Fused imidazole derivatives as IL-17 modulators

Abstract

A series of substituted fused bicyclic imidazole derivatives, including benzimidazole derivatives and analogues thereof, being potent modulators of human IL-17 activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.

Claims

1. A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: ##STR00198## wherein A represents C—R.sup.1 or N; B represents C—R.sup.2 or N; D represents C—R.sup.3 or N; E represents C—R.sup.4 or N; R.sup.0 represents hydrogen or C.sub.1-6 alkyl; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, —OR.sup.a, —SR.sup.a, —SOR.sup.a, —SO.sub.2R.sup.a, —NR.sup.bR.sup.c, —NR.sup.cCOR.sup.d, —NR.sup.cCO.sub.2R.sup.d, —NHCONR.sup.bR.sup.c, —NR.sup.cSO.sub.2R.sup.e, —NHSO.sub.2NR.sup.bR.sup.c, —N═S(O)R.sup.bR.sup.c, —COR.sup.d, —CO.sub.2R.sup.d, —CONR.sup.bR.sup.c, —CON(OR.sup.a)R.sup.b, —SO.sub.2NR.sup.bR.sup.c or —S(O)(NR.sup.c)R.sup.a; or C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-9 cycloalkyl, C.sub.3-9 cycloalkyl(C.sub.1-6)alkyl, C.sub.4-9 cycloalkenyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, C.sub.3-7 hetero-cycloalkenyl, C.sub.4-9 heterobicycloalkyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R.sup.5 represents C.sub.3-9 cycloalkyl, C.sub.4-12 bicycloalkyl, C.sub.5-9 spirocycloalkyl(C.sub.1-6)alkyl, or C.sub.7-13 dispirocycloalkyl, any of which groups is optionally substituted by one or more substituents; R.sup.6 represents —OR.sup.6a; or R.sup.6 represents C.sub.1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one, two or three substituents independently selected from C.sub.1-6 alkyl, tetrahydropyranyl and di(C.sub.1-6)alkylsulfoximinyl; R.sup.6a represents C.sub.3-9 cycloalkyl, which group may be optionally substituted by one or more substituents; R.sup.a represents trifluoromethyl; or R.sup.a represents C.sub.1-6 alkyl, C.sub.3-9 cycloalkyl, C.sub.3-9 cycloalkyl(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl-(C.sub.1-6)alkyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R.sup.b and R.sup.c independently represent hydrogen or trifluoromethyl; or C.sub.1-6 alkyl, C.sub.3-9 cycloalkyl, C.sub.3-9 cycloalkyl(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or R.sup.b and R.sup.c, when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents; R.sup.d represents hydrogen; or R.sup.d represents C.sub.1-6 alkyl, C.sub.3-9 cycloalkyl, aryl, C.sub.3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and R.sup.e represents C.sub.1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

2. A compound as claimed in claim 1 represented by formula (I-1), (I-2), (I-3), (I-4), (I-5) or (I-6) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: ##STR00199## wherein R.sup.0, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined in claim 1.

3. A compound as claimed in claim 1 wherein R.sup.1 represents hydrogen, halogen, cyano or —OR.sup.a, in which R.sup.a is as defined in claim 1.

4. A compound as claimed in claim 1 wherein R.sup.3 represents hydrogen, halogen or —NR.sup.bR.sup.c, in which R.sup.b and R.sup.c are as defined in claim 1; or R.sup.3 represents C.sub.1-6 alkyl, aryl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl or heteroaryl, any of which groups may be optionally substituted by one, two or three substituents independently selected from C.sub.1-6 alkylsulfonyl, C.sub.2-6 alkylcarbonyl, C.sub.2-6 alkoxycarbonyl, di(C.sub.1-6)alkylaminocarbonyl and difluoroazetidinylcarbonyl.

5. A compound as claimed in claim 1 wherein R.sup.4 represents hydrogen, halogen or —OR.sup.a, in which R.sup.a is as defined in claim 1.

6. A compound as claimed in claim 1 represented by formula (IIA) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: ##STR00200## wherein R.sup.16 represents methyl or ethyl; and D, E, R.sup.2 and R.sup.5 are as defined in claim 1.

7. A compound as claimed in claim 1 represented by formula (IIB) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: ##STR00201## wherein R.sup.26 represents methyl or ethyl; and D, E, R.sup.2 and R.sup.5 are as defined in claim 1.

8. A compound as claimed in claim 1 wherein R.sup.2 represents hydrogen, cyano, —OR.sup.a, —SOR.sup.a, —NR.sup.bR.sup.c, —NR.sup.cCOR.sup.d or —N═S(O)R.sup.bR.sup.c, in which R.sup.a, R.sup.b, R.sup.c and R.sup.d are as defined in claim 1; or R.sup.2 represents C.sub.1-6 alkyl, aryl, aryl(C.sub.1-6)-alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkenyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, cyano, C.sub.1-6 alkyl, oxetanyl, oxadiazolyl, (C.sub.1-6)alkyloxadiazolyl, hydroxy, oxo, (C.sub.1-6)alkyl(imino)sulfinyl, C.sub.1-6 alkylsulfonyl, C.sub.2-6 alkylcarbonylamino, C.sub.1-6 alkylsulfonylamino, C.sub.2-6 alkylcarbonyl, hydroxy(C.sub.1-6)alkylcarbonyl, carboxy, C.sub.2-6 alkoxycarbonyl, aminocarbonyl, C.sub.1-6 alkyl-aminocarbonyl, chloro(C.sub.1-6)alkylaminocarbonyl, di(C.sub.1-6)alkylaminocarbonyl, azetidinyl-carbonyl, hydroxyazetidinylcarbonyl, difluoroazetidinylcarbonyl, (hydroxy)(trifluoro-methyl)azetidinylcarbonyl, (hydroxy)(methyl)azetidinylcarbonyl, morpholinylcarbonyl and (C.sub.1-6)alkylpyrazolylcarbonyl.

9. A compound as claimed in claim 1 wherein the optional substituents on R.sup.5 are one, two or three substituents independently selected from halogen, cyano, C.sub.1-6 alkyl, trifluoromethyl, phenyl, hydroxy, C.sub.1-6 alkoxy and aminocarbonyl.

10. A compound as claimed in claim 1 which is N-[Cyclooctyl(4-methoxy-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-[Cyclooctyl(4-fluoro-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-[Cyclooctyl(4,7-difluoro-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-[Cyclooctyl(4-fluoro-1H-benzimidazol-2-yl)methyl]-5-methyl-1-(tetrahydropyran-4-yl)pyrazole-4-carboxamide; N-[(4-Fluoro-1H-benzimidazol-2-yl)(trans-4-methylcyclohexyl)methyl]-3-methyl-isoxazole-4-carboxamide; N-[(4-Chloro-1H-benzimidazol-2-yl)(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide; N-[Cyclooctyl(4-fluoro-1H-benzimidazol-2-yl)methyl]-2-methylpyrazole-3-carboxamide; N-[Cyclooctyl(4-methoxy-1H-imidazolo[4,5-c]pyridin-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-[Cyclooctyl(4-fluoro-5-methoxy-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-[(4-Cyano-1H-benzimidazol-2-yl)(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(1H-pyrazol-5-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide; N-{[5-(Benzenesulfinyl)-4-fluoro-1H-benzimidazol-2-yl](cyclooctyl)methyl}-3-methyl-isoxazole-4-carboxamide; tert-Butyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)acetate; tert-Butyl rel-(2S)-2-(4-acetylpiperazin-1-yl)-2-(4-fluoro-2-{rel-(S)-cyclooctyl[(3-methyl-isoxazole-4-carbonyl)amino]methyl}-1H-benzimidazol-5-yl)acetate; tert-Butyl rel-(2R)-2-(4-acetylpiperazin-1-yl)-2-(4-fluoro-2-{rel-(R)-cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-1H-benzimidazol-5-yl)acetate; tert-Butyl 3-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)propanoate; tert-Butyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)benzoate; N-{Cyclooctyl[4-(cyclopentoxy)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[7-methoxy-6-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-7-methoxy-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]-methyl}-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-6-(morpholin-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide; N-[{5-[Cyano(pyridin-3-yl)methyl]-4-fluoro-1H-benzimidazol-2-yl}(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide; N-(Cyclooctyl{4-fluoro-5-[1-(pyridin-4-yl)ethyl]-1H-benzimidazol-2-yl}methyl)-2-methylpyrazole-3-carboxamide; N-[Cyclooctyl(4-fluoro-5-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(morpholin-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide; tert-Butyl 6-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-3,4-dihydro-2H-pyridine-1-carboxylate; tert-Butyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)piperidine-1-carboxylate; N-[Cyclooctyl(4-fluoro-5-{[1-(methylsulfonyl)piperidin-4-yl]amino}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; tert-Butyl 4-[(2-{cyclooctyl[(2-methylpyrazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)methyl]piperazine-1-carboxylate; N-[Cyclooctyl(4,7-difluoro-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-[Cyclooctyl(4,7-difluoro-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-2-ethylpyrazole-3-carboxamide; N-[(S)-Cyclooctyl(4,7-difluoro-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-2-ethylpyrazole-3-carboxamide; N-[(R)-Cyclooctyl(4,7-difluoro-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-2-ethylpyrazole-3-carboxamide; N-[Cyclooctyl(4-fluoro-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-[{6-[(4-Acetylpiperazin-1-yl)methyl]-4-fluoro-1H-benzimidazol-2-yl}(cyclooctyl)-methyl]-3-methylisoxazole-4-carboxamide; tert-Butyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-1-carboxylate; tert-Butyl 5-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-2,3-dihydro-1,4-oxazine-4-carboxylate; tert-Butyl 3-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-6,7-dihydro-5H-1,4-oxazepine-4-carboxylate; tert-Butyl 3-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)morpholine-4-carboxylate; tert-Butyl 3-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-1,4-oxazepane-4-carboxylate; Ethyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-2-phenylacetate; tert-Butyl 3-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-7-fluoro-3H-benzimidazol-5-yl)propanoate; 3-(2-{Cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)propanoic acid; N-(Cyclooctyl{5-[3-(dimethylamino)-3-oxopropyl]-4-fluoro-1H-benzimidazol-2-yl}-methyl)-3-methylisoxazole-4-carboxamide; N-(Cyclooctyl{4-fluoro-5-[3-(methylamino)-3-oxopropyl]-1H-benzimidazol-2-yl}-methyl)-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4,6-difluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4,7-difluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; Ethyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-2-(pyridin-4-yl)acetate; N-(Cyclooctyl{4-fluoro-5-[2-hydroxy-1-(pyridin-4-yl)ethyl]-1H-benzimidazol-2-yl}-methyl)-3-methylisoxazole-4-carboxamide; N-[{5-[Cyano(pyridin-4-yl)methyl]-4-fluoro-1H-benzimidazol-2-yl}(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide; N-[Cyclooctyl(7-fluoro-4-methoxy-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(pyridin-4-yloxy)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(tetrahydropyran-4-yloxy)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(oxetan-3-yloxy)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide; N-{Cyclooctyl[6-fluoro-4-(tetrahydropyran-4-yloxy)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(pyridazin-4-yloxy)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(tetrahydropyran-4-ylamino)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; Methyl (2S)-1-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-2-carboxylate; Methyl (2R)-1-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-2-carboxylate; Methyl 1-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)piperidine-3-carboxylate; Methyl 1-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)piperidine-2-carboxylate; N-{Cyclooctyl[4-fluoro-6-(tetrahydropyran-4-ylamino)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-[(S)-{5-[(4-Acetylpiperazin-1-yl)methyl]-4-fluoro-1H-benzimidazol-2-yl}(4-methyl-cyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; N-[(S)-{5-[2-(Dimethylcarbamoyl)phenyl]-4-fluoro-1H-benzimidazol-2-yl}(4-methyl-cyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; N-(Cyclooctyl{5-[2-(dimethylcarbamoyl)phenyl]-4-fluoro-1H-benzimidazol-2-yl}-methyl)-2-ethylpyrazole-3-carboxamide; Ethyl 3-(2-{cyclooctyl[(2-ethylpyrazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)pyridine-4-carboxylate; N-{[5-(7-Acetyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4-fluoro-1H-benzimidazol-2-yl](cyclooctyl)methyl}-2-ethylpyrazole-3-carboxamide; 2-Ethyl-N-{(S)-[4-fluoro-5-(tetrahydropyran-3-yl)-1H-benzimidazol-2-yl](4-methyl-cyclohexyl)methyl}pyrazole-3-carboxamide; N-[(S)-{5-[4-(Dimethylcarbamoyl)-5-fluoropyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-{5-[4-(Dimethylcarbamoyl)pyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-{5-[4-(Dimethylcarbamoyl)-1-oxopyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}-(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-{5-[3-(Dimethylcarbamoyl)pyridin-2-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; Ethyl 5-(2-{(S)-[(2-ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)-3,6-dihydro-2H-pyran-4-carboxylate; N-[(S)-{5-[4-(Dimethylcarbamoyl)-3,6-dihydro-2H-pyran-5-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-{5-[4-(Dimethylcarbamoyl)-3,6-dihydro-2H-pyran-5-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; Ethyl 3-(2-{(S)-[(2-ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-3H-benzimidazol-5-yl)tetrahydropyran-4-carboxylate; N-[(S)-{5-[4-(Dimethylcarbamoyl)tetrahydropyran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; Methyl 4-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)tetrahydrofuran-3-carboxylate; 4-(2-{(S)-[(3-Ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)tetrahydrofuran-3-carboxylic acid; N-[(S)-{5-[4-(Dimethylcarbamoyl)tetrahydrofuran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}-(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)tetrahydrofuran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; Ethyl 4-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl]-1-(methylsulfonyl)pyrrolidine-3-carboxylate; Ethyl 1-acetyl-4-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)-methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-3-carboxylate; Ethyl 2-(2-{cyclooctyl[(2-ethylpyrazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-2-(pyridin-3-yl)acetate; Ethyl 2-(2-{cyclooctyl[(2-ethylpyrazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-2-(pyridin-4-yl)acetate; N-{Cyclooctyl[4-fluoro-5-(pyridin-4-ylmethyl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide; N-[{5-[2-Amino-2-oxo-1-(pyridin-4-yl)ethyl]-4-fluoro-1H-benzimidazol-2-yl}-(cyclooctyl)methyl]-2-ethylpyrazole-3-carboxamide; N-(Cyclooctyl{4-fluoro-5-[(5-methyl-1,3,4-oxadiazol-2-yl)(pyridin-4-yl)methyl]-1H-benzimidazol-2-yl}methyl)-2-ethylpyrazole-3-carboxamide; N-(Cyclooctyl{4-fluoro-5-[(5-methyl-1,3,4-oxadiazol-2-yl)(pyridin-4-yl)methyl]-1H-benzimidazol-2-yl}methyl)-3-methylisoxazole-4-carboxamide; tert-Butyl 3-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)morpholine-4-carboxylate; tert-Butyl (3S)-3-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)-methyl}-4-fluoro-1H-benzimidazol-5-yl)morpholine-4-carboxylate; tert-Butyl (3R)-3-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)-methyl}-4-fluoro-1H-benzimidazol-5-yl)morpholine-4-carboxylate; 3-Ethyl-N-[(S)-{4-fluoro-5-[4-(2-hydroxyacetyl)morpholin-3-yl]-1H-benzimidazol-2-yl}-(4-methylcyclohexyl)methyl]isoxazole-4-carboxamide; tert-Butyl 2-(2-{(S)-[(2-ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)piperidine-1-carboxylate; 2-Ethyl-N-[{4-fluoro-5-[1-(2-hydroxyacetyl)piperidin-2-yl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]pyrazole-3-carboxamide; 2-Ethyl-N-[(S)-{5-[1-(2-ethylpyrazole-3-carbonyl)piperidin-2-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]pyrazole-3-carboxamide; 2-(2-{(S)-[(2-Ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)-N,N-dimethylpiperidine-1-carboxamide; N-[(S)-{5-[(2S)-2-(Dimethylcarbamoyl)piperidin-1-yl]-4-fluoro-1H-benzimidazol-2-yl}-(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-{5-[2-(Dimethylamino)-2-oxoethyl]-4-fluoro-1H-benzimidazol-2-yl}(4-methyl-cyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-{5-[2-(Dimethylcarbamoyl)phenyl]-4,6-difluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-{5-[2-(Dimethylcarbamoyl)phenyl]-4,6-difluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; N-(Cyclooctyl{4-fluoro-5-[2-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}methyl)-2-ethylpyrazole-3-carboxamide; N-(Cyclooctyl{4-fluoro-5-[3-(methanesulfonamido)phenyl]-1H-benzimidazol-2-yl}-methyl)-2-ethylpyrazole-3-carboxamide; N-[(S)-{5-[2-(Dimethylcarbamoyl)phenyl]-1H-imidazo[4,5-b]pyridin-2-yl}(4-methyl-cyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; N-(Cyclooctyl{6-[2-(dimethylcarbamoyl)phenyl]-4-methoxy-1H-imidazo[4,5-c]pyridin-2-yl}methyl)-2-methylpyrazole-3-carboxamide; N-{Cyclooctyl[6-(3,6-dihydro-2H-pyran-4-yl)-7-fluoro-3H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(piperidin-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(piperazin-1-ylmethyl)-1H-benzimidazol-2-yl]methyl}-2-methylpyrazole-3-carboxamide; N-{Cyclooctyl[4-fluoro-5-(morpholin-3-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(1,4-oxazepan-3-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide; N-[(S)-{5-[4-(Dimethylcarbamoyl)pyrrolidin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-5-(1-methylpiperidin-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-(Cyclooctyl{4-fluoro-5-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-2-yl}-methyl)-2-methylpyrazole-3-carboxamide; N-[Cyclooctyl(4-fluoro-5-{[4-(oxetan-3-yl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-2-methylpyrazole-3-carboxamide; N-{[5-(1-Acetylpiperidin-4-yl)-4-fluoro-1H-benzimidazol-2-yl](cyclooctyl)methyl}-3-methylisoxazole-4-carboxamide; N-{[5-(4-Acetylmorpholin-3-yl)-4-fluoro-1H-benzimidazol-2-yl](cyclooctyl)methyl}-3-methylisoxazole-4-carboxamide; N-[{5-[(4-Acetylpiperazin-1-yl)methyl]-4-fluoro-1H-benzimidazol-2-yl}(cyclooctyl)-methyl]-2-methylpyrazole-3-carboxamide; N-[{5-[(4-Acetylpiperazin-1-yl)methyl]-1H-benzimidazol-2-yl}(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide; N-[{6-[(4-Acetylpiperazin-1-yl)methyl]-4-methoxy-1H-imidazo[4,5-c]pyridin-2-yl}-(cyclooctyl)methyl]-2-methylpyrazole-3-carboxamide; N-[(5-{Acetyl[1-(methylsulfonyl)piperidin-4-yl]amino}-4-fluoro-1H-benzimidazol-2-yl)-(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide; N-[(S)-(5-Cyano-4-fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methyl]-2-ethyl-pyrazole-3-carboxamide; N-{(S)-[5-(1-Acetamidoethyl)-4-fluoro-1H-benzimidazol-2-yl](4-methylcyclohexyl)-methyl}-2-ethylpyrazole-3-carboxamide; N-{(S)-[5-(1-Acetamido-1-methylethyl)-4-fluoro-1H-benzimidazol-2-yl](4-methyl-cyclohexyl)methyl}-2-ethylpyrazole-3-carboxamide; N-[Cyclooctyl(4-methoxy-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-[Cyclooctyl(4-fluoro-5-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-2-methylpyrazole-3-carboxamide; N-[Cyclooctyl(5-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)-methyl]-3-methylisoxazole-4-carboxamide; N-[Cyclooctyl(4-fluoro-5-{[1-(methylsulfonyl)piperidin-4-yl]methyl}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-[Cyclooctyl(4-fluoro-6-{[1-(methylsulfonyl)piperidin-4-yl]methyl}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide; N-[Cyclooctyl(4-methoxy-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-imidazo-[4,5-c]pyridin-2-yl)methyl]-2-methylpyrazole-3-carboxamide; N-{Cyclooctyl[4-fluoro-5-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-{Cyclooctyl[4-fluoro-6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; Methyl (2S)-1-[(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)-methyl}-4-fluoro-1H-benzimidazol-5-yl)methyl]pyrrolidine-2-carboxylate; Methyl (2R)-1-[(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)-methyl}-4-fluoro-1H-benzimidazol-5-yl)methyl]pyrrolidine-2-carboxylate; (2S)-1-[(2-{(S)-[(3-Ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)methyl]pyrrolidine-2-carboxylic acid; (2R)-1-[(2-{(S)-[(3-Ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)methyl]pyrrolidine-2-carboxylic acid; N-[(S)-(5-{[(2R)-2-(Dimethylcarbamoyl)pyrrolidin-1-yl]methyl}-4-fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; N-[{5-[2-(Dimethylcarbamoyl)phenyl]-4-fluoro-1H-benzimidazol-2-yl}(3,3-dimethyl-cyclohexyl)methyl]-3-methylisoxazole-4-carboxamide; N-[{5-[2-(Dimethylcarbamoyl)phenyl]-4-fluoro-1H-benzimidazol-2-yl}(spiro[2.5]octan-7-yl)methyl]-3-ethylisoxazole-4-carboxamide; N-[(3,3-Difluorocyclohexyl){5-[2-(dimethylcarbamoyl)phenyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-3-ethylisoxazole-4-carboxamide; N-{[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](4-methylcyclohexyl)-methyl}-3-methylisoxazole-4-carboxamide; N-{(S)-[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](4-methylcyclohexyl)-methyl}-3-methylisoxazole-4-carboxamide; N-{(S)-[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](4-methylcyclohexyl)-methyl}-3-methylisoxazole-4-carboxamide; N-{Cycloheptyl[4-fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-{Cyclohexyl[4-fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-{Dispiro[2.0.24.13]heptan-7-yl[4-fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide; N-{[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](norcaran-3-yl)methyl}-3-methylisoxazole-4-carboxamide; N-{[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](3-methylcyclohexyl)-methyl}-3-methylisoxazole-4-carboxamide; N-{[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](norcaran-7-yl)methyl}-3-methylisoxazole-4-carboxamide; N-{[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](2-methylcyclohexyl)-methyl}-3-methylisoxazole-4-carboxamide; N-{(3,5-Dimethylcyclohexyl)[4-fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]-methyl}-3-methylisoxazole-4-carboxamide; tert-Butyl 3-(4-fluoro-2-{(S)-(4-methylcyclohexyl)[(3-methylisoxazole-4-carbonyl)-amino]methyl}-1H-benzimidazol-5-yl)morpholine-4-carboxylate; Methyl 3-(4-fluoro-2-{(S)-(4-methylcyclohexyl)[(3-methylisoxazole-4-carbonyl)amino]-methyl}-1H-benzimidazol-5-yl)morpholine-4-carboxylate; N-[(S)-{4-Fluoro-5-[4-(methylsulfonyl)morpholin-3-yl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide; N-[(S)-{4-Fluoro-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-3-yl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide; N-Ethyl-3-(4-fluoro-2-{(S)-(4-methylcyclohexyl)[(3-methylisoxazole-4-carbonyl)amino]-methyl}-1H-benzimidazol-5-yl)morpholine-4-carboxamide; tert-Butyl 3-{2-[(S)-acetamido(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}morpholine-4-carboxylate; tert-Butyl 3-(2-{(S)-[(3-{[dimethyl(oxo)-λ.sup.6-sulfanylidene]amino}benzoyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)morpholine-4-carboxylate; N-[(S)-{5-[3-(Dimethylcarbamoyl)pyrazin-2-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide; N-[(S)-{5-[4-(Dimethylcarbamoyl)-2-methylpyrimidin-5-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide; N-[(S)-{4-Fluoro-5-[4-(3-hydroxy-3-methylazetidine-1-carbonyl)pyridin-3-yl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide; N-[(S)-{5-[4-(Azetidine-1-carbonyl)pyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide; N-[(S)-{5-[4-(3-Chloropropylcarbamoyl)pyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)-1-oxidopyridin-1-ium-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide; 3-Ethyl-N-[(S)-{4-fluoro-5-[4-(methylsulfonimidoyl)pyridin-3-yl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]isoxazole-4-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyridin-3-yl]-1H-imidazo[4,5-b]pyridin-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)-1-oxidopyridin-3-yl]-1H-imidazo[4,5-b]-pyridin-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)-1-oxidopyridin-3-yl]-4-hydroxy-1H-imidazo[4,5-b]pyridin-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)furan-3-yl]-1H-imidazo[4,5-b]pyridin-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)tetrahydrofuran-3-yl]-1H-imidazo[4,5-b]-pyridin-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide; Ethyl 3-(4-fluoro-2-{(S)-(4-methylcyclohexyl)[(3-methylisoxazole-4-carbonyl)amino]-methyl}-1H-benzimidazol-5-yl)morpholine-4-carboxylate; N-[(S)-Cyclopentyl{5-[4-(3,3-difluoroazetidine-1-carbonyl)tetrahydrofuran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-Cyclopentyl(4-fluoro-5-{4-[3-hydroxy-3-(trifluoromethyl)azetidine-1-carbonyl]-tetrahydrofuran-3-yl}-1H-benzimidazol-2-yl)methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-Cyclopentyl{4-fluoro-5-[4-(3-hydroxyazetidine-1-carbonyl)tetrahydrofuran-3-yl]-1H-benzimidazol-2-yl}methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-Cyclopentyl{4-fluoro-5-[4-(morpholine-4-carbonyl)tetrahydrofuran-3-yl]-1H-benzimidazol-2-yl}methyl]-3-ethylisoxazole-4-carboxamide; N-[(S)-Cyclopentyl{5-[4-(3,3-difluoroazetidine-1-carbonyl)tetrahydrofuran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-3-methylisoxazole-4-carboxamide; 3,3-Difluorocyclobutyl N-[(S)-cyclopentyl{5-[4-(3,3-difluoroazetidine-1-carbonyl)-tetrahydrofuran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}methyl]carbamate; N-[(S)-{5-[3-(3,3-Difluoroazetidine-1-carbonyl)-1H-pyrazol-4-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)-2-methylpyrimidin-5-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyrimidin-5-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide; N-[(S)-(5-{[Dimethyl(oxo)-λ.sup.6-sulfanylidene]amino}-4-fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide; 3-(2-{(S)-[(2-Ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-7-fluoro-3H-imidazo[4,5-c]pyridin-6-yl)-N,N-dimethylpyridine-4-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)morpholin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide; N-[(S)-{2-[4-(3,3-difluoroazetidine-1-carbonyl)pyridin-3-yl]-7H-purin-8-yl}(4-methyl-cyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyridin-3-yl]-1H-imidazo[4,5-b]pyrazin-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; 3-Ethyl-N-[(S)-{4-fluoro-5-[(2-oxopyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]isoxazole-4-carboxamide; tert-Butyl 3-(3,3-difluoroazetidine-1-carbonyl)-4-(2-{(S)-[(2-ethylpyrazole-3-carbonyl)-amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)-2,5-dihydro-pyrrole-1-carboxylate; tert-Butyl 3-(3,3-difluoroazetidine-1-carbonyl)-4-(2-{(S)-[(2-ethylpyrazole-3-carbonyl)-amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-1-carboxylate; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyrrolidin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide; N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyridin-3-yl]-4-fluoro-1-methyl-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide; or N-[(S)-{6-[4-(3,3-Difluoroazetidine-1-carbonyl)pyridin-3-yl]-7-fluoro-1-methyl-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide.

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

12. A pharmaceutical composition comprising a first pharmaceutically active ingredient which is a compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, and further comprising an additional pharmaceutically active ingredient.

Description

EXAMPLES

Abbreviations

(1) DCM: dichloromethane DMF: N,N-dimethylformamide MeOH: methanol THF: tetrahydrofuran DMSO: dimethyl sulfoxide DIPEA: N,N-diisopropylethylamine EtOAc: ethyl acetate TFA: trifluoroacetic acid EtOH: ethanol AcOH: acetic acid DMAP: 4-(dimethylamino)pyridine NMP: 1-methyl-2-pyrrolidinone 9-BBN: 9-borabicyclo[3.3.1]nonane TPP: triphenylphosphine DAST: (diethylamino)sulfur trifluoride CDI: 1,1′-carbonyldiimidazole AIBN: 2,2′-azobis(2-methylpropionitrile) NBS: N-bromosuccinimide HOBT: 1-hydroxybenzotriazole hydrate MCPBA: 3-chloroperbenzoic acid MeMgCl: methylmagnesium chloride TMEDA: N,N,N′,N′-tetramethylethylenediamine EDC.HCl: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU: O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate T3P®: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide solution Pd(PPh.sub.3).sub.4: tetrakis(triphenylphosphine)palladium(0) Pd.sub.2(dba).sub.3: tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl.sub.2.DCM: [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane XPhos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene RuPhos: 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl {Ir[dF(CF.sub.3)ppy].sub.2(dtbpy)}PF.sub.6: [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N.sup.1,N.sup.1′]bis-{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C}iridium(III) hexafluoro-phosphate h: hour r.t.: room temperature M: mass RT: retention time HPLC: High Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry
Analytical Conditions

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

(3) NMR spectra were recorded on a Bruker Avance III HD 500 MHz, 400 MHz, 300 MHz or 250 MHz spectrometer.

(4) HPLC-MS was performed on an Agilent 1200-6120 LC-MS system coupled to UV Detection (230 to 400 nm and 215 nm) and Mass Spec Detection Agilent 6120 Mass Spectrometer (ES) m/z 120 to 800.

(5) Method 1

(6) X-Bridge C18 Waters 2.1×20 mm, 2.5 μm column

(7) Mobile Phase A: 10 mM ammonium formate in water+0.1% formic acid

(8) Mobile Phase B: acetonitrile+5% water+0.1% formic acid

(9) Gradient program: Flow rate Pump 1: 1 mL/minute

(10) TABLE-US-00001 Time A % B % 0.00 94.00 6.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 94.00 6.00
Method 2
X-Bridge C18 Waters 2.1×20 mm, 2.5 μm column
Mobile Phase A: 10 nM ammonium formate in water+0.1% formic acid
Mobile Phase B: acetonitrile+5% water+0.1% formic acid
Gradient program: Flow rate Pump 1: 1 mL/minute

(11) TABLE-US-00002 Time A % B % 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 96.00 4.00
Method 3
X-Bridge C18 Waters 2.1×20 mm, 2.5 μm column
Mobile Phase A: 10 nM ammonium formate in water+0.1% ammonia solution
Mobile Phase B: acetonitrile+5% water+0.1% ammonia solution
Gradient program: Flow rate 1 mL/minute

(12) TABLE-US-00003 Time A % B % 0.00 96.00 4.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 96.00 4.00
Method 4
X-Bridge C18 Waters 2.1×20 mm, 2.5 μm column
Mobile Phase A: 10 mM ammonium formate in water+0.1% ammonia solution
Mobile Phase B: acetonitrile+5% water+0.1% ammonia solution
Gradient program: Flow rate 1 mL/minute

(13) TABLE-US-00004 Time A % B % 0.00 96.00 4.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 96.00 4.00
Method 5
X-Select CSH C18 3×50 mm, 2.5 μm column
Mobile Phase A: 5 mM ammonium bicarbonate in water
Mobile Phase B: acetonitrile
Gradient program: Flow rate 1.2 mL/minute

(14) TABLE-US-00005 Time A % B % 0.00 100 0 2.00 2.00 98.00 3.00 2.00 98.00
Method 6
X-Bridge C18 Waters 2.1×30 mm, 2.5 μm column
Mobile Phase A: 5 mM ammonium formate in water+0.1% ammonia solution
Mobile Phase B: acetonitrile+5% water+0.1% ammonia solution
Gradient program: Flow rate 1 mL/minute

(15) TABLE-US-00006 Time A % B % 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00
Automated preparative reverse phase HPLC purification was performed using a Gilson system with a Gilson 331&332 pump, a Gilson GX281 autoinjector, a Gilson GX281 fraction collector and a Gilson 159 UV detector.
Method 7
X-Bridge C18 Waters 30×100 mm, 10 μm column
Mobile Phase A: water+0.2% ammonia solution
Mobile Phase B: acetonitrile+0.2% ammonia solution
Gradient program: Flow rate 40 mL/minute

(16) TABLE-US-00007 Time A % B % 0.00 70 30 0.55 70 30 11.00 5 95 13.10 5 95 13.31 70 30
Method 8
Waters Sunfire C18 Waters 30×100 mm, 10 μm column
Mobile Phase A: water+0.1% formic acid
Mobile Phase B: acetonitrile+0.1% formic acid
Gradient program: Flow rate 40 mL/minute

(17) TABLE-US-00008 Time A % B % 0.00 70 30 0.55 70 30 11.00 5 95 13.10 5 95 13.31 70 30
Method 9
Phenomenex Kinetex-XB, C18 2.1×100 mm, 1.7 μm column
Mobile Phase A: 0.1% formic acid in water
Mobile Phase B: 0.1% formic acid in acetonitrile
Gradient program: Flow rate 0.6 mL/minute; column temperature 40° C.

(18) TABLE-US-00009 Time A % B % 0.00 95.00 5.00 5.30 0.00 100.0 5.80 0.00 100.0 5.82 95.00 5.00 7.00 95.00 5.00
Method 10
Phenomenex Kinetex Core-Shell C8 50×2.1 mm, 5 μm column, protected by
Phenomenex ‘Security Guard’ column
Mobile Phase A: 0.1% formic acid in water
Mobile Phase B: 0.1% formic acid in acetonitrile
Gradient program: Flow rate 1.2 mL/minute; column temperature 40° C.

(19) TABLE-US-00010 Time A % B % 0.00 95.00 5.00 1.20 0.00 100.0 1.30 0.00 100.0 1.31 95.00 5.00
Column chromatography separations were performed using a Biotage® Isolera 4 system with Biotage® SNAP KP-Sil pre-packed silica gel columns.

Intermediate 1

Methyl 2-cyclooctylidene-2-formamidoacetate

(20) A 1M solution of potassium tert-butoxide in THF (48 mL, 48 mmol) was added dropwise to a solution of methyl isocyanoacetate (4.0 mL, 41.8 mmol) in anhydrous THF (40 mL) at approximately −65° C. under nitrogen. After stirring for 5 minutes, a solution of cyclooctanone (5 g, 39.6 mmol) in anhydrous THF (20 mL) was added slowly at −70° C. The reaction mixture was stirred at −70° C. for 30 minutes, then warmed to 20° C. and stirred under nitrogen for 60 h. The solution was quenched with water (100 mL) and stirred at 20° C. for 1 h. The residue was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (50 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting crude orange oil was purified by flash column chromatography, using a gradient of ethyl acetate in heptane (0-90%), to afford the title compound (5.37 g, 58%) as an orange viscous oil, which solidified upon standing. δH (500 MHz, DMSO-d.sub.6) 9.31 (s, 1H), 8.01 (d, J 1.5 Hz, 1H), 3.60 (s, 3H), 2.52-2.47 (m, 2H), 2.31-2.23 (m, 2H), 1.74-1.60 (m, 4H), 1.50-1.31 (m, 6H) (major rotamer). LCMS (Method 5): [M+Na].sup.+ m/z 248, RT 1.63 minutes.

Intermediate 2

Methyl 2-cyclooctyl-2-formamidoacetate

(21) Magnesium turnings (3.15 g, 130 mmol) were added carefully to a stirred solution of Intermediate 1 (3.04 g, 12.9 mmol) in anhydrous methanol (65 mL) at 0° C. under nitrogen. The suspension was stirred at 0° C. for 1 h, then warmed to 20° C. over 2 h. Stirring of the suspension was continued at 20° C. for 16 h. An additional portion of magnesium turnings (1 g, 41.14 mmol) was added, and the suspension was stirred at 20° C. for 3.5 h under nitrogen. The mixture was carefully concentrated in vacuo. The residue was suspended in EtOAc (100 mL) and water (200 mL), then cooled to 0° C. Aqueous hydrochloric acid (1M, 100 mL) was added, and the pH was adjusted to 5 with concentrated hydrochloric acid. The organic phase was separated, and the aqueous suspension was further extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (50 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting crude orange oil was purified by flash column chromatography, using a gradient of ethyl acetate in heptane (0-80%), to afford the title compound (1.53 g, 48%) as an orange viscous oil. δ.sub.H (500 MHz, DMSO-d.sub.6) 8.46 (d, J 8.5 Hz, 1H), 8.06 (s, 1H), 4.29 (dd, J 8.6, 6.1 Hz, 1H), 3.64 (s, 3H), 2.04-1.93 (m, 1H), 1.73-1.19 (m, 14H) (major rotamer). LCMS (Method 4): [M+H].sup.+ m/z 228, RT 3.94 minutes.

Intermediate 3

Methyl 2-amino-2-cyclooctylacetate hydrochloride

(22) Acetyl chloride (1.9 mL, 26.7 mmol) was added cautiously at 0° C. to a stirred solution of Intermediate 2 (1.69 g, 6.77 mmol) in methanol (68 mL) under nitrogen. After stirring for 5 minutes, the solution was heated at 50° C. for 2 h. The volatiles were concentrated in vacuo. The resulting crude orange powder was triturated with diethyl ether (40 mL). The solids were collected by filtration and washed with diethyl ether (2×20 mL), then dried in vacuo at 50° C., to afford the title compound (1.43 g, 81%) as a tan powder. δ.sub.H (500 MHz, DMSO-d.sub.6) 8.61 (br s, 3H), 3.86 (d, J 4.4 Hz, 1H), 3.73 (s, 3H), 2.19-2.09 (m, 1H), 1.68-1.37 (m, 13H), 1.32-1.20 (m, 1H). LCMS (Method 5): [M+H].sup.+ m/z 200, RT 0.75 and 0.86 minutes.

