracel OJ-H, 250?30 mm, 5 ?M, eluent: heptane/EtOH/MeOH, 2/1/1, flow=30 ml/min). The first eluting isomer (8.4 min) was collected and the fractions evaporated to yield Example 209 (57 mg, 19.4%). .sup.1H NMR (400 MHz, DMSO-d6) ? ppm 7.95 (d, J 8.4 Hz, 2H), 7.80 (d, J 8.4 Hz, 1H), 7.77 (d, J 8.4 Hz, 2H), 7.60 (dd, J 8.4, 1.77 Hz, 1H), 7.48 (dd, J 8.8, 2.7 Hz, 1H), 7.44 (t, J 73.4 Hz, 1H), 7.38 (m, 2H), 7.01 (d, J 2.6 Hz, 1H), 6.13 (d, J 5.5 Hz, 1H), 5.88 (dd, J 8.4, 4.0 Hz, 1H), 5.23 (m, 1H), 4.19 (s, 1H), 3.50 (m, 1H), 3.07 (s, 3H), 2.34 (m, 1H). LCMS (ES.sup.+) RT 1.39 min, 504.14 (M+H).sup.+
The second eluting isomer (13.9 min) was collected and the fractions evaporated to yield Example 210 (56 mg, 19%). LCMS (ES.sup.+) RT 1.39 min, 504.14 (M+H).sup.+.
The absolute configuration at the sulfoximine residue was not assigned.

Examples 211 and 212

(1R,3R)-1-(2-(difluoromethoxy)phenyl)-7-(4-((R or S)S-methylsulfonimidoyl)phenyl)-2,3-dihydro-1-H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol and (1R,3R)-1-(2-(difluoromethoxy)phenyl)-7-(4-((S or R)S-methylsulfonimidoyl)phenyl)-2,3-dihydro-1-H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol

(408) ##STR00257##
The title compounds were prepared as described in examples 212 and 213 from Intermediate 148 (500 mg, 1.27 mmol) and 4,4,5,5-tetramethyl-2-(4-(S-methylsulfonimidoyl)phenyl)-1,3,2-dioxaborolane (356 mg, 1.27 mmol) to yield 330 mg (55.6%) as a mixture of 2 diastereoisomers which were separated by chromatography 5 (Chiralpak AY, 230?100 mm, 20 ?m, eluent: heptane/ethanol 1/1, flow=400 ml/min). The first eluting isomer (9.6 min) was collected and the fractions evaporated to yield Example 211 (146 mg, 24%). .sup.1H NMR (400 MHz, DMSO-d6) ? ppm 7.93 (d, J 8.4 Hz, 2H), 7.78 (d, J 8.4 Hz, 1H), 7.72 (d, J 8.4 Hz, 2H), 7.56 (dd, J 8.4, 1.7 Hz, 1H), 7.41 (t, J 73.7 Hz, 1H), 7.40 (m, 1H), 7.33 (d, J 7.8 Hz, 1H), 7.24 (m, 1H), 7.18 (dd, J 7.8, 1.0 Hz, 1H), 7.00 (dd, J 7.8, 1.3 Hz, 1H), 6.09 (d, J 5.5 Hz, 1H), 5.88 (dd, J 8.2, 4.8 Hz, 1H), 5.25 (m, 1H), 4.18 (s, 1H), 3.49 (m, 1H), 3.07 (s, 3H), 2.31 (m, 1H). LCMS (ES.sup.+) RT 1.28 min, 470.22 (M+H).sup.+.
The second eluting isomer (12.9 min) was collected, the fractions evaporated and the residue further purified by chromatography (SiO.sub.2, 5% MeOH in DCM) to yield Example 212 (115 mg, 19%). LCMS (ES+) RT 1.28 min, 470.17 (M+H).sup.+.
The absolute configuration at the sulfoximine residue was not assigned.

Examples 213-235

(409) The following Examples were prepared using Method J from the assigned precursor using the appropriate boronate ester or boronic acid, either available commercially or prepared as set out in the Intermediates above.