Intermediate 4

Methyl 2-cyclooctyl-2-[(2-methylpyrazole-3-carbonyl)amino]acetate

(23) DIPEA (1.05 mL, 6.35 mmol) was added to a stirred solution of Intermediate 3 (500 mg, 2.12 mmol), 1-methyl-1H-pyrazole-5-carboxylic acid (269 mg, 2.12 mmol) and HBTU (969 mg, 2.55 mmol) in anhydrous DMF (10 mL) under a nitrogen atmosphere. The mixture was stirred at 20° C. for 18 h, then quenched with saturated aqueous sodium hydrogen carbonate solution (50 mL) and water (50 mL). The residue was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×50 mL) and dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was purified by flash column chromatography, using a gradient of EtOAc in heptane (0-100%), to afford the title compound (618 mg, 80%) as a yellow-orange oil. δ.sub.H (500 MHz, DMSO-d.sub.6) 8.60 (d, J 8.3 Hz, 1H), 7.46 (d, J 2.1 Hz, 1H), 7.01 (d, J 2.1 Hz, 1H), 4.37 (t, J 8.1 Hz, 1H), 4.01 (s, 3H), 3.66 (s, 3H), 2.22-2.08 (m, 1H), 1.80-1.38 (m, 13H), 1.37-1.29 (m, 1H). LCMS (Method 5): [M+H].sup.+ m/z 308, RT 1.87 minutes.

Intermediate 5

Lithium 2-cyclooctyl-2-[(2-methylpyrazole-3-carbonyl)amino]acetate

(24) To a stirred solution of Intermediate 4 (618 mg, 1.69 mmol) in THF (9 mL) and water (4.5 mL) was added lithium hydroxide monohydrate (0.106 g, 2.53 mmol). The reaction mixture was stirred at 20° C. for 22 h, then concentrated and dried in vacuo, to afford the title compound (640 mg, quantitative) as a yellow solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 7.60 (d, J 7.6 Hz, 1H), 7.42 (d, J 2.0 Hz, 1H), 6.74 (d, J 2.0 Hz, 1H), 4.01 (s, 3H), 3.88 (dd, J 7.6, 4.3 Hz, 1H), 2.11-2.01 (m, 1H), 1.74-1.22 (m, 14H). LCMS (Method 5): [M+H].sup.+ m/z 294, RT 1.71 minutes.

Intermediate 6

Methyl 2-cyclooctyl-2-[(3-methylisoxazole-4-carbonyl)amino]acetate

(25) To a solution of 3-methylisoxazole-4-carboxylic acid (12.9 g, 66.1 mmol) in dry DMF (100 mL) at 0° C. were added DIPEA (54.9 g, 425 mmol), EDC.HCl (19.5 g, 102 mmol) and HOBT (13.8 g, 102 mmol). The reaction mixture was stirred for 15 minutes at 0° C., then Intermediate 3 (20.0 g, 84.92 mmol) was added and the mixture was stirred at r.t. for 48 h. The reaction mixture was poured into ice-cold water (500 mL) and extracted with ethyl acetate (2×400 mL). The organic layer was separated, then washed with ice-cold water (2×100 mL) and 1N hydrochloric acid (2×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, then filtered and evaporated under vacuum. The crude residue was purified by silica-gel flash column chromatography, using 15% EtOAc in hexane as eluting solvent, to afford the title compound (7.9 g, 41%) as a pale yellow oil. LCMS (Method 5): [M+H].sup.+ m/z 309, RT 1.07 minutes.

Intermediate 7

2-Cyclooctyl-2-[(3-methylisoxazole-4-carbonyl)amino]acetic Acid

(26) To a solution of Intermediate 6 (11.0 g, 35.7 mmol) in THF (90 mL) at r.t. were added water (30 mL) and lithium hydroxide monohydrate (2.25 g, 53.6 mmol). The mixture was stirred for 16 h, then evaporated under vacuum. The residue was suspended in diethyl ether (50 mL), then stirred for 10 minutes and filtered. The resultant solid was washed with diethyl ether (50 mL) and pentane (50 mL), then dried under vacuum, to afford an off-white solid (9.51 g). The solid (9.0 g) was suspended in water (30 mL) and EtOAc (100 mL), then acidified with a 2M aqueous HCl solution (35 mL). The resulting mixture was extracted with EtOAc (2×75 mL). The combined organic extracts were washed with water (30 mL) and brine (50 mL), then dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue crystallised upon standing and was triturated with acetonitrile, to give the title compound (7.0 g, 80%) as a pale powder. δ.sub.H (500 MHz, DMSO-d.sub.6) 12.71 (s, 1H), 9.41 (d, J 0.6 Hz, 1H), 8.36 (d, J 8.6 Hz, 1H), 4.35 (dd, J 8.6, 6.6 Hz, 1H), 2.37 (s, 3H), 2.11-2.02 (m, 1H), 1.68-1.37 (m, 14H). LCMS (Method 8): [M+H].sup.+ m/z 295, RT 1.90 minutes.

Intermediate 8 (Procedure A)

N-[2-(2-Amino-3-methoxyanilino)-1-cyclooctyl-2-oxoethyl]-3-methylisoxazole-4-carboxamide

(27) To a solution of Intermediate 7 (110 mg, 0.37 mmol), 3-methoxybenzene-1,2-diamine (50 mg, 0.34 mmol) and DIPEA (0.2 mL, 1 mmol) in DMF (2 mL) was added HATU (160 mg, 0.41 mmol). The reaction mixture was stirred at r.t. for 48 h, then partitioned between DCM and water. The organic phase was separated, then dried and concentrated in vacuo. The crude residue was purified by flash column chromatography (0-100% EtOAc/hexanes) to give the title compound (28.7 mg, 20%) as a white solid. LCMS (Method 5): [M+H].sup.+ m/z 415, RT 1.31 minutes.

Intermediate 9

N-[2-(2-Amino-3-fluoroanilino)-1-cyclooctyl-2-oxoethyl]-3-methylisoxazole-4-carboxamide

(28) The title compound (134 mg, 44%) was prepared from Intermediate 7 (233 mg, 0.79 mmol) and 3-fluorobenzene-1,2-diamine (100 mg, 0.75 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 403, RT 1.33 minutes.

Intermediate 10

N-{2-[2-Amino-3-fluoro-4-(tetrahydropyran-4-yl)anilino]-1-cyclooctyl-2-oxoethyl}-3-methylisoxazole-4-carboxamide

(29) The title compound (160 mg, 58%) was prepared from Intermediate 7 (65 mg, 0.22 mmol) and Intermediate 24 (50 mg, 0.22 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 487, RT 2.34 minutes.

Intermediate 11

N-{2-[2-Amino-3-fluoro-4-(4-methylpiperazin-1-yl)anilino]-1-cyclooctyl-2-oxoethyl}-3-methylisoxazole-4-carboxamide

(30) The title compound (144 mg, quantitative) was prepared from Intermediate 7 (85 mg, 0.29 mmol) and 3-fluoro-4-(4-methylpiperazin-1-yl)benzene-1,2-diamine (70 mg, 0.29 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 501, RT 1.24 minutes.

Intermediate 12

N-[2-(2-Amino-3,6-difluoroanilino)-1-cyclooctyl-2-oxoethyl]-3-methylisoxazole-4-carboxamide

(31) The title compound (40 mg, 14%) was prepared from Intermediate 7 (204 mg, 0.69 mmol) and 3,6-difluorobenzene-1,2-diamine (100 mg, 0.66 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 421, RT 1.36 minutes.

Intermediate 13

tert-Butyl N-[2-(2-amino-3-fluoroanilino)-1-cyclooctyl-2-oxoethyl]carbamate

(32) The title compound (2.99 g, 100%) was prepared from 2-(tert-butoxycarbonyl-amino)-2-cyclooctylacetic acid (2.26 g, 7.92 mmol) and 3-fluorobenzene-1,2-diamine (1 g, 7.53 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 394.2, RT 1.48 minutes.

Intermediate 14

Cyclooctyl(4-fluoro-1H-benzimidazol-2-yl)methanamine

(33) To a solution of Example 6 (2.8 g, 7.50 mmol) in DCM (30 mL) at −78° C. was added TFA (5 mL, 66.13 mmol). The reaction mixture was warmed slowly to r.t. and stirred for 24 h, then concentrated under vacuum. The residue was run down an SCX column, eluting with 7N NH.sub.3 in MeOH, to give the title compound (1.67 g, 82%) as a light brown solid. LCMS (Method 5): [M+H].sup.+ m/z 276, RT 1.19 minutes.

Intermediate 15

2-(tert-Butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid

(34) To a solution of 2-amino-2-(4-methylcyclohexyl)acetic acid (3 g, 18 mmol), dissolved in 1,4-dioxane (35 mL) and water (17 mL), was added a 2M aqueous solution of NaOH (8.75 mL, 17.5 mmol). The reaction mixture was cooled to 0° C. Di-tert-butyl dicarbonate (5.8 g, 26 mmol) and sodium bicarbonate (1.5 g, 18 mmol) were added. The reaction mixture was stirred at r.t. for 24 h, then concentrated under vacuum to half the volume. The residue was diluted with EtOAc (40 mL), and the pH of the solution was adjusted to 2-3 with a 1M aqueous KHSO.sub.4 solution. The aqueous layer was extracted with EtOAc (2×50 mL). The organic layer was washed with water, then concentrated under vacuum, to give the title compound (4.7 g, 99%) as a white solid. LCMS (Method 5): [M-BOC].sup.+ m/z 172, RT 0.96 minutes.

Intermediate 16

tert-Butyl N-[2-(2-amino-3-fluoroanilino)-1-(4-methylcyclohexyl)-2-oxoethyl]carbamate

(35) The title compound (568 mg, 99%) was prepared from Intermediate 15 (430 mg, 1.58 mmol) and 3-fluorobenzene-1,2-diamine (200 mg, 1.51 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 380, RT 1.43 minutes.

Intermediate 17 (Procedure B)

tert-Butyl N-[(4-fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methyl]carbamate

(36) A solution of Intermediate 16 (568 mg, 1.50 mmol) in AcOH (4 mL) was heated at 70° C. for 3 h, then concentrated in vacuo. The residue was purified by chromatography using an SCX column, eluting with 7N NH.sub.3 in MeOH, to give the title compound (541 mg, quantitative). LCMS (Method 5): [M+H].sup.+ m/z 362, RT 1.44 minutes.

Intermediate 18

(4-Fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methanamine

(37) To a solution of Intermediate 17 (541 mg, 1.50 mmol) in DCM (6 mL) at −78° C. was added TFA (0.5 mL, 93.6 mmol). The reaction mixture was warmed slowly to r.t. and stirred for 24 h, then concentrated in vacuo. The residue was run down an SCX column, eluting with 7N NH.sub.3 in MeOH, to give the title compound (397 mg, 100%). LCMS (Method 5): [M+H].sup.+ m/z 262, RT 1.16 minutes.

Intermediate 19

N-[2-(2-Amino-3-chloroanilino)-1-cyclooctyl-2-oxoethyl]-3-methylisoxazole-4-carboxamide

(38) The title compound (264 mg, 100%) was prepared from Intermediate 7 (195 mg, 0.66 mmol) and 3-chlorobenzene-1,2-diamine (100 mg, 0.63 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 419, RT 1.38 minutes.

Intermediate 20

N-[2-(2-Amino-3-fluoroanilino)-1-cyclooctyl-2-oxoethyl]-2-methylpyrazole-3-carboxamide

(39) The title compound (60 mg, 41%) was prepared from Intermediate 5 (50 mg, 0.17 mmol) and 3-fluorobenzene-1,2-diamine (26 mg, 0.206 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 402, RT 2.07 minutes.

Intermediate 21 tert-Butyl N-(2-amino-4-bromo-3-fluorophenyl)carbamate

(40) To a solution of 4-bromo-3-fluorobenzene-1,2-diamine (556 mg, 2.71 mmol) in DCM (10 mL) at r.t. was added 2M aqueous sodium hydroxide solution (3.1 mL, 6.10 mmol), followed by di-tert-butyl dicarbonate (2.8 g, 12 mmol). The reaction mixture was stirred overnight, then diluted with DCM (30 mL) and washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography, eluting with EtOAc in hexanes (2-20%), gave the title compound (549 mg, 66%) as a white solid. δ.sub.H (400 MHz, CDCl.sub.3) 7.05 (dd, J 8.8, 1.6 Hz, 1H), 6.95 (dd, J 8.7, 7.1 Hz, 1H), 6.30 (s, 1H), 3.35 (s, 2H), 1.54 (s, 9H). LCMS (Method 5): [M+H].sup.+ m/z 305, RT 1.30 minutes.

Intermediate 22

tert-Butyl N-[2-amino-4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]carbamate

(41) To a mixture of Intermediate 21 (200 mg, 0.66 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (142 mg, 0.66 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (59 mg, 0.065 mmol) in 1,4-dioxane (2 mL) at r.t. was added aqueous sodium carbonate solution (2M, 2 mL, 4 mmol). The mixture was de-gassed under nitrogen, then heated in a microwave reactor for 60 minutes at 100° C. The reaction mixture was filtered through Celite®, washing with EtOAc (10 mL), then the combined washings were concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and washed with water (50 mL), then dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography, eluting with a solution of EtOAc in hexanes (15-100%), gave the title compound (176 mg, 86%) as a beige solid. δ.sub.H (400 MHz, CDCl.sub.3) 7.10 (dd, J 8.4, 1.5 Hz, 1H), 6.71 (t, J 8.3 Hz, 1H), 6.37 (s, 1H), 6.11-5.91 (m, 1H), 4.39-4.26 (m, 2H), 3.93 (t, J 5.4 Hz, 2H), 2.58-2.42 (m, 2H), 1.54 (s, 9H). LCMS (method 5): [M+H-.sup.tBu].sup.+ m/z 253, RT 1.22 minutes.

Intermediate 23

tert-Butyl N-[2-amino-3-fluoro-4-(tetrahydropyran-4-yl)phenyl]carbamate

(42) To a solution of Intermediate 22 (176 mg, 0.57 mmol) in ethanol (10 mL) was added 10% Pd on charcoal (17 mg). The mixture was de-gassed under nitrogen, then stirred under an atmosphere of hydrogen for 2 h. The reaction mixture was filtered through Celite® and evaporated to dryness, to give the title compound (173 mg, 91%) as a grey solid. δ.sub.H (400 MHz, CDCl.sub.3) 7.11-6.96 (m, 1H), 6.72-6.59 (m, 1H), 6.27 (s, 1H), 4.15-3.99 (m, 2H), 3.65-3.49 (m, 2H), 3.17-2.97 (m, 1H), 1.92-1.76 (m, 4H), 1.75-1.66 (m, 2H), 1.54 (s, 9H). LCMS (Method 5): [M+H-.sup.tBu].sup.+ m/z 255, RT 1.20 minutes.

Intermediate 24

3-Fluoro-4-(tetrahydropyran-4-yl)benzene-1,2-diamine

(43) To a solution of Intermediate 23 (76 mg, 0.23 mmol) in ethanol (10 mL) was added a 4M solution of hydrochloric acid in 1,4-dioxane (2 mL). The mixture was stirred for 1 h at r.t., then evaporated to dryness. The residue was dissolved in methanol (2 mL) and purified with an SCX-2 column (washed with methanol). The resulting material was treated with a 4M solution of ammonia in methanol (10 mL) and evaporated to dryness, to give the title compound (50 mg, 97%) as a beige solid. δ.sub.H (400 MHz, CDCl.sub.3) 6.56-6.35 (m, 2H), 4.12-3.91 (m, 2H), 3.62-3.44 (m, 2H), 3.09-2.89 (m, 1H), 1.87-1.58 (m, 4H). LCMS (Method 5): [M+H].sup.+ m/z 210, RT 0.79 minutes.

Intermediate 25 (Procedure C)

3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine

(44) A solution of 4-bromo-3-fluorobenzene-1,2-diamine (5.0 g, 24.39 mmol), bis(pinacolato)diboron (6.5 g, 26 mmol) and potassium acetate (7.2 g, 73 mmol) in 1,4-dioxane (50 mL) was degassed with N.sub.2 for 10 minutes, then Pd(dppf)Cl.sub.2.DCM (1.3 g, 1.58 mmol) was added. The mixture was degassed with N.sub.2 for a further 10 minutes, then the reaction mixture was heated at 105° C. overnight. The reaction mixture was cooled and filtered through Celite®, washing the plug with EtOAc. The filtrate was concentrated in vacuo, then the residue was partitioned between DCM and water. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo, then purified by flash chromatography, eluting with EtOAc/hexanes (0-65% gradient), to give the title compound (3.7 g, 60%) as a brown solid. LCMS (Method 5): [M+H].sup.+ m/z 253, RT 1.02 minutes.

Intermediate 26 (Procedure D)

tert-Butyl N-(3-bromo-2,5-difluoro-6-nitrophenyl)-N-(tert-butoxycarbonyl)carbamate

(45) To a stirred solution of 3-bromo-2,5-difluoro-6-nitroaniline (510 mg, 2.02 mmol) in THF (10 mL) was added DIPEA (1.05 mL, 6.02 mmol), followed by di-tert-butyl dicarbonate (530 mg), at 0° C. After stirring for 10 minutes, DMAP (125 mg, 1.02 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 15 minutes, then warmed to r.t. After 1 h, further di-tert-butyl dicarbonate (790 mg) was added. The reaction mixture was stirred for 2.5 h, then concentrated in vacuo. The crude residue was purified by flash column chromatography, eluting with EtOAc/hexanes (0-50% gradient), to give the title compound (509 mg, 56%). LCMS (Method 5): [M+H−2(BOC)].sup.+ m/z 254, RT 1.66 minutes.

Intermediate 27

N,N-Dibenzyl-3-bromo-2-fluoro-6-nitroaniline

(46) To a solution of 2,3-difluoro-4-bromonitrobenzene (1 g, 4.12 mmol) in DMSO (10 mL) were added K.sub.2CO.sub.3 and dibenzylamine (0.86 mL, 4.3 mmol). The reaction mixture was heated at 100° C. and stirred overnight, then partitioned between EtOAc and water. The organic layers were separated and dried over Na.sub.2SO.sub.4, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-50% gradient), to give the title compound (1.07 g, 52%). LCMS (Method 5): [M+H].sup.+ m/z 417, RT 1.71 minutes.

Intermediate 28

tert-Butyl N-(4-bromo-2-fluoro-6-nitrophenyl)-N-(tert-butoxycarbonyl)carbamate

(47) The title compound (9.6 g, quantitative) was prepared from 4-bromo-2-fluoro-6-nitroaniline (5 g, 20.22 mmol) in accordance with Procedure D. LCMS (Method 5): [M+H−2(BOC)].sup.+ m/z 236, RT 1.65 minutes.

Intermediate 29

3-Fluoro-4-(1H-pyrazol-3-yl)benzene-1,2-diamine

(48) To a mixture of Intermediate 21 (200 mg, 0.65 mmol), 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester (376 mg, 1.31 mmol) and Pd(dppf)Cl.sub.2.DCM (59 mg, 0.09 mmol) in 1,4-dioxane (2 mL) was added aqueous Na.sub.2CO.sub.3 solution (2M, 1.9 mL). The mixture was degassed under N.sub.2 sparge for 10 minutes, then heated under focused microwave irradiation for 60 minutes at 100° C. After cooling, the mixture was filtered through Celite® (1 g), washing the plug with EtOAc (20 mL). The organic layers were concentrated in vacuo, then partitioned between EtOAc and water. The organic layers were dried over Na.sub.2SO.sub.4, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (12-100% gradient). The resulting yellow glass was taken up in 4M HCl in 1,4-dioxane (2 mL). The reaction mixture was stirred for 1 h, then concentrated in vacuo. The residue was taken up in MeOH (2 mL) and eluted onto an SCX cartridge (2 g). After MeOH washing, the residue was eluted with a 4M solution of NH.sub.3 in MeOH (10 mL), then concentrated in vacuo, to furnish the title compound (80 mg, 63%) as a pale yellow solid. LCMS (Method 5): [M+H].sup.+ m/z 193, RT 0.49 minutes.

Intermediate 30

4-(Benzenesulfinyl)-3-fluorobenzene-1,2-diamine

(49) To a solution of 4-bromo-3-fluorobenzene-1,2-diamine (300 mg, 1.46 mmol), thiophenol (300 μL, 2.90 mmol) and K.sub.2CO.sub.3 (613 mg, 4.39 mmol) in DMF (7 mL) was added copper(I) chloride. The mixture was heated in a sealed vial at 150° C. overnight, then poured onto water and filtered through Celite®, eluting with EtOAc. The organic layers were separated and dried over MgSO.sub.4, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient). The resulting dark oil was taken up in DMF (3 mL), and H.sub.2O.sub.2 (3 mL, 29.37 mmol, 30% mass) was added. The mixture was stirred overnight, then poured slowly onto a saturated aqueous solution of Na.sub.2S.sub.2O.sub.5 (20 mL). The mixture was diluted with EtOAc (20 mL). The organic layers were separated and washed with brine, then dried over MgSO.sub.4 and concentrated in vacuo. Purification of the residue by flash chromatography, eluting with EtOAc/hexanes (30-100% gradient), afforded the title compound (85 mg, 23% overall) as a brown solid. LCMS (Method 5): [M+H].sup.+ m/z 251, RT 0.87 minutes.

Intermediate 31

tert-Butyl 2-(3,4-diamino-2-fluorophenyl)acetate

(50) A mixture of Intermediate 27 (916 mg, 2.2 mmol), XPhos (325 mg, 0.66 mmol) and Pd.sub.2(dba).sub.3 (312 mg, 0.33 mmol) in anhydrous THF (20 mL) was degassed under N.sub.2 sparge for 10 minutes at r.t., then 2-tert-butoxy-2-oxoethylzinc chloride (10 mL, 5 mmol) was added. The reaction mixture was stirred for 3 h at 70° C., then cooled and diluted with EtOAc (50 mL). The organic layers were washed with saturated NH.sub.4C1 solution, then dried over MgSO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-20% gradient), then reverse-phase HPLC. The resulting yellow solid was taken up in EtOH (13 mL), and 10% Pd/C (20 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite® (1 g), washing the plug with EtOH. The residue was concentrated in vacuo to give the title compound (116 mg, 22% overall) as a red oil. LCMS (Method 5): [M+H].sup.+ m/z 241, RT 1.08 minutes.

Intermediate 32 (Procedure E)

tert-Butyl 3-(3,4-diamino-2-fluorophenyl)propanoate

(51) To a solution of 4-bromo-3-fluorobenzene-1,2-diamine (500 mg, 2.34 mmol), dissolved in DMF (1.7 mL), was added DIPEA (1.7 mL), then tert-butyl acrylate (0.43 mL, 2.9 mmol), tri-o-tolylphosphine (285 mg, 0.94 mmol) and palladium(II) acetate (26 mg, 0.12 mmol). The mixture was heated at 110° C. overnight under an atmosphere of argon, then allowed to cool, and concentrated in vacuo. The residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic layers were separated and dried over MgSO.sub.4, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0%-70% gradient). The resulting brown oil was taken up in EtOH (56 mL), and 10% Pd/C (57 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite® (2.5 g), washing the plug with EtOH. The residue was concentrated in vacuo to give the title compound (486 mg, 82% overall) as a brown oil. δ.sub.H (400 MHz, CDCl.sub.3) 6.57-6.45 (m, 1H), 6.41 (dd, J 8.1, 1.3 Hz, 1H), 3.37 (s, 4H), 2.87-2.79 (m, 2H), 2.52-2.44 (m, 2H), 1.42 (s, 9H). LCMS (Method 5): [M+H].sup.+ m/z 255, RT 1.14 minutes.

Intermediate 33 (Procedure F)

tert-Butyl 2-(3,4-diamino-2-fluorophenyl)benzoate

(52) To a solution of 4-bromo-3-fluorobenzene-1,2-diamine (1.0 g, 4.68 mmol), 2-(tert-butoxycarbonyl)phenylboronic acid pinacol ester (2.23 g, 7.04 mmol) and K.sub.2CO.sub.3 (1.63 g, 11.7 mmol) in 1,4-dioxane (32 mL) and water (17 mL) was added Pd(dppf)Cl.sub.2.DCM (382 mg, 0.47 mmol). The reaction mixture was degassed for 10 minutes with N.sub.2 sparging, and heated at 80° C. for 48 h, then cooled, diluted with water and extracted into EtOAc. The organic layers were dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to give the title compound (1.31 g, 84%) as a brown oil. LCMS (Method 5): [M+H].sup.+ m/z 303, RT 1.21 minutes.

Intermediate 34 (Procedure G)

2-(3,4-Diamino-2-fluorophenyl)-N,N-dimethylbenzamide

(53) A solution of Intermediate 25 (206 mg, 0.82 mmol), 2-bromo-N,N-dimethyl-benzamide (200 mg, 0.88 mmol) and K.sub.2CO.sub.3 (327 mg, 2.37 mmol) in water (0.5 mL) and 1,4 dioxane (3.2 mL) in a microwave vial was sparged with N.sub.2 for 5 minutes, prior to the addition of Pd(dppf)Cl.sub.2.DCM (35 mg, 0.05 mmol). The reaction mixture was heated under microwave irradiation for 1 h at 100° C., then concentrated in vacuo. The residue was purified using flash chromatography, eluting with EtOAc/hexanes (10-100% gradient), to furnish the title compound (150 mg, 48%) as a brown foam. LCMS (Method 5): [M+H].sup.+ m/z 274, RT 0.48 minutes.

Intermediate 35 (Procedure H)

3-(Cyclopentyloxy)benzene-1,2-diamine

(54) To a solution of 2,3-dinitrophenol (250 mg, 1.36 mmol) in DMF (2.5 mL) at r.t. was added K.sub.2CO.sub.3 (375 mg, 2.71 mmol), followed by cyclopentyl bromide (6.7 mL, 61 mmol). The reaction mixture was heated at 100° C. for 1 h, then cooled, poured onto water (50 mL) and extracted with diethyl ether (2×30 mL). The organic phase was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (15-60% gradient). The resulting beige solid was taken up in EtOH (20 mL), and 10% Pd/C (24 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite® (1 g), washing the plug with EtOH. The residue was concentrated in vacuo to give the title compound (166 mg, 63% overall) as a brown oil. δ.sub.H (400 MHz, CD.sub.3OD) 6.63-6.52 (m, 1H), 6.43-6.33 (m, 2H), 4.84-4.73 (m, 1H), 2.04-1.76 (m, 6H), 1.75-1.57 (m, 2H). LCMS (Method 5): [M+H].sup.+ m/z 193, RT 1.11 minutes.

Intermediate 36 (Procedure I)

3-Methoxy-4-(tetrahydropyran-4-yl)benzene-1,2-diamine

(55) To a mixture of 4-bromo-3-methoxy-2-nitroaniline (200 mg, 0.81 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (177 mg, 0.82 mmol) and aqueous Na.sub.2CO.sub.3 solution (2M, 2.43 mL) in 1,4-dioxane (3 mL) was added Pd(dppf)Cl.sub.2.DCM (73 mg, 0.08 mmol). The reaction mixture was degassed by N.sub.2 sparging for 10 minutes, then heated under focused microwave irradiation for 1 h at 100° C. The reaction mixture was cooled and filtered through Celite® (1 g), washing with MeOH (20 mL), then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (10-80% gradient). The resulting beige solid was taken up in EtOH (20 mL), and 10% Pd/C (24 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite® (1 g), washing the plug with EtOH. The residue was concentrated in vacuo to give the title compound (56 mg, 31% overall) as a brown solid. δ.sub.H (400 MHz, CD.sub.3OD) 6.58-6.42 (m, 2H), 4.09-3.95 (m, 2H), 3.74 (s, 3H), 3.62-3.52 (m, 2H), 3.12-2.99 (m, 1H), 1.82-1.60 (m, 4H). LCMS (Method 5): [M+H].sup.+ m/z 223, RT 0.73 minutes.

Intermediate 37

3-Bromo-2,5-difluoro-6-nitroaniline

(56) To a stirred solution of 1-bromo-2,3,5-trifluoro-4-nitrobenzene (265 mg, 0.96 mmol) in MeOH (1 mL) at 0° C. was added dropwise a 7N solution of NH.sub.3 in MeOH (481 μL). The reaction mixture was stirred at r.t. for 1 h, then concentrated in vacuo. The crude residue was purified by flash chromatography, eluting with EtOAc/hexanes (5-40% gradient), to give the title compound (178 mg, 72%) as a yellow solid. δ.sub.H (400 MHz, CDCl.sub.3) 6.73 (dd, J 10.7, 5.6 Hz, 1H), 5.94 (s, 2H).

Intermediate 38

3-Fluoro-6-methoxy-4-(tetrahydropyran-4-yl)benzene-1,2-diamine

(57) To a mixture of Intermediate 37 (178 mg, 0.70 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (146 mg, 0.70 mmol) and aqueous Na.sub.2CO.sub.3 solution (2M, 1.74 mL) in 1,4-dioxane (3 mL) was added Pd(dppf)Cl.sub.2.DCM (73 mg, 0.08 mmol). The reaction mixture was degassed by N.sub.2 sparging for 10 minutes, then heated under focused microwave irradiation for 1 h at 100° C. The reaction mixture was cooled and filtered through Celite® (1 g), washing with MeOH (20 mL), then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (10-80% gradient). The resulting yellow solid was taken up in MeOH (5 mL) and stirred at 70° C. under focused microwave irradiation for 1 h. The cooled reaction mixture was concentrated in vacuo and purified by flash chromatography, eluting with EtOAc:hexanes (10-100% gradient). The resulting orange solid was taken up in EtOH (20 mL), and 10% Pd/C (8 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite® (1 g), washing the plug with EtOH. The residue was concentrated in vacuo to give the title compound (63 mg, 34% overall) as a tan glass. δ.sub.H (400 MHz, CD.sub.3OD) 6.23 (d, J 6.3 Hz, 1H), 4.10-4.01 (m, 2H), 3.82 (s, 3H), 3.62-3.49 (m, 2H), 3.08-2.93 (m, 1H), 1.90-1.64 (m, 4H). LCMS (Method 5): [M+H].sup.+ m/z 241, RT 0.92 minutes.

Intermediate 39 (Procedure J)

3-Fluoro-5-(morpholin-4-yl)benzene-1,2-diamine

(58) A solution of Intermediate 28 (300 mg, 0.69 mmol), morpholine (90 μL, 1.03 mmol) and Cs.sub.2CO.sub.3 (450 mg, 1.38 mmol) in toluene (12 mL) was degassed with N.sub.2 for 10 minutes, then Xantphos (80 mg, 0.14 mmol) and Pd.sub.2(dba).sub.3 (65 mg, 0.07 mmol) were added. The reaction mixture was heated at 100° C. for 1 h, then cooled and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient). The recovered material was dissolved in DCM (5 mL), and TFA (500 μL) was added. After 1 h, the reaction mixture was run down an SCX column, eluting with a 7N solution of NH.sub.3 in MeOH (10 mL). The residue was concentrated in vacuo. The resulting red solid was taken up in EtOH (2 mL), and 10% Pd/C (2 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen for 1 h, then filtered through Celite® (1 g), washing the plug with EtOH. The residue was concentrated in vacuo to give the title compound (53 mg, 34% overall). LCMS (Method 5): [M+H].sup.+ m/z 212, RT 0.53 minutes.

Intermediate 40 (Procedure K)

2-(3,4-Diamino-2-fluorophenyl)-2-(pyridin-3-yl)acetonitrile

(59) To a solution of pyridin-3-ylacetonitrile (0.32 mL, 3.0 mmol) in THF (10 mL) under N.sub.2 at 0° C. was added potassium tert-butoxide (348 mg, 3.04 mmol) portionwise. The reaction mixture was stirred for 30 minutes, then a solution of 2,3 difluoro-6-nitro-aniline (500 mg, 2.82 mmol) in THF (3 mL) was added. The solution was stirred for a further 30 minutes. The reaction mixture was quenched with 2M aqueous HCl (1.5 mL) and stirred for 1 h, then concentrated in vacuo. The crude residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient). The resulting material was taken up in EtOH (5 mL), and 10% Pd/C (22 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite® (1 g), washing the plug with EtOAc. The residue was concentrated in vacuo to give the title compound (325 mg, 40% overall) as a brown oil. LCMS (Method 5): [M+H].sup.+ m/z 243, RT 0.78 minutes.

Intermediate 41

tert-Butyl N-tert-butoxycarbonyl-N-(2,3-difluoro-6-nitrophenyl)carbamate

(60) The title compound (6.5 g, quantitative) was prepared from 2,3-difluoro-6-nitro-aniline (3 g, 17.23 mmol) in accordance with Procedure D. LCMS (Method 5): [M+H].sup.+ m/z 375, RT 1.08 minutes.

Intermediate 42

3-Fluoro-4-[1-(pyridin-4-yl)ethyl]benzene-1,2-diamine

(61) To a solution of ethyl pyridin-4-ylacetate (191 mg, 0.79 mmol) in dry THF (20 mL) at 0° C. was added NaH (60% mass, 38 mg, 0.95 mmol) and the mixture was stirred for 20 minutes. A solution of Intermediate 41 (300 mg, 0.79 mmol) in THF (5 mL) was added dropwise over 5 minutes. The reaction mixture was stirred for 1 h, then quenched with saturated aqueous NH.sub.4Cl solution. The mixture was extracted with EtOAc, then dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (30-100% gradient). The resulting solid was taken up in THF (4 mL) and treated with LiOH.H.sub.2O (43 mg, 1.02 mmol) in water (1 mL). The reaction mixture was stirred overnight, then neutralised with 2N aqueous HCl and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (30-100% gradient). The resultant solid was stirred for 90 minutes in TFA (0.5 mL) and DCM (5 mL), then concentrated in vacuo. The residue was taken up in EtOH (5 mL), and 10% Pd/C (10 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite® (1 g), washing the plug with EtOAc. The residue was concentrated in vacuo to give the title compound (70 mg, 38% overall) as a brown oil. LCMS (Method 5): [M+H].sup.+ m/z 232, RT 0.92 minutes.

Intermediate 43 (Procedure L)

3-Fluoro-4-{[1-(methylsulfonyl)piperidin-4-yl]oxy}benzene-1,2-diamine

(62) NaH (180 mg, 3.99 mmol) was added portionwise to a solution of 1-(methyl-sulfonyl)piperidin-4-ol (425 mg, 2.25 mmol) in dry THF (10 mL). After 20 minutes, 2,3 difluoro-6-nitroaniline (200 mg, 1.13 mmol) was added portionwise. The reaction mixture was stirred at 70° C. overnight, then quenched with saturated aqueous NH.sub.4Cl solution (1 mL) and concentrated in vacuo. The crude residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient). The resulting material was taken up in EtOH (10 mL), and 10% Pd/C (35 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite® (1 g), washing the plug with EtOAc. The residue was concentrated in vacuo to give the title compound (150 mg, 43% overall) as a brown solid. LCMS (Method 5): [M+H].sup.+ m/z 304, RT 0.79 minutes.

Intermediate 44 (Procedure M)

3-Fluoro-4-(morpholin-4-yl)benzene-1,2-diamine

(63) To a solution of 2,3 difluoro-6-nitroaniline (300 mg, 1.69 mmol) in NMP (1 mL) at r.t. was added morpholine (150 μL, 1.69 mmol), followed by triethylamine (710 μL, 5.1 mmol). The reaction mixture was heated under focused microwave irradiation for 1 h at 90° C., then cooled to r.t., poured onto water (80 mL) and stood at r.t. for 1 h. The mixture was cooled to 0° C. in an ice bath, then filtered and dried for 4 h on a sintered funnel under suction. The resulting yellow solid was taken up in EtOH (10 mL), and 10% Pd/C (35 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite® (1 g). The residue was concentrated in vacuo to give the title compound as a brown solid (301 mg, 92% overall). LCMS (Method 5): [M+H].sup.+ m/z 225, RT 0.36 minutes.

Intermediate 45 (Procedure N)

tert-Butyl 6-(3,4-diamino-2-fluorophenyl)-3,4-dihydro-2H-pyridine-1-carboxylate

(64) To a solution of tert-butyl 2-oxopiperidine-1-carboxylate (1 g, 5.02 mmol) in THF (10 mL), cooled to −30° C., was added lithium bis(trimethylsilyl)amide (1M in THF, 5.52 mL) dropwise over 15 minutes. The reaction mixture was stirred for 1 h at −30° C., then diphenyl chlorophosphate (1.1 mL, 5.3 mmol) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to r.t. and stirred for 48 h. The mixture was poured onto saturated aqueous NH.sub.4Cl solution (10 mL) and extracted with EtOAc. The organic layers were washed with saturated aqueous NaHCO.sub.3 solution and brine, then dried over Na.sub.2SO.sub.4. The residue was concentrated in vacuo. The resulting oil was purified by flash chromatography, eluting with EtOAc/hexanes (0-30% gradient), to furnish tert-butyl 6-diphenoxyphosphoryloxy-3,4-dihydro-2H-pyridine-1-carboxylate (1.92 g, 89%) as a colourless oil.

(65) Intermediate 25 (200 mg, 0.79 mmol), tert-butyl 6-diphenoxyphosphoryloxy-3,4-dihydro-2H-pyridine-1-carboxylate (342 mg, 0.79 mmol), Pd(dppf)Cl.sub.2.DCM (65 mg, 0.08 mmol), aqueous Na.sub.2CO.sub.3 solution (2M, 2.4 mL) and 1,4-dioxane (3.2 mL) were added to a microwave vial, sparged with N.sub.2 for 10 minutes, then heated under microwave irradiation for 1 h at 100° C. The reaction mixture was filtered through Celite® (1 g), eluting with MeOH (20 mL). The washings were concentrated in vacuo, and the residue was partitioned between EtOAc and water. The organic layers were washed with brine and dried over MgSO.sub.4, then concentrated in vacuo. The residue was purified using flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to furnish the title compound (143 mg, 59%) as a tan-coloured solid. δ.sub.H (400 MHz, CDCl.sub.3) 6.58 (t, J 8.1 Hz, 1H), 6.43 (dd, J 8.2, 1.3 Hz, 1H), 5.20 (td, J 3.8, 0.9 Hz, 1H), 3.88-3.55 (m, 2H), 3.63-3.08 (br s, 4H, 2×NH.sub.2), 2.25 (td, J 6.9, 3.8 Hz, 2H), 1.98-1.75 (m, 2H), 1.13 (s, 9H). LCMS (Method 5): [M+H].sup.+ m/z 308, RT 1.17 minutes.

Intermediate 46 (Procedure O)

tert-Butyl 2-(3,4-diamino-2-fluorophenyl)piperidine-1-carboxylate

(66) To a solution of Intermediate 45 (60 mg, 0.19 mmol) in EtOH (6 mL) at r.t. was added 10% Pd/C (6 mg). The reaction mixture was stirred under an atmosphere of hydrogen overnight, then filtered through Celite® (1 g), washing with EtOAc. The residue was concentrated in vacuo to give the title compound (50 mg, 83%) as a brown solid. δ.sub.H (400 MHz, CDCl.sub.3) 6.48 (td, J 8.1, 0.8 Hz, 1H), 6.43 (dd, J 8.3, 1.0 Hz, 1H), 5.41 (dd, J 6.0, 3.1 Hz, 1H), 4.11-3.99 (m, 1H, proton alpha to nitrogen), 3.55-3.23 (very br s, 4H, 2×NH.sub.2), 3.04 (ddd, J 13.4, 11.9, 3.8 Hz, 1H, proton alpha to nitrogen), 2.16-2.04 (m, 1H), 1.97-1.77 (m, 1H), 1.71-1.41 (m, 4H), 1.38 (s, 9H). LCMS (Method 5): [M+H].sup.+ m/z 310, RT 1.23 minutes.

Intermediate 47

tert-Butyl 4-(3-amino-2-fluoro-4-nitroanilino)piperidine-1-carboxylate

(67) To a solution of 2,3-difluoro-6-nitroaniline (350 mg, 1.97 mmol) in NMP (3 mL) were added tert-butyl 4-aminopiperidine-1-carboxylate (415 mg, 1.97 mmol) and triethyl-amine (0.82 mL, 5.9 mmol). The reaction mixture was heated under focused microwave irradiation for 1 h at 90° C. Further aliquots of tert-butyl 4-aminopiperidine-1-carboxylate (2×450 mg) were added and, after each addition, the mixture was heated for a further 1 h at 90° C. The reaction mixture was cooled, then partitioned between EtOAc and water. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to give the title compound (686 mg, 98%) as a solid. LCMS (Method 5): [M+H].sup.+ m/z 355, RT 1.37 minutes.

Intermediate 48 (Procedure P)

2-Fluoro-4-nitro-Ni-(piperidin-4-yl)benzene-1,3-diamine

(68) To a solution of Intermediate 47 (686 mg, 1.94 mmol) in DCM (10 mL) was added TFA (1 mL). The reaction mixture was stirred for 4 h at r.t., then concentrated in vacuo. The residue was taken up in MeOH, and loaded onto an SCX column, eluting with a 7N solution of NH.sub.3 in MeOH. The washings were concentrated in vacuo to give the title compound (493 mg, 99%). LCMS (Method 5): [M+H].sup.+ m/z 255, RT 0.37 minutes.

Intermediate 49 (Procedure Q)

3-Fluoro-N.SUP.4.-[1-(methylsulfonyl)piperidin-4-yl]benzene-1,2,4-triamine

(69) Intermediate 48 (488 mg, 1.9 mmol) was taken up in DCM (5 mL). Triethylamine (268 μL, 1.92 mmol) and methanesulfonyl chloride (149 μL, 1.93 mmol) were added. The solution was stirred at r.t. overnight, then concentrated in vacuo and purified by flash column chromatography, eluting with EtOAc/hexanes (0-100% gradient). The residue was taken up in EtOH (10 mL), and 10% Pd/C (20 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen for 5 h, then filtered through Celite® (1 g), washing the plug with EtOAc. The residue was concentrated in vacuo to give the title compound (360 mg, 62% overall) as a brown solid. LCMS (Method 5): [M+H].sup.+ m/z 303, RT 0.59 minutes.

Intermediate 50 (Procedure R)

tert-Butyl 4-[(3,4-diamino-2-fluorophenyl)methyl]piperazine-1-carboxylate

(70) A solution of 4-bromo-3-fluorobenzene-1,2-diamine (1.91 g, 8.84 mmol), potassium (4-tert-butoxycarbonylpiperazin-1-yl)methyltrifluoroborate (4.06 g, 13.3 mmol) and Cs.sub.2CO.sub.3 (8.64 g, 26.5 mmol) in THF (48 mL) and water (12 mL) was degassed with N.sub.2 for 10 minutes, then XPhos (930 mg, 1.77 mmol) and palladium(II) acetate (200 mg, 0.89 mmol) were added. The reaction mixture was heated at 70° C. under N.sub.2 overnight. After cooling, the mixture was filtered through Celite®, washing with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to give the title compound (2.87 g, quantitative) as a brown solid. LCMS (Method 5): [M+H].sup.+ m/z 325, RT 1.07 minutes.

Intermediate 51

tert-Butyl 4-[(3-amino-2,5-difluoro-4-nitrophenyl)methyl]piperazine-1-carboxylate

(71) The title compound (1.11 g, quantitative) was prepared from 3-bromo-2,5-difluoro-6-nitroaniline (750 mg, 2.96 mmol) in accordance with Procedure R. LCMS (Method 5): [M+H].sup.+ m/z 373, RT 1.41 minutes.

Intermediate 52

2,5-Difluoro-6-nitro-3-(piperazin-1-ylmethyl)aniline

(72) The title compound (1.1 g, quantitative) was prepared from Intermediate 51 (1.8 g, 4.04 mmol) in accordance with Procedure P. LCMS (Method 5): [M+H].sup.+ m/z 273, RT 0.64 minutes.

Intermediate 53

3,6-Difluoro-4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}benzene-1,2-diamine

(73) The title compound (366 mg, 30%) was prepared from Intermediate 52 (1.03 g, 3.8 mmol) in accordance with Procedure Q. LCMS (Method 5): [M+H].sup.+ m/z 321, RT 0.85 minutes.

Intermediate 54

tert-Butyl 4-({4-[bis(tert-butoxycarbonyl)amino]-3-fluoro-5-nitrophenyl}methyl)-piperazine-1-carboxylate

(74) The title compound (316 mg, quantitative) was prepared from Intermediate 28 (248 mg, 0.57 mmol) in accordance with Procedure R. LCMS (Method 5): [M+H].sup.+ m/z 556, RT 1.73 minutes.

Intermediate 55

2-Fluoro-6-nitro-4-(piperazin-1-ylmethyl)aniline

(75) The title compound (130 mg, 89%) was prepared from Intermediate 54 (316 mg, 0.57 mmol) in accordance with Procedure P. LCMS (Method 5): [M+H].sup.+ m/z 255, RT 0.68 minutes.

Intermediate 56

3-Fluoro-5-{[4-(methylsulfonyl)piperazin-1-yl]methyl}benzene-1,2-diamine

(76) The title compound (61 mg, 39%) was prepared from Intermediate 55 (130 mg, 0.51 mmol) in accordance with Procedure Q. LCMS (Method 5): [M+H].sup.+ m/z 303, RT 0.81 minutes.

Intermediate 57

1-{4-[(3,4-diamino-5-fluorophenyl)methyl]piperazin-1-yl}ethanone

(77) To a solution of Intermediate 55 (70 mg, 0.28 mmol) in DCM (1 mL) were added triethylamine (40 μL, 0.29 mmol) and acetic anhydride (26 μL, 0.28 mmol). The reaction mixture was stirred at r.t. for 90 minutes, then partitioned between DCM and water. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was taken up in THF (1 mL), then acetonitrile (1 mL), NH.sub.4Cl (33 mg, 0.62 mmol) and zinc dust (40 mg, 0.62 mmol) were added. The reaction mixture was stirred for 3 days, then two further aliquots of zinc (40 mg) and NH.sub.4Cl (33 mg) were added. Stirring was continued for a further 2 days, then the mixture was filtered through Celite®, washing with EtOAc. The residue was concentrated in vacuo to give the title compound (49 mg, 66% overall) as an oil. LCMS (Method 5): [M+H].sup.+ m/z 267, RT 0.71 minutes.

Intermediate 58 (Procedure S)

tert-Butyl 4-[(3,4-diamino-2-fluorophenyl)methyl]piperidine-1-carboxylate

(78) A mixture of tert-butyl-4-methylenepiperidine-1-carboxylate (157 mg, 0.79 mmol) and 9-BBN (1.6 mL, 0.80 mmol) was heated at 70° C. for 2 h. After cooling, 4-bromo-3-fluorobenzene-1,2-diamine (150 mg, 0.73 mmol), K.sub.2CO.sub.3 (133 mg, 0.95 mmol), DMF (1.46 mL), water (0.15 mL) and Pd(dppf)Cl.sub.2.DCM (18 mg, 0.02 mmol) were added. The mixture was heated at 60° C. for 3 h, then cooled and partitioned between EtOAc and water. The organic layers were washed with brine and dried over MgSO.sub.4, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to yield the title compound (70 mg, 30%) as a yellow oil. LCMS (Method 5): [M+H-BOC].sup.+ m/z 224, RT 1.33 minutes.

Intermediate 59

3-Fluoro-4-(piperazin-1-ylmethyl)benzene-1,2-diamine

(79) The title compound (2.10 g, quantitative) was prepared from Intermediate 50 (2.88 g, 8.88 mmol) in accordance with Procedure P. LCMS (Method 5): [M+H].sup.+ m/z 255, RT 0.68 minutes.

Intermediate 60

1-{4-[(3,4-diamino-2-fluorophenyl)methyl]piperazin-1-yl}ethanone

(80) To a solution of Intermediate 59 (2.14 g, 9.56 mmol) in DCM (25 mL) at 0° C. was added triethylamine (1.3 mL, 9.3 mmol), followed by acetic anhydride (0.9 mL, 10 mmol). The reaction mixture was warmed to r.t. and stirred for 4 h, then partitioned between EtOAc and water. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with MeOH/EtOAc (0-20% gradient), to give the title compound (501 mg, 20%). LCMS (Method 5): [M+H].sup.+ m/z 267, RT 0.63 minutes.

Intermediate 61 (Procedure T)

Ethyl 5-(3,4-diamino-2-fluorophenyl)-3,6-dihydro-2H-pyran-4-carboxylate

(81) To a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (1.01 g, 5.58 mmol,) dissolved in DCM (28 mL) and cooled under N.sub.2 to −78° C., was added DIPEA (1.2 mL, 6.9 mmol). The reaction mixture was stirred under N.sub.2, then a 1M solution of trifluoromethanesulfonic anhydride in DCM (6.07 mL, 6.07 mmol) was added. The reaction mixture was stirred at −78° C. for 30 minutes, then warmed to r.t. and stirred for 4 h. Saturated aqueous NaHCO.sub.3 solution (30 mL) was added. The mixture was stirred rapidly at room temperature for 5 minutes, then filtered. The organic layer was concentrated in vacuo to afford ethyl 5-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-4-carboxylate (1.7 g, quantitative) as a brown oil.

(82) To a solution of ethyl 5-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-4-carboxylate (1.7 g, 5.58 mmol) in 1,4-dioxane (20 mL) were added Intermediate 25 (1.12 g, 4.41 mmol), K.sub.2CO.sub.3 (2.32 g, 16.81 mmol) and water (6 mL), and the mixture was sparged with N.sub.2. Pd(dppf)Cl.sub.2.DCM (440 mg, 0.57 mmol) was added, and the mixture was further sparged with N.sub.2, then heated at 100° C. overnight. The mixture was cooled and concentrated in vacuo, then the residue was partitioned between DCM and water. The organic layers were separated and concentrated in vacuo. The crude residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), yielding the title compound (541 mg, 35%) as an orange solid. LCMS (Method 5): [M+H].sup.+ m/z 281, RT 1.20 minutes.

Intermediate 62 (Procedure U)

Ethyl 3-(3,4-diamino-2-fluorophenyl)tetrahydropyran-4-carboxylate

(83) To a solution of Intermediate 61 (156 mg, 0.56 mmol) in EtOH (8 mL) was added 10% Pd/C (130 mg). The reaction mixture was stirred under an atmosphere of hydrogen for three days, then filtered through Celite® (1 g), washing with DCM. The residue was concentrated in vacuo to give the title compound (1:1 mixture of cis isomers) (156 mg, quantitative) as a brown solid. LCMS (Method 5): [M+H].sup.+ m/z 283, RT 0.89 minutes.

Intermediate 63

tert-Butyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]acetate

(84) A mixture of Intermediate 27 (916 mg, 2.21 mmol), XPhos (325 mg, 0.66 mmol) and Pd.sub.2(dba).sub.3 (312 mg, 0.33 mmol) in anhydrous THF was degassed under a N.sub.2 sparge for 10 minutes at r.t., then 2-tert-butoxy-2-oxoethylzinc chloride (10 mL, 5 mmol) was added. The reaction mixture was stirred at r.t. for 10 minutes under N.sub.2, then at 70° C. for 3 h, then cooled to r.t. and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NH.sub.4Cl solution (20 mL), then dried over MgSO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-20% gradient), then preparative HPLC, to give the title compound (517 mg, 52%) as an off-white solid. LCMS (Method 5): [M+H].sup.+ m/z 451, RT 1.84 minutes.

Intermediate 64

2-(3,4-Diamino-2-fluorophenyl)-N,N-dimethylacetamide

(85) To a solution of Intermediate 63 (248 mg, 0.55 mmol) in DCM (2 mL) was added TFA (0.35 mL). The mixture was stirred at r.t. overnight, then concentrated in vacuo. The residue was taken up in DCM (3 mL), then HATU (260 mg, 0.66 mmol), DIPEA (0.55 mL, 1.1 mmol) and a 2M solution of dimethylamine in THF (0.55 mL, 1.1 mmol) were added. After 2 h, the mixture was partitioned between DCM and water. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was dissolved in EtOH (10 mL), to which was added 10% Pd/C (20 mg), then stirred under an atmosphere of hydrogen for 2 h. The reaction mixture was filtered through Celite® (1 g), washing with EtOAc. The residue was concentrated in vacuo to give the title compound (63 mg, 56% overall). LCMS (Method 5): [M+H].sup.+ m/z 212, RT 0.35 minutes.

Intermediate 65

6-Bromo-2-methoxypyridine-3,4-diamine

(86) A suspension of 6-bromo-2-chloropyridine-3,4-diamine (1 g, 4.49 mmol) and sodium methoxide (4.86 g, 90.0 mmol) in MeOH (38 mL) was stirred at 140° C. in an autoclave. After 55 h, the reaction mixture was partitioned between EtOAc and water. The organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with MeOH/DCM (0-10% gradient), to give the title compound (357 mg, 36% yield). LCMS (Method 5): [M+H].sup.+ m/z 220, RT 0.77 minutes.

Intermediate 66

tert-Butyl 4-[(3-amino-4-nitrophenyl)methyl]piperazine-1-carboxylate

(87) The title compound (779 mg, quantitative) was prepared from 5-bromo-2-nitro-aniline (500 mg, 2.30 mmol) in accordance with Procedure R. LCMS (Method 5): [M+H].sup.+ m/z 337, RT 1.31 minutes.

Intermediate 67

tert-Butyl 4-[(3,4-diaminophenyl)methyl]piperazine-1-carboxylate

(88) To a solution of Intermediate 66 (779 mg, 2.32 mmol) in EtOH (10 mL) at r.t. was added 10% Pd/C (10 mg). The reaction mixture was stirred under a hydrogen atmosphere overnight, then filtered through Celite®, washing with EtOAc. The filtrate was concentrated in vacuo. Purification by flash chromatography, eluting with MeOH/EtOAc (0-20% gradient) gave the title compound (248 mg, 35%). LCMS (Method 5): [M+H].sup.+ m/z 307, RT 1.03 minutes.

Intermediate 68

tert-Butyl 4-[(3-fluoro-5-methoxy-4-nitrophenyl)methyl]piperazine-1-carboxylate

(89) The title compound (594 mg, 64%) was prepared from 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (663 mg, 2.52 mmol) in accordance with Procedure R. LCMS (Method 5): [M+H].sup.+ m/z 370, RT 1.51 minutes.

Intermediate 69

tert-Butyl 4-[(3,4-diamino-5-methoxyphenyl)methyl]piperazine-1-carboxylate

(90) To a solution of Intermediate 68 (594 mg, 1.61 mmol) in DMSO (2 mL) was added sodium azide (115 mg, 1.77 mmol). The reaction mixture was heated at 50° C. for 6 h, then further sodium azide (115 mg, 1.77 mmol) was added and the mixture was stirred overnight. A final aliquot of sodium azide (115 mg, 1.77 mmol) was added. The mixture was left for 3 h, then cooled, and partitioned between EtOAc and water. The organic layers were washed with brine and dried over Na.sub.2SO.sub.4, then concentrated in vacuo. The crude residue was taken up in EtOH (20 mL), and 10% Pd/C (50 mg) was added. The reaction mixture was stirred at r.t. under an atmosphere of hydrogen overnight, then filtered through Celite®, washing with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (50-100% gradient), to give the title compound (117 mg, 22% overall). δ.sub.H (400 MHz, DMSO-d.sub.6) 6.19 (d, J 1.7 Hz, 1H), 6.14 (d, J 1.7 Hz, 1H), 4.46 (s, 2H), 3.91 (s, 2H), 3.70 (s, 3H), 3.29 (d, J 4.9 Hz, 4H), 3.23 (s, 2H), 2.25 (t, J 5.0 Hz, 4H), 1.38 (s, 9H).

Intermediates 70 to 99

(91) The following diamines were prepared from the indicated starting materials in accordance with the indicated Procedures:

(92) TABLE-US-00011 LCMS (Method 5) RT Int. Name Starting Material(s) Proc [M + H].sup.+ (min) 70 tert-Butyl 3-(3,4-diamino-5- 5-Bromo-3-fluorobenzene-1,2- E 255.0 1.12 fluoro-phenyl)propanoate diamine 71 3,5-Difluoro-4-(tetrahydropyran- 3-Chloro-2,4-difluoro-6-nitro- I 229.0 0.91 4-yl)benzene-1,2-diamine aniline and 2-(3,6-dihydro-2H- pyran-4-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane 72 3,6-Difluoro-4-(tetrahydropyran- Intermediate 37 and 2-(3,6- I 229.0 0.92 4-yl)benzene-1,2-diamine dihydro-2H-pyran-4-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane 73 3-Fluoro-4-(tetrahydropyran-3- 4-Bromo-3-fluorobenzene-1,2- I 211.2 0.63 yl)-benzene-1,2-diamine diamine and 2-(3,4-dihydro-2H- pyran-5-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane 74 tert-Butyl 4-(3,4-diamino-2- 4-Bromo-3-fluorobenzene-1,2- I 254.0 1.26 fluoro-phenyl)piperidine-1- diamine and tert-butyl 4-(4,4,5,5- carboxylate tetramethyl-1,3,2-dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1- carboxylate 75 Ethyl 2-(3,4-diamino-2-fluoro- Ethyl pyridin-3-ylacetate and K 290.0 0.92 phenyl)-2-(pyridin-3-yl)acetate 2,3-difluoro-6-nitroaniline 76 Ethyl 2-(3,4-diamino-2-fluoro- Ethyl pyridin-4-ylacetate and K 290.0 0.68 phenyl)-2-(pyridin-4-yl)acetate 2,3-difluoro-6-nitroaniline 77 2-(3,4-Diamino-2-fluorophenyl)- Pyridin-4-ylacetonitrile and 2,3- K 243.0 0.92 2-(pyridin-4-yl)acetonitrile difluoro-6-nitroaniline 78 Ethyl 2-(3,4-diamino-2-fluoro- Ethyl 2-phenylacetate and 2,3- K 289.0 1.20 phenyl)-2-phenylacetate difluoro-6-nitroaniline 79 3-Fluoro-6-methoxybenzene- 4-Fluoro-2,3-dinitrophenol and H 157.0 0.68 1,2-diamine methyl iodide 80 5-Fluoro-3-[(tetrahydropyran-4- 3,5-Difluoro-2-nitroaniline and L 227.0 0.87 yl)-oxy]benzene-1,2-diamine 4-hydroxytetrahydropyran 81 3-Fluoro-4-[(pyridazin-4-yl)oxy]- 4-Hydroxypyridazine and 2,3- L 221.0 0.21 benzene-1,2-diamine difluoro-6-nitroaniline 82 3-Fluoro-4-[(pyridin-4-yl)oxy]- 4-Hydroxypyridine and 2,3- L 220.0 0.17 benzene-1,2-diamine difluoro-6-nitroaniline 83 3-Fluoro-4-[(tetrahydropyran-4- 4-Hydroxytetrahydropyran and L 227.0 0.70 yl)-oxy]benzene-1,2-diamine 2,3-difluoro-6-nitroaniline 84 3-Fluoro-4-[(oxetan-3-yl)oxy]- 3-Hydroxyoxetane and 2,3- L 199.0 0.35 benzene-1,2-diamine difluoro-6-nitroaniline 85 Methyl (2S)-1-(3,4-diamino-2- Methyl (2S)-pyrrolidine-2- M 254.0 0.85 fluorophenyl)pyrrolidine-2- carboxylate and 2,3-difluoro-6- carboxylate nitroaniline 86 Methyl (2R)-1-(3,4-diamino-2- Methyl (2R)-pyrrolidine-2- fluorophenyl)pyrrolidine-2- carboxylate and 2,3-difluoro-6- M 254.0 0.85 carboxylate nitroaniline 87 Methyl 1-(3,4-diamino-2-fluoro- Methyl piperidine-2-carboxylate M 268.0 0.93 phenyl)piperidine-2-carboxylate and 2,3-difluoro-6-nitroaniline 88 (2S)-1-(3,4-Diamino-2-fluoro- (2S)-N,N-Dimethylpiperidine- M 281.0 0.91 phenyl)-N,N-dimethylpiperidine- 2-carboxamide and 2,3- 2-carboxamide difluoro-6-nitroaniline 89 3-Fluoro-N.sup.4-(tetrahydropyran- 4-Aminotetrahydropyran and M 226.0 0.45 4-yl)-benzene-1,2,4-triamine 2,3-difluoro-6-nitroaniline 90 tert-Butyl 5-(3,4-diamino-2-fluoro- tert-Butyl 2-oxopyrrolidine-1- N 238 1.12 phenyl)-2,3-dihydropyrrole-1- carboxylate and Intermediate 25 (-.sup.tBu) carboxylate 91 tert-Butyl 2-(3,4-diamino-2-fluoro- Intermediate 90 O 240 1.12 phenyl)pyrrolidine-1-carboxylate (-.sup.tBu) 92 tert-Butyl 5-(3,4-diamino-2- tert-Butyl 3-oxomorpholine-4- N 254 1.05 fluoro-phenyl)-2,3-dihydro-1,4- carboxylate and Intermediate 25 (-.sup.tBu) oxazine-4-carboxylate 93 tert-Butyl 3-(3,4-diamino-2- tert-Butyl 3-oxo-1,4-oxazepane- N 268 1.10 fluoro-phenyl)-6,7-dihydro-5H- 4-carboxylate and (-.sup.tBu) 1,4-oxazepine-4-carboxylate Intermediate 25 94 tert-Butyl 4-[(3,4-diamino-5- 5-Bromo-3-fluorobenzene-1,2- S 224.2 1.33 fluoro-phenyl)methyl]piperidine- diamine and tert-butyl-4- (-BOC) 1-carboxylate methylenepiperidine-1- carboxylate 95 Methyl 4-(3,4-diamino-2-fluoro- Methyl 4-oxotetrahydrofuran-3- T 253.0 0.80 phenyl)-2,5-dihydrofuran-3- carboxylate and Intermediate 25 carboxylate 96 Methyl 4-(3,4-diamino-2-fluoro- Intermediate 95 U 255.2 0.63 phenyl)tetrahydrofuran-3- carboxylate 97 O.sup.1-tert-Butyl O.sup.3-ethyl 4-(3,4- O.sup.1-tert-Butyl O.sup.3-ethyl 4-oxo- T 266.2 1.20 diamino-2-fluorophenyl)-2,5- pyrrolidine-1,3-dicarboxylate (-BOC) dihydropyrrole-1,3-dicarboxylate and Intermediate 25 98 O.sup.1-tert-butyl O.sup.3-ethyl 4-(3,4- Intermediate 97 U 268.2 1.14 diamino-2-fluorophenyl)- (-BOC) pyrrolidine-1,3-dicarboxylate 99 2-(3,4-Diamino-2,6-difluoro- 3-Chloro-2,4-difluoro-6-nitro- I 292.2 0.89 phenyl)-N,N-dimethylbenzamide aniline and N,N-dimethyl-2- (4,4,5,5-tetramethyl-1,3,2- dioxa-borolan-2-yl)benzamide

Intermediate 100

tert-Butyl 3-(3,4-diamino-2-fluorophenyl)morpholine-4-carboxylate

(93) To a solution of Intermediate 92 (1.78 g, 5.75 mmol) in methanol (20 mL) was added Pd/C (metal loading 20%; 480 mg, 0.9 mmol). The mixture was placed in a stainless steel reactor and hydrogenated at 70° C. at 10 bar for 140 h. The mixture was cooled down to r.t., then passed through a pad of Celite®, washing thoroughly with MeOH. The filtrate was concentrated in vacuo and purified by flash chromatography, eluting with EtOAc/heptane (30-50% gradient), to give the title compound (1.18 g, 60%) as a colourless oil. LCMS (Method 5): [M+H-BOC].sup.+ m/z 212, RT 1.01 minutes.

Intermediate 101

tert-Butyl 3-(3,4-diamino-2-fluorophenyl)-1,4-oxazepane-4-carboxylate

(94) To a solution of Intermediate 93 (130 mg, 0.40 mmol) in MeOH (3 mL) was added 10% Pd/C (4.2 mg, 0.004 mmol). The mixture was placed in a stainless steel reactor and hydrogenated at 60° C. at 20 bar for 16 h. The mixture was cooled down to r.t., then passed through a pad of Celite®, washing thoroughly with DCM. The filtrate was concentrated in vacuo to give the title compound (99 mg, 76%) as a colourless oil. LCMS (Method 5): [M+H-BOC].sup.+ m/z 226, RT 1.01 minutes.

Intermediate 102

Ethyl 4-(3,4-diamino-2-fluorophenyl)pyrrolidine-3-carboxylate

(95) To a solution of Intermediate 98 (241 mg, 0.66 mmol) in MeOH (9 mL) was added 4N HCl in 1,4-dioxane (1.64 mL, 6.56 mmol). The reaction mixture was stirred for 6 h, then concentrated in vacuo. The residue was run down an SCX column, eluting with a 7N solution of NH.sub.3 in MeOH, to give the title compound (1:1 mixture of cis isomers) (157 mg, 90%). LCMS (Method 5): [M+H].sup.+ m/z 268, RT 0.30 minutes.

Intermediate 103

Ethyl 4-(3,4-diamino-2-fluorophenyl)-1-(methylsulfonyl)pyrrolidine-3-carboxylate

(96) To a solution of Intermediate 102 (80 mg, 0.29 mmol) in DCM (2 mL) at 0° C. were added triethylamine (42 μL, 0.30 mmol) and methanesulfonyl chloride (23 μL, 0.30 mmol). The reaction mixture was warmed to r.t. and stirred overnight. After standing for 4 days, the mixture was partitioned between DCM and water. The organic layers were separated and dried over Na.sub.2SO.sub.4, then concentrated in vacuo, to give the title compound (1:1 mixture of cis isomers) (100 mg, 97%). LCMS (Method 5): [M+H].sup.+ m/z 346, RT 0.80 minutes.

Intermediate 104

Ethyl 1-acetyl-4-(3,4-diamino-2-fluorophenyl)pyrrolidine-3-carboxylate

(97) To a solution of Intermediate 102 (80 mg, 0.29 mmol) in DCM (2 mL) at 0° C. were added triethylamine (42 μL, 0.30 mmol) and acetic anhydride (28 μL, 0.30 mmol). The reaction mixture was warmed to r.t. and stirred overnight. After standing for 4 days, the mixture was partitioned between DCM and water. The organic layers were separated and dried over Na.sub.2SO.sub.4, then concentrated in vacuo, to yield the title compound (1:1 mixture of cis isomers) (91 mg, 99%). LCMS (Method 5): [M+H].sup.+ m/z 310, RT 0.69

Intermediate 105

Ethyl 2-{3-[bis(tert-butoxycarbonyl)amino]-2-fluoro-4-nitrophenyl}-2-(pyridin-4-yl)-acetate

(98) To a suspension of NaH (1.7 g, 43 mmol) in DMF (100 mL) at 0° C. was added ethyl pyridin-4-ylacetate (6.6 mL, 43 mmol) dropwise over 10 minutes. Intermediate 41 (6.28 g, 16.8 mmol) was then added portionwise over 10 minutes. The mixture was allowed to warm to r.t. overnight. Saturated aqueous NH.sub.4Cl solution (10 mL) was added, and the mixture was extracted with EtOAc. The organic layers were washed with brine and dried over MgSO.sub.4, then concentrated in vacuo. The crude residue was purified using flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to give the title compound (5.97 g, 69%) as a yellow oil. LCMS (Method 5): [M+H].sup.+ m/z 520, RT 1.51 minutes.

Intermediate 106

tert-Butyl N-{2-fluoro-3-[(5-methyl-1,3,4-oxadiazol-2-yl)(pyridin-4-yl)methyl]-6-nitro-phenyl}carbamate

(99) Intermediate 105 (2.3 g, 4.4 mmol) was dissolved in MeOH (8 mL) and hydrazine monohydrate (25% in water, 2.0 mL, 10 mmol) was added. The mixture was heated at 70° C. for several hours, then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layers were again concentrated in vacuo. The isolated material was dissolved in acetonitrile (30 mL) and cooled to 0° C., then acetic anhydride (0.28 mL, 3.0 mmol) was added dropwise. After 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in DMF (30 mL) and T3P® (2.1 mL, 3.6 mmol) was added. The reaction mixture was heated at 90° C., then concentrated in vacuo. The crude material was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to furnish the title compound (1.0 g, 53% overall) as a yellow oil. LCMS (Method 5): [M+H].sup.+ m/z 430, RT 1.43 minutes.

Intermediate 107

3-Fluoro-4-[(5-methyl-1,3,4-oxadiazol-2-yl)(pyridin-4-yl)methyl]benzene-1,2-diamine

(100) To a solution of Intermediate 106 (1.2 g, 2.8 mmol) in EtOH (40 mL) was added 10% Pd/C (150 mg). The mixture was stirred under an atmosphere of hydrogen for three days, then filtered through Celite® (1 g), washing with DCM. The residue was concentrated in vacuo. The crude material was taken up in DCM (10 mL) and TFA (3 mL) was added. The reaction mixture was stirred for 3 h, then concentrated in vacuo. The residue was dissolved in EtOAc, and washed with saturated aqueous NaHCO.sub.3 solution. The organic layers were dried over Na.sub.2SO.sub.4, then concentrated in vacuo, to give the title compound (388 mg, 46% overall) as a brown oil. LCMS (Method 5): [M+H].sup.+ m/z 300, RT 0.88 minutes.

Intermediate 108

tert-Butyl N-(3-fluoro-4-formyl-2-nitrophenyl)carbamate

(101) To a solution of 4-bromo-3-fluoro-2-nitroaniline (100 g, 426 mmol) in DMF (1000 mL) was added NaH (25.5 g, 638 mmol) at 0° C. The reaction mixture was stirred for 30 minutes, then di-tert-butyl dicarbonate (196 mL, 851 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 12 h, then poured into ice-cold water (2 L) and extracted with EtOAc (2×1 L). The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by column chromatography, eluting with EtOAc/hexanes (5-10% gradient). The resulting solid was taken up in 1,4-dioxane (300 mL) and water (90 mL), then 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (12.7 g, 82.7 mmol) and Na.sub.2CO.sub.3 (21.9 g, 207 mmol) were added at 0° C. The reaction mixture was purged with nitrogen for 30 minutes. Pd(PPh.sub.3).sub.4 (7.97 g, 6.89 mmol) was added, and the reaction mixture was again purged with N.sub.2 for 30 minutes. The reaction mixture was heated at 100° C. for 16 h, then diluted with water (400 mL) and extracted with EtOAc (3×400 mL). The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 8% EtOAc in hexanes) and taken up in DCM (1.2 L), then purged with ozone gas at −78° C. for 4 h. The reaction mixture was warmed to r.t., and TPP (33.5 g, 128 mmol) was added. The reaction mixture was stirred at r.t. for 16 h, then concentrated in vacuo. The crude material was purified by column chromatography, eluting with EtOAc/hexanes (20-30% gradient), to furnish the title compound (15.0 g, 12% overall) as a light yellow solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 10.28 (s, 1H), 10.09 (s, 1H), 7.96-8.00 (m, 1H), 7.46 (d, J 8.80 Hz, 1H), 1.44 (s, 9H).

Intermediate 109

Methyl (2S)-1-{[4-(tert-butoxycarbonylamino)-2-fluoro-3-nitro-phenyl]methyl}-pyrrolidine-2-carboxylate

(102) DIPEA (0.2 mL, 1.15 mmol) was added to a stirred suspension of Intermediate 108 (250 mg, 0.88 mmol) and methyl L-prolinate hydrochloride (1:1) (175 mg, 1.06 mmol) in anhydrous 1,2-dichloroethane (3 mL). The resulting solution was stirred at 20° C. for 5 minutes under N.sub.2. Sodium triacetoxyborohydride (280 mg, 1.32 mmol) was added in one portion, and the suspension was stirred at 0° C. for 64 h. The reaction mixture was quenched with saturated aqueous NaHCO.sub.3 solution (10 mL) and the biphasic mixture was stirred at 20° C. for 30 minutes. The residue was extracted with DCM (3×20 mL), using a hydrophobic frit, and the organic filtrate was concentrated in vacuo. The resultant yellow viscous oil was separated by flash column chromatography (KP-NH SiO.sub.2), eluting with EtOAc/heptane (0-40% gradient), to afford the title compound (309 mg, 86%) as a viscous golden yellow oil. LCMS (Method 1): [M+H].sup.+ m/z 398, RT 1.77 minutes.

Intermediate 110

Methyl (2R)-1-{[4-(tert-butoxycarbonylamino)-2-fluoro-3-nitrophenyl]methyl}-pyrrolidine-2-carboxylate

(103) Prepared in an analogous fashion to Intermediate 109 from methyl D-prolinate hydrochloride (1:1) (175 mg, 1.06 mmol) and Intermediate 108 (250 mg, 0.88 mmol), furnishing the title compound (322 mg, 86%) as a viscous golden yellow oil. LCMS (Method 1): [M+H].sup.+ m/z 398, RT 1.77 minutes.

Intermediate 111

Methyl (2S)-1-{[3-amino-4-(tert-butoxycarbonylamino)-2-fluorophenyl]methyl}-pyrrolidine-2-carboxylate

(104) Iron powder (336 mg, 6.02 mmol) was added to a stirred suspension of Intermediate 109 (309 mg, 0.75 mmol) in an 8:1:1 mixture of MeOH-water-saturated aqueous NH.sub.4Cl solution (10 mL). The mixture was heated at 60° C. under N.sub.2 for 3 h. After cooling to 20° C., the mixture was diluted with EtOAc (50 mL). The solids were removed by filtration through kieselguhr, washing with EtOAc (2×25 mL), MeOH (20 mL) and water (50 mL). The organic phase was separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL) and dried over MgSO.sub.4, then concentrated in vacuo, to afford the title compound (255 mg, 88%) as an off-white gum. LCMS (Method 1): [M+H].sup.+ m/z 368, RT 1.45 minutes.

Intermediate 112

Methyl (2R)-1-{[3-amino-4-(tert-butoxycarbonylamino)-2-fluorophenyl]methyl}-pyrrolidine-2-carboxylate

(105) Prepared in an analogous fashion to Intermediate 111 from Intermediate 110 (322 mg, 0.81 mmol), furnishing the title compound (255 mg, 80%) as an off-white gum. LCMS (Method 1): [M+H].sup.+ m/z 368, RT 1.45 minutes.

Intermediate 113

Methyl (2S)-1-[(3,4-diamino-2-fluorophenyl)methyl]pyrrolidine-2-carboxylate

(106) TFA (0.50 mL, 6.73 mmol) was added to a solution of Intermediate 111 (258 mg, 0.67 mmol) in anhydrous DCM (3.5 mL). The mixture was stirred at 20° C. under N.sub.2 for 19 h, then quenched with saturated aqueous NaHCO.sub.3 solution (pH 11, 10 mL). The residue was extracted successively with DCM (3×20 mL) and 4:1 DCM-isopropanol (4×25 mL), using a hydrophobic frit to separate the phases. The organic filtrate was concentrated in vacuo to afford the title compound (221 mg, quantitative) as a brown viscous oil. LCMS (Method 3): [M+H].sup.+ m/z 268, RT 1.96 minutes.

Intermediate 114

Methyl (2R)-1-[(3,4-diamino-2-fluorophenyl)methyl]pyrrolidine-2-carboxylate

(107) Prepared in an analogous fashion to Intermediate 113 from Intermediate 112 (255 mg, 0.70 mmol), furnishing the title compound (250 mg, quantitative) as a brown viscous oil. LCMS (Method 5): [M+H].sup.+ m/z 268, RT 1.95 minutes.