(410) TABLE-US-00008 Example No. Precursor Compound Name LCMS 213 Int 148 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3- LCMS (ES.sup.+) hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2- RT 1.15 min, a]imidazol-7-yl]-1H-pyridin-2-one 410.13 (M + H).sup.+. 214 Int 150 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-(2- LCMS (ES.sup.+) hydroxy-ethoxy)-2,3-dihydro-1H- RT 1.25 min, benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-1H-pyridin- 454.17 2-one (M + H).sup.+. 215 Int 151 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-(3- LCMS (ES.sup.+) hydroxy-propoxy)-2,3-dihydro-1H- RT 1.37 min, benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-1H-pyridin- 468.15 2-one (M + H).sup.+. 0 216 Int 148 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3- LCMS (ES.sup.+) hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2- RT 1.25 min, a]imidazol-7-yl]-3-methyl-1H-pyridin-2-one 424.15 (M + H).sup.+. 217 Int 153 5-{(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3-[2-(2- LCMS (ES.sup.+) oxo-pyrrolidin-1-yl)-ethoxy]-2,3-dihydro-1H- RT 1.35 min, benzo[d]pyrrolo[1,2-a]imidazol-7-yl}-1H-pyridin- 521.22 2-one (M + H).sup.+. 218 Int 161 5-[(1R,3R)-1-(5-Chloro-2-difluoromethoxy- LCMS (ES.sup.+) phenyl)-3-hydroxy-2,3-dihydro-1H- RT 1.35 min, benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-3-methyl- 458.15 1H-pyridin-2-one (M + H).sup.+. 219 Int 148 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3- LCMS (ES.sup.+) hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2- RT 1.16 min, a]imidazol-7-yl]-6-methyl-1H-pyridin-2-one 424.2 (M + H).sup.+. 220 Int 148 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3- LCMS (ES.sup.+) hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2- RT 1.19 min, a]imidazol-7-yl]-4-methyl-1H-pyridin-2-one 424.16 (M + H).sup.+. 221 Int 150 2-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-7-(4- LCMS (ES.sup.+) methylsulfonimidoyl-phenyl)-2,3-dihydro-1H- RT 1.36 min, benzo[d]pyrrolo[1,2-a]imidazol-3-yloxy]-ethanol 514.2 (M + H).sup.+. 222 Int 150 2-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-7-(4 LCMS (ES.sup.+) methanesulfonyl-phenyl)-2,3-dihydro-1H- RT 1.53 min, benzo[d]pyrrolo[1,2-a]imidazol-3-yloxy]-ethanol 515.19 (M + H).sup.+. 223 Int 148 (1R,3R)-1-(2-Difluoromethoxy-phenyl)-7-(4 LCMS (ES.sup.+) methanesulfonyl-phenyl)-2,3-dihydro-1H- RT 1.47 min, benzo[d]pyrrolo[1,2-a]imidazol-3-ol 471.17 (M + H).sup.+. 224 Int 148 (1R,3R)-7-(4-Cyclopropanesulfonyl-phenyl)-1-(2- LCMS (ES.sup.+) difluoromethoxy-phenyl)-2,3-dihydro-1H- RT 1.57 min, benzo[d]pyrrolo[1,2-a]imidazol-3-ol 497.22 (M + H).sup.+. 225 Int 161 (1R,3R)-1-(5-Chloro-2-difluoromethoxy-phenyl)- LCMS (ES.sup.+) 7-(4-methanesulfonyl-phenyl)-2,3-dihydro-1H- RT 1.56 min, benzo[d]pyrrolo[1,2-a]imidazol-3-ol 505.14 0 (M + H).sup.+. 226 Int 161 (1R,3R)-1-(5-Chloro-2-difluoromethoxy-phenyl)- LCMS (ES.sup.+) 7-(4-cyclopropanesulfonyl-phenyl)-2,3-dihydro- RT 1.65 min, 1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol 531.14 (M + H).sup.+. 227 Int 150 2-[(1R,3R)-7-(4-Cyclopropanesulfonyl-phenyl)-1- LCMS (ES.sup.+) (2-difluoromethoxy-phenyl)-2,3-dihydro-1H- RT 1.63 min, benzo[d]pyrrolo[1,2-a]imidazol-3-yloxy]-ethanol 541.22 (M + H).sup.+. 228 Int 148 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3- LCMS (ES.sup.+) hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2- RT 1.24 min, a]imidazol-7-yl]-1-methyl-1H-pyridin-2-one 424.2 (M + H).sup.+. 229 Int 148 4-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3- LCMS (ES.sup.+) hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2- RT 1.35 min, a]imidazol-7-yl]-benzenesulfonamide 472.13 (M + H).sup.+. 230 Int 152 2-[(1R,3R)-1-(5-Chloro-2-difluoromethoxy- LCMS (ES.sup.+) phenyl)-7-(4-methanesulfonyl-phenyl)-2,3- RT 1.6 min, dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3- 549.09 yloxyl-ethanol (M + H).sup.+. 231 Int 152 2-[(1R,3R)-1-(5-Chloro-2-difluoromethoxy- LCMS (ES.sup.+) phenyl)-7-(4-cyclopropanesulfonyl-phenyl)-2,3- RT 1.68 min, dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3- 575.09 yloxy]-ethanol (M + H).sup.+. 232 Int 148 (1R,3R)-1-(2-Difluoromethoxy-phenyl)-7-[4- LCMS (ES.sup.+) (propane-2-sulfonyl)-phenyl]-2,3-dihydro-1H- RT 1.6 min, benzo[d]pyrrolo[1,2a]imidazol-3-ol 499.18 (M + H).sup.+. 233 Int 148 4-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3- LCMS (ES.sup.+) hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2- RT 1.36 min, a]imidazol-7-yl]-N-(2-hydroxy-ethyl)- 516.14 benzenesulfonamide (M + H).sup.+. 234 Int 148 5-[(1R,3R)-1-(2-Difluoromethoxy-phenyl)-3- LCMS (ES.sup.+) hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2- RT 1.33 min, a]imidazol-7-yl]-1,3-dimethyl-1H-pyridin-2-one 438.19 (M + H).sup.+. 235 Int 148 3-Cyclopropyl-5-[(1R,3R)-1-(2-difluoromethoxy- LCMS (ES.sup.+) phenyl)-3-hydroxy-2,3-dihydro-1H- RT 1.34 min, benzo[d]pyrrolo[1,2-a]imidazol-7-yl]-1H-pyridin- 450.18 2-one (M + H).sup.+. 0