Intermediate 115 (Procedure V)

Ethyl 2-amino-2-(3,3-dimethylcyclohexyl)acetate

(108) To a solution of TiCl.sub.4 (1M in DCM, 15.4 mL, 15.4 mmol) in THF (7.7 mL) at 0° C. was added ethyl nitroacetate (0.85 mL, 7.70 mmol) dropwise over 5 minutes. The reaction mixture was stirred for 5 minutes, then 3,3-dimethylcyclohexanone (1.10 mL, 7.70 mmol) was added dropwise over 5 minutes. Following an additional 15 minutes at 0° C., a solution of 4-methylmorpholine (3.40 mL, 30.8 mmol) in THF (31 mL) was added via syringe pump dropwise over 2 h. The reaction mixture was slowly warmed to r.t. over 2 days, then diluted with EtOAc (30 mL) and H.sub.2O (30 mL). The layers were separated. The aqueous layer was re-extracted with EtOAc (2×50 mL), and the combined organic layers were dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with EtOAc/hexanes (0-20% gradient). The isolated material was taken up in CHCl.sub.3 (24 mL) and isopropanol (7.2 mL). To this solution was added silica (3.82 g), followed by NaBH.sub.4 (365 mg, 9.26 mmol), portionwise over 5 minutes. The mixture was stirred vigorously at r.t. over 16 h, then AcOH (0.56 mL) was added. The mixture was filtered and concentrated in vacuo. The residue was re-dissolved in DCM (30 mL), and water (30 mL) was added. The aqueous layer was re-extracted with DCM (2×50 mL), and the combined organic layers were dried (MgSO.sub.4) and concentrated in vacuo. The crude material was re-dissolved in EtOH (56 mL), and 10% Pd/C (56 mg) was added. The suspension was evacuated and back-filled three times with hydrogen, then left to stir at r.t. under a hydrogen atmosphere for 2 days. The mixture was filtered through a pad of Celite® (10 g) under suction using EtOH (100 mL), and concentrated in vacuo. Purification by flash column chromatography, eluting with EtOAc/hexanes (0-100% gradient), gave the title compound (1:1 mixture of diastereomers) (80 mg, 16% overall) as a colourless oil. R.sub.f 0.14 (EtOAc:isohexanes, 70:30), KMnO.sub.4 stain.

Intermediate 116

Ethyl 2-(3,3-dimethylcyclohexyl)-2-[(3-methylisoxazole-4-carbonyl)amino]acetate

(109) The title compound (114 mg, 74%) was prepared from Intermediate 115 (102 mg, 0.48 mmol) and 3-methylisoxazole-4-carboxylic acid (61 mg, 0.48 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 323, RT 1.37 minutes.

Intermediate 117 (Procedure W)

2-(3,3-Dimethylcyclohexyl)-2-[(3-methylisoxazole-4-carbonyl)amino]acetic Acid

(110) To a solution of Intermediate 116 (100 mg, 0.31 mmol) in THF (2.8 mL) and water (0.70 mL) at r.t. was added LiOH.H.sub.2O (19.5 mg, 0.47 mmol) in one portion. The mixture was stirred at r.t. for 3 days, then acidified to pH 3 using 2N aqueous HCl and extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO.sub.4), then concentrated in vacuo, to give the title compound (1:1 mixture of diastereomers) (100 mg, quantitative) as a pale yellow oil. LCMS (Method 5): [M+H].sup.+ m/z 295, RT 0.84 minutes.

Intermediate 118

Ethyl 2-amino-2-(spiro[2.5]octan-7-yl)acetate

(111) The title compound (126 mg, 5%) was prepared from spiro[2.5]octan-7-one (1.50 g, 12.0 mmol) in accordance with Procedure V. R.sub.f 0.16 (EtOAc:isohexanes, 70:30), KMnO.sub.4 stain.

Intermediate 119

Ethyl 2-[(3-ethylisoxazole-4-carbonyl)amino]-2-(spiro[2.5]octan-7-yl)acetate

(112) The title compound (117 mg, 59%) was prepared from Intermediate 118 (126 mg, 0.59 mmol) and 3-ethylisoxazole-4-carboxylic acid (84 mg, 0.59 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 335, RT 1.38 minutes.

Intermediate 120

2-[(3-Ethylisoxazole-4-carbonyl)amino]-2-(spiro[2.5]octan-7-Yl)acetic acid

(113) The title compound (100 mg, 93%) was prepared from Intermediate 119 (117 mg, 0.35 mmol) in accordance with Procedure W. LCMS (Method 5): [M+H].sup.+ m/z 307, RT 0.86 minutes.

Intermediate 121

Ethyl 2-amino-2-(3,3-difluorocyclohexyl)acetate

(114) To a solution of ethyl 2-nitro-2-(3-oxocyclohexyl)acetate (1.00 g, 4.14 mmol) in DCM (8.6 mL) at 0° C. was added DAST (1.10 mL, 8.33 mmol) dropwise over 10 minutes. The reaction mixture was warmed to r.t. slowly over 16 h, then poured onto ice (10 g) and neutralised with saturated aqueous Na.sub.2CO.sub.3 solution. The layers were separated, and the aqueous layer was re-extracted with DCM (2×30 mL). The combined organic layers were dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with EtOAc/hexanes (0-12% gradient). The resulting colourless oil was taken up in AcOH (13 mL) at r.t., to which was added Zn (470 mg, 7.04 mmol) in one portion. The mixture was stirred vigorously for 16 h, then filtered through Celite® (1 g), eluting with AcOH (2×10 mL). The filtrate was concentrated in vacuo to about one-third volume, then diluted with water (10 mL). The mixture was basified dropwise with aqueous NH.sub.4OH solution, and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried (MgSO.sub.4) and concentrated in vacuo. Purification by flash column chromatography, eluting with EtOAc/hexanes (0-100% gradient), gave the title compound (1:1 mixture of diastereomers) (183 mg, 20% overall) as a colourless oil. R.sub.f 0.30 (EtOAc:isohexanes, 70:30), KMnO.sub.4 stain.

Intermediate 122

Ethyl 2-(3,3-difluorocyclohexyl)-2-[(3-ethylisoxazole-4-carbonyl)amino]acetate

(115) The title compound (312 mg, quantitative) was prepared from Intermediate 121 (183 mg, 0.82 mmol) and 3-ethylisoxazole-4-carboxylic acid (117 mg, 0.82 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 345, RT 1.23 minutes.

Intermediate 123

2-(3,3-Difluorocyclohexyl)-2-[(3-ethylisoxazole-4-carbonyl)amino]acetic Acid

(116) The title compound (264 mg, 92%) was prepared from Intermediate 122 (312 mg, 0.91 mmol) in accordance with Procedure W. LCMS (Method 5): [M+H].sup.+ m/z 317, RT 0.76 minutes.

Intermediate 124

2-Cyclooctyl-2-[(2-ethylpyrazole-3-carbonyl)amino]acetic Acid

(117) To a solution of 1-ethyl-1H-pyrazole-5-carboxylic acid (315 mg, 2.14 mmol) and Intermediate 3 (500 mg, 2.12 mmol) in DMF (4 mL) at 0° C. was added HATU (1 g, 2.55 mmol), followed by DIPEA (1.5 mL, 8.6 mmol). The reaction mixture was warmed to r.t. and stirred for 3 days, then diluted with water (100 mL) and extracted with EtOAc (2×80 mL). The organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with EtOAc/hexanes (0-80% gradient), and the residue was taken up in THF (5 mL). LiOH.H.sub.2O (55 mg, 1.31 mmol) in water (1 mL) was added. The reaction mixture was stirred at r.t. overnight, then diluted with water, acidified to pH 3 with 2N aqueous HCl solution, and extracted with EtOAc. The organic layers were dried over Na.sub.2SO.sub.4 and filtered, then concentrated in vacuo, to give the title compound (271 mg, 41% overall). LCMS (Method 5): [M+H].sup.+ m/z 308, RT 0.94 minutes.

Intermediate 125

(2S)-2-[(2-Ethylpyrazole-3-carbonyl)amino]-2-(4-methylcyclohexyl)acetic Acid

(118) The title compound (130 mg, quantitative) was prepared in an analogous fashion to Intermediate 124 from trans-methyl (2S)-2-amino-2-(4-methylcyclohexyl)acetate (82 mg, 0.44 mmol) and 1-ethyl-1H-pyrazole-5-carboxylic acid (80 mg, 0.54 mmol). LCMS (Method 5): [M+H].sup.+ m/z 294, RT 0.83 minutes.

Intermediate 126

(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-2-(4-methylcyclohexyl)acetic Acid (Trans Isomer)

(119) To a solution of trans-methyl (2S)-2-amino-2-(4-methylcyclohexyl)acetate (3 g, 16.2 mmol) in 1,4-dioxane (25 mL) and water (12.5 mL) at r.t. was added NaHCO.sub.3 (3.4 g, 40 mmol). The stirred suspension was treated with 9-fluorenylmethyl chloroformate (4.19 g, 16.2 mmol) portionwise over 5 minutes. The reaction mixture was stirred at r.t. for 50 h, then partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with 1N aqueous HCl (100 mL) and brine (100 mL), then dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with EtOAc/hexanes (0-15% gradient). The recovered material was suspended in water (46 mL), then 4M HCl in 1,4-dioxane (55 mL, 221 mmol) was added dropwise. The mixture was heated at 80° C. overnight, then further 4M HCl in 1,4-dioxane (18.4 mL) was added, and the mixture was heated at 80° C. for another 24 h. The residue was concentrated in vacuo, then partitioned between EtOAc (100 mL) and water (50 mL). The organic layers were separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to yield the title compound (3.1 g, 49% overall) as a white solid. LCMS (Method 5): [M+H].sup.+ m/z 394.2, RT 1.12 minutes.

Intermediate 127 (Procedure X)

1-[4-({2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-methyl)piperazin-1-yl]ethanone (Trans Isomer)

(120) To a solution of trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (380 mg, 1.4 mmol) and Intermediate 60 (396 mg, 1.49 mmol) in DCM (8 mL) were added HATU (660 mg, 1.68 mmol) and DIPEA (0.5 mL, 3.0 mmol). The reaction mixture was stirred at r.t. for 5 h, then partitioned between DCM and water. The organic layers were dried over Na.sub.2SO.sub.4, then concentrated in vacuo. The residue was taken up in AcOH (10 mL) and stirred at reflux temperature for 16 h. The residue was concentrated in vacuo, then stirred in a mixture of MeOH (15 mL) and 4M HCl in 1,4-dioxane (5 mL). After 18 h, the reaction mixture was concentrated in vacuo. The isolated material was purified by flash chromatography, eluting with a 7N solution of NH.sub.3 in MeOH/EtOAc (0-20% gradient), to give the title compound (376 mg, 62% overall) as a solid. LCMS (Method 5): [M+H].sup.+ m/z 402, RT 1.04 minutes.

Intermediate 128

[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](4-methylcyclohexyl)-methanamine

(121) The title compound (137 mg, 27%) was prepared from Intermediate 15 (385 mg, 1.42 mmol) and Intermediate 24 (313 mg, 1.49 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 346, RT 1.24 minutes.

Intermediate 129

2-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N,N-dimethylbenzamide (Trans Isomer)

(122) The title compound (157 mg, 97%) was prepared from trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (106 mg, 0.39 mmol) and Intermediate 34 (150 mg, 0.40 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 409, RT 1.14 minutes.

Intermediate 130 (Procedure Y)

tert-Butyl N-[(5-bromo-4-fluoro-1H-benzimidazol-2-yl)(cyclooctyl)methyl]carbamate

(123) To a solution of 2-(tert-butoxycarbonylamino)-2-cyclooctylacetic acid (1.35 g, 4.74 mmol), 4-bromo-3-fluorobenzene-1,2-diamine (1.00 g, 4.70 mmol) and DIPEA (1.23 mL, 7.07 mmol) in DMF (6 mL) was added T3P® (2.8 mL, 4.7 mmol). The reaction mixture was heated overnight at 70° C., then concentrated in vacuo, and partitioned between EtOAc and water. The organic layers were dried over Na.sub.2SO.sub.4, then the solvent was removed in vacuo. The residue was taken up in AcOH (10 mL) and heated in a sealed vial at 70° C. overnight. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography, eluting with EtOAc/hexanes (0-100% gradient), to give the title compound (862 mg, 37% overall) as a brown foam. LCMS (Method 5): [M+H].sup.+ m/z 456.0, RT 1.59 minutes.

Intermediate 131

tert-Butyl N-{cyclooctyl[4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]methyl}carbamate

(124) The title compound (108 mg, 52%) was prepared from Intermediate 130 (146 mg, 0.32 mmol) in accordance with Procedure C. LCMS (Method 5): [M+H].sup.+ m/z 502, RT 1.59 minutes.

Intermediate 132

tert-Butyl N-(cyclooctyl{5-[2-(dimethylcarbamoyl)phenyl]-4-fluoro-1H-benzimidazol-2-yl}methyl)carbamate

(125) The title compound (30 mg, 82%) was prepared from Intermediate 131 (54 mg, 0.07 mmol) and 2-bromo-N,N-dimethylbenzamide (24 mg, 0.10 mmol) in accordance with Procedure G. LCMS (Method 5): [M+H].sup.+ m/z 523, RT 1.45 minutes.

Intermediate 133 (Procedure Z)

2-{2-[Amino(cyclooctyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N,N-dimethyl-benzamide

(126) To a solution of Intermediate 132 (30 mg, 0.06 mmol) in DCM (5 mL) was added 4N HCl in 1,4-dioxane (0.26 mL). The reaction mixture was stirred overnight, then concentrated in vacuo. The residue was dissolved in MeOH (2 mL) and eluted onto an Isolute SCX-2 cartridge (5 g), washing through with MeOH (20 mL). The material was released with a 7M solution of NH.sub.3 in MeOH (20 mL), and concentrated in vacuo, to give the title compound (25 mg, quantitative) as a straw-coloured oil. LCMS (Method 5): [M+H].sup.+ m/z 423, RT 1.10 minutes.

Intermediate 134

Ethyl 3-{2-[amino(cyclooctyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}pyridine-4-carboxylate

(127) The title compound (39 mg, 47%) was prepared from Intermediate 131 (108 mg, 0.17 mmol) and ethyl 3-bromoisonicotinate (65 mg, 0.28 mmol) in a sequential fashion in accordance with Procedures G and Z. LCMS (Method 5): [M+H].sup.+ m/z 425, RT 1.23 minutes.

Intermediate 135

1-(3-Bromo-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)ethanone

(128) To a suspension of 3-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (142 mg, 0.59 mmol) in DCM (5 mL) and triethylamine (0.17 mL, 1.2 mmol) was added acetic anhydride (0.06 mL, 0.6 mmol). The reaction mixture was stirred under N.sub.2 at r.t. overnight, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient) then MeOH/DCM (0-30% gradient), to furnish the title compound (101 mg, 70%) as a straw-coloured oil. δ.sub.H NMR (400 MHz, DMSO-d.sub.6) 4.91-4.71 (m, 2H), 4.06-3.83 (m, 4H), 2.18-2.07 (m, 3H). LCMS (Method 5): [M+H].sup.+ m/z 425, RT 1.23 minutes.

Intermediate 136

1-(3-{2-[Amino(cyclooctyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)ethanone

(129) The title compound (35 mg, 44%) was prepared from Intermediate 131 (108 mg, 0.17 mmol) and Intermediate 135 (65 mg, 0.28 mmol) in a sequential fashion in accordance with Procedures G and Z. LCMS (Method 5): [M+H].sup.+ m/z 440, RT 0.96 minutes.

Intermediate 137

(S)-[4-Fluoro-5-(tetrahydropyran-3-yl)-1H-benzimidazol-2-yl](4-methylcyclohexyl)-methanamine (Trans Isomer)

(130) The title compound (77 mg, 28%) was prepared from Intermediate 73 (170 mg, 0.81 mmol) and trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (224 mg, 0.83 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 346, RT 1.19 minutes.

Intermediate 138 (Procedure AA)

tert-Butyl N-[(S)-(5-bromo-4-fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methyl]-carbamate (Trans Isomer)

(131) To a solution of trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (5 g, 18.42 mmol) in DCM were added 4-bromo-3-fluorobenzene-1,2-diamine (3.97 g, 19.4 mmol), HATU (8.67 g, 22.1 mmol) and DIPEA (6.4 mL, 37 mmol). The mixture was stirred at r.t. overnight, then partitioned between DCM and water. The organic layers were dried over Na.sub.2SO.sub.4, then concentrated in vacuo. The residue was taken up in AcOH (40 mL) and heated at reflux temperature overnight, then poured onto saturated aqueous NaHCO.sub.3 solution and partitioned between EtOAc and water. The organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-50% gradient), giving the title compound (7.04 g, 87% overall). LCMS (Method 5): [M+H].sup.+ m/z 442, RT 1.52 minutes.

Intermediate 139

tert-Butyl N-{(S)-[4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl](4-methylcyclohexyl)methyl}carbamate

(132) The title compound (538 mg, 49%) was prepared from Intermediate 138 (1 g, 2.27 mmol) in accordance with Procedure C. LCMS (Method 5): [M+H].sup.+ m/z 488, RT 1.54 minutes.

Intermediate 140

3-Bromo-5-fluoro-N,N-dimethylpyridine-4-carboxamide

(133) The title compound (312 mg, quantitative) was prepared from 3-bromo-5-fluoro-isonicotinic acid (255 mg, 1.16 mmol) and a 2M solution of dimethylamine in THF (1.2 mL, 2.4 mmol) in accordance with Procedure A, with DCM (5 mL) as solvent. LCMS (Method 5): [M+H].sup.+ m/z 249, RT 0.62 minutes.

Intermediate 141

3-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-5-fluoro-N,N-dimethylpyridine-4-carboxamide (Trans Isomer)

(134) The title compound (56 mg, 52%) was prepared from Intermediate 139 (100 mg, 0.21 mmol) and Intermediate 140 (56 mg, 0.23 mmol) in a sequential fashion in accordance with Procedures G and Z. LCMS (Method 5): [M+H].sup.+ m/z 528, RT 1.29 minutes.

Intermediate 142

3-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N,N-dimethylpyridine-4-carboxamide (Trans Isomer)

(135) The title compound (54 mg, 67%) was prepared from Intermediate 139 (100 mg, 0.21 mmol) and 3-bromo-N,N-dimethylpyridine-4-carboxamide (52 mg, 0.23 mmol) in a sequential fashion in accordance with Procedures G and Z. LCMS (Method 5): [M+H].sup.+ m/z 410, RT 0.99 minutes.

Intermediate 143

2-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N,N-dimethylpyridine-3-carboxamide (Trans Isomer)

(136) The title compound (25 mg, 29%) was prepared from Intermediate 139 (100 mg, 0.21 mmol) and 2-bromo-N,N-dimethylnicotinamide (55 mg, 0.23 mmol) in a sequential fashion in accordance with Procedures G and Z. LCMS (Method 5): [M+H].sup.+ m/z 410, RT 0.97 minutes.

Intermediate 144

Ethyl 5-{2-[(S)-amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-3,6-dihydro-2H-pyran-4-carboxylate (Trans Isomer)

(137) The title compound (240 mg, 83%) was prepared from Intermediate 61 (151 mg, 0.56 mmol) and trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (151 mg, 0.55 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 416, RT 1.19 minutes.

Intermediate 145

5-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N,N-dimethyl-3,6-dihydro-2H-pyran-4-carboxamide (Trans Isomer)

(138) To a solution of trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (151 mg, 0.55 mmol) and Intermediate 61 (151 mg, 0.55 mmol) in DCM (5 mL) were added HATU (255 mg, 0.65 mmol) and DIPEA (0.19 mL, 1.1 mmol). The reaction mixture was stirred at r.t. for 5 h, then partitioned between DCM and water. The organic layers were dried over Na.sub.2SO.sub.4, then concentrated in vacuo. The residue was taken up in AcOH (5 mL) and stirred at reflux temperature for 16 h, then concentrated in vacuo. The residue was taken up in THF (2.5 mL) and water (2.5 mL), and LiOH.H.sub.2O (100 mg) was added. The mixture was stirred for 24 h at 70° C., then cooled and concentrated in vacuo. The residue was taken up in DCM (5 mL) and DMF (3 mL), then DIPEA (0.25 mL, 1.4 mmol), HATU (242 mg, 0.61 mmol) and a 2M solution of dimethylamine in THF (0.49 mL, 0.98 mmol) were added. After stirring for 3 days, further 2M dimethylamine solution in THF (1.0 mL), HATU (245 mg) and DIPEA (0.25 mL) were added. The mixture was stirred at r.t. for a further 24 h, then partitioned between water and EtOAc. The organic layers were washed with water and aqueous LiCl solution, then dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient). The resulting solid was taken up in DCM (5 mL) and treated with 4M HCl in 1,4-dioxane (2 mL). After 3 h, the reaction mixture was concentrated in vacuo to give the title compound (117 mg, 47% overall) as a straw-coloured oil. LCMS (Method 5): [M+H].sup.+ m/z 415.2, RT 1.09 minutes.

Intermediate 146

Ethyl 3-{2-[(S)-amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-tetrahydropyran-4-carboxylate (Trans Isomer)

(139) The title compound (62 mg, 22%) was prepared from Intermediate 62 (157 mg, 0.56 mmol) and trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (146 mg, 0.54 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 418, RT 1.19 minutes.

Intermediate 147

Methyl 4-{2-[(S)-amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-tetrahydrofuran-3-carboxylate (Trans Isomer)

(140) The title compound (367 mg, 93%) was prepared from trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (275 mg, 1.01 mmol) and Intermediate 96 (272 mg, 1.07 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 409, RT 1.14 minutes.

Intermediate 148

Ethyl 2-{2-[amino(cyclooctyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-2-(pyridin-3-yl)-acetate

(141) The title compound (80 mg, 18%) was prepared from 2-(tert-butoxycarbonyl-amino)-2-cyclooctylacetic acid (296 mg, 1.04 mmol) and Intermediate 75 (294 mg, 1.02 mmol) in a sequential fashion in accordance with Procedures Y and Z. LCMS (Method 5): [M+H].sup.+ m/z 439, RT 1.21 minutes.

Intermediate 149

Ethyl 2-{2-[(tert-butoxycarbonylamino)(cyclooctyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-2-(pyridin-4-yl)acetate

(142) The title compound (390 mg, 22%) was prepared from 2-(tert-butoxycarbonyl-amino)-2-cyclooctylacetic acid (951 mg, 3.33 mmol) and Intermediate 76 (953 mg, 3.29 mmol) in accordance with Procedure Y. LCMS (Method 5): [M+H].sup.+ m/z 539, RT 1.46 minutes.

Intermediate 150

Ethyl 2-{2-[amino(cyclooctyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-2-(pyridin-4-yl)-acetate

(143) The title compound (45 mg, quantitative) was prepared from Intermediate 149 (56 mg, 0.10 mmol) in accordance with Procedure P. LCMS (Method 5): [M+H].sup.+ m/z 439, RT 1.26 minutes.

Intermediate 151

Cyclooctyl[4-fluoro-5-(pyridin-4-ylmethyl)-1H-benzimidazol-2-yl]methanamine

(144) To a solution of Intermediate 150 (58 mg, 0.11 mmol) in EtOH (3 mL) was added LiOH.H.sub.2O, dissolved in water (1 mL). The reaction mixture was stirred at r.t. overnight.

(145) The acidity was adjusted to pH 1 with 2M aqueous HCl solution, and water (10 mL) was added. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography, eluting with MeOH/DCM (0-35% gradient), to give the title compound (39 mg, 17%). LCMS (Method 5): [M+H].sup.+ m/z 367, RT 1.21 minutes.

Intermediate 152

tert-Butyl N-[{5-[cyano(pyridin-4-yl)methyl]-4-fluoro-1H-benzimidazol-2-yl}-(cyclooctyl)methyl]carbamate

(146) The title compound (800 mg, 12%) was prepared from 2-(tert-butoxycarbonyl-amino)-2-cyclooctylacetic acid (4.0 g, 14.0 mmol) and Intermediate 77 (3.4 g, 14.0 mmol) in accordance with Procedure Y. LCMS (Method 5): [M+H].sup.+ m/z 492, RT 1.16 minutes.

Intermediate 153

2-{2-[Amino(cyclooctyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-2-(pyridin-4-yl)-acetamide

(147) To a cooled (0° C.) solution of Intermediate 152 (55 mg, 0.11 mmol) in DCM (2 mL) was added H.sub.2SO.sub.4 (40 μL, 0.7 mmol). The reaction mixture was warmed to r.t. overnight with stirring, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with MeOH/DCM (0-70% gradient). The relevant fractions were concentrated in vacuo to give the title compound (19 mg, 41%) as an off-white solid. LCMS (Method 5): [M+H].sup.+ m/z 410, RT 1.00 minutes.

Intermediate 154

Cyclooctyl{4-fluoro-5-[(5-methyl-1,3,4-oxadiazol-2-yl)(pyridin-4-yl)methyl]-1H-benzimidazol-2-yl}methanamine

(148) The title compound (160 mg, 27%) was prepared from 2-(tert-butoxycarbonyl-amino)-2-cyclooctylacetic acid (370 mg, 1.30 mmol) and Intermediate 107 (388 mg, 1.30 mmol) in a sequential fashion in accordance with Procedures Y and Z. LCMS (Method 5): [M+H].sup.+ m/z 449, RT 1.09 minutes.

Intermediate 155

tert-Butyl 3-{2-[(S)-(9H-fluoren-9-ylmethoxycarbonylamino)(4-methylcyclohexyl)-methyl]-4-fluoro-1H-benzimidazol-5-yl}morpholine-4-carboxylate (Trans Isomer)

(149) To a solution of Intermediate 126 (800 mg, 2.03 mmol) and Intermediate 100 (665 mg, 2.14 mmol) in DCM (11 mL) were added HATU (928 mg, 2.44 mmol) and DIPEA (0.71 mL, 4.1 mmol). The reaction mixture was stirred at r.t. overnight, then partitioned between DCM and water. The organic layers were dried over MgSO.sub.4, and concentrated in vacuo. The residue was taken up in AcOH (7 mL), and heated at 70° C. After 5 h, the reaction mixture was cooled, and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to give the title compound (1.15 g, 85% overall) as an orange foam. LCMS (Method 5): [M+H].sup.+ m/z 669, RT 1.67 minutes.

Intermediate 156

1-(3-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}morpholin-4-yl)-2-hydroxyethanone

(150) To a solution of Intermediate 155 (60 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred for 2 h, then concentrated in vacuo. The crude material was taken up in DCM (3 mL), and triethylamine (16 μL, 0.11 mmol) was added, followed by acetoxyacetyl chloride (13 μL, 0.12 mmol). The reaction mixture was stirred at r.t. for 1 h, then concentrated in vacuo. The residue was dissolved in MeOH (5 mL) and water (1 mL), then NaOH (70 μL, 0.1 mmol) was added. The reaction mixture was stirred overnight, then concentrated in vacuo, and partitioned between DCM and water. The organic layers were separated and dried over Na.sub.2SO.sub.4, then concentrated in vacuo. The crude orange glass was dissolved in acetonitrile (1 mL), and diethylamine (250 μL, 2.4 mmol) was added. After 2 h at r.t. the reaction mixture was concentrated in vacuo, to give the title compound (14 mg, 37% overall). LCMS (Method 5): [M+H].sup.+ m/z 405, RT 0.95 minutes.

Intermediate 157

(2S)-1-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N,N-dimethylpiperidine-2-carboxamide (Trans Isomer)

(151) The title compound (174 mg, 66%) was prepared from Intermediate 88 (179 mg, 0.64 mmol) and trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (115 mg, 0.42 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 416, RT 1.12 minutes.

Intermediate 158

2-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N,N-dimethylacetamide (Trans Isomer)

(152) The title compound (102 mg, 96%) was prepared from Intermediate 64 (63 mg, 0.30 mmol) and trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (80 mg, 0.29 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 347, RT 1.01 minutes.

Intermediate 159

Ethyl 4-{2-[(S)-amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-1-(methylsulfonyl)pyrrolidine-3-carboxylate (Trans Isomer)

(153) The title compound (144 mg, quantitative) was prepared from Intermediate 103 (100 mg, 0.30 mmol) and trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (80 mg, 0.30 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 481, RT 1.13 minutes.

Intermediate 160

Ethyl 1-acetyl-4-{2-[(S)-amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}pyrrolidine-3-carboxylate (Trans Isomer)

(154) The title compound (133 mg, quantitative) was prepared from Intermediate 104 (91 mg, 0.30 mmol) and trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (80 mg, 0.29 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 446, RT 1.05 minutes.

Intermediate 161

2-{2-[(S)-amino(4-methylcyclohexyl)methyl]-4,6-difluoro-H-benzimidazol-5-yl}-N,N-dimethylbenzamide (Trans Isomer)

(155) The title compound (274 mg, 95%) was prepared from Intermediate 99 (165 mg, 0.57 mmol) and trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (161 mg, 0.59 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 427, RT 1.18 minutes.

Intermediate 162

(5-Bromo-4-fluoro-1H-benzimidazol-2-yl)(cyclooctyl)methanamine

(156) The title compound (186 mg, quantitative) was prepared from Intermediate 130 (235 mg, 0.48 mmol) in accordance with Procedure Z. LCMS (Method 5): [M+H].sup.+ m/z 354, RT 1.08 minutes.

Intermediate 163

N-[(5-Bromo-4-fluoro-1H-benzimidazol-2-yl)(cyclooctyl)methyl]-2-ethylpyrazole-3-carboxamide

(157) The title compound (184 mg, 81%) was prepared from Intermediate 162 (165 mg, 0.57 mmol) and 1-ethyl-1H-pyrazole-5-carboxylic acid (78 mg, 0.55 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 476, RT 1.45 minutes.

Intermediate 164

tert-Butyl N-[(S)-(5-bromo-1H-imidazo[4,5-b]pyridin-2-yl)(4-methylcyclohexyl)methyl]-carbamate (Trans Isomer)

(158) To a solution of trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (350 mg, 1.29 mmol) and 6-bromopyridine-2,3-diamine (280 mg, 1.42 mmol) in DCM (5 mL) were added HATU (590 mg, 1.55 mmol) and DIPEA (0.45 mL, 2.6 mmol). The reaction mixture was stirred at r.t. for 2 days, then partitioned between DCM and water. The organic layers were separated and dried over Na.sub.2SO.sub.4, then concentrated in vacuo. The residue was taken up in EtOH (5.4 mL) and water (0.6 mL), and NaOH (260 mg, 6.5 mmol) was added. The reaction mixture was heated at 80° C. overnight, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (50-100% gradient), to give the title compound (69 mg, 12%). LCMS (Method 5): [M+H].sup.+ m/z 423, RT 1.36 minutes.

Intermediate 165

(S)-(5-Bromo-1H-imidazo[4,5-b]pyridin-2-yl)(4-methylcyclohexyl)methanamine (Trans Isomer)

(159) The title compound (30 mg, 58%) was prepared from Intermediate 164 (69 mg, 0.16 mmol) in accordance with Procedure Z. LCMS (Method 5): [M+H].sup.+ m/z 325, RT 1.08 minutes.

Intermediate 166

N-[(S)-(5-Bromo-1H-imidazo[4,5-b]pyridin-2-yl)(4-methylcyclohexyl)methyl]-2-ethyl-pyrazole-3-carboxamide (Trans Isomer)

(160) The title compound (38 mg, 92%) was prepared from Intermediate 165 (30 mg, 0.09 mmol) and 1-ethyl-1H-pyrazole-5-carboxylic acid (17 mg, 0.11 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 447, RT 1.27 minutes.

Intermediate 167

N-[(6-Bromo-4-methoxy-1H-imidazo[4,5-c]pyridin-2-yl)(cyclooctyl)methyl]-2-methyl-pyrazole-3-carboxamide

(161) To a solution of Intermediate 5 (400 mg, 1.36 mmol), Intermediate 65 (297 mg, 1.36 mmol) and DIPEA (0.36 mL, 2.1 mmol) in DMF (3 mL) was added T3P® (0.81 mL, 1.4 mmol). The reaction mixture was heated overnight at 70° C., then concentrated in vacuo, and partitioned between EtOAc and water. The organic layers were dried over Na.sub.2SO.sub.4, then the solvent was removed in vacuo. The residue was taken up in EtOH (5.4 mL) and water (0.6 mL), and NaOH (260 mg, 6.5 mmol) was added. The reaction mixture was heated at 80° C. overnight, then concentrated in vacuo, to furnish the title compound (155 mg, 61% overall). LCMS (Method 5): [M+H].sup.+ m/z 423, RT 1.36 minutes.

Intermediate 168

N-[(5-Bromo-4-fluoro-1H-benzimidazol-2-yl)(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide

(162) The title compound (82 mg, 12%) was prepared from Intermediate 7 (362 mg, 1.23 mmol) and 4-bromo-3-fluorobenzene-1,2-diamine (251 mg, 1.18 mmol) in accordance with Procedure Y. LCMS (Method 5): [M+H].sup.+ m/z 465, RT 1.45 minutes.

Intermediate 169

tert-Butyl 4-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)piperidine-1-carboxylate

(163) The title compound (463 mg, 75%) was prepared from Intermediate 7 (444 mg, 1.51 mmol) and Intermediate 74 (476 mg, 1.51 mmol) in accordance with Procedure Y. LCMS (Method 5): [M+H].sup.+ m/z 568, RT 1.65 minutes.

Intermediate 170

O.SUP.1.-tert-Butyl O.SUP.3.-ethyl 4-{2-[(S)-benzyloxycarbonylamino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}pyrrolidine-1,3-dicarboxylate (Trans Isomer)

(164) The title compound (220 mg, quantitative) was prepared from trans-(2S)-2-(benzyloxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (125 mg, 0.33 mmol) and Intermediate 98 (162 mg, 0.44 mmol) in accordance with Procedure AA. LCMS (Method 5): [M+H].sup.+ m/z 637, RT 1.56 minutes.

Intermediate 171

tert-Butyl 3-{2-[(S)-benzyloxycarbonylamino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4-(dimethylcarbamoyl)pyrrolidine-1-carboxylate (Trans Isomer)

(165) To a solution of LiOH.H.sub.2O (10 mg, 0.42 mmol) in water (0.5 mL) was added Intermediate 170 (220 mg, 0.35 mmol) in EtOH (2 mL). The reaction mixture was stirred for 8 h, then concentrated in vacuo. The residue was suspended in DCM (3 mL), and HATU (165 mg, 0.42 mmol), DIPEA (0.35 mL, 46.8 mmol) and a 2M solution of dimethylamine in THF (0.35 mL, 0.7 mmol) were added. The mixture was stirred under N.sub.2 for 4 days, then partitioned between DCM and water. The organic layers were separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was flashed down an SCX column, eluting with a 7N solution of NH.sub.3 in MeOH, to give the title compound (153 mg, 69%). LCMS (Method 5): [M+H].sup.+ m/z 636.4, RT 1.44 minutes.

Intermediate 172

tert-Butyl 3-(dimethylcarbamoyl)-4-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-1-carboxylate (Trans Isomer)

(166) To a solution of Intermediate 171 (153 mg, 0.24 mmol) in EtOH at r.t. was added 10% Pd/C (20 mg). The reaction mixture was stirred under an atmosphere of hydrogen for 2 h, then filtered through Celite®, washing with EtOAc. The filtrate was concentrated in vacuo. The residue was taken up in DCM (2 mL), and HATU (110 mg, 0.28 mmol), 3-ethylisoxazole-4-carboxylic acid (42 mg, 0.28 mmol) and DIPEA (80 μL, 0.5 mmol) were added. The reaction mixture was stirred at r.t. overnight, then partitioned between DCM and water. The organic layers were dried over Na.sub.2SO.sub.4, then concentrated in vacuo, to yield the crude title compound (205 mg. 60% overall). LCMS (Method 5): [M+H].sup.+ m/z 625, RT 1.37 minutes.

Intermediate 173

tert-Butyl 4-[(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-1H-benzimidazol-5-yl)methyl]piperazine-1-carboxylate

(167) The title compound (94 mg, 20%) was prepared from Intermediate 7 (240 mg, 0.82 mmol) and Intermediate 67 (248 mg, 0.81 mmol) in accordance with Procedure Y. LCMS (Method 5): [M+H].sup.+ m/z 565, RT 1.49 minutes.

Intermediate 174

N-{Cyclooctyl[5-(piperazin-1-ylmethyl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(168) The title compound (80 mg, quantitative) was prepared from Intermediate 173 (94 mg, 0.17 mmol) in accordance with Procedure P. LCMS (Method 5): [M+H].sup.+ m/z 465, RT 1.09 minutes.

Intermediate 175

tert-Butyl 4-[(2-{cyclooctyl[(2-methylpyrazole-3-carbonyl)amino]methyl}-4-methoxy-1H-imidazo[4,5-c]pyridin-6-yl)methyl]piperazine-1-carboxylate

(169) The title compound (122 mg, quantitative) was prepared from Intermediate 167 (98 mg, 0.21 mmol) in accordance with Procedure R. LCMS (Method 5): [M+H].sup.+ m/z 595, RT 1.42 minutes.

Intermediate 176

N-{Cyclooctyl[4-methoxy-6-(piperazin-1-ylmethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-methyl}-2-methylpyrazole-3-carboxamide

(170) The title compound (100 mg, quantitative) was prepared from Intermediate 175 (122 mg, 0.21 mmol) in accordance with Procedure P. LCMS (Method 5): [M+H].sup.+ m/z 495, RT 1.25 minutes.

Intermediate 177

2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazole-5-carbonitrile (Trans Isomer)

(171) The title compound (157 mg, 97%) was prepared from trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (1 g, 3.69 mmol) and 3,4-diamino-2-fluorobenzonitrile (585 mg, 3.87 mmol) in accordance with Procedure X. LCMS (Method 5): [M+H].sup.+ m/z 287, RT 1.13 minutes.

Intermediate 178

tert-Butyl 4-[(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-7-methoxy-3H-benzimidazol-5-yl)methyl]piperazine-1-carboxylate

(172) The title compound (33 mg, 16%) was prepared from Intermediate 7 (103 mg, 0.35 mmol) and Intermediate 69 (117 mg, 0.35 mmol) in accordance with Procedure Y. LCMS (Method 5): [M+H].sup.+ m/z 595, RT 1.47 minutes.

Intermediate 179

N-{Cyclooctyl[4-methoxy-6-(piperazin-1-ylmethyl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(173) The title compound (25 mg, 93%) was prepared from Intermediate 178 (33 mg, 0.05 mmol) in accordance with Procedure P. LCMS (Method 5): [M+H].sup.+ m/z 495, RT 1.17 minutes.

Intermediate 180

tert-Butyl 4-[(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)methyl]piperidine-1-carboxylate

(174) The title compound (45 mg, 16%) was prepared from Intermediate 7 (67 mg, 0.23 mmol) and Intermediate 58 (70 mg, 0.22 mmol) in accordance with Procedure Y. LCMS (Method 5): [M+H].sup.+ m/z 582, RT 1.56 minutes.

Intermediate 181

N-{Cyclooctyl[4-fluoro-5-(piperidin-4-ylmethyl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(175) The title compound (19 mg, 59%) was prepared from Intermediate 180 (45 mg, 0.03 mmol) in accordance with Procedure P. LCMS (Method 5): [M+H].sup.+ m/z 482, RT 1.17 minutes.

Intermediate 182

tert-Butyl 4-[(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-7-fluoro-3H-benzimidazol-5-yl)methyl]piperidine-1-carboxylate

(176) The title compound (277 mg, 24%) was prepared from Intermediate 7 (423 mg, 1.44 mmol) and Intermediate 94 (443 mg, 1.37 mmol) in accordance with Procedure Y. LCMS (Method 5): [M+H].sup.+ m/z 582, RT 1.68 minutes.

Intermediate 183

N-{Cyclooctyl[4-fluoro-6-(piperidin-4-ylmethyl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(177) The title compound (210 mg, quantitative) was prepared from Intermediate 182 (255 mg, 0.44 mmol) in accordance with Procedure P. LCMS (Method 5): [M+H].sup.+ m/z 482, RT 1.20 minutes.

Intermediate 184

N-[(6-Bromo-4-fluoro-1H-benzimidazol-2-yl)(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide

(178) The title compound (220 mg, 46%) was synthesized from Intermediate 7 (300 mg, 0.99 mmol) and 5-bromo-3-fluorobenzene-1,2-diamine (210 mg, 1.03 mmol) in accordance with Procedure Y. LCMS (Method 5): [M+H].sup.+ m/z 463, RT 2.61 minutes.

Intermediate 185

Methyl (2S)-1-({2-[(S)-amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}methyl)pyrrolidine-2-carboxylate (Trans Isomer)

(179) The title compound (127 mg, 57%), an off white powder, was prepared from Intermediate 113 (221 mg, 0.55 mmol) and trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (181 mg, 0.67 mmol) in accordance with Procedure X. LCMS (Method 1): [M+H].sup.+ m/z 403, RT 1.39 minutes.

Intermediate 186

Methyl (2R)-1-({2-[(S)-amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}methyl)pyrrolidine-2-carboxylate (Trans Isomer)

(180) The title compound (125 mg, 62%), a tan gum, was prepared from Intermediate 114 (220 mg, 0.50 mmol) and trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methyl-cyclohexyl)acetic acid (163 mg, 0.50 mmol) in accordance with Procedure X. LCMS (Method 1): [M+H].sup.+ m/z 403, RT 1.40 minutes.

Intermediate 187 (Procedure BB)

(NE)-N-(Cycloheptylmethylene)-2-methylpropane-2-sulfinamide

(181) To a solution of cycloheptane carbaldehyde (170 mg, 1.35 mmol) in DCM (2 mL) at r.t. were added 2-methylpropane-2-sulfinamide (1.35 mmol), MgSO.sub.4 (6 mmol) and pyridinium p-toluenesulfonate (0.07 mmol) sequentially. The reaction mixture was stirred for 16 h, then filtered. The filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography, eluting with EtOAc/hexanes (0-50% gradient), gave the title compound (134 mg, 43%) as a colourless oil. LCMS (Method 5): [M+H].sup.+ m/z 230, RT 1.53 minutes.

Intermediate 188

(NE)-N-(Cyclohexylmethylene)-2-methylpropane-2-sulfinamide

(182) The title compound (740 mg, 86%) was prepared from cyclohexane carbaldehyde (0.50 mL, 4.00 mmol) in accordance with Procedure BB. LCMS (Method 5): [M+H].sup.+ m/z 216, RT 1.37 minutes.

Intermediate 189

(NE)-N-(Dispiro[2.0.24.13]heptan-7-ylmethylene)-2-methylpropane-2-sulfinamide

(183) The title compound (189 mg, 53%) was prepared from dispiro[2.0.24.13]heptane-7-carbaldehyde (192 mg, 1.57 mmol) in accordance with Procedure BB. LCMS (Method 5): [M+H].sup.+ m/z 226, RT 1.33 minutes.

Intermediate 190

(NE)-2-Methyl-N-(norcaran-3-ylmethylene)propane-2-sulfinamide

(184) The title compound (254 mg, 77%) was prepared from norcarane-3-carbaldehyde (179 mg, 1.44 mmol) in accordance with Procedure BB. LCMS (Method 5): [M+H].sup.+ m/z 228, RT 1.44 minutes.

Intermediate 191

(NE)-2-Methyl-N-[(3-methylcyclohexyl)methylene]propane-2-sulfinamide

(185) The title compound (666 mg, 73%) was prepared from 3-methylcyclohexane carbaldehyde (500 mg, 3.96 mmol) in accordance with Procedure BB. LCMS (Method 5): [M+H].sup.+ m/z 230, RT 1.53 minutes.

Intermediate 192

(NE)-2-Methyl-N-(norcaran-7-ylmethylene)propane-2-sulfinamide

(186) The title compound (332 mg, 91%) was prepared from rac-(1S,6R)-norcarane-7-carbaldehyde (200 mg, 1.61 mmol) in accordance with Procedure BB. LCMS (Method 5): [M+H].sup.+ m/z 228, RT 1.35 minutes.

Intermediate 193

(NE)-2-Methyl-N-[(2-methylcyclohexyl)methylene]propane-2-sulfinamide

(187) The title compound (391 mg, 43%) was prepared from 2-methylcyclohexane carbaldehyde (500 mg, 3.96 mmol) in accordance with Procedure BB. LCMS (Method 5): [M+H].sup.+ m/z 230, RT 1.50 minutes.

Intermediate 194

(NE)-N-[(3,5-Dimethylcyclohexyl)methylene]-2-methylpropane-2-sulfinamide

(188) The title compound (395 mg, 48%) was prepared from 3,5-dimethylcyclohexane carbaldehyde (470 mg, 3.35 mmol) in accordance with Procedure BB. LCMS (Method 5): [M+H].sup.+ m/z 244, RT 1.54 and 1.56 minutes (observable diastereomer separation).

Intermediate 195

2-{[7-Fluoro-6-(tetrahydropyran-4-yl)benzimidazol-1-yl]methoxy}ethyl(trimethyl)silane

(189) A solution of Intermediate 24 (1 g, 4.75 mmol) in formic acid (24 mL) was heated at 110° C. overnight. The reaction mixture was cooled, then concentrated in vacuo. The residue was dissolved in EtOAc (30 mL). The organic layers were washed with saturated aqueous NaHCO.sub.3 solution (30 mL), dried over MgSO.sub.4, and concentrated in vacuo. The crude residue was purified by flash column chromatography, eluting with EtOAc (100%) then MeOH/DCM (gradient 0-10%). NaH (60% by mass, 185 mg, 4.64 mmol) was suspended in DMF (8 mL), and the purified solid was added as a solution in DMF (8 mL) dropwise over 10 minutes. After a further 90 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (0.82 mL, 4.6 mmol) was added dropwise over 10 minutes. The mixture was stirred at r.t. overnight. Water (50 mL) was added, and the mixture was extracted with EtOAc (100 mL). The organic layers were separated, dried over MgSO.sub.4, and concentrated in vacuo. The crude residue was purified by flash chromatography, eluting with EtOAc/hexanes (30-80% gradient), to furnish the title compound (1.34 g, 80%) as a colourless oil. LCMS (Method 5): [M+H].sup.+ m/z 351, RT 1.45 minutes.

Intermediate 196

Methyl 1-(3,4-diamino-2-fluorophenyl)piperidine-3-carboxylate

(190) The title compound (299 mg, 79%) was prepared from 2,3-difluoro-6-nitroaniline (250 mg, 1.40 mmol) and methyl piperidine-3-carboxylate (425 mg, 2.82 mmol) in accordance with Procedure M. LCMS (Method 5): [M+H].sup.+ m/z 268, RT 0.90 minutes.

Intermediate 197

6-Fluoro-N.SUP.4.-(tetrahydropyran-4-yl)benzene-1,2,4-triamine

(191) The title compound (132 mg, 84%) was prepared from Intermediate 28 (300 mg, 0.70 mmol) and tetrahydropyran-4-amine (110 mg, 1.03 mmol) in accordance with Procedure J. LCMS (Method 5): [M+H].sup.+ m/z 226, RT 0.59 minutes.

Intermediate 198

3-Bromo-N,N-dimethylpyrazine-2-carboxamide

(192) The title compound (548 mg, 70%) was prepared from 3-bromopyrazine-2-carboxylic acid (502 mg, 2.47 mmol) and a 2M solution of dimethylamine in THF (2.5 mL, 5.0 mmol) in accordance with Procedure A, with DCM (5 mL) as solvent. LCMS (Method 5): [M+H].sup.+ m/z 230, RT 0.30 minutes.

Intermediate 199

3-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N,N-dimethylpyrazine-2-carboxamide (Trans Isomer)

(193) The title compound (41 mg, 44%) was prepared from Intermediate 139 (103 mg, 0.21 mmol) and Intermediate 198 (109 mg, 0.35 mmol) in a sequential fashion in accordance with Procedures G and Z. LCMS (Method 5): [M+H].sup.+ m/z 411, RT 0.98

Intermediate 200

5-{2-[(S)-(tert-Butoxycarbonylamino)(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-2-methylpyrimidine-4-carboxylic Acid (Trans Isomer)

(194) The title compound (82 mg, 80%) was prepared from Intermediate 139 (100 mg, 0.21 mmol) and 5-bromo-2-methylpyrimidine-4-carboxylic acid (58 mg, 0.27 mmol) in accordance with Procedure G. LCMS (Method 5): [M+H].sup.+ m/z 498, RT 1.02 minutes.

Intermediate 201

tert-Butyl N-[(S)-{5-[4-(dimethylcarbamoyl)-2-methylpyrimidin-5-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]carbamate (Trans Isomer)

(195) The title compound (6.4 mg, 7%) was prepared from Intermediate 200 (82 mg, 0.16 mmol) and a 2M solution of dimethylamine in THF (0.17 mL, 0.34 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 525, RT 1.24 minutes.

Intermediate 202

5-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N,N,2-trimethylpyrimidine-4-carboxamide (Trans Isomer)

(196) The title compound (5.6 mg, quantitative) was prepared from Intermediate 201 (6.4 mg, 0.012 mmol) in accordance with Procedure Z. LCMS (Method 5): [M+H].sup.+ m/z 425, RT 1.00 minute.

Intermediate 203

(3-Bromopyridin-4-yl)(3,3-difluoroazetidin-1-yl)methanone

(197) The title compound (384 mg, 55%) was prepared from 3-bromopyridine-4-carboxylic acid (523 mg, 2.50 mmol) and 3,3-difluroazetidine hydrochloride (679 mg, 5.24 mmol) in accordance with Procedure A, with DCM (5 mL) as solvent. LCMS (Method 5): [M+H].sup.+ m/z 277, RT 0.75 minutes.

Intermediate 204

(3-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}pyridin-4-yl)(3,3-difluoroazetidin-1-yl)methanone (Trans Isomer)

(198) The title compound (24 mg, 49%) was prepared from Intermediate 139 (51 mg, 0.10 mmol) and Intermediate 203 (32 mg, 0.12 mmol) in a sequential fashion in accordance with Procedures G and Z. LCMS (Method 5): [M+H].sup.+ m/z 458, RT 1.07 minutes.

Intermediate 205

(3-Bromopyridin-4-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone

(199) The title compound (148 mg, 23%) was prepared from 3-bromopyridine-4-carboxylic acid (523 mg, 2.50 mmol) and 3-methylazetidin-3-ol hydrochloride (661 mg, 5.08 mmol) in accordance with Procedure A, with DCM (5 mL) as solvent. LCMS (Method 5): [M+H].sup.+ m/z 273, RT 0.31 minutes.

Intermediate 206

(3-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}pyridin-4-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone (Trans Isomer)

(200) The title compound (42 mg, 86%) was prepared from Intermediate 139 (51 mg, 0.10 mmol) and Intermediate 205 (48 mg, 0.18 mmol) in a sequential fashion in accordance with Procedures G and Z. LCMS (Method 5): [M+H].sup.+ m/z 452, RT 0.95 minutes.

Intermediate 207

Azetidin-1-yl(3-bromopyridin-4-yl)methanone

(201) The title compound (302 mg, 52%) was prepared from 3-bromopyridine-4-carboxylic acid (523 mg, 2.50 mmol) and azetidine (0.24 mL, 3.60 mmol) in accordance with Procedure A, with DCM (5 mL) as solvent. LCMS (Method 5): [M+H].sup.+ m/z 241, RT 0.59 minutes.

Intermediates 208 & 209

(3-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}pyridin-4-yl)(azetidin-1-yl)methanone (trans isomer) (Intermediate 208)

3-{2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N-(3-chloropropyl)pyridine-4-carboxamide (trans isomer) (Intermediate 209)

(202) Intermediate 139 (101 mg, 0.21 mmol), 1,4-dioxane (3 mL), water (0.5 mL), K.sub.2CO.sub.3 (100 mg, 0.72 mmol) and Intermediate 207 (111 mg, 0.46 mmol) were sparged with N.sub.2 for 5 minutes, then Pd(dppf)Cl.sub.2.DCM (13 mg, 0.02 mmol) was added. The reaction mixture was further sparged with N.sub.2 for 5 minutes, then heated at 110° C. in a PLS synthesiser overnight. The reaction mixture was cooled to r.t. and water (5 mL) was added, followed by DCM (10 mL). The mixture was filtered through a phase separation frit, washing further with DCM. The organic phase was concentrated in vacuo. The residue was purified by flash column chromatography, eluting with EtOAc/hexanes (0-100% gradient) then MeOH/DCM (0-20% gradient). The recovered material was taken up in DCM (5 mL) and treated with 4M HCl in dioxane (1 mL). The reaction mixture was stirred for 4 h, then concentrated in vacuo, to provide the title compounds (85 mg). LCMS confirmed that the product was a mixture of Intermediate 208 and Intermediate 209 in a ratio of 85:11 respectively. LCMS (Method 5): [M+H].sup.+ m/z 422, RT 0.99 minutes (Intermediate 208); and [M+H].sup.+ m/z 458, RT 1.05 minutes (Intermediate 209).

Intermediate 210

(S)-{4-Fluoro-5-[4-(methylsulfanyl)pyridin-3-yl]-1H-benzimidazol-2-yl}(4-methyl-cyclohexyl)methanamine (Trans Isomer)

(203) The title compound (82 mg, 68%) was prepared from Intermediate 139 (150 mg, 0.31 mmol) and 3-bromo-4-(methylthio)pyridine (65 mg, 0.32 mmol) in a sequential fashion in accordance with Procedures G and Z. LCMS (Method 5): [M+H].sup.+ m/z 385, RT 1.14 minutes.

Intermediate 211

3-Ethyl-N-[(S)-{4-fluoro-5-[4-(methylsulfanyl)pyridin-3-yl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]isoxazole-4-carboxamide (Trans Isomer)

(204) The title compound (109 mg, quantitative) was prepared from Intermediate 210 (82 mg, 0.21 mmol) and 3-ethylisoxazole-4-carboxylic acid (40 mg, 0.27 mmol) in accordance with Procedure A, with DCM (5 mL) as solvent. LCMS (Method 5): [M+H].sup.+ m/z 508, RT 1.31 minutes.

Intermediate 212

3-(2-{(S)-[(2-Ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-1H-imidazo[4,5-b]pyridin-5-yl)pyridine-4-carboxylic Acid (Trans Isomer)

(205) The title compound (93 mg, 42%) was prepared from Intermediate 166 (204 mg, 0.46 mmol) and 3-boronoisonicotinic acid (102 mg, 0.55 mmol) in accordance with Procedure G. LCMS (Method 5): [M+H].sup.+ m/z 488, RT 0.91 minutes.

Intermediate 213

N-[(S)-(5-Bromo-1H-imidazo[4,5-b]pyridin-2-yl)(4-methylcyclohexyl)methyl]-2-methyl-pyrazole-3-carboxamide (Trans Isomer)

(206) The title compound (612 mg, 65%) was prepared from Intermediate 165 (707 mg, 2.19 mmol) and 1-methyl-1H-pyrazole-5-carboxylic acid (350 mg, 2.64 mmol) in accordance with Procedure A, with DCM (5 mL) as solvent. LCMS (Method 5): [M+H].sup.+ m/z 431, RT 1.18 minutes.

Intermediate 214

Methyl 4-(2-{(S)-(4-methylcyclohexyl)[(2-methylpyrazole-3-carbonyl)amino]methyl}-1H-imidazo[4,5-b]pyridin-5-yl)furan-3-carboxylate (Trans Isomer)

(207) The title compound (124 mg, 55%) was prepared from Intermediate 213 (204 mg, 0.47 mmol) and 4-(methoxycarbonyl)furan-3-boronic acid pinacol ester (150 mg, 0.58 mmol) in accordance with Procedure G. LCMS (Method 5): [M+H].sup.+ m/z 477, RT 1.25 minutes.

Intermediate 215

4-(2-{(S)-(4-Methylcyclohexyl)[(2-methylpyrazole-3-carbonyl)amino]methyl}-1H-imidazo[4,5-b]pyridin-5-yl)furan-3-carboxylic Acid (Trans Isomer)

(208) A solution of LiOH.H.sub.2O (10 mg, 0.42 mmol) in water (0.5 mL) was added to a solution of Intermediate 214 (124 mg, 0.26 mmol) in EtOH (2 mL). The mixture was stirred at r.t. for 3.5 h, then concentrated in vacuo, to give the title compound (120 mg, quantitative). LCMS (Method 5): [M+H].sup.+ m/z 463, RT 0.95 minutes.

Intermediate 216

tert-Butyl 3-{2-[(S)-amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-morpholine-4-carboxylate (Trans Isomer)

(209) To a solution of Intermediate 155 (1.15 g, 1.72 mmol) in acetonitrile (24 mL) at r.t. was added diethylamine (6 mL, 57.95 mmol). The mixture was stirred overnight, then concentrated in vacuo. The residue was filtered through an SCX column, washing with MeOH before eluting with a 7N solution of NH.sub.3 in MeOH. The washings were concentrated in vacuo and purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient) then MeOH/DCM (0-10% gradient), to give the title compound (608 mg, 79%) as a foam. LCMS (Method 5): [M+H].sup.+ m/z 447, RT 1.26 minutes.

Intermediate 217

Methyl 4-{2-[(S)-(tert-butoxycarbonylamino)(cyclopentyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydrofuran-3-carboxylate

(210) The title compound (272 mg, 41%) was prepared from Intermediate 96 (321 mg, 1.26 mmol) and (2S)-2-(tert-butoxycarbonylamino)-2-cyclopentylacetic acid (310 mg, 1.21 mmol) in accordance with Procedure AA. LCMS (Method 5): [M+H].sup.+ m/z 462, RT 1.20 minutes.

Intermediate 218

4-{2-[(S)-(tert-Butoxycarbonylamino)(cyclopentyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydrofuran-3-carboxylic Acid

(211) A solution of LiOH.H.sub.2O (20 mg, 0.84 mmol) in water (0.5 mL) was added to a solution of Intermediate 217 (318 mg, 0.69 mmol) in EtOH (2 mL). The mixture was stirred at r.t. for 3.5 h, then concentrated in vacuo, to give the title compound (309 mg, quantitative). LCMS (Method 5): [M+H].sup.+ m/z 448, RT 0.89 minutes.

Intermediate 219

Methyl 4-{2-[(S)-amino(cyclopentyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-tetrahydrofuran-3-carboxylate

(212) The title compound (194 mg, quantitative) was prepared from Intermediate 217 (271 mg, 0.52 mmol) in accordance with Procedure Z. LCMS (Method 5): [M+H].sup.+ m/z 362, RT 0.94 minutes.

Intermediate 220

Methyl 4-(2-{(S)-cyclopentyl[(3-ethylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)tetrahydrofuran-3-carboxylate

(213) The title compound (229 mg, 88%) was prepared from Intermediate 219 (194 mg, 0.54 mmol) and 3-ethylisoxazole-4-carboxylic acid (100 mg, 0.67 mmol) in accordance with Procedure A, with DCM (5 mL) as solvent. LCMS (Method 5): [M+H].sup.+ m/z 485, RT 1.14 minutes.

Intermediate 221

4-(2-{(S)-Cyclopentyl[(3-ethylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)tetrahydrofuran-3-carboxylic acid

(214) A solution of LiOH.H.sub.2O (15 mg, 0.63 mmol) in water (0.5 mL) was added to a solution of Intermediate 220 (229 mg, 0.47 mmol) in EtOH (2 mL). The mixture was stirred at r.t. for 3.5 h, then concentrated in vacuo, to give the title compound (222 mg, quantitative). LCMS (Method 5): [M+H].sup.+ m/z 471, RT 0.87 minutes.

Intermediate 222

(4-{2-[(S)-Amino(cyclopentyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydrofuran-3-yl)(3,3-difluoroazetidin-1-yl)methanone

(215) The title compound (234 mg, 80%) was prepared from Intermediate 218 (309 mg, 0.69 mmol) and 3,3-difluoroazetidine hydrochloride (145 mg, 1.40 mmol) in a sequential manner in accordance with Procedures A and Z. LCMS (Method 5): [M+H].sup.+ m/z 423, RT 0.93 minutes.

Intermediate 223

(S)-(5-Bromo-4-fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methanamine (Trans Isomer)

(216) The title compound (3.9 g, quantitative) was prepared from Intermediate 138 (3.8 g, 8.7 mmol) in accordance with Procedure Z. LCMS (Method 5): [M+H].sup.+ m/z 342, RT 1.27 minutes.

Intermediate 224

N-[(S)-(5-Bromo-4-fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methyl]-2-methyl-pyrazole-3-carboxamide (Trans Isomer)

(217) The title compound (4.6 g, 61%) was prepared from Intermediate 223 (5.7 g, 16.7 mmol) and 1-methyl-1H-pyrazole-5-carboxylic acid (2.65 g, 19.9 mmol) in accordance with Procedure A, using DCM as solvent. LCMS (Method 5): [M+H].sup.+ m/z 451, RT 1.36

Intermediate 225

N-{(S)-[4-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-(4-methylcyclohexyl)methyl}-2-methylpyrazole-3-carboxamide (Trans Isomer)

(218) The title compound (1.77 g, 50%) was prepared from Intermediate 224 (1 g, 2.27 mmol) in accordance with Procedure C. LCMS (Method 5): [M+H].sup.+ m/z 451, RT 1.36 minutes.

Intermediate 226

(4-Bromo-1H-pyrazol-3-yl)(3,3-difluoroazetidin-1-yl)methanone

(219) The title compound (143 mg, 38.7%) was prepared from 4-bromo-1H-pyrazole-3-carboxylic acid (266 mg, 1.39 mmol) and 3,3-difluoroazetidine hydrochloride (197 mg, 1.52 mmol) in accordance with Procedure A, with DCM (5 mL) as solvent. LCMS (Method 5): [M+H].sup.+ m/z 268, RT 0.71 minutes.

Intermediate 227

(5-Bromo-2-methylpyrimidin-4-yl)(3,3-difluoroazetidin-1-yl)methanone

(220) The title compound (415 mg, 61%) was prepared from 5-bromo-2-methyl-pyrimidine-4-carboxylic acid (510 mg, 2.62 mmol) and 3,3-difluoroazetidine hydrochloride (340 mg, 2.62 mmol) in accordance with Procedure A, with DCM (5 mL) as solvent. LCMS (Method 5): [M+H].sup.+ m/z 294, RT 0.79 minutes.

Intermediate 228

(5-Bromopyrimidin-4-yl)(3,3-difluoroazetidin-1-yl)methanone

(221) The title compound (68 mg, 11%) was prepared from 5-bromopyrimidine-4-carboxylic acid (468 mg, 2.30 mmol) and 3,3-difluoroazetidine hydrochloride (354 mg, 2.73 mmol) in accordance with Procedure A, with DCM (5 mL) as solvent. LCMS (Method 5): [M+H].sup.+ m/z 280, RT 0.66 minutes.

Intermediate 229

[4-(Dimethylcarbamoyl)pyridin-3-yl]boronic Acid

(222) A 2.5M solution of n-butyllithium in hexane (6.1 mL, 15.3 mmol) was added over 10 minutes to a stirred solution of diisopropylamine (2.2 mL, 16.0 mmol) in anhydrous THF (16 mL) at −10° C. under N.sub.2. The orange solution was stirred at −10° C. for 5 minutes, then at 0° C. for 10 minutes. The resultant orange solution was added over approximately 10 minutes to a stirred solution of N,N-dimethylisonicotinamide (2.00 g, 13.3 mmol) and triisopropyl borate (4.0 mL, 17.3 mmol) in anhydrous THF (22 mL) at approximately −5° C. under N.sub.2. The mixture was stirred between −5° C. and 5° C. under nitrogen over 50 minutes. To the resulting brown suspension was added pinacol (2.36 g, 20.0 mmol), and the suspension was stirred at 20° C. under nitrogen for 1 h. The resultant canary yellow suspension was diluted with DCM (25 mL) and filtered through a Celite® pad, washing with DCM (4×25 mL). The filtrate was stood at r.t. overnight and the additional precipitated solids were removed by filtration, washing with DCM (2×30 mL). The filtrate was concentrated in vacuo. The resultant orange solid was purified by flash column chromatography, eluting with EtOAc/heptane (25-100% gradient) followed by MeOH/EtOAc (0-40% gradient), to afford the title compound (688 mg, 20%) as an orange powder. δ.sub.H (500 MHz, DMSO-d.sub.6) 8.73-8.71 (m, 1H), 8.19 (d, J 4.9 Hz, 1H), 6.84 (d, J 4.8 Hz, 1H), 2.96 (s, 3H), 2.75 (s, 3H). LCMS (Method 2): [M+H].sup.+ m/z 195, RT 0.11 minutes.

Intermediate 230

(3,3-Difluoroazetidin-1-yl)(3-methylimidazol-3-ium-1-yl)methanone Iodide

(223) To a solution of 3,3-difluoroazetidine hydrochloride (1.00 g, 10.7 mmol) in acetonitrile (10.8 mL, 205 mmol) and DMF (3.30 mL, 43.0 mmol) at r.t. was added CDI (1.98 g, 11.8 mmol) in one portion. The mixture was stirred at r.t. for 16 h, then concentrated in vacuo. The residue was purified by flash column chromatography, eluting with EtOAc/hexanes (0-100% gradient) then MeOH/DCM (0-10% gradient). The resulting yellow oil was taken up in acetonitrile (18.9 mL) at r.t., to which was added iodomethane (2.88 mL, 45.8 mmol). The mixture was stirred at r.t. over 2 days, then concentrated in vacuo, to afford the title compound (2.49 g, quantitative overall) as a yellow solid. LCMS (Method 5): [M+H].sup.+ m/z 202, RT 0.46 minutes.

Intermediate 231

Mixture of tert-butyl N-[(S)-{5-bromo-4-fluoro-1-[2-(trimethylsilyl)ethoxymethyl]-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]carbamate (trans isomer) and tert-butyl N-[(S)-{6-bromo-7-fluoro-1-[2-(trimethylsilyl)ethoxymethyl]benzimidazol-2-yl}(4-methylcyclohexyl)methyl]carbamate (Trans Isomer)

(224) 2-(Trimethylsilyl)ethoxymethyl chloride (0.11 mL, 0.62 mmol) was added to a stirred suspension of Intermediate 138 (250 mg, 0.57 mmol) and K.sub.2CO.sub.3 (196 mg, 1.42 mmol) in anhydrous DMF (5.7 mL). The reaction mixture was stirred at 20° C. under N.sub.2 for 64 h. An additional portion of 2-(trimethylsilyl)ethoxymethyl chloride (0.03 mL, 0.17 mmol) was added, and stirring continued at 20° C. under N.sub.2 for 24 h. The mixture was quenched with water (30 mL), and the resulting material was extracted with tert-butyl methyl ether (3×30 mL). The combined organic extracts were washed sequentially with water (20 mL) and brine (2×20 mL), then dried over MgSO.sub.4 and concentrated in vacuo. The resultant viscous oil was purified by flash column chromatography, eluting with EtOAc/heptane (0-20% gradient), to afford the title compounds (55:45 ratio of regio-isomers) (266 mg, 82%) as a viscous oil. LCMS (Method 1): [M+H].sup.+ m/z 570 and 572, RT 2.70 and 2.76 minutes.

Intermediate 232

Mixture of tert-butyl N-[(S)-(5-{[dimethyl(oxo)-λ.SUP.6.-sulfanylidene]amino}-4-fluoro-1-[2-(trimethylsilyl)ethoxymethyl]benzimidazol-2-yl)(4-methylcyclohexyl)methyl]carbamate (Trans Isomer) and tert-butyl N-[(S)-(6-{[dimethyl(oxo)-λ.SUP.6.-sulfanylidene]amino}-7-fluoro-1-[2-(trimethylsilyl)ethoxymethyl]benzimidazol-2-yl)(4-methylcyclohexyl)-methyl]carbamate (Trans Isomer)

(225) A sealed tube was charged with Intermediate 231 (55:45 mixture of isomers, 116 mg, 0.20 mmol), S,S-dimethylsulfoximine (38 mg, 0.41 mmol), Cs.sub.2CO.sub.3 (200 mg, 0.61 mmol), Pd.sub.2(dba).sub.3 (9.3 mg, 0.01 mmol) and RuPhos (9.5 mg, 0.02 mmol) under N.sub.2. The reagents were suspended in anhydrous 1,4-dioxane (2 mL), and the mixture was degassed by sparging with N.sub.2 whilst sonicating for 5 minutes. The reaction mixture was sealed under N.sub.2 and heated at 110° C. for 24 h. After cooling, the mixture was diluted with EtOAc (20 mL), and the solids were removed by filtration through a Celite® pad. The residue was washed with EtOAc (2×20 mL), and the filtrate was concentrated in vacuo. The resultant orange viscous oil was separated by flash column chromatography, eluting with EtOAc/heptane (0-100% gradient), to afford the title compounds (91 mg total mass, 76% overall) as tan powders. LCMS (Method 1): [M+H].sup.+ m/z 583, RT 2.22 minutes and 2.23 minutes.

Intermediate 233

tert-Butyl N-(6-chloro-5-fluoropyridin-3-yl)carbamate

(226) A dried sealed tube was charged with 5-bromo-2-chloro-3-fluoropyridine (1.00 g, 4.75 mmol), tert-butyl carbamate (612 mg, 5.22 mmol) and Cs.sub.2CO.sub.3 (3.10 g, 9.51 mmol), and the reagents were suspended in anhydrous 1,4-dioxane (9.5 mL). The mixture was sparged with N.sub.2 for 5 minutes whilst sonicating. The reaction mixture was charged with Pd.sub.2(dba).sub.3 (109 mg, 0.12 mmol) and Xantphos (137 mg, 0.24 mmol), and the mixture was sparged with N.sub.2 for 5 minutes whilst sonicating. The mixture was sealed under N.sub.2 and heated at 85° C. for 24 h. After cooling, the mixture was diluted with EtOAc (10 mL) and the solids were removed via filtration through a Celite® pad, washing with EtOAc (3×20 mL). The filtrate was concentrated in vacuo. The resultant orange viscous oil was purified by flash column chromatography, eluting with EtOAc/heptane (0-20% gradient), to afford the title compound (844 mg, 67%) as an off-white powder. δ.sub.H (500 MHz, CDCl.sub.3) 8.04 (d, J 8.7 Hz, 1H), 7.98 (d, J 2.4 Hz, 1H), 6.71 (s, 1H), 1.52 (s, 9H). LCMS (Method 1): [M+H].sup.+ m/z 247 and 249, RT 1.88 minutes.

Intermediate 234

tert-Butyl N-(6-chloro-5-fluoro-4-iodopyridin-3-yl)carbamate

(227) A 2.5 μM solution of n-butyllithium in hexanes (4.1 mL, 10.2 mmol) was added dropwise to a stirred solution of Intermediate 233 (840 mg, 3.41 mmol) and TMEDA (1.5 mL, 10.2 mmol) in anhydrous diethyl ether (17 mL) at −78° C. After 5 minutes, the light orange solution was warmed to −20° C. and stirred for 1.5 h. The resultant olive-green suspension was cooled to −78° C. and a solution of iodine (2.70 g, 10.6 mmol) in anhydrous THF (4.7 mL) was added dropwise. The mixture was allowed to warm to 20° C. over 16 h, then quenched with 1M aqueous HCl (20 mL). The material was extracted with tert-butyl methyl ether (40 mL). The organic layer was washed with 1M aqueous HCl (10 mL), and the combined aqueous washings were extracted with tert-butyl methyl ether (2×40 mL). The combined organic extracts were washed with water (30 mL), saturated aqueous Na.sub.2CO.sub.3 solution (30 mL), saturated aqueous Na.sub.2S.sub.2O.sub.3 solution (30 mL) and brine (30 mL). The organic phase was dried over MgSO.sub.4, filtered and concentrated in vacuo. The resultant light-yellow powder was purified by flash column chromatography, eluting with EtOAc/heptane (0-20% gradient), to afford the title compound (1.03 g, 81%) as an off-white powder. δ.sub.H (500 MHz, CDCl.sub.3) 8.82 (s, 1H), 6.71 (br s, 1H), 1.55 (s, 9H). LCMS (Method 1): [M+H].sup.+ m/z 373 and 375, RT 1.97 minutes.

Intermediate 235

tert-Butyl N-[4-(benzhydrylideneamino)-6-chloro-5-fluoropyridin-3-yl]carbamate

(228) A dried sealed tube was charged with Intermediate 234 (100 mg, 0.27 mmol), Cs.sub.2CO.sub.3 (262 mg, 0.81 mmol), Pd.sub.2(dba).sub.3 (12 mg, 0.01 mmol) and Xantphos (16 mg, 0.03 mmol), and the tube was evacuated and back-filled with N.sub.2 three times. The reagents were suspended in anhydrous 1,4-dioxane (1.1 mL), and 1,1-diphenylmethanimine (0.05 mL, 0.30 mmol) was added. The suspension was sparged with N.sub.2 whilst sonicating for 5 minutes. The mixture was sealed under N.sub.2 and heated at 100° C. for 24 h. After cooling to r.t., the mixture was diluted with EtOAc (10 mL) and filtered through a Celite® pad, washing with EtOAc (3×10 mL). The filtrate was concentrated in vacuo. The resultant viscous oil was purified by flash column chromatography, eluting with EtOAc/heptane (0-20% gradient), to afford the title compound (55 mg, 45%) as an orange powder. δ.sub.H (500 MHz, CDCl.sub.3) 8.89 (br s, 1H), 7.89-7.75 (m, 2H), 7.67-7.56 (m, 1H), 7.55-7.30 (m, 5H), 7.11 (d, J 7.0 Hz, 2H), 6.65 (s, 1H), 1.53 (s, 9H). LCMS (Method 1): [M+H].sup.+ m/z 426 and 428, RT 2.20 minutes.

Intermediate 236

6-Chloro-5-fluoropyridine-3,4-diamine

(229) 2M aqueous HCl (2 mL) was added to a stirred solution of Intermediate 235 (213 mg, 0.44 mmol) in anhydrous THF (2 mL). The mixture was heated at 60° C. under N.sub.2 for 5 h. After cooling to r.t., the mixture was diluted with water (10 mL) and 1M aqueous HCl (10 mL), then washed with tert-butyl methyl ether (2×20 mL). The combined organic washings were extracted with 1M aqueous HCl (20 mL). The combined aqueous extracts were treated with 5M aqueous NaOH (pH 14) and extracted with EtOAc (4×25 mL). The combined organic extracts were dried over MgSO.sub.4 and filtered, then concentrated in vacuo, to afford the title compound (56 mg, 79%) as a pale tan powder. δ.sub.H (500 MHz, CDCl.sub.3) 7.59 (s, 1H), 4.10 (br s, 2H), 3.27 (br s, 2H). LCMS (Method 1): [M+H].sup.+ m/z 162 and 164, RT 0.34 minutes.

Intermediate 237

(S)-(6-Chloro-7-fluoro-3H-imidazo[4,5-c]pyridin-2-yl)(4-methylcyclohexyl)methanamine (Trans Isomer)

(230) DIPEA (0.20 mL, 1.15 mmol) was added to a stirred suspension of Intermediate 236 (76 mg, 0.47 mmol), trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (153 mg, 0.56 mmol) and HATU (232 mg, 0.61 mmol) in anhydrous DCM (4.7 mL). The mixture was stirred at 20° C. under N.sub.2 for 40 h. Additional portions of trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (25 mg, 0.09 mmol), HATU (39 mg, 0.10 mmol) and DIPEA (0.07 mL, 0.41 mmol) were added, and stirring was continued at 20° C. under N.sub.2 for 24 h. The mixture was diluted with DCM (10 mL), and quenched with saturated aqueous Na.sub.2CO.sub.3 solution (5 mL) and water (5 mL). The biphasic mixture was stirred at 20° C. for 30 minutes, then the organic phase was separated using a hydrophobic frit. The aqueous layer was extracted with DCM (2×20 mL), and the organic filtrate was concentrated in vacuo. The resultant tan powder was dissolved in EtOH (7 mL), and K.sub.2CO.sub.3 (280 mg, 2.02 mmol) was added. The suspension was heated at 80° C. in a sealed vial for 16 h. After cooling, the mixture was diluted with water (20 mL), and the material was extracted with DCM (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO.sub.4 and concentrated in vacuo. The resultant tan viscous oil was dissolved in DCM (2 mL), and TFA (0.12 mL, 1.62 mmol) was added. The mixture was stirred at 20° C. under air for 22 h. The volatiles were removed in vacuo. The resultant brown viscous oil was dissolved in DCM (2 mL) and adsorbed onto an SCX-2 column (2 g). The column was eluted sequentially with DCM, MeOH and a 1M solution of ammonia in MeOH. The ammonia-MeOH fractions were combined, then concentrated in vacuo, to afford the title compound (53 mg, 28% overall) as a light brown viscous oil. δ.sub.H (500 MHz, CDCl.sub.3) 8.49 (s, 1H), 4.19 (d, J 5.3 Hz, 1H), 1.98-1.87 (m, 1H), 1.76-1.67 (m, 2H), 1.67-1.54 (m, 2H), 1.32-1.07 (m, 3H), 0.99-0.87 (m, 2H), 0.85 (d, J 6.5 Hz, 3H). LCMS (Method 1): [M+H].sup.+ m/z 297 and 299, RT 1.60 minutes.