Example 236

(8-anti)-3-(5-{(1R,3R)-1-[2-(difluoromethoxy)phenyl]-6-fluoro-3-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid

(411) ##STR00281##
The title compound was prepared from Intermediate 163 (501 mg, 0.86 mmol), by the Method G (418 mg, 85%). LCMS (ES+) RT 1.08 min, 566.0 (M+H).sup.+.

Example 237 Method L

(1R,3R or S)-1-[2-(difluoromethoxy)phenyl]-8-fluoro-7-[4-(methylsulfonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol

(412) ##STR00282##

(413) In a microwave vessel (20 ml), Intermediate 164 (50 mg, 121 ?mol), sodium carbonate (52 mg, 484 ?mol), 4-(methylsulphonyl)phenylboronic acid (49 mg, 242 ?mol), and 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20 mg, 24 ?mol) were mixed with DME (4 mL) and water (1 mL). After heating for 15 minutes at 100? C. and cooling to r.t. water was added and the aqueous phase was extracted with DCM (?3). The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, 0-10% EtOH in DCM). The residue was further purified by preparative HPLC (M2b) yielding the title compound (42 mg, 71%). LCMS [M 1b](ES.sup.+) RT 1.57 min, 489.1 (M+H).sup.+.

Examples 238-239

(414) The following Examples were prepared from the given starting material using the appropriate boronate ester or boronic acid by the Method L.

(415) TABLE-US-00009 Example No. Precursor Compound Name LCMS 238 Int 164 (1R,3R or S)-[2-(difluoromethoxy)phenyl]-8- LCMS [M fluoro-7-[2-(2-hydroxypropan-2-yl)pyrimidin- 1b] (ES.sup.+) 5-yl]-2,3-dihydro-1H-pyrrolo[1,2- RT 1.56 min, a]benzimidazol-3-ol 471.2 (M + H).sup.+ 239 Int 164 (1R,3R or S)-7-[4- LCMS [M (cyclopropylsulfonyl)phenyl]-1-[2- 1b] (ES+) (difluoromethoxy)phenyl)-8-fluoro-2,3- RT 1.66 min, dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-ol 515.1 (M + H)+

Example 240

(416) Example 40 was prepared from the given starting material using the appropriate boronate ester or boronic acid by the Method L

(417) TABLE-US-00010 Example No. Precursor Compound Name LCMS 240 Int 164 (1R,3R or S)-1-[2-(difluoromethoxy)phenyl]-8- LCMS [M fluoro-7-(6-methoxy-3-pyridyl)-2,3-dihydro- 1b] (ES.sup.+) 1H-pyrrolo[1,2-a]benzimidazol-3-ol RT 1.70 min; 442.1 (M + H).sup.+.

Example 241

2-(5-{4-[2-(difluoromethoxy)phenyl]-8-fluoro-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazol-7-yl}pyrimidin-2-yl)propan-2-ol

(418) ##STR00286##

(419) Intermediate 165 (210 mg, 369 ?mol) was dissolved in dioxane (5 mL) and hydrogen chloride solution (1 mL) followed by TFA (0.5 mL) were added at r.t. After stirring for 1 h the mixture stood for 18 h and was heated to 60? C. for 1.5 h. An additional amount of TFA (0.5 mL) was added and after 1.25 h, the mixture was cooled to r.t. and EtOAc and saturated sodium bicarbonate solution were added. After phase separation the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (M2d) yielding the title compound (105 mg, 61%). LCMS [M 1b](ES.sup.+) RT 1.31 min, 470.3 (M+H).sup.+.