Intermediate 238

tert-Butyl N-[(S)-(2-chloro-7H-purin-8-yl)(4-methylcyclohexyl)methyl]carbamate (Trans Isomer)

(231) DIPEA (0.35 mL, 2.03 mmol) was added to a stirred suspension of 2-chloro-4,5-diaminopyrimidine (100 mg, 0.69 mmol), trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (271 mg, 0.99 mmol) and HATU (410 mg, 1.08 mmol) in DCM (5 mL) at 20° C. The reaction mixture was stirred at 20° C. for 18 h, then diluted with DCM (15 mL) and washed with saturated aqueous NaHCO.sub.3 solution (10 mL). The organic layer was filtered through a hydrophobic frit, and the solvent was concentrated in vacuo. The resulting dark brown oil was dissolved in EtOH (10 mL), and K.sub.2CO.sub.3 (398 mg, 2.88 mmol) was added. The suspension was heated at 80° C. in a sealed vial for 40 h. After cooling, the mixture was diluted with water (10 mL), and the aqueous layer was extracted with DCM (3×15 mL). The combined organic extracts were filtered through a hydrophobic frit, and the solvent was concentrated in vacuo. The resultant dark brown oil was separated by flash column chromatography, eluting with EtOAc/heptane (0-50% gradient), to afford the title compound (80 mg, 30%) as a yellow oil that slowly solidified on standing. δ.sub.H (250 MHz, CDCl.sub.3) 11.73 (br s, 1H), 8.90 (s, 1H), 5.87-5.64 (m, 1H), 4.74-4.62 (m, 1H), 1.75-1.68 (m, 4H), 1.41 (s, 9H), 1.28-1.04 (m, 6H), 0.88-0.84 (m, 3H). LCMS (Method 10): [M+H].sup.+ m/z 380 and 382, RT 1.18 minutes.

Intermediate 239

(S)-(2-Chloro-7H-purin-8-yl)(4-methylcyclohexyl)methanamine (Trans Isomer)

(232) TFA (0.31 mL, 4.23 mmol) was added to a stirred solution of Intermediate 238 (80 mg, 0.19 mmol) in DCM (4 mL) at 20° C. The reaction mixture was stirred at 20° C. for 2 h, then diluted with DCM (11 mL) and quenched with saturated aqueous NaHCO.sub.3 solution (10 mL). The biphasic mixture was stirred at 20° C. for 15 minutes, then the organic layer was separated using a hydrophobic frit. The aqueous layer was extracted with 4:1 CHCl.sub.3/isopropanol (2×30 mL). The combined organic extracts were filtered through a hydrophobic frit, then the solvent was concentrated in vacuo, to afford the title compound (43 mg, 78%) as a pale brown solid. LCMS (Method 10): [M+H].sup.+ m/z 280 and 282, RT 0.81 minutes.

Intermediate 240

N-[(S)-(2-Chloro-7H-purin-8-yl)(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer)

(233) DIPEA (65 μL, 0.37 mmol) was added to a stirred suspension of Intermediate 239 (43 mg, 0.15 mmol), 1-ethylpyrazole-4-carboxylic acid (31 mg, 0.22 mmol) and HATU (91 mg, 0.24 mmol) in DCM (2 mL) at 20° C. The reaction mixture was stirred at 20° C. for 24 h, then diluted with DCM (5 mL) and washed with saturated aqueous NaHCO.sub.3 solution (5 mL). The organic layer was filtered through a hydrophobic frit, and the solvent was concentrated in vacuo. The resulting dark yellow oil was separated by flash column chromatography, eluting with EtOAc/heptane (0-100% gradient), to afford the title compound (52 mg, 62%) as a yellow solid. LCMS (Method 10): [M+H].sup.+ m/z 402 and 404, RT 1.09 minutes.

Intermediate 241

N-[(5-Bromo-1H-imidazo[4,5-b]pyrazin-2-yl)(4-methylcyclohexyl)methyl]-2-ethyl-pyrazole-3-carboxamide (Trans Isomer)

(234) A sealed tube was charged with Intermediate 125 (509 mg, 1.73 mmol) in DCM (5 mL), and EDC.HCl (333 mg, 1.73 mmol) was added at 20° C. The reaction mixture was stirred at 20° C. for 3 h. The solvent was removed under a flow of N.sub.2. The residue was dissolved in THF (5 mL), and 5-bromopyrazine-2,3-diamine (183 mg, 0.97 mmol) was added. The reaction mixture was sealed and stirred at 80° C. for 60 h. The reaction mixture was re-treated twice with 5-bromopyrazine-2,3-diamine (91.6 mg, 0.485 mmol) whilst stirring at 80° C. for an additional 48 h. After cooling, the reaction mixture was diluted with saturated aqueous NaHCO.sub.3 solution (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with saturated aqueous NaHCO.sub.3 solution (20 mL) and brine (2×20 mL), then dried over Na.sub.2SO.sub.4. The solvent was concentrated in vacuo. The resulting brown solid was dissolved in EtOH (25 mL), and K.sub.2CO.sub.3 (688 mg, 4.98 mmol) was added. The reaction mixture was heated at 80° C. in a sealed vial for 6 h. After cooling, the solvent was concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with 4:1 CHCl.sub.3/isopropanol (2×30 mL). The combined organic extracts were washed with brine (20 mL) and dried over Na.sub.2SO.sub.4. The solvent was concentrated in vacuo. The reddish-brown solid was purified by flash column chromatography, eluting with EtOAc/heptane (0-100% gradient), to afford the title compound (116 mg, 15% overall) as a beige solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 3.77 (s, 1H), 9.04-8.78 (m, 1H), 8.60-8.42 (m, 1H), 7.49 (d, J 2.0 Hz, 1H), 7.04 (d, J 2.0 Hz, 1H), 5.02 (t, J 8.2 Hz, 1H), 4.42 (q, J 7.1 Hz, 2H), 2.15-2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.76-1.57 (m, 2H), 1.45-1.33 (m, 1H), 1.31-1.20 (m, 1H), 1.24 (t, J 7.1 Hz, 3H), 1.17-1.03 (m, 2H), 0.95-0.78 (m, 5H). LCMS (Method 10): [M+H].sup.+ m/z 446 and 448, RT 1.15 minutes.

Intermediate 242

tert-Butyl N-[3-Bromo-6-(tert-butoxycarbonylamino)-2-fluorophenyl]carbamate

(235) Di-tert-butyl dicarbonate (1.33 g, 6.09 mmol) was added to a stirred solution of 4-bromo-3-fluorobenzene-1,2-diamine (500 mg, 2.44 mmol) in tert-butanol (24 mL). The mixture was stirred at 20° C. under N.sub.2 for a total of 122 h, and at 50° C. for a further 96 h, re-treating twice with di-tert-butyl dicarbonate (0.5 g, 2.29 mmol). The volatiles were removed in vacuo. The resultant brown viscous oil was separated by flash column chromatography, eluting with EtOAc/heptane (0-30% gradient), to afford the title compound (675 mg, 63%) as an off-white powder. δ.sub.H (500 MHz, DMSO-d.sub.6) 8.55 (br s, 1H), 8.46 (br s, 1H), 7.52-7.46 (m, 2H), 1.47 (s, 9H), 1.43 (s, 9H). LCMS (Method 1): [M+Na].sup.+ m/z 427 and 429, RT 2.09 minutes.

Intermediate 243

tert-Butyl N-{2-(tert-butoxycarbonylamino)-3-fluoro-4-[(2-oxopyrrolidin-1-yl)methyl]-phenyl}carbamate

(236) 2-tert-Butyl-1,1,3,3-tetramethylguanidine (0.15 mL, 0.74 mmol) was added to a solution of Intermediate 242 (100 mg, 0.25 mmol), (2-oxopyrrolidin-1-yl)acetic acid (106 mg, 0.74 mmol), {Ir[dF(CF.sub.3)ppy]2(dtbpy)}PF.sub.6 (2.8 mg, 0.025 mmol), dichloronickel, 1,2-dimethoxyethane (5.4 mg, 0.024 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridyl (10 mg, 0.037 mmol) in anhydrous DMF (12 mL). The mixture was sparged with N.sub.2 whilst sonicating for 10 minutes. The mixture was sealed under N.sub.2 and irradiated with a 40W blue LED lamp whilst stirring for 24 h at approximately 21° C. The mixture was diluted with water (20 mL), and the material was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with saturated aqueous Na.sub.2CO.sub.3 solution (20 mL), 1M aqueous HCl (20 mL) and brine (2×20 mL), then dried over MgSO.sub.4 and concentrated in vacuo. The resultant brown viscous oil was purified by flash column chromatography, eluting with EtOAc/heptane (20-100% gradient), to afford the title compound (28 mg, 24%) as an orange viscous oil. δ.sub.H (500 MHz, CDCl.sub.3) 7.59 (d, J 8.3 Hz, 1H), 7.34 (br s, 1H), 7.12 (t, J 8.3 Hz, 1H), 6.23 (br s, 1H), 4.47 (s, 2H), 3.27 (t, J 7.1 Hz, 2H), 2.40 (t, J 8.1 Hz, 2H), 2.02-1.92 (m, 2H), 1.51 (s, 9H), 1.50 (s, 9H). LCMS (Method 10): [M+H].sup.+ m/z 424, RT 1.86 minutes.

Intermediate 244

1-[(3,4-Diamino-2-fluorophenyl)methyl]pyrrolidin-2-one

(237) 4M HCl in 1,4-dioxane (0.6 mL, 2.4 mmol) was added to a stirred solution of Intermediate 243 (100 mg, 0.24 mmol) in DCM (2.4 mL) at 20° C. under N.sub.2. The solution was stirred at 20° C. for 26 h, re-treating once with 4M HCl in 1,4-dioxane (0.3 mL, 1.2 mmol). The volatiles were removed in vacuo, to afford the title compound (59 mg, 96%) as a light cream powder (assumed to be an HCl salt of indeterminate stoichiometry). δ.sub.H (500 MHz, DMSO-d.sub.6) 6.85 (d, J 8.2 Hz, 1H), 6.55 (app. t, J 7.9 Hz, 1H), 4.33 (s, 2H), 3.24-3.20 (obs. m, 2H), 2.25 (t, J 8.1 Hz, 2H), 1.91 (p, J 7.5 Hz, 2H). LCMS (Method 10): [M+H].sup.+ m/z 224, RT 0.47 minutes.

Intermediate 245

tert-Butyl N-[(S)-{4-fluoro-5-[(2-oxopyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]carbamate (Trans Isomer)

(238) The title compound (55 mg, 53%) was prepared from trans-(2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (75 mg, 0.28 mmol) and Intermediate 244 (59 mg, 0.23 mmol) in accordance with Procedure Y. LCMS (Method 1): [M+H].sup.+ m/z 459, RT 1.90 minutes.

Intermediate 246

1-({2-[(S)-Amino(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}methyl)-pyrrolidin-2-one (Trans Isomer)

(239) TFA (0.10 mL, 1.35 mmol) was added to a stirred solution of Intermediate 245 (55 mg, 0.12 mmol) in DCM (1.2 mL). The mixture was stirred at 20° C. under air for 16 h, then quenched with saturated aqueous Na.sub.2CO.sub.3 solution (10 mL). The material was extracted with DCM (3×10 mL), using a hydrophobic frit to separate the phases. The organic filtrate was concentrated in vacuo to afford the title compound (40 mg, 84%) as a tan viscous oil. δ.sub.H (500 MHz, CDCl.sub.3) 10.86 (br s, 1H), 7.22 (br s, 1H), 7.12-7.06 (m, 1H), 4.62 (s, 2H), 4.10 (d, J 5.7 Hz, 1H), 3.32 (t, J 7.1 Hz, 2H), 2.40 (t, J 8.1 Hz, 2H), 1.96 (p, J 7.6 Hz, 2H), 1.91-1.80 (m, 1H), 1.76-1.52 (m, 3H), 1.34-1.07 (m, 4H), 0.94-0.79 (m, 5H). LCMS (Method 1): [M+H].sup.+ m/z 359, RT 1.54 minutes.

Intermediate 247

N-[(S)-(5-Bromo-4-fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methyl]-2-ethyl-pyrazole-3-carboxamide (Trans Isomer)

(240) The title compound (1.9 g, 81.2%) was prepared from Intermediate 223 (1.7 g, 4.5 mmol) and 1-ethyl-1H-pyrazole-5-carboxylic acid (714.5 mg, 5.1 mmol) in accordance with Procedure A, using DCM as solvent. LCMS (Method 5): [M+H].sup.+ m/z 462.0 and 464.0, RT 1.39 minutes.

Intermediate 248

2-Ethyl-N-{(S)-[4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl](4-methylcyclohexyl)methyl}pyrazole-3-carboxamide (Trans Isomer)

(241) The title compound (765.2 mg, 70%) was prepared from Intermediate 247 (1 g, 2.2 mmol) in accordance with Procedure C. LCMS (Method 5): [M+H].sup.+ m/z 510.2, RT 1.45 minutes.

Intermediate 249

O.SUP.1.-tert-Butyl O.SUP.3.-ethyl 4-(2-{(S)-[(2-ethylpyrazole-3-carbonyl)amino](4-methyl-cyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)-2,5-dihydropyrrole-1,3-dicarboxylate (Trans Isomer)

(242) The title compound (553 mg, 44%) was prepared from O.sup.1-tert-butyl O.sup.3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (550 mg, 2.03 mmol) and Intermediate 248 (765 mg, 1.50 mmol) according to Procedure T. LCMS (Method 5): [M+H].sup.+ m/z 623.2, RT 1.52 minutes.

Intermediate 250

Mixture of N-[(S)-(5-bromo-4-fluoro-1-methylbenzimidazol-2-yl)(4-methylcyclohexyl)-methyl]-2-methylpyrazole-3-carboxamide (trans isomer) and N-[(S)-(6-bromo-7-fluoro-1-methylbenzimidazol-2-yl)(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide (Trans Isomer)

(243) To Intermediate 224 (500 mg, 1.11 mmol) and sodium carbonate (130 mg, 1.23 mmol) in DMF (5 mL) was added iodomethane (237 mg, 1.67 mmol). The mixture was stirred at r.t. for 24 h, then diluted with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by chromatography (silica, gradient of 0-65% EtOAc in isohexanes) to afford the mixture of title compounds (150 mg, 29%) as a white solid, which was utilised without separation. LCMS (pH 10): [M+H].sup.+ m/z 462/464 (Br isotopes), RT 2.37 and 2.45 minutes (˜1:1).

Example 1

(244) ##STR00012##

N-[Cyclooctyl(4-methoxy-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(245) The title compound (2 mg, 7%), a white solid, was prepared from Intermediate 8 (30 mg, 0.09 mmol) in accordance with Procedure B. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.21 (s, 1H), 9.38 (d, J 0.6 Hz, 1H), 8.39 (s, 1H), 7.04 (m, 2H), 6.64 (s, 1H), 5.13 (d, J 7.7 Hz, 1H), 3.94 (s, 3H), 2.48-2.32 (m, 4H), 1.96-1.08 (m, 14H). LCMS (Method 7): [M+H].sup.+, 100%, m/z 397, RT 2.20 minutes. LCMS (Method 6): [M+H].sup.+, 100%, m/z 397, RT 1.92 minutes.

Example 2

(246) ##STR00013##

N-[Cyclooctyl(4-fluoro-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(247) The title compound (29 mg, 3%), a white solid, was prepared from Intermediate 9 (133.9 mg, 0.33 mmol) in accordance with Procedure B. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.80 (s, 1H), 9.45 (s, 1H), 8.85 (d, J 8.2 Hz, 1H), 7.31 (d, J 6.7 Hz, 1H), 7.14 (td, J 8.0, 5.0 Hz, 1H), 6.96 (t, J 9.4 Hz, 1H), 5.12 (t, J 8.7 Hz, 1H), 2.47-2.29 (m, 4H), 1.78-1.26 (m, 14H). LC-MS (Method 7): [M−H].sup.−, 100%, m/z 383, RT 2.28 minutes. LCMS (Method 6): [M−H].sup.−, 100%, m/z 383, RT 2.26 minutes.

Example 3

(248) ##STR00014##

N-{Cyclooctyl[4-fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(249) The title compound (20.5 mg, 34%), a beige solid, was prepared from Intermediate 10 (160 mg, 0.13 mmol) in accordance with Procedure B. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.61 (s, 1H), 9.43 (d, J 0.7 Hz, 1H), 9.00-8.56 (m, 1H), 7.44-6.92 (m, 2H), 5.24-4.96 (m, 1H), 4.15-3.85 (m, 2H), 3.61-3.42 (m, 2H), 3.24-3.10 (m, 1H), 2.44-2.25 (m, 4H), 1.93-1.14 (m, 18H). LCMS (Method 7): [M+H].sup.+ m/z 469, RT 2.34 minutes.

Example 4

(250) ##STR00015##

N-{Cyclooctyl[4-fluoro-5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(251) The title compound (23 mg, 17%), a white solid, was prepared from Intermediate 11 (89 mg, 0.12 mmol) in accordance with Procedure B. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.11-12.17 (m, 1H), 9.43 (s, 1H), 8.98-8.55 (m, 1H), 7.41-7.07 (m, 1H), 7.04-6.82 (m, 1H), 5.17-4.96 (m, 1H), 3.08-2.89 (m, 4H), 2.50-2.43 (m, 4H), 2.43-2.30 (m, 4H), 2.23 (s, 3H), 1.82-1.16 (m, 14H). LCMS (Method 7): [M+H].sup.+ m/z 483, RT 2.08 minutes.

Example 5

(252) ##STR00016##

N-[Cyclooctyl(4,7-difluoro-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(253) The title compound (7 mg, 18%), a white solid, was prepared from Intermediate 12 (40 mg, 0.10 mmol) in accordance with Procedure B. δ.sub.H (300 MHz, DMSO-d.sub.6) 13.39 (s, 1H), 9.45 (d, J 0.6 Hz, 1H), 8.87 (d, J 9.0 Hz, 1H), 7.15-6.82 (m, 2H), 5.13 (t, J 8.8 Hz, 1H), 2.48-2.25 (m, 4H), 1.86-1.11 (m, 14H). LC-MS (method 7): [M−H].sup.−, 100%, m/z 401.2, RT 2.38 minutes. LCMS (Method 6): [M−H].sup.− m/z 401, RT 2.40 minutes.

Example 6

(254) ##STR00017##

tert-Butyl N-[cyclooctyl(4-fluoro-1H-benzimidazol-2-yl)methyl]carbamate

(255) The title compound (13.9 mg, 1%), a white solid, was prepared from Intermediate 13 (2.99 g, 7.60 mmol) in accordance with Procedure B. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.28 (s, 1H), 7.31 (s, 1H), 7.12 (td, J 8.0, 4.9 Hz, 1H), 6.93 (t, J 9.2 Hz, 1H), 6.78 (s, 1H), 4.69-4.61 (m, 1H), 2.19 (d, J 7.3 Hz, 1H), 1.97-0.95 (m, 23H). LCMS (Method 6): [M−H].sup.− m/z 374, RT 2.51 minutes.

Example 7

(256) ##STR00018##

N-[Cyclooctyl(4-fluoro-1H-benzimidazol-2-yl)methyl]-5-methyl-1-(tetrahydropyran-4-yl)pyrazole-4-carboxamide

(257) The title compound (17.5 mg, 10%), a white solid, was prepared from Intermediate 14 (100 mg, 0.36 mmol) and 5-methyl--(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid (85 mg, 0.38 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6, T=350 K) 12.42 (s, 1H), 8.04 (s, 1H), 7.94 (d, J 7.7 Hz, 1H), 7.31 (d, J 7.2 Hz, 1H), 7.12 (td, J 8.0, 4.9 Hz, 1H), 6.92 (dd, J 10.8, 8.1 Hz, 1H), 5.16 (t, J 8.6 Hz, 1H), 4.42 (tt, J 11.2, 4.3 Hz, 1H), 3.97 (dtd, J 11.6, 4.8, 1.5 Hz, 2H), 3.60-3.39 (m, 2H), 2.53 (s, 3H), 2.47-2.32 (m, 1H), 2.30-0.77 (m, 18H). LCMS (Method 7): [M+H].sup.+ m/z 468, RT 2.20 minutes. LCMS (Method 6): [M−H].sup.− m/z 466, RT 2.15 minutes.

Example 8

(258) ##STR00019##

N-[(4-Fluoro-1H-benzimidazol-2-yl)(trans-4-methylcyclohexyl)methyl]-3-methyl-isoxazole-4-carboxamide

(259) The title compound (28 mg, 15%) a white solid, was prepared from Intermediate 18 (130 mg, 0.50 mmol) and 3-methylisoxazole-4-carboxylic acid (70 mg, 0.52 mmol) in accordance with Procedure A. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.63 (s, 1H), 9.45 (d, J 0.7 Hz, 1H), 8.85 (d, J 8.4 Hz, 1H), 7.30 (s, 1H), 7.14 (td, J 8.0, 5.0 Hz, 1H), 7.04-6.87 (m, 1H), 5.04 (t, J 8.5 Hz, 1H), 2.36 (s, 3H), 2.10-1.80 (m, 2H), 1.78-1.55 (m, 2H), 1.44-1.26 (m, 2H), 1.19-0.77 (m, 7H). LCMS (Method 7): [M+H].sup.+ m/z 371, RT 2.62 minutes. LCMS (Method 6): [M+H].sup.+ m/z 371, RT 2.61 minutes.

Example 9

(260) ##STR00020##

N-[(4-Chloro-1H-benzimidazol-2-yl)(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide

(261) The title compound (15 mg, 6%), a white solid, was prepared from Intermediate 19 (264 mg, 0.63 mmol) in accordance with Procedure B. δ.sub.H (300 MHz, DMSO-d.sub.6) 13.15-12.50 (m, 1H), 9.66-9.28 (m, 1H), 9.13-8.65 (m, 1H), 7.59-7.32 (m, 1H), 7.28-7.04 (m, 2H), 5.32-4.93 (m, 1H), 2.46-2.22 (m, 4H), 1.83-1.24 (m, 14H). LCMS (Method 7): [M+H].sup.+ m/z 401, RT 2.39 minutes. LCMS (Method 6): [M−H].sup.− m/z 399, RT 2.35 minutes.

Example 10

(262) ##STR00021##

N-[Cyclooctyl(4-fluoro-1H-benzimidazol-2-yl)methyl]-2-methylpyrazole-3-carboxamide

(263) The title compound (26 mg, 54%), a white solid, was prepared from Intermediate 20 (50 mg, 0.125 mmol) in accordance with Procedure B. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.72 (br s, 1H), 8.90 (d, J 8.8 Hz, 1H), 7.46 (d, J 2.0 Hz, 1H), 7.30 (d, J 7.8 Hz, 1H), 7.12-7.17 (m, 1H), 7.07 (d, J 2.0 Hz, 1H), 6.92-6.97 (m, 1H), 5.05-5.15 (m, 1H), 4.02 (s, 3H), 1.21-1.71 (m, 15H). LCMS (Method 10): [M+H].sup.+ m/z 384, RT 2.83 minutes.

Example 11

(264) ##STR00022##

N-[Cyclooctyl(4-methoxy-1H-imidazolo[4,5-c]pyridin-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(265) HATU (310 mg, 0.82 mmol) was added to a stirred suspension of 2-methoxy-pyridine-3,4-diamine (104 mg, 0.75 mmol), Intermediate 7 (200 mg, 0.68 mmol) and DIPEA (0.17 mL, 1.03 mmol) in anhydrous DMF (4 mL). The mixture was stirred at 20° C. under N.sub.2 for 22 h, then saturated aqueous NaHCO.sub.3 solution (50 mL), water (50 mL) and EtOAc (50 mL) were added. The layers were separated, then the aqueous phase was further extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (2×50 mL) and dried over MgSO.sub.4, then filtered and concentrated in vacuo. The crude residue was taken up in AcOH (4 mL) and heated at 100° C. for 18 h. Upon cooling to r.t., water (30 mL) was added, followed by 4M aqueous NaOH solution (40 mL). The mixture was extracted with EtOAc (3×40 mL) and the combined organic extracts were dried over MgSO.sub.4, then filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (2.3 mg, 1%) as a pale yellow solid. δ.sub.H (250 MHz, 353K, DMSO-d.sub.6) 9.37 (s, 1H), 8.48 (br s, 1H), 7.80 (d, J 5.7 Hz, 1H), 7.12 (d, J 5.7 Hz, 1H), 6.15 (br s, 1H), 5.36-5.02 (m, 1H), 4.02 (s, 3H), 2.44-2.27 (m, 4H), 1.98-1.12 (m, 14H). LCMS (Method 2): [M+H].sup.+ m/z 398, RT 2.93 minutes.

Example 12

(266) ##STR00023##

N-[Cyclooctyl(4-fluoro-5-methoxy-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(267) The title compound (38 mg, 18%), a white solid, was prepared from Intermediate 7 (150 mg, 0.51 mmol) and 3-fluoro-4-methoxybenzene-1,2-diamine (57 mg, 0.34 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.59 (s, 1H), 9.43 (s, 1H), 8.81 (s, 1H), 7.22 (s, 1H), 7.05 (t, J 8.2 Hz, 1H), 5.08 (t, J 8.6 Hz, 1H), 3.85 (s, 3H), 2.41-2.28 (m, 4H), 1.86-1.15 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 415, RT 2.22 minutes.

Example 13

(268) ##STR00024##

N-[(4-Cyano-1H-benzimidazol-2-yl)(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide

(269) The title compound (7 mg, 1%), a white solid, was prepared from Intermediate 7 (412 mg, 1.4 mmol) and 2,3-diaminobenzonitrile (196 mg, 1.4 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 13.04 (s, 1H), 9.43 (d, J 0.7 Hz, 1H), 8.90 (d, J 8.6 Hz, 1H), 7.81 (d, J 8.0 Hz, 1H), 7.63 (d, J 7.5 Hz, 1H), 7.30 (t, J 7.8 Hz, 1H), 5.12 (t, J 8.7 Hz, 1H), 2.47-2.39 (m, 1H), 2.36 (s, 3H), 1.75-1.26 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 392, RT 2.21 minutes.

Example 14

(270) ##STR00025##

N-{Cyclooctyl[5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(271) The title compound (30 mg, 27%), a light brown solid, was prepared from Intermediate 7 (198 mg, 0.67 mmol) and 4-(tetrahydropyran-4-yl)benzene-1,2-diamine (129 mg, 0.67 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.27 (s, 1H), 9.43 (d, J 0.7 Hz, 1H), 8.74 (d, J 8.8 Hz, 1H), 7.53-7.22 (m, 2H), 7.06 (d, J 8.2 Hz, 1H), 5.08 (t, J 8.6 Hz, 1H), 4.01-3.91 (m, 2H), 3.53-3.38 (m, 2H), 2.84 (s, 1H), 2.44-2.30 (m, 4H), 1.77-1.10 (m, 18H). LCMS (Method 6): [M+H].sup.+ m/z 451, RT 2.24 minutes.

Example 15

(272) ##STR00026##

N-{Cyclooctyl[4-fluoro-5-(1H-pyrazol-5-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(273) The title compound (20 mg, 25%), a white solid, was prepared from Intermediate 7 (123 mg, 0.42 mmol) and Intermediate 29 (80 mg, 0.42 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 3.40-12.05 (m, 2H), 9.45 (s, 1H), 8.97-8.71 (m, 1H), 7.87-7.54 (m, 2H), 7.43-7.25 (m, 1H), 6.70-6.57 (m, 1H), 5.20-5.04 (m, 1H), 2.44-2.22 (m, 4H), 1.88-1.02 (m, 14H). LCMS (Method 6): [M+H].sup.+, m/z 451, RT 2.07 minutes.

Example 16

(274) ##STR00027##

N-{[5-(Benzenesulfinyl)-4-fluoro-1H-benzimidazol-2-yl](cyclooctyl)methyl}-3-methyl-isoxazole-4-carboxamide

(275) The title compound (1:1 mixture of diastereomers) (2 mg, 3%), a white solid, was prepared from Intermediate 7 (49 mg, 0.17 mmol) and Intermediate 30 (40 mg, 0.16 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.36 (s, 1H), 9.44 (s, 1H), 8.70 (s, 1H), 7.68-7.61 (m, 2H), 7.57-7.46 (m, 3H), 7.43-7.36 (m, 1H), 7.32-7.18 (m, 1H), 5.08 (t, J 8.6 Hz, 1H), 2.36 (m, 4H), 2.05-0.88 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 509, RT 2.45 minutes.

Example 17

(276) ##STR00028##

tert-Butyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)acetate

(277) The title compound (43 mg, 18%), a white solid, was prepared from Intermediate 7 (150 mg, 0.51 mmol) and Intermediate 31 (116 mg, 0.49 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.69 (s, 1H), 9.43 (d, J 0.7 Hz, 1H), 8.82 (s, 1H), 7.33-7.15 (m, 1H), 7.13-6.98 (m, 1H), 5.10 (t, J 8.7 Hz, 1H), 3.67 (s, 2H), 2.37 (m, 4H), 1.85-1.11 (m, 14H), 1.40 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 499, RT 2.90 minutes.

Examples 18 & 19

(278) ##STR00029##

tert-Butyl rel-(2S)-2-(4-acetylpiperazin-1-yl)-2-(4-fluoro-2-{rel-(S)-cyclooctyl[(3-methyl-isoxazole-4-carbonyl)amino]methyl}-1H-benzimidazol-5-yl)acetate (Example 18) tert-Butyl rel-(2R)-2-(4-acetylpiperazin-1-yl)-2-(4-fluoro-2-{rel-(R)-cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-1H-benzimidazol-5-yl)acetate (Example 19)

(279) To a solution of Example 17 (40 mg, 0.08 mmol) in CHCl.sub.3 (1 mL) were added AIBN (2 mg, 0.01 mmol) and NBS (15 mg, 0.08 mmol) under N.sub.2. The reaction mixture was heated at reflux temperature overnight, then further aliquots of AIBN (2 mg) and NBS (15 mg) were added. The mixture was heated at reflux temperature for a further 6 h, then cooled and concentrated in vacuo. The residue was taken up in acetonitrile (1 mL). DIPEA (18 μL, 0.10 mmol) and 1-acetylpiperazine (14 mg, 0.11 mmol) were added, and the mixture was stirred at r.t. overnight. Further aliquots of DIPEA (18 μL, 0.10 mmol) and 1-acetylpiperazine (14 mg, 0.11 mmol) were added, and the mixture was stirred at r.t. for 24 h, then concentrated in vacuo. The residue was subject to reverse-phase HPLC, to yield the title compounds (Peak 1, 0.5 mg, 1%: and Peak 2, 1 mg, 2%) as white solids.

(280) Peak 1 (diastereomer 1): δ.sub.H (400 MHz, CD.sub.3OD) 9.18 (d, J 0.7 Hz, 1H), 7.38-7.32 (m, 2H), 5.15 (d, J 8.1 Hz, 1H), 4.51 (s, 1H), 3.60-3.51 (m, 4H), 2.57-2.47 (m, 4H), 2.44-2.36 (m, 4H), 2.05 (s, 3H), 1.76-1.44 (m, 14H), 1.38 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 625, RT 2.29 minutes.

(281) Peak 2 (diastereomer 2): δ.sub.H (400 MHz, CD.sub.3OD) 9.20 (d, J 0.7 Hz, 1H), 7.41-7.33 (m, 2H), 5.17 (d, J 8.2 Hz, 1H), 4.53 (s, 1H), 3.62-3.53 (m, 4H), 2.58-2.48 (m, 4H), 2.47-2.40 (m, 4H), 2.06 (s, 3H), 1.80-1.46 (m, 14H), 1.41 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 625, RT 2.33 minutes.

Example 20

(282) ##STR00030##

tert-Butyl 3-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)propanoate

(283) The title compound (210 mg, 210%), a white solid, was prepared from Intermediate 7 (591 mg, 2.01 mmol) and Intermediate 32 (486 mg, 1.91 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.88-12.63 (m, 1H), 9.44 (s, 1H), 8.86-8.73 (m, 1H), 7.32-7.20 (m, 1H), 7.05 (t, J 7.3 Hz, 1H), 5.12-5.08 (t, J 8.8 Hz, 1H), 2.98-2.87 (m, 2H), 2.56-2.46 (m, 2H), 2.36 (m, 4H), 1.77-1.21 (m, 14H), 1.34 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 513, RT 2.74 minutes.

Example 21

(284) ##STR00031##

tert-Butyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)benzoate

(285) The title compound (63 mg, 12%), a white solid, was prepared from Intermediate 7 (279 mg, 0.95 mmol) and Intermediate 33 (300 mg, 0.90 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.06-12.81 (s, 1H), 9.44 (s, 1H), 8.92-8.77 (m, 1H), 7.31 (d, J 7.7 Hz, 1H), 7.68-7.59 (i, 1H), 7.55-7.47 (m, 1H), 7.41 (d, J 7.7 Hz, 1H), 7.35 (d, J 8.2 Hz, 1H), 7.11-7.02 (m, 1H), 5.16-5.09 (m, 1H), 2.45-2.34 (m, 4H), 1.81-1.17 (m, 14H), 1.07 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 561, RT 2.86 minutes.

Example 22

(286) ##STR00032##

N-{Cyclooctyl[4-(cyclopentoxy)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(287) The title compound (26 mg, 14%), an off-white solid, was prepared from Intermediate 7 (125 mg, 0.43 mmol) and Intermediate 35 (82 mg, 0.43 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.39 (s, 1H), 9.42 (s, 1H), 8.99-8.50 (m, 1H), 7.31-6.88 (m, 2H), 6.80-6.52 (m, 1H), 5.24-4.82 (m, 2H), 2.40-2.19 (m, 4H), 2.07-1.14 (m, 22H). LCMS (Method 6): [M+H].sup.+ m/z 451, RT 2.75 minutes.

Example 23

(288) ##STR00033##

N-{Cyclooctyl[7-methoxy-6-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(289) The title compound (33.7 mg, 27%), an off-white solid, was prepared from Intermediate 7 (75 mg, 0.26 mmol) and Intermediate 36 (56 mg, 0.25 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.70-12.06 (m, 1H), 9.60-9.30 (m, 1H), 8.88-8.54 (m, 1H), 7.38-6.90 (m, 2H), 5.22-4.95 (m, 1H), 4.20 (s, 2H), 4.08-3.77 (m, 3H), 3.54-3.39 (m, 2H), 3.28-3.15 (m, 1H), 2.37 (d, J 3.4 Hz, 4H), 1.86-1.17 (m, 18H). LCMS (Method 6): [M+H].sup.+ m/z 481, RT 2.34 minutes.

Example 24

(290) ##STR00034##

N-{Cyclooctyl[4-fluoro-7-methoxy-5-(tetrahydroyran-4-yl)-1H-benzimidazol-2-yl]-methyl}-3-methylisoxazole-4-carboxamide

(291) The title compound (5 mg, 4%), a white solid, was prepared from Intermediate 7 (70 mg, 0.24 mmol) and Intermediate 38 (63 mg, 0.26 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.87 (s, 1H), 9.45 (s, 1H), 8.79 (s, 1H), 6.60 (s, 1H), 5.27-4.99 (m, 1H), 4.07-3.82 (m, 5H), 3.55-3.41 (m, 2H), 3.23-3.08 (m, 1H), 2.39-2.24 (m, 4H), 1.96-1.78 (m, 2H), 1.77-1.37 (m, 14H), 1.31-1.22 (m, 2H). LCMS (Method 6): [M+H].sup.+ m/z 499, RT 2.43 minutes.

Example 25

(292) ##STR00035##

N-{Cyclooctyl[4-fluoro-6-(morpholin-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(293) The title compound (mixture of diastereomers) (2 mg, 2%), a white solid, was prepared from Intermediate 7 (70 mg, 0.24 mmol) and Intermediate 39 (50 mg, 0.24 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, CD.sub.3OD) 9.18 (s, 1H), 6.89-6.67 (m, 2H), 5.11 (d, J 8.1 Hz, 1H), 3.88-3.82 (m, 4H), 3.17-3.10 (m, 4H), 2.50-2.33 (m, 4H), 1.80-1.42 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 470, RT 2.18 minutes.

Example 26

(294) ##STR00036##

N-[{5-[Cyano(pyridin-3-yl)methyl]-4-fluoro-1H-benzimidazol-2-yl}(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide

(295) The title compound (mixture of diastereomers) (2 mg, 2%), a white solid, was prepared from Intermediate 7 (59 mg, 0.20 mmol) and Intermediate 40 (46 mg, 0.19 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 9.42 (s, 1H), 8.92-8.73 (m, 1H), 8.63 (d, J 2.4 Hz, 1H), 8.56 (dd, J 4.8, 1.6 Hz, 1H), 7.81 (d, J 8.1 Hz, 1H), 7.52-7.34 (m, 2H), 7.28 (t, J 7.4 Hz, 1H), 6.17 (s, 1H), 5.08 (t, J 8.7 Hz, 1H), 2.40-2.32 (m, 4H), 1.76-1.25 (m, 16H). LCMS (Method 6): [M+H].sup.+ m/z 501, RT 2.32 minutes.

Example 27

(296) ##STR00037##

N-(Cyclooctyl{4-fluoro-5-[1-(pyridin-4-yl)ethyl]-1H-benzimidazol-2-yl}methyl)-2-methylpyrazole-3-carboxamide

(297) The title compound (mixture of diastereomers) (14 mg, 10%), a white solid, was prepared from Intermediate 5 (90 mg, 0.30 mmol) and Intermediate 42 (70 mg, 0.30 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.71 (s, 1H), 8.88 (s, 1H), 8.61-8.28 (m, 2H), 7.45 (dt, J 2.1, 1.1 Hz, 1H), 7.37-7.19 (m, 3H), 7.15-7.08 (m, 1H), 7.06 (d, J 2.1 Hz, 1H), 5.06 (t, J 8.8 Hz, 1H), 4.53 (q, J 7.3 Hz, 1H), 4.02 (d, J 0.7 Hz, 3H), 2.47-2.38 (m, 1H), 1.69-1.23 (m, 17H). LCMS (Method 6): [M+H].sup.+ m/z 489, RT 2.42 minutes.

Example 28

(298) ##STR00038##

N-[Cyclooctyl(4-fluoro-5-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(299) The title compound (56 mg, 20%), a white solid, was prepared from Intermediate 7 (145 mg, 0.49 mmol) and Intermediate 43 (149 mg, 0.49 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.99-12.60 (m, 1H), 9.43 (s, 1H), 8.91-8.71 (m, 1H), 7.38-7.15 (m, 1H), 7.06 (t, J 8.0 Hz, 1H), 5.06 (t, J 8.8 Hz, 1H), 4.41-4.31 (m, 1H), 3.37 (ddd, J 11.5, 7.4, 3.7 Hz, 2H), 3.09 (ddd, J 11.7, 7.8, 3.6 Hz, 2H), 2.90 (s, 3H), 2.46-2.30 (m, 4H), 2.02-1.91 (m, 2H), 1.86-1.11 (m, 16H). LCMS (Method 6): [M+H].sup.+ m/z 562, RT 2.42 minutes.

Example 29

(300) ##STR00039##

N-{Cyclooctyl[4-fluoro-5-(morpholin-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(301) The title compound (33 mg, 21%), a beige solid, was prepared from Intermediate 7 (139 mg, 0.47 mmol) and Intermediate 44 (100 mg, 0.47 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.03-12.31 (m, 1H), 9.43 (d, J 0.7 Hz, 1H), 8.97-8.61 (m, 1H), 7.40-7.12 (m, 1H), 7.05-6.81 (m, 1H), 5.22-4.95 (m, 1H), 3.88-3.65 (m, 4H), 3.10-2.87 (m, 4H), 2.42-2.23 (m, 4H), 1.86-1.15 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 470, RT 2.17 minutes.

Example 30

(302) ##STR00040##

tert-Butyl 6-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-3,4-dihydro-2H-pyridine-1-carboxylate

(303) The title compound (16 mg, 12%), a white solid, was prepared from Intermediate 7 (70.4 mg, 0.24 mmol) and Intermediate 45 (70 mg, 0.23 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.91-12.66 (m, 1H), 9.46-9.44 (m, 1H), 8.90-8.74 (m, 1H), 7.21 (d, J 8.3 Hz, 1H), 7.21 (dd, J 8.3 Hz, 1H), 5.28-5.22 (m, 1H), 5.14-5.07 (m, 1H), 3.74-3.65 (m, 1H), 3.65-3.57 (m, 1H), 2.36 (m, 4H), 2.30-2.21 (m, 2H), 1.85-1.76 (m, 2H), 1.75-1.17 (m, 14H), 0.88 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 566, RT 3.02 minutes.

Example 31

(304) ##STR00041##

tert-Butyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)piperidine-1-carboxylate

(305) The title compound (1:1 mixture of diastereomers) (2.6 mg, 3%), a white solid, was prepared from Intermediate 7 (50 mg, 0.17 mmol) and Intermediate 46 (50 mg, 0.16 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.70 (s, 1H), 9.45 (s, 1H), 8.77 (s, 1H), 7.33-7.09 (m, 1H), 7.03-6.77 (m, 1H), 5.49-5.43 (m, 1H), 5.12-5.02 (m, 1H), 4.02-3.94 (m, 1H), 3.14 (t, J 12.7 Hz, 1H), 2.37 (m, 4H), 2.10-2.00 (m, 1H), 1.91-1.79 (m, 1H), 1.79-1.19 (m, 18H), 1.28 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 568, RT 2.88 minutes.

Example 32

(306) ##STR00042##

N-[Cyclooctyl(4-fluoro-5-{[1-(methylsulfonyl)piperidin-4-yl]amino}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(307) The title compound (636 mg, 95%), a white solid, was prepared from Intermediate 7 (350 mg, 1.2 mmol) and Intermediate 49 (360 mg, 1.2 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.53-12.24 (m, 1H), 9.44 (d, J 0.6 Hz, 1H), 8.88-8.60 (m, 1H), 7.25-7.03 (m, 1H), 6.77 (t, J 7.6 Hz, 1H), 5.11-4.97 (m, 1H), 4.91-4.57 (m, 1H), 3.56 (d, J 12.0 Hz, 2H), 3.48-3.36 (m, 1H), 2.97-2.70 (m, 5H), 2.45-2.22 (m, 4H), 1.97 (d, J 11.4 Hz, 2H), 1.80-1.20 (m, 16H). LCMS (Method 6): [M+H].sup.+ m/z 561, RT 2.31 minutes.

Example 33

(308) ##STR00043##

tert-Butyl 4-[(2-{cyclooctyl[(2-methylpyrazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)methyl]piperazine-1-carboxylate

(309) The title compound (510 mg, 55%), a white solid, was prepared from Intermediate 5 (475 mg, 1.6 mmol) and Intermediate 50 (522 mg, 1.6 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.69 (s, 1H), 8.91 (d, J 8.4 Hz, 1H), 7.45 (d, J 2.1 Hz, 1H), 7.24 (d, J 8.2 Hz, 1H), 7.14 (t, J 7.2 Hz, 1H), 7.06 (s, 1H), 5.06 (t, J 9.0 Hz, 1H), 4.02 (d, J 2.1 Hz, 3H), 3.60 (s, 2H), 3.28 (s, 4H), 2.33 (s, 4H), 1.74-1.27 (m, 24H). LCMS (Method 6): [M+H].sup.+ m/z 582, RT 2.72 minutes.

Example 34

(310) ##STR00044##

N-[Cyclooctyl(4,7-difluoro-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(311) The title compound (26 mg, 16%), a white solid, was prepared from Intermediate 7 (85 mg, 0.29 mmol) and Intermediate 53 (92 mg, 0.29 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 13.32 (s, 1H), 9.43 (d, J 0.7 Hz, 1H), 8.84 (d, J 8.6 Hz, 1H), 6.98 (s, 1H), 5.10 (t, J 8.7 Hz, 1H), 3.64 (s, 2H), 3.08 (d, J 5.3 Hz, 4H), 2.85 (s, 3H), 2.50-2.47 (m, 4H), 2.44-2.25 (m, 4H), 1.81-1.21 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 579, RT 2.25 minutes.

Example 35

(312) ##STR00045##

N-[Cyclooctyl(4,7-difluoro-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-2-ethylpyrazole-3-carboxamide

(313) The title compound (70 mg, 14%), a white solid, was prepared from Intermediate 124 (272 mg, 0.88 mmol) and Intermediate 53 (275 mg, 0.86 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 13.32 (s, 1H), 8.90-8.86 (m, 1H), 7.47 (d, J 2.0 Hz, 1H), 7.02 (d, J 2.1 Hz, 1H), 6.97 (s, 1H), 5.09 (t, J 9.0 Hz, 1H), 4.45 (q, J 7.1 Hz, 2H), 3.64 (s, 2H), 3.08 (d, J 5.3 Hz, 4H), 2.85 (s, 3H), 2.52-2.36 (m, 5H), 1.76-1.22 (m, 17H). LCMS (Method 6): [M+H].sup.+ m/z 592, RT 2.31 minutes.

Examples 36 & 37

(314) ##STR00046##

N-[(S)-Cyclooctyl(4,7-difluoro-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-2-ethylpyrazole-3-carboxamide (Example 36)

N-[(R)-Cyclooctyl(4,7-difluoro-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-2-ethylpyrazole-3-carboxamide (Example 37)

(315) Example 35 (70 mg) was subject to chiral HPLC (Waters Prep 100-SQD2 equipped with a CHIRALCEL OJ-H 20×250 mm, 5 μm column), flow rate 5 mL/min, eluting with MeOH (+0.1% NH.sub.4OH) and water (gradient of 5-15%), to yield, after freeze-drying, the title compounds (Peak 1, 19 mg, 27%; and Peak 2, 20 mg, 29%) as white solids.

(316) Peak 1: δ.sub.H (300 MHz, DMSO-d.sub.6) 13.35 (s, 1H), 8.90 (d, J 8.8 Hz, 1H), 7.47 (d, J 2.0 Hz, 1H), 7.03 (d, J 2.1 Hz, 1H), 6.98 (s, 1H), 5.10 (t, J 8.9 Hz, 1H), 4.45 (q, J 7.1 Hz, 2H), 3.64 (s, 2H), 3.09 (t, J 4.8 Hz, 4H), 2.85 (s, 3H), 2.50-2.36 (m, 5H), 1.74-1.22 (m, 17H). LCMS (Method 6): [M+H].sup.+ m/z 592, RT 2.31 minutes.

(317) Peak 2: δ.sub.H (300 MHz, DMSO-d.sub.6) 13.37 (s, 1H), 8.91 (d, J 8.7 Hz, 1H), 7.47 (d, J 2.0 Hz, 1H), 7.03 (d, J 2.1 Hz, 1H), 6.98 (s, 1H), 5.10 (t, J 9.0 Hz, 1H), 4.45 (q, J 7.1 Hz, 2H), 3.64 (s, 2H), 3.09 (t, J 4.9 Hz, 4H), 2.85 (s, 3H), 2.50-2.32 (m, 5H), 1.80-1.19 (m, 17H). LCMS (Method 6): [M+H].sup.+ m/z 592, RT 2.31 minutes.

Example 38

(318) ##STR00047##

N-[Cyclooctyl(4-fluoro-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(319) The title compound (3 mg, 3%), a white solid, was prepared from Intermediate 7 (60 mg, 0.2 mmol) and Intermediate 56 (61 mg, 0.2 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.75 (s, 1H), 9.43 (s, 1H), 8.81 (s, 1H), 7.20 (s, 1H), 6.89 (s, 1H), 5.08 (t, J 8.6 Hz, 1H), 3.59 (s, 2H), 3.10 (d, J 5.2 Hz, 4H), 2.86 (s, 3H), 2.48-2.44 (m, 4H), 2.41-2.36 (m, 4H), 1.20-1.80 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 561, RT 2.01 minutes.

Example 39

(320) ##STR00048##

N-[{6-[(4-Acetylpiperazin-1-yl)methyl]-4-fluoro-1H-benzimidazol-2-yl}(cyclooctyl)-methyl]-3-methylisoxazole-4-carboxamide

(321) The title compound (3 mg, 3%), a white solid, was prepared from Intermediate 7 (55 mg, 0.19 mmol) and Intermediate 57 (50 mg, 0.19 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.70 (s, 1H), 9.43 (s, 1H), 8.85-8.81 (m, 1H), 7.21 (s, 1H), 6.90 (d, J 12.0 Hz, 1H), 5.08 (t, J 8.7 Hz, 1H), 3.56 (s, 2H), 3.41 (d, J 5.0 Hz, 4H), 2.40-2.25 (m, 8H), 1.96 (s, 3H), 1.74-1.30 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 525, RT 2.00 minutes.

Example 40

(322) ##STR00049##

tert-Butyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-1-carboxylate

(323) The title compound (1:1 mixture of diastereomers) (23.1 mg, 14%), a white solid, was prepared from Intermediate 7 (95.3 mg, 0.32 mmol) and Intermediate 91 (91.1 mg, 0.31 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.88-12.65 (s, 1H), 9.44 (s, 1H), 8.84 (s, 1H), 7.39-7.14 (m, 1H), 7.01-6.81 (m, 1H), 5.19-5.00 (m, 2H), 3.63-3.40 (m, 2H), 2.36 (m, 4H), 1.95-1.19 (m, 18H), 1.04 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 554, RT 2.67 minutes.

Example 41

(324) ##STR00050##

tert-Butyl 5-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-2,3-dihydro-1,4-oxazine-4-carboxylate

(325) The title compound (2 mg, 2%), a white solid, was prepared from Intermediate 7 (50 mg, 0.17 mmol) and Intermediate 92 (50 mg, 0.16 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.86 (s, 1H), 9.47 (s, 1H), 8.92 (s, 1H), 7.25-7.11 (m, 1H), 7.02-6.87 (m, 1H), 6.22 (s, 1H), 5.08 (t, J 8.1 Hz, 1H), 4.19-4.09 (m, 2H), 3.81-3.64 (m, 2H), 2.36 (m, 4H), 1.77-1.19 (m, 14H), 0.92 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 568, RT 2.77 minutes.

Example 42

(326) ##STR00051##

tert-Butyl 3-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-6,7-dihydro-5H-1,4-oxazepine-4-carboxylate

(327) The title compound (33 mg, 14%), a white solid, was prepared from Intermediate 7 (123 mg, 0.42 mmol) and Intermediate 93 (129 mg, 0.40 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.93-12.69 (s, 1H), 9.44 (s, 1H), 8.88-8.76 (m, 1H), 7.37-7.21 (m, 1H), 7.06-6.95 (m, 1H), 6.28-6.23 (m, 1H), 5.09 (t, J 8.3 Hz, 1H), 4.15-4.00 (m, 2H), 3.88-3.77 (m, 2H), 2.37 (m, 4H), 2.07-1.91 (m, 2H), 1.77-1.18 (m, 14H), 0.93 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 582, RT 2.86 minutes.

Example 43

(328) ##STR00052##

tert-Butyl 3-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)morpholine-4-carboxylate

(329) The title compound (1:1 mixture of diastereomers) (18 mg, 5%), a white solid, was prepared from Intermediate 7 (217 mg, 0.73 mmol) and Intermediate 100 (219 mg, 0.70 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.71 (s, 1H), 9.44 (s, 1H), 8.83 (s, 1H), 7.32-7.21 (m, 2H), 5.27 (s, 1H), 5.09 (t, J 8.7 Hz, 1H), 4.17-3.99 (m, 1H), 3.99-3.64 (m, 3H), 3.53 (td, J 11.4, 3.1 Hz, 1H), 3.36-3.23 (m, 1H), 2.37 (m, 4H), 1.85-1.08 (m, 14H), 1.33 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 570, RT 2.80

Example 44

(330) ##STR00053##

tert-Butyl 3-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-1,4-oxazepane-4-carboxylate

(331) The title compound (1:1 mixture of diastereomers) (54 mg, 19%), a white solid, was prepared from Intermediate 7 (85.5 mg, 0.29 mmol) and Intermediate 101 (90 mg, 0.28 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.74 (s, 1H), 9.45 (s, 1H), 8.81 (s, 1H), 7.36-7.14 (m, 1H), 7.06-6.86 (m, 1H), 5.57-5.23 (m, 1H), 5.16-4.99 (m, 1H), 4.31-4.87 (m, 3H), 3.77-3.41 (m, 3H), 2.37 (m, 4H), 1.83-1.08 (m, 16H), 1.16 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 584, RT 2.78 minutes.

Example 45

(332) ##STR00054##

Ethyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-2-phenylacetate

(333) The title compound (1:1 mixture of diastereomers) (208 mg, 23%), a white solid, was prepared from Intermediate 7 (510 mg, 1.73 mmol) and Intermediate 78 (476 mg, 1.65 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.00-12.75 (m, 1H), 9.43-9.42 (m, 1H), 8.86-8.75 (m, 1H), 7.40-7.22 (m, 6H), 7.01-7.93 (m, 1H), 5.44-5.42 (m, 1H), 5.11-5.07 (m, 1H), 4.21-4.11 (m, 2H), 2.43-2.32 (m, 4H), 1.79-1.22 (m, 14H), 1.20-1.13 (m, 3H). LCMS (Method 6): [M+H].sup.+ m/z 547, RT 2.98 minutes.

Example 46

(334) ##STR00055##

tert-Butyl 3-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-7-fluoro-3H-benzimidazol-5-yl)propanoate

(335) The title compound (49 mg, 23%), a white solid, was prepared from Intermediate 7 (128.9 mg, 0.44 mmol) and Intermediate 70 (114 mg, 0.42 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.65 (s, 1H), 9.43 (s, 1H), 8.81 (d, J 9.0 Hz, 1H), 7.13 (s, 1H), 6.85 (d, J 12.0 Hz, 1H), 5.08 (t, J 8.7 Hz, 1H), 2.89 (t, J 7.4 Hz, 2H), 2.52 (t, J 7.4 Hz, 2H), 2.42-2.32 (m, 4H), 1.77-1.18 (m, 14H), 1.36 (s, 9H). LCMS (Method 6): [M+H].sup.+ m/z 513, RT 2.76 minutes.

Example 47

(336) ##STR00056##

3-(2-{Cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)propanoic Acid

(337) To a solution of Example 20 (119 mg, 0.23 mmol) in DCM (3 mL) was added TFA (0.56 mL, 7.4 mmol). The reaction mixture was stirred overnight at r.t., then concentrated in vacuo. The crude material was subject to purification by reverse-phase HPLC to yield the title compound (26 mg, 23%) as a white solid. δ.sub.H (300 MHz, DMSO-d6) 12.79 (s, 1H), 12.03 (br s, 1H), 9.45 (s, 1H), 8.96-8.84 (m, 1H), 7.37-7.19 (m, 1H), 7.11-7.02 (m, 1H), 5.08 (t, J 8.9 Hz, 1H), 2.93 (t, J 7.7 Hz, 2H), 2.57-2.48 (m, 2H), 2.44-2.30 (m, 4H), 1.81-1.20 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 457, RT 1.54

Example 48

(338) ##STR00057##

N-(Cyclooctyl{5-[3-(dimethylamino)-3-oxopropyl]-4-fluoro-1H-benzimidazol-2-yl}-methyl)-3-methylisoxazole-4-carboxamide

(339) The title compound (12 mg, 38%), a white solid, was prepared from Example 47 (30 mg, 0.07 mmol) and a 2M solution of dimethylamine in THF (33 μL, 0.07 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.63 (s, 1H), 9.44 (s, 1H), 8.83 (s, 1H), 7.19 (d, J 8.2 Hz, 1H), 7.07 (t, J 7.4 Hz, 1H), 5.09 (d, J 9.0 Hz, 1H), 2.93 (s, 3H), 2.89 (t, J 8.0 Hz, 2H), 2.82 (s, 3H), 2.59 (t, J 7.9 Hz, 2H), 2.42-2.34 (m, 4H), 1.89-1.14 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 484, RT 2.05 minutes.

Example 49

(340) ##STR00058##

N-(Cyclooctyl{4-fluoro-5-[3-(methylamino)-3-oxopropyl]-1H-benzimidazol-2-yl}-methyl)-3-methylisoxazole-4-carboxamide

(341) The title compound (11 mg, 36%), a white solid, was prepared from Example 47 (30 mg, 0.07 mmol) and a 2M solution of methylamine in THF (33 μL, 0.07 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.94-12.72 (m, 1H), 9.44 (s, 1H), 8.90-8.81 (m, 1H), 7.75 (d, J 5.1 Hz, 1H), 7.35-7.18 (m, 1H), 7.01 (t, J 7.5 Hz, 1H), 5.07 (t, J 8.7 Hz, 1H), 3.38-3.26 (m, 2H), 2.90 (t, J 7.7 Hz, 2H), 2.55 (d, J 4.6 Hz, 3H), 2.41-2.32 (m, 4H), 1.79-1.18 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 470, RT 1.94

Example 50

(342) ##STR00059##

N-{Cyclooctyl[4,6-difluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(343) The title compound (9 mg, 7%), a beige solid, was prepared from Intermediate 7 (80 mg, 0.27 mmol) and Intermediate 71 (80 mg, 0.29 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.86 (s, 1H), 9.42 (s, 1H), 8.82 (d, J 7.7 Hz, 1H), 7.18 (d, J 10.8 Hz, 1H), 5.25-4.87 (m, 1H), 4.29-3.86 (m, 2H), 3.55-3.42 (m, 2H), 3.30-3.17 (m, 2H), 2.41-2.25 (m, 4H), 2.17-1.96 (m, 2H), 1.86-1.10 (m, 15H). LCMS (Method 6): [M+H].sup.+ m/z 487, RT 2.44 minutes.

Example 51

(344) ##STR00060##

N-{Cyclooctyl[4,7-difluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(345) The title compound (5 mg, 3%), a white solid, was prepared from Intermediate 7 (89 mg, 0.30 mmol) and Intermediate 72 (121 mg, 0.42 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.16 (s, 1H), 9.44 (s, 1H), 8.82 (s, 1H), 6.96 (s, 1H), 5.10 (t, J 8.8 Hz, 1H), 4.02-3.90 (m, 2H), 3.54-3.40 (m, 2H), 3.24-3.07 (m, 1H), 2.40-2.29 (m, 4H), 1.87-1.23 (m, 18H). LCMS (Method 6): [M+H].sup.+ m/z 487, RT 2.46

Example 52

(346) ##STR00061##

Ethyl 2-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-2-(pyridin-4-yl)acetate

(347) The title compound (mixture of diastereomers) (29 mg, 7%), a white solid, was prepared from Intermediate 7 (220 mg, 0.71 mmol) and Intermediate 76 (240 mg, 0.72 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.86 (s, 1H), 9.43 (d, J 2.4 Hz, 1H), 9.01-8.75 (m, 1H), 8.53 (dt, J 4.5, 1.7 Hz, 2H), 7.47-7.20 (m, 3H), 7.10-6.93 (m, 1H), 5.50 (s, 1H), 5.19-4.98 (m, 1H), 4.28-4.06 (m, 2H), 2.43-2.22 (m, 4H), 1.77-1.24 (m, 14H), 1.21-1.06 (m, 3H). LCMS (Method 6): [M+H].sup.+ m/z 548, RT 2.31 minutes.

Example 53

(348) ##STR00062##

N-(Cyclooctyl{4-fluoro-5-[2-hydroxy-1-(pyridin-4-yl)ethyl]-1H-benzimidazol-2-yl}-methyl)-3-methylisoxazole-4-carboxamide

(349) A solution of Example 52 (23 mg, 0.04 mmol) in THF (1 mL) at −70° C. was treated with a 2M solution of LiAlH.sub.4 in THF (25 μL, 0.05 mmol). The solution was allowed to warm to 0° C. and stirred for 2 h, then cooled again to −70° C. A further aliquot of a 2M solution of LiAlH.sub.4 in THF (25 μL, 0.05 mmol) was added. After 1 h at r.t., the reaction mixture was quenched with saturated aqueous NaHCO.sub.3 solution and extracted with EtOAc (3×10 mL). The organic layers were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by reverse-phase HPLC to yield the title compound (mixture of diastereomers) (6 mg, 28%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.73 (s, 1H), 9.44 (s, 1H), 8.87 (s, 1H), 8.60-8.26 (m, 2H), 7.41-7.18 (m, 3H), 7.16-7.05 (m, 1H), 5.06 (t, J 8.8 Hz, 1H), 5.01-4.91 (m, 1H), 4.47 (t, J 7.2 Hz, 1H), 4.17-3.88 (m, 2H), 2.43-2.25 (m, 4H), 1.75-1.26 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 506, RT 1.96 minutes.

Example 54

(350) ##STR00063##

N-[{5-[Cyano(pyridin-4-yl)methyl]-4-fluoro-1H-benzimidazol-2-yl}(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide

(351) The title compound (mixture of diastereomers) (26 mg, 4%), a white solid, was prepared from Intermediate 7 (447 mg, 1.52 mmol) and Intermediate 77 (324 mg, 1.34 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.71 (s, 1H), 9.48-9.38 (m, 1H), 8.92-8.51 (m, 2H), 7.66-7.00 (m, 4H), 6.57-6.10 (m, 1H), 5.93 (s, 1H), 5.17-5.02 (m, 1H), 2.44-2.30 (m, 4H), 1.83-1.19 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 501, RT 2.33 minutes.

Example 55

(352) ##STR00064##

N-[Cyclooctyl(7-fluoro-4-methoxy-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(353) The title compound (22 mg, 18%), a white solid, was prepared from Intermediate 7 (85 mg, 0.29 mmol) and Intermediate 79 (52 mg, 0.31 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.85 (s, 1H), 9.57-9.37 (m, 1H), 8.90-8.63 (m, 1H), 7.00-6.78 (m, 1H), 6.75-6.48 (m, 1H), 5.13 (t, J 8.8 Hz, 1H), 3.90 (s, 3H), 2.43-2.22 (m, 4H), 1.78-1.38 (m, 12H), 1.33-1.22 (m, 2H). LCMS (Method 6): [M+H].sup.+ m/z 415, RT 2.35 minutes.

Example 56

(354) ##STR00065##

N-{Cyclooctyl[4-fluoro-5-(pyridin-4-yloxy)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(355) The title compound (27 mg, 23%), a white solid, was prepared from Intermediate 7 (200 mg, 0.65 mmol) and Intermediate 82 (180 mg, 0.82 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 9.45 (s, 1H), 9.03 (d, J 8.6 Hz, 1H), 7.94-7.76 (m, 2H), 7.50-7.40 (m, 1H), 7.37-7.26 (m, 1H), 6.30-6.12 (m, 2H), 5.12 (t, J 8.7 Hz, 1H), 2.37 (s, 4H), 1.88-1.01 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 478, RT 1.82 minutes.

Example 57

(356) ##STR00066##

N-{Cyclooctyl[4-fluoro-5-(tetrahydropyran-4-yloxy)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(357) The title compound (53 mg, 45%), a beige solid, was prepared from Intermediate 7 (147 mg, 0.50 mmol) and Intermediate 83 (130 mg, 0.42 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.65 (s, 1H), 9.43 (s, 1H), 8.83 (s, 1H), 7.20 (s, 1H), 7.12-6.95 (m, 1H), 5.07 (t, J 8.7 Hz, 1H), 4.38 (s, 1H), 3.95-3.77 (m, 2H), 3.60-3.38 (m, 2H), 2.42-2.27 (m, 4H), 2.00-1.85 (m, 2H), 1.81-1.18 (m, 16H). LCMS (Method 6): [M+H].sup.+ m/z 485, RT 2.27 minutes.

Example 58

(358) ##STR00067##

N-{Cyclooctyl[4-fluoro-5-(oxetan-3-yloxy)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(359) The title compound (45 mg, 39%), a beige solid, was prepared from Intermediate 7 (147 mg, 0.49 mmol) and Intermediate 84 (120 mg, 0.52 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.67 (s, 1H), 9.43 (s, 1H), 8.82 (s, 1H), 7.19 (s, 1H), 6.79 (t, J 8.1 Hz, 1H), 5.37-5.20 (m, 1H), 5.08 (t, J 8.7 Hz, 1H), 4.95-4.81 (m, 2H), 4.69-4.56 (m, 2H), 2.41-2.24 (m, 4H), 1.88-1.10 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 457, RT 2.12 minutes.

Example 59

(360) ##STR00068##

N-{Cyclooctyl[6-fluoro-4-(tetrahydropyran-4-yloxy)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(361) The title compound (58 mg, 16%), a white solid, was prepared from Intermediate 7 (230 mg, 0.78 mmol) and Intermediate 80 (175 mg, 0.77 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.80-12.32 (m, 1H), 9.42 (s, 1H), 8.81 (d, J 9.4 Hz, 1H), 7.08-6.50 (m, 2H), 5.22-4.62 (m, 2H), 3.90 (d, J 11.0 Hz, 2H), 3.48 (d, J 11.2 Hz, 2H), 2.36 (m, 4H), 2.02 (d, J 12.5 Hz, 2H), 1.80-1.18 (m, 16H). LCMS (Method 6): [M+H].sup.+ m/z 485, RT 2.36 minutes.

Example 60

(362) ##STR00069##

N-{Cyclooctyl[4-fluoro-5-(pyridazin-4-yloxy)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(363) The title compound (39 mg, 11%), a white solid, was prepared from Intermediate 7 (211 mg, 0.72 mmol) and Intermediate 81 (158 mg, 0.72 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 13.14 (s, 1H), 9.64-9.27 (m, 1H), 8.99 (d, J 8.3 Hz, 1H), 8.64-8.49 (m, 1H), 7.96 (d, J 2.7 Hz, 1H), 7.56-7.30 (m, 2H), 6.51 (dd, J 7.9, 3.2 Hz, 1H), 5.13 (t, J 8.8 Hz, 1H), 2.48-2.30 (m, 4H), 1.77-1.29 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 479, RT 2.00 minutes.

Example 61

(364) ##STR00070##

N-{Cyclooctyl[4-fluoro-5-(tetrahydropyran-4-ylamino)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(365) The title compound (15 mg, 5%), an off-white solid, was prepared from Intermediate 7 (100 mg, 0.34 mmol) and Intermediate 89 (92 mg, 0.34 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.47 (s, 1H), 9.45 (s, 1H), 9.13-8.64 (m, 1H), 7.07 (s, 1H), 6.91-6.62 (m, 1H), 5.04 (t, J 8.8 Hz, 1H), 4.88-4.34 (m, 1H), 4.00-3.77 (m, 2H), 3.57-2.95 (m, 3H), 2.37 (s, 4H), 1.89-1.81 (m, 2H), 1.74-1.18 (m, 16H). LCMS (Method 6): [M+H].sup.+ m/z 484, RT 2.12 minutes.

Example 62

(366) ##STR00071##

Methyl (2S)-1-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-2-carboxylate

(367) The title compound (36 mg, 10%), a white solid, was prepared from Intermediate 7 (208 mg, 0.71 mmol) and Intermediate 85 (179 mg, 0.71 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.53-12.32 (m, 1H), 9.43 (d, J 1.7 Hz, 1H), 8.82-8.64 (m, 1H), 7.24-7.07 (m, 1H), 6.80-6.60 (m, 1H), 5.09-5.00 (m, 1H), 4.51-4.43 (m, 1H), 3.67-3.47 (m, 4H), 3.41-3.34 (m, 1H), 2.42-2.22 (m, 5H), 2.00-1.88 (m, 3H), 1.79-1.19 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 512, RT 2.04 minutes.

Example 63

(368) ##STR00072##

Methyl (2R)-1-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-2-carboxylate

(369) The title compound (9 mg, 6%), a white solid, was prepared from Intermediate 7 (85 mg, 0.29 mmol) and Intermediate 86 (204 mg, 0.29 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.52 (s, 1H), 9.48-9.42 (m, 1H), 8.79 (s, 1H), 7.09 (s, 1H), 6.69-6.62 (m, 1H), 5.08-5.01 (m, 1H), 4.50-4.42 (m, 1H), 3.62-3.47 (m, 4H), 2.39-2.24 (m, 5H), 1.94 (q, J 8.2, 6.8 Hz, 3H), 1.76-1.19 (m, 15H). LCMS (Method 6): [M+H].sup.+ m/z 512, RT 2.41 minutes.

Example 64

(370) ##STR00073##

Methyl 1-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)piperidine-3-carboxylate

(371) The title compound (mixture of diastereomers) (78 mg, 13%), a white solid, was prepared from Intermediate 7 (330 mg, 1.12 mmol) and Intermediate 196 (299 mg, 1.12 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.78-12.50 (m, 1H), 9.43 (s, 1H), 8.90-8.68 (m, 1H), 7.31-7.15 (m, 1H), 6.97 (d, J 8.4 Hz, 1H), 5.11-4.99 (m, 1H), 3.62 (s, 3H), 3.31-3.23 (m, 1H), 3.09 (d, J 11.1 Hz, 1H), 2.90 (t, J 10.3 Hz, 1H), 2.80-2.68 (m, 2H), 2.42-2.29 (m, 4H), 1.95-1.87 (m, 1H), 1.83-1.20 (m, 17H). LCMS (Method 6): [M+H].sup.+ m/z 526, RT 2.49 minutes.

Example 65

(372) ##STR00074##

Methyl 1-(2-{cyclooctyl[(3-methylisoxazole-4-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)piperidine-2-carboxylate

(373) The title compound (mixture of diastereomers) (9.8 mg, 7%), a white solid, was prepared from Intermediate 7 (80 mg, 0.27 mmol) and Intermediate 87 (70 mg, 0.26 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.87-12.38 (m, 1H), 9.43 (d, J 2.9 Hz, 1H), 8.96-8.66 (m, 1H), 7.31-7.05 (m, 1H), 7.05-6.84 (m, 1H), 5.16-4.94 (m, 1H), 4.24-4.03 (m, 1H), 3.52-3.39 (m, 4H), 2.99-2.78 (m, 1H), 2.36 (s, 3H), 2.00-1.85 (m, 2H), 1.78-1.22 (m, 19H). LCMS (Method 6): [M+H].sup.+ m/z 526, RT 2.54

Example 66

(374) ##STR00075##

N-{Cyclooctyl[4-fluoro-6-(tetrahydropyran-4-ylamino)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(375) The title compound (9 mg, 3%), a white solid, was prepared from Intermediate 7 (175 mg, 0.6 mmol) and Intermediate 197 (135 mg, 0.6 mmol) in accordance with Procedure Y. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.29 (s, 1H), 9.45 (s, 1H), 8.86 (s, 1H), 6.44-6.22 (m, 2H), 5.41 (s, 1H), 5.00 (t, J 8.2 Hz, 1H), 3.93-3.76 (m, 2H), 3.47-3.36 (m, 2H), 2.41-2.22 (m, 4H), 1.96-1.80 (m, 2H), 1.76-1.17 (m, 17H). LCMS (Method 6): [M+H].sup.+ m/z 484, RT 2.15 minutes.

Example 67

(376) ##STR00076##

N-[(S)-{5-[(4-Acetylpiperazin-1-yl)methyl]-4-fluoro-1H-benzimidazol-2-yl}(4-methyl-cyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer)

(377) The title compound (199 mg, 41%), a white solid, was prepared from Intermediate 127 (376 mg, 0.94 mmol) and 2-ethylpyrazole-3-carboxylic acid (166 mg, 0.94 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.65 (s, 1H), 8.87 (d, J 8.5 Hz, 1H), 7.48 (d, J 2.0 Hz, 1H), 7.26 (d, J 8.2 Hz, 1H), 7.14 (dd, J 8.2, 6.3 Hz, 1H), 7.04 (d, J 2.1 Hz, 1H), 5.00 (t, J 8.6 Hz, 1H), 4.50-4.40 (m, 2H), 3.63 (s, 2H), 3.39 (q, J 5.4 Hz, 4H), 2.39 (t, J 5.0 Hz, 2H), 2.32 (t, J 4.8 Hz, 2H), 2.11-1.99 (m, 1H), 1.99-1.86 (m, 4H), 1.71 (d, J 12.8 Hz, 1H), 1.62 (d, J 12.2 Hz, 1H), 1.38-1.21 (m, 5H), 1.15-0.99 (m, 2H), 0.96-0.78 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 524, RT 1.89 minutes.

Example 68

(378) ##STR00077##

N-[(S)-{5-[2-(Dimethylcarbamoyl)phenyl]-4-fluoro-1H-benzimidazol-2-yl}(4-methyl-cyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer)

(379) The title compound (77 mg, 38%), a white solid, was prepared from Intermediate 129 (157 mg, 0.38 mmol) and 2-ethylpyrazole-3-carboxylic acid (68 mg, 0.49 mmol) in accordance with Procedure A, using DCM (5 mL) as solvent. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.69 (s, 1H), 9.00-8.72 (m, 1H), 7.55-7.24 (m, 6H), 7.08-6.97 (m, 2H), 5.05 (t, J 8.7 Hz, 1H), 4.47 (qd, J 7.1, 1.4 Hz, 2H), 2.73 (s, 3H), 2.63 (s, 3H), 2.15-1.98 (m, 1H), 1.92 (d, J 12.7 Hz, 1H), 1.68 (dd, J 31.3, 12.8 Hz, 2H), 1.42 (d, J 12.4 Hz, 1H), 1.36-1.20 (m, 4H), 1.20-0.99 (m, 2H), 0.98-0.78 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 531, RT 2.20 minutes.

Example 69

(380) ##STR00078##

N-(Cyclooctyl{5-[2-(dimethylcarbamoyl)phenyl]-4-fluoro-1H-benzimidazol-2-yl}-methyl)-2-ethylpyrazole-3-carboxamide

(381) The title compound (16 mg, 31%), a white solid, was prepared from Intermediate 133 (44 mg, 0.10 mmol) and 2-ethylpyrazole-3-carboxylic acid (16.6 mg, 0.12 mmol) in accordance with Procedure A. δ.sub.H (300 MHz, DMSO-d.sub.6) 8.87 (br s, 1H), 7.56-7.21 (m, 8H), 7.09-6.92 (m, 2H), 5.13 (t, J 8.7 Hz, 1H), 4.48 (q, J 7.1 Hz, 2H), 2.73 (s, 3H), 2.63 (s, 3H), 1.84-1.22 (m, 18H). LCMS (Method 6): [M+H].sup.+ m/z 545, RT 2.47 minutes.

Example 70

(382) ##STR00079##

Ethyl 3-(2-{cyclooctyl[(2-ethylpyrazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)pyridine-4-carboxylate

(383) The title compound (14 mg, 31%), a white solid, was prepared from Intermediate 134 (39 mg, 0.08 mmol) and 2-ethylpyrazole-3-carboxylic acid (24 mg, 0.17 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.32-12.58 (m, 1H), 9.12-8.79 (m, 1H), 8.79-8.67 (m, 2H), 7.76 (d, J 4.9 Hz, 1H), 7.48 (d, J 2.0 Hz, 1H), 7.39 (d, J 8.0 Hz, 1H), 7.14 (s, 1H), 7.03 (d, J 2.0 Hz, 1H), 5.11 (t, J 8.7 Hz, 1H), 4.47 (q, J 7.1 Hz, 2H), 4.15-3.95 (m, 2H), 1.79-1.24 (m, 18H), 0.91 (t, J 7.1 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 547, RT 2.34 minutes.

Example 71

(384) ##STR00080##

N-{[5-(7-Acetyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4-fluoro-1H-benzimidazol-2-yl}(cyclooctyl)methyl]-2-ethylpyrazole-3-carboxamide

(385) The title compound (4 mg, 10%), a white solid, was prepared from Intermediate 136 (35.4 mg, 0.074 mmol) and 2-ethylpyrazole-3-carboxylic acid (14.8 mg, 0.11 mmol) in accordance with Procedure A. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.80 (s, 1H), 8.85 (s, 1H), 7.52-7.37 (m, 2H), 7.35-7.17 (m, 1H), 7.03 (d, J 2.0 Hz, 1H), 5.13 (t, J 8.7 Hz, 1H), 5.02-4.78 (m, 2H), 4.47 (q, J 7.1 Hz, 2H), 4.06-3.78 (m, 4H), 2.21-2.08 (m, 3H), 1.82-1.23 (m, 18H). LCMS (Method 6): [M+H].sup.+ m/z 562, RT 1.93 minutes.

Example 72

(386) ##STR00081##

2-Ethyl-N-{(S)-[4-fluoro-5-(tetrahydropyran-3-yl)-1H-benzimidazol-2-yl](4-methyl-cyclohexyl)methyl}pyrazole-3-carboxamide (Trans Isomer)

(387) The title compound (17 mg, 15%), a white solid, was prepared from Intermediate 137 (214 mg, 0.23 mmol) and 2-ethylpyrazole-3-carboxylic acid (106 mg, 0.76 mmol) in accordance with Procedure A, using DCM (5 mL) as solvent. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.07-12.38 (m, 1H), 8.97-8.58 (m, 1H), 7.48 (d, J 2.1 Hz, 1H), 7.43-7.19 (m, 1H), 7.11 (dd, J 8.4, 6.3 Hz, 1H), 7.04 (d, J 2.0 Hz, 1H), 4.99 (t, J 8.7 Hz, 1H), 4.45 (q, J 7.1 Hz, 2H), 3.89 (d, J 11.2 Hz, 1H), 3.85-3.75 (m, 1H), 3.48-3.37 (m, 2H), 3.24-3.08 (m, 1H), 2.13-1.97 (m, 1H), 1.97-1.78 (m, 3H), 1.78-1.57 (m, 4H), 1.39-1.19 (m, 5H), 1.19-0.97 (m, 2H), 0.97-0.78 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 468, RT 2.42 minutes.

Example 73

(388) ##STR00082##

N-[(S)-{5-[4-(Dimethylcarbamoyl)-5-fluoropyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(389) The title compound (21 mg, 36%), a white solid, was prepared from Intermediate 141 (45 mg, 0.11 mmol) and 3-ethylisoxazole-4-carboxylic acid (19 mg, 0.13 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.85 (s, 1H), 9.43 (d, J 1.3 Hz, 1H), 8.87-8.78 (m, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 7.40-7.33 (m, 1H), 7.10-7.01 (m, 1H), 5.05 (t, J 8.4 Hz, 1H), 2.93-2.69 (m, 8H), 2.05-1.96 (m, 1H), 1.92-1.86 (m, 1H), 1.71 (d, J 12.8 Hz, 1H), 1.63 (d, J 12.9 Hz, 1H), 1.45-1.37 (m, 1H), 1.32-1.25 (m, 1H), 1.18-1.01 (m, 5H), 0.95-0.79 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 551, RT 2.15 minutes.

Example 74

(390) ##STR00083##

N-[(S)-{5-[4-(Dimethylcarbamoyl)pyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(391) The title compound (30 mg, 420%), a white solid, was prepared from Intermediate 142 (55 mg, 0.14 mmol) and 3-ethylisoxazole-4-carboxylic acid (25 mg, 0.17 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.87 (s, 1H), 9.43 (s, 1H), 8.86 (s, 1H), 8.69-8.62 (i, 2H), 7.43 (d, J 5.0 Hz, 1H), 7.35 (d, J 8.3 Hz, 1H), 7.08-7.02 (m, 1H), 5.06 (t, J 8.5 Hz, 1H), 2.83 (qd, J 7.5, 2.4 Hz, 2H), 2.78-2.62 (m, 6H), 2.04-1.98 (m, 1H), 1.90 (d, J 12.9 Hz, 1H), 1.71 (d, J 12.8 Hz, 1H), 1.64 (d, J 12.9 Hz, 1H), 1.41 (d, J 12.5 Hz, 1H), 1.32-1.26 (m, 1H), 1.16 (t, J 7.5 Hz, 3H), 1.11-1.01 (m, 2H), 0.97-0.79 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 533, RT 2.02 minutes.

Example 75

(392) ##STR00084##

N-[(S)-{5-[4-(Dimethylcarbamoyl)-1-oxopyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}-(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(393) To a solution of Example 74 (10 mg, 0.02 mmol) in DCM (1 mL) was added MCPBA (4 mg, 0.02 mmol). The reaction mixture was stirred at r.t. for 3 h, then quenched with water and saturated aqueous Na.sub.2CO.sub.3 solution. The material was extracted with DCM. The organic layers were separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by HPLC to give, after freeze-drying, the title compound (2 mg, 19%) as a white solid. δ.sub.H (400 MHz, CD.sub.3OD) 9.19 (s, 1H), (8.49 (t, J 1.5 Hz, 1H), 8.42 (dd, J 6.6, 1.8 Hz, 1H), 7.63 (d, J 6.7 Hz, 1H), 7.44 (d, J 8.4 Hz, 1H), 7.21 (dd, J 8.3, 6.6 Hz, 1H), 5.08 (d, J 8.35 Hz, 1H), 5.02-4.51 (m, 2H), 2.98-2.81 (m, 5H), 2.77 (s, 3H), 2.10-1.95 (m, 2H), 1.80 (dt, J 13.1, 3.0 Hz, 1H), 1.71 (dt, J 13.1, 2.9 Hz, 1H), 1.46 (dt, J 12.8, 3.0 Hz, 1H), 1.35 (dtd, J 10.9, 7.5, 6.7, 4.1 Hz, 1H), 1.26-1.09 (m, 5H), 1.00 (dtd, J 21.1, 12.5, 12.0, 3.3 Hz, 2H), 0.90 (d, J 6.5 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 549, RT 1.75 minutes.

Example 76

(394) ##STR00085##

N-[(S)-{5-[3-(Dimethylcarbamoyl)pyridin-2-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(395) The title compound (27 mg, 83%), a white solid, was prepared from Intermediate 143 (25 mg, 0.06 mmol) and 3-ethylisoxazole-4-carboxylic acid (11 mg, 0.07 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.85 (s, 1H), 9.44 (s, 1H), 8.83 (s, 1H), 8.72 (dd, J 4.8, 1.8 Hz, 1H), 7.83 (d, J 7.7 Hz, 1H), 7.47 (dd, J 7.7, 4.8 Hz, 1H), 7.34-7.28 (m, 1H), 7.18-7.11 (m, 1H), 5.06 (t, J 8.4 Hz, 1H), 2.98-2.68 (m, 8H), 1.88 (d, J 12.8 Hz, 1H), 1.71 (d, J 12.7 Hz, 1H), 1.63 (d, J 12.9 Hz, 1H), 1.42 (d, J 12.6 Hz, 1H), 1.32-1.24 (m, 1H), 1.16 (t, J 7.5 Hz, 3H), 1.12-1.00 (m, 2H), 0.96-0.78 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 533, RT 1.96 minutes.

Example 77

(396) ##STR00086##

Ethyl 5-(2-{(S)-[(2-ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)-3,6-dihydro-2H-pyran-4-carboxylate (Trans Isomer)

(397) The title compound (15 mg, 5%), a white solid, was prepared from Intermediate 144 (241 mg, 0.53 mmol) and 2-ethylpyrazole-3-carboxylic acid (82 mg, 0.59 mmol) in accordance with Procedure A, using DCM (5 mL) as the solvent. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.10-12.49 (m, 1H), 9.00-8.63 (m, 1H), 7.48 (d, J 2.0 Hz, 1H), 7.43-7.19 (m, 1H), 7.04 (d, J 2.1 Hz, 1H), 6.99-6.89 (m, 1H), 5.00 (t, J 8.6 Hz, 1H), 4.45 (q, J 7.1 Hz, 2H), 4.25 (s, 2H), 3.94-3.76 (m, 4H), 2.48-2.42 (m, 2H), 2.11-1.97 (m, 1H), 1.90 (d, J 12.5 Hz, 1H), 1.71 (d, J 12.6 Hz, 1H), 1.62 (d, J 12.8 Hz, 1H), 1.37-1.22 (m, 5H), 1.16-0.97 (m, 2H), 0.97-0.90 (m, 1H), 0.90-0.80 (m, 4H), 0.72 (t, J 7.1 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 528, RT 1.94 minutes.

Example 78

(398) ##STR00087##

N-[(S)-{5-[4-(Dimethylcarbamoyl)-3,6-dihydro-2H-pyran-5-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(399) The title compound (17 mg, 24%), a white solid, was prepared from Intermediate 145 (58.35 mg, 0.13 mmol) and 3-ethylisoxazole-4-carboxylic acid (21.7 mg, 0.15 mmol) in accordance with Procedure A, using DCM (5 mL) as solvent. δ.sub.H (400 MHz, DMSO-d6) 12.74 (s, 1H), 9.42 (s, 1H), 8.92-8.66 (m, 1H), 7.23 (d, J 8.3 Hz, 1H), 6.97-6.79 (m, 1H), 5.03 (t, J 8.3 Hz, 1H), 4.24 (s, 2H), 3.86 (t, J 5.5 Hz, 2H), 2.83 (qd, J 7.5, 2.6 Hz, 2H), 2.74 (s, 3H), 2.57 (s, 3H), 2.39-2.28 (m, 2H), 2.06-1.93 (m, 1H), 1.88 (d, J 12.9 Hz, 1H), 1.71 (d, J 12.8 Hz, 1H), 1.63 (d, J 12.6 Hz, 1H), 1.42-1.23 (m, 2H), 1.18-1.00 (m, 5H), 0.94-0.81 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 538, RT 2.06 minutes.

Example 79

(400) ##STR00088##

N-[(S)-{5-[4-(Dimethylcarbamoyl)-3,6-dihydro-2H-pyran-5-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer)

(401) The title compound (14 mg, 20%), a white solid, was prepared from Intermediate 145 (58.35 mg, 0.13 mmol) and 2-ethylpyrazole-3-carboxylic acid (25 mg, 0.18 mmol) in accordance with Procedure A, using DCM (5 mL) as the solvent. δ.sub.H (400 MHz, DMSO-d6) 12.75 (s, 1H), 8.82 (s, 1H), 7.48 (d, J 2.0 Hz, 1H), 7.31-7.12 (m, 1H), 7.04 (d, J 2.1 Hz, 1H), 6.92 (s, 1H), 5.02 (t, J 8.5 Hz, 1H), 4.51-4.39 (m, 2H), 4.24 (s, 2H), 3.86 (t, J 5.5 Hz, 2H), 2.73 (s, 3H), 2.57 (s, 3H), 2.37-2.31 (m, 2H), 2.12-1.97 (m, 1H), 1.89 (d, J 12.3 Hz, 1H), 1.71 (d, J 12.9 Hz, 1H), 1.62 (d, J 12.8 Hz, 1H), 1.39 (d, J 8.5 Hz, 1H), 1.32-1.22 (m, 4H), 1.16-0.98 (m, 2H), 0.96-0.80 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 537, RT 1.99 minutes.

Example 80

(402) ##STR00089##

Ethyl 3-(2-{(S)-[(2-ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-3H-benzimidazol-5-yl)tetrahydroyran-4-carboxylate (Trans Isomer)

(403) The title compound (3 mg, 5%), a white solid, was prepared from Intermediate 146 (54 mg, 0.12 mmol) and 2-ethylpyrazole-3-carboxylic acid (25.2 mg, 0.18 mmol) in accordance with Procedure A, using DCM (5 mL) as the solvent. δ.sub.H (400 MHz, DMSO-d6) 12.64 (s, 1H), 8.78 (s, 1H), 7.47 (t, J 1.7 Hz, 1H), 7.43-7.07 (m, 2H), 7.02 (s, 1H), 4.99 (s, 1H), 4.45 (q, J 7.2 Hz, 2H), 4.14-3.97 (m, 2H), 3.93-3.72 (m, 3H), 3.66-3.53 (m, 2H), 3.09 (s, 1H), 2.08-1.81 (m, 3H), 1.80-1.66 (m, 2H), 1.61 (d, J 13.3 Hz, 1H), 1.47-1.18 (m, 6H), 1.18-0.98 (m, 2H), 0.96-0.80 (m, 7H). LCMS (Method 6): [M+H].sup.+ m/z 540, RT 2.39 minutes.

Example 81

(404) ##STR00090##

N-[(S)-{5-[4-(Dimethylcarbamoyl)tetrahydropyran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer)

(405) To a solution of Example 80 (17 mg, 0.03 mmol) in THF (2.5 mL) and water (2.5 mL) was added LiOH.H.sub.2O (10 mg, 0.13 mmol). The reaction mixture was heated at 70° C. for 4h, then another aliquot of LiOH.H.sub.2O (9 mg) was added. The mixture was heated overnight, then cooled, diluted with EtOAc, and neutralized with 2M aqueous HCl solution. The material was concentrated in vacuo. The yellow gum was taken up in DCM (2.5 mL) and treated with a 2M solution of dimethylamine in THF (60 μL, 0.12 mmol), in accordance with Procedure A, to yield the title compound (2 mg, 100%) as a white solid. δ.sub.H (400 MHz, CD.sub.3OD) 7.78-7.61 (m, 1H), 7.51 (dd J 2.1, 0.8 Hz, 1H), 7.29 (d, J 8.5 Hz, 1H), 6.94 (t, J 2.0 Hz, 1H), 5.09 (dd, J 8.6, 1.7 Hz, 1H), 4.59-4.47 (m, 2H), 4.34-4.19 (m, 2H), 3.95 (dd, J 11.5, 3.6 Hz, 1H), 3.80-3.63 (m, 2H), 3.57-3.47 (m, 1H), 3.07 (d, J 7.6 Hz, 3H), 2.79 (d, J 9.7 Hz, 3H), 2.18-1.95 (m, 3H), 1.87-1.76 (m, 1H), 1.71 (d, J 13.1 Hz, 1H), 1.66-1.57 (m, 1H), 1.48-1.26 (m, 6H), 1.26-1.07 (m, 2H), 1.07-0.86 (m, 4H). LCMS (Method 6): [M+H].sup.+ m/z 539, RT 2.02 minutes and 2.05 minutes (apparent separation of tetrahydropyran cis isomers).

Example 82

(406) ##STR00091##

Methyl 4-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)tetrahydrofuran-3-carboxylate (Trans Isomer)

(407) The title compound (237 mg, quantitative), a white solid, was prepared from Intermediate 147 (180 mg, 0.46 mmol) and 3-ethylisoxazole-4-carboxylic acid (85 mg, 0.57 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 513, RT 1.28 minutes.

Example 83

(408) ##STR00092##

4-(2-{(S′)-[(3-Ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)tetrahydrofuran-3-carboxylic Acid (Trans Isomer)

(409) To a solution of LiOH.H.sub.2O (11 mg, 0.46 mmol) in water (0.5 mL) was added Example 82 (237 mg, 0.46 mmol) in EtOH (2 mL). The reaction mixture was stirred at r.t. overnight, then concentrated in vacuo. The crude material was purified by reverse-phase HPLC to yield the title compound (54 mg, 23%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.87 (s, 1H), 9.44 (s, 1H), 9.04 (s, 1H), 7.29-7.18 (m, 1H), 7.15 (t, J 7.4 Hz, 1H), 5.01 (t, J 8.6 Hz, 1H), 4.15 (dt, J 16.1, 8.2 Hz, 2H), 3.99-3.88 (m, 2H), 3.65 (t, J 8.1 Hz, 1H), 3.19 (q, J 7.8 Hz, 1H), 2.81 (qd, J 7.5, 2.2 Hz, 2H), 1.95 (d, J 10.3 Hz, 1H), 1.91-1.83 (m, 1H), 1.68 (d, J 12.4 Hz, 1H), 1.60 (d, J 12.7 Hz, 1H), 1.36-1.22 (m, 2H), 1.14 (t, J 7.5 Hz, 3H), 1.09-0.96 (m, 2H), 0.93-0.72 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 499, RT 2.08 minutes.

Example 84

(410) ##STR00093##

N-[(S)-{5-[4-(Dimethylcarbamoyl)tetrahydrofuran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}-(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(411) The title compound (5 mg, 6%), a white solid, was prepared from Example 83 (85 mg, 0.17 mmol) and a 2M solution of dimethylamine in THF (170 μL, 0.34 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.74 (s, 1H), 9.43 (s, 1H), 8.75 (s, 1H), 7.24-7.18 (m, 1H), 7.11-7.04 (m, 1H), 4.99 (t, J 8.1 Hz, 1H), 4.22 (t, J 8.2 Hz, 1H), 4.10 (t, J 7.8 Hz, 1H), 4.01 (d, J 7.8 Hz, 1H), 3.81-3.76 (m, 1H), 3.74-3.58 (m, 3H), 2.86-2.72 (m, 6H), 1.94 (d, J 10.5 Hz, 1H), 1.85 (d, J 13.0 Hz, 1H), 1.69 (d, J 12.7 Hz, 1H), 1.60 (d, J 12.9 Hz, 1H), 1.39-1.33 (m, 1H), 1.30-1.24 (m, 1H), 1.15 (t, J 7.5 Hz, 3H), 1.11-0.95 (m, 3H), 0.93-0.75 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 526, RT 2.02 minutes.

Example 85

(412) ##STR00094##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)tetrahydrofuran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (trans isomer)

(413) The title compound (9 mg, 9%), a white solid, was prepared from Example 83 (85 mg, 0.17 mmol) and 3,3-difluoroazetidine hydrochloride (35 mg, 0.34 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.89 (s, 1H), 9.45 (s, 1H), 8.74 (s, 1H), 7.19-7.14 (m, 1H), 7.05-6.97 (m, 1H), 5.00 (t, J 7.8 Hz, 1H), 4.55 (q, J 12.3 Hz, 2H), 4.27-4.14 (m, 3H), 4.10 (t, J 8.0 Hz, 1H), 4.02-3.96 (m, 1H), 3.87 (t, J 7.7 Hz, 1H), 3.70 (t, J 8.2 Hz, 1H), 2.83 (td, J 8.5, 6.6 Hz, 2H), 1.96-1.90 (m, 1H), 1.84-1.77 (m, 1H), 1.67 (d, J 13.4 Hz, 1H), 1.59 (d, J 11.2 Hz, 1H), 1.42-1.36 (m, 1H), 1.29-1.24 (m, 1H), 1.15 (t, J 7.5 Hz, 3H), 1.12-0.96 (m, 3H), 0.91-0.73 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 574, RT 2.17 minutes.

Example 86

(414) ##STR00095##

Ethyl 4-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl]-1-(methylsulfonyl)pyrrolidine-3-carboxylate (Trans Isomer)

(415) The title compound (1 mg, 1%), a white solid, was prepared from Intermediate 159 (327 mg, 0.31 mmol) and 3-ethylisoxazole-4-carboxylic acid (55 mg, 0.31 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, CD.sub.3OD) 9.18 (s, 1H), 7.29 (d, J 8.5 Hz, 1H), 7.13 (dd, J 8.5, 6.4 Hz, 1H), 5.05 (d, J 8.3 Hz, 1H), 4.54-4.49 (m, 1H), 4.29 (q, J 7.9 Hz, 1H), 3.84-3.61 (m, 6H), 3.03 (s, 3H), 2.88 (qd, J 7.5, 1.3 Hz, 2H), 2.06-1.93 (m, 2H), 1.82-1.74 (m, 1H), 1.69 (d, J 13.2 Hz, 1H), 1.43-1.31 (m, 2H), 1.22 (t, J 7.5 Hz, 3H), 1.19-0.91 (m, 4H), 0.89 (d, J 6.5 Hz, 3H), 0.67 (td, J 7.1, 0.8 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 604, RT 2.27 minutes.

Example 87

(416) ##STR00096##

Ethyl 1-acetyl-4-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)-methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-3-carboxylate (Trans Isomer)

(417) The title compound (3 mg, 2%), a white solid, was prepared from Intermediate 160 (183 mg, 0.31 mmol) and 3-ethylisoxazole-4-carboxylic acid (55 mg, 0.37 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, CD.sub.3OD) 9.18 (s, 1H), 7.29 (dd, J 8.5, 2.0 Hz, 1H), 7.05 (ddd, J 10.0, 8.5, 6.5 Hz, 1H), 5.05 (dd, J 8.3, 1.4 Hz, 1H), 4.27 (dq, J 24.9, 7.7 Hz, 1H), 4.04 (dd, J 8.0, 2.4 Hz, 1H), 4.01-3.56 (m, 6H), 2.88 (qd, J 7.5, 1.3 Hz, 2H), 2.16 (s, 3H), 2.06-1.92 (m, 2H), 1.78 (dt, J 13.1, 2.9 Hz, 1H), 1.69 (dt, J 12.8, 3.1 Hz, 1H), 1.44-1.29 (m, 2H), 1.22 (t, J 7.5 Hz, 3H), 1.19-0.91 (m, 4H), 0.89 (d, J 6.5 Hz, 3H), 0.83-0.64 (m, 3H). LCMS (Method 6): [M+H].sup.+ m/z 568, RT 2.09 minutes.

Example 88

(418) ##STR00097##

Ethyl 2-(2-{cyclooctyl[(2-ethylpyrazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-2-(pyridin-3-yl)acetate

(419) The title compound (24 mg, 25%), a white solid, was prepared from Intermediate 148 (80 mg, 0.17 mmol) and 2-ethylpyrazole-3-carboxylic acid (28 mg, 0.20 mmol) in accordance with Procedure A. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.79 (s, 1H), 8.86 (br d, J 5.6 Hz, 1H), 8.55 (br s, J 2.1 Hz, 1H), 8.47 (dt, J 4.8, 1.3 Hz, 1H), 7.71 (dq, J 8.0, 2.0 Hz, 1H), 7.47 (t, J 1.8 Hz, 1H), 7.37 (dd, J 8.0, 4.8 Hz, 1H), 7.29 (d, J 8.4 Hz, 1H), 7.06-6.96 (m, 2H), 5.51 (s, 1H), 5.07 (t, J 8.9 Hz, 1H), 4.45 (q, J 7.2 Hz, 2H), 4.18 (q, J 7.1 Hz, 2H), 2.46-2.36 (m, 1H), 1.81-1.22 (m, 17H), 1.16 (t, J 7.2 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 561, RT 2.40 minutes.

Example 89 (Procedure CC)

(420) ##STR00098##

Ethyl 2-(2-{cyclooctyl[(2-ethylpyrazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-2-(pyridin-4-yl)acetate

(421) To a solution of Intermediate 150 (44.5 mg, 0.10 mmol) and 1-ethyl-H-pyrazole-5-carboxylic acid (17.0 mg, 0.12 mmol), dissolved in DMF (2 mL), were added T3P® (0.06 mL, 0.1 mmol) and DIPEA (0.03 mL, 0.2 mmol). The reaction mixture was placed in a sealed vial and heated at 70° C. overnight, then partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was separated and re-extracted with EtOAc (10 mL). The organic layers were combined, and washed with water (10 mL) followed by 5% aqueous LiCl solution (10 mL), then dried over Na.sub.2SO.sub.4, and filtered under reduced pressure. The solvent was removed in vacuo. The isolated straw-coloured oil was purified by preparative HPLC to give, after freeze-drying, the title compound (mixture of diastereomers) (6 mg, 11%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 8.88 (s, 1H), 8.59-8.48 (m, 2H), 7.50-7.44 (m, 1H), 7.35-7.19 (m, 3H), 7.03-6.89 (m, 2H), 5.48 (s, 1H), 5.07 (t, J 8.8 Hz, 1H), 4.46 (q, J 7.1 Hz, 2H), 4.17 (q, J 7.1 Hz, 2H), 2.47-2.36 (m, 1H), 1.72-1.69 (m, 1H), 1.68-1.32 (m, 12H), 1.25-1.20 (m, 3H), 1.19-1.10 (m, 3H). LCMS (Method 6): [M+H].sup.+ m/z 561, RT 2.29 minutes.

Example 90

(422) ##STR00099##

N-{Cyclooctyl[4-fluoro-5-(pyridin-4-ylmethyl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(423) The title compound (5 mg, 14%), a white solid, was prepared from Intermediate 151 (39 mg, 0.076 mmol) and 3-methylisoxazole-4-carboxylic acid (16.7 mg, 0.13 mmol) in accordance with Procedure CC. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.80 (s, 1H), 9.43 (s, 1H), 8.95-8.78 (m, 1H), 8.52-8.28 (m, 2H), 7.30-7.17 (m, 3H), 7.11 (t, 1H), 5.08 (t, J 8.8 Hz, 1H), 4.08 (s, 2H), 2.44-2.34 (m, 4H), 1.79-1.19 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 476, RT 2.36 minutes.

Example 91

(424) ##STR00100##

N-[{5-[2-Amino-2-oxo-1-(pyridin-4-yl)ethyl]-4-fluoro-1H-benzimidazol-2-yl}-(cyclooctyl)methyl]-2-ethylpyrazole-3-carboxamide

(425) The title compound (mixture of diastereomers) (4.0 mg, 16%), a white solid, was prepared from Intermediate 153 (19 mg, 0.046 mmol) and 2-ethylpyrazole-3-carboxylic acid (12 mg, 0.086 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.15-12.57 (m, 1H), 9.10-8.69 (m, 1H), 8.56-8.38 (m, 2H), 7.93-7.62 (m, 1H), 7.47 (t, J 1.9 Hz, 1H), 7.42-7.09 (m, 5H), 7.09-6.91 (m, 1H), 5.31 (s, 1H), 5.18-4.98 (m, 1H), 4.45 (q, J 7.1 Hz, 2H), 2.43 (s, 1H), 1.79-1.21 (m, 17H). LCMS (Method 6): [M+H].sup.+ m/z 532, RT 1.84 minutes.

Example 92

(426) ##STR00101##

N-(Cyclooctyl{4-fluoro-5-[(5-methyl-1,3,4-oxadiazol-2-yl)(pyridin-4-yl)methyl]-1H-benzimidazol-2-yl}methyl)-2-ethylpyrazole-3-carboxamide

(427) The title compound (mixture of diastereomers) (2 mg, 2%), a white solid, was prepared from Intermediate 154 (80 mg, 0.16 mmol) and 2-ethylpyrazole-3-carboxylic acid (12 mg, 0.09 mmol) in accordance with Procedure A. LCMS (Method 6): [M+H].sup.+ m/z 571, RT 1.84 minutes. LCMS (Method 2): [M+H].sup.+ m/z 571, RT 2.08 minutes.

Example 93

(428) ##STR00102##

N-(Cyclooctyl{4-fluoro-5-[(5-methyl-1,3,4-oxadiazol-2-yl)(pyridin-4-yl)methyl]-1H-benzimidazol-2-yl}methyl)-3-methylisoxazole-4-carboxamide

(429) The title compound (mixture of diastereomers) (3 mg, 3%), a white solid, was prepared from Intermediate 154 (80 mg, 0.16 mmol) and 3-methylisoxazole-4-carboxylic acid (23 mg, 0.18 mmol) in accordance with Procedure A. LCMS (Method 6): [M+H].sup.+ m/z 558, RT 2.23 minutes. LCMS (Method 2): [M+H].sup.+ m/z 558, RT 2.02 minutes.

Example 94

(430) ##STR00103##

tert-Butyl 3-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)morpholine-4-carboxylate (Trans Isomer)

(431) To a solution of Intermediate 155 (48 mg, 0.07 mmol) in acetonitrile (1 mL) was added diethylamine (0.25 mL, 2.4 mmol). The mixture was stirred overnight, then concentrated in vacuo. The residue was filtered through an SCX column, washing with MeOH, then eluting with a 7N solution of NH.sub.3 in MeOH. The semi-pure material was dissolved in DCM (2 mL), then 3-ethylisoxazole-4-carboxylic acid (10 mg, 0.07 mmol), DIPEA (25 μL, 0.14 mmol) and HATU (34 mg, 0.09 mmol) were added. The mixture was stirred for 3 h at r.t., then partitioned between DCM and water. The organic layers were separated and dried over MgSO.sub.4, then concentrated in vacuo. The crude material was subject to preparative HPLC to yield the title compound (1:1 mixture of diastereomers) (12 mg, 29% overall). δ.sub.H (400 MHz, DMSO-d.sub.6) 12.94-12.69 (m, 1H), 9.43-9.42 (m, 1H), 8.86-8.78 (m, 1H), 7.33-7.16 (m, 2H), 5.30-5.26 (m, 1H), 5.02 (t, J 8.5 Hz, 1H), 4.08 (d, J 11.9 Hz, 1H), 3.95-3.88 (m, 1H), 3.83 (dd, J 11.9, 4.1 Hz, 1H), 3.78-3.70 (m, 1H), 3.53 (td, J 11.5, 3.3 Hz, 1H), 3.34-3.24 (m, 1H), 2.82 (q, J 7.6 Hz, 2H), 2.05-1.93 (m, 1H), 1.93-1.83 (m, 1H), 1.75-1.66 (m, 1H), 1.66-1.57 (m, 1H), 1.36-1.22 (m, 2H), 1.34-1.33 (m, 9H), 1.16-1.98 (m, 2H), 1.15 (td, J 7.5, 2.8 Hz, 3H), 0.96-0.77 (m, 2H), 0.85 (d, J 6.4 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 570, RT 2.66 minutes.

Examples 95 & 96

(432) ##STR00104##

tert-Butyl (3S)-3-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)-methyl}-4-fluoro-1H-benzimidazol-5-yl)morpholine-4-carboxylate (Trans Isomer) (Example 95)

tert-Butyl (3R)-3-(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)-methyl}-4-fluoro-1H-benzimidazol-5-yl)morpholine-4-carboxylate (Trans Isomer) (Example 96)

(433) Example 94 was subject to chiral HPLC (Waters Prep 100-SQD2 equipped with a Lux Cellulose-1 250×21.2 mm, 5 μm column), flow rate 100 mL/min, column temperature 40° C., eluting with MeOH (+0.1% NH.sub.4OH) and food fresh grade liquid C02 (gradient of 5-15%), to yield, after freeze drying, the title compounds (Peak 1, 2 mg; and Peak 2, 2 mg) as white solids.

(434) Peak 1: δ.sub.H (400 MHz, DMSO-d.sub.6) 12.94-12.69 (m, 1H), 9.42 (s, 1H), 8.86-8.78 (m, 1H), 7.33-7.16 (m, 2H), 5.30-5.26 (m, 1H), 5.02 (t, J 8.5 Hz, 1H), 4.08 (d, J 11.9 Hz, 1H), 3.95-3.88 (m, 1H), 3.83 (dd, J 11.9, 4.1 Hz, 1H), 3.78-3.70 (m, 1H), 3.53 (td, J 11.5, 3.3 Hz, 1H), 3.34-3.24 (m, 1H), 2.82 (q, J 7.6 Hz, 2H), 2.05-1.93 (m, 1H), 1.93-1.83 (m, 1H), 1.75-1.66 (m, 1H), 1.66-1.57 (m, 1H), 1.36-1.22 (m, 2H), 1.34 (s, 9H), 1.16-1.98 (m, 2H), 1.15 (td, J 7.5, 2.8 Hz, 3H), 0.96-0.77 (m, 2H), 0.85 (d, J 6.4 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 570, RT 2.66 minutes.

(435) Peak 2: δ.sub.H (400 MHz, DMSO-d.sub.6) 12.94-12.69 (m, 1H), 9.43 (s, 1H), 8.86-8.78 (m, 1H), 7.33-7.16 (m, 2H), 5.30-5.26 (m, 1H), 5.02 (t, J 8.5 Hz, 1H), 4.08 (d, J 11.9 Hz, 1H), 3.95-3.88 (m, 1H), 3.83 (dd, J 11.9, 4.1 Hz, 1H), 3.78-3.70 (m, 1H), 3.53 (td, J 11.5, 3.3 Hz, 1H), 3.34-3.24 (m, 1H), 2.82 (q, J 7.6 Hz, 2H), 2.05-1.93 (m, 1H), 1.93-1.83 (m, 1H), 1.75-1.66 (m, 1H), 1.66-1.57 (m, 1H), 1.36-1.22 (obscured m, 2H), 1.33 (s, 9H), 1.16-1.98 (m, 2H), 1.15 (td, J 7.5, 2.8 Hz, 3H), 0.96-0.77 (m, 2H), 0.85 (d, J 6.4 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 484, RT 2.65 minutes.

Example 97

(436) ##STR00105##

3-Ethyl-N-[(S)-{4-fluoro-5-[4-(2-hydroxyacetyl)morpholin-3-yl]-1H-benzimidazol-2-yl}-(4-methylcyclohexyl)methyl]isoxazole-4-carboxamide

(437) The title compound (mixture of diastereomers) (6 mg, 34%), a white solid, was prepared from Intermediate 156 (14 mg, 0.034 mmol) and 3-ethylisoxazole-4-carboxylic acid (12 mg, 0.084 mmol) in accordance with Procedure A, using DCM (3 mL) as solvent. δ.sub.H (400 MHz, CD.sub.3OD) 9.25-9.13 (m, 1H), 7.57-7.50 (m, 1H), 7.36 (d, J 8.5 Hz, 1H), 5.07 (d, J 8.2 Hz, 1H), 4.47-4.24 (m, 3H), 4.06-3.93 (m, 2H), 3.68 (td, J 11.6, 3.2 Hz, 1H), 2.90 (qd, J 7.5, 1.5 Hz, 2H), 2.09-1.91 (m, 2H), 1.85-1.76 (m, 1H), 1.76-1.66 (m, 1H), 1.48-1.41 (m, 1H), 1.41-1.29 (m, 1H), 1.28-1.09 (m, 5H), 1.08-0.88 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 528, RT 1.94 minutes.

Example 98

(438) ##STR00106##

tert-Butyl 2-(2-{(S)-[(2-ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)piperidine-1-carboxylate (Trans Isomer)

(439) The title compound (mixture of diastereomers) (72 mg, 13%), a white solid, was prepared from Intermediate 46 (130 mg, 0.44 mmol) and Intermediate 125 (140 mg, 0.45 mmol) in accordance with Procedure Y. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.69 (s, 1H), 8.84 (s, 1H), 7.47 (dd, J 2.1, 1.1 Hz, 1H), 7.29-7.20 (m, 1H), 7.04 (t, J 2.7 Hz, 1H), 6.95 (t, J 7.7 Hz, 1H), 5.45 (t, J 4.9 Hz, 1H), 5.00 (t, J 8.3 Hz, 1H), 4.50-4.39 (m, 2H), 4.02-3.93 (m, 1H), 3.17-3.08 (m, 1H), 2.11-0.75 (m, 31H). LCMS (Method 6): [M+H].sup.+ m/z 567, RT 2.84 minutes.

Example 99

(440) ##STR00107##

2-Ethyl-N-[{4-fluoro-5-[1-(2-hydroxyacetyl)piperidin-2-yl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]pyrazole-3-carboxamide (Trans Isomer)

(441) Example 98 (36 mg, 0.06 mmol) in MeOH (2 mL) was treated with 4M HCl in 1,4-dioxane (0.3 mL). The reaction mixture was stirred at r.t. overnight, then concentrated in vacuo. The residue was dissolved in MeOH and run down an SCX column, eluting with a 7N solution of NH.sub.3 in MeOH. The residue was taken up in DCM (1 mL) and triethylamine (9 μL, 0.06 mmol), and acetoxyacetyl chloride (7 μL, 0.06 mmol) was added. The reaction mixture was stirred overnight. Further aliquots of triethylamine (9 μL) and acetoxyacetyl chloride (7 μL) were added. The reaction mixture was left a further 24 h, then concentrated in vacuo. The residue was dissolved in MeOH, and NaOH (3 mg) in water (1 mL) was added. After 24 h, the reaction mixture was concentrated in vacuo, and partitioned between DCM and water. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified using preparative HPLC to yield the title compound (mixture of diastereomers) (7 mg, 21%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.97-12.59 (m, 1H), 8.90-8.70 (m, 1H), 7.47 (d, J 2.0 Hz, 1H), 7.24 (d, J 8.4 Hz, 1H), 7.03 (t, J 2.4 Hz, 1H), 6.98 (d, J 8.9 Hz, 1H), 5.65 (s, 1H), 4.98 (t, J 8.6 Hz, 1H), 4.58-4.34 (m, 4H), 4.23-4.19 (m, 1H), 3.20-3.10 (m, 1H), 2.18-1.83 (m, 6H), 1.74-1.38 (m, 7H), 1.25 (t, J 7.1 Hz, 3H), 1.06-1.02 (m, 3H), 0.95-0.80 (m, 4H). LCMS (Method 6): [M+H].sup.+ m/z 525, RT 2.10 minutes.

Example 100

(442) ##STR00108##

2-Ethyl-N-[(S′)-{5-[1-(2-ethylpyrazole-3-carbonyl)piperidin-2-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]pyrazole-3-carboxamide (Trans Isomer)

(443) Example 98 (36 mg, 0.06 mmol) in MeOH (2 mL) was treated with 4M HCl in 1,4-dioxane (0.3 mL). The reaction mixture was stirred at r.t. overnight, then concentrated in vacuo. The residue was dissolved in MeOH and eluted down an SCX column with a 7N solution of NH.sub.3 in MeOH. After concentration in vacuo, the residue was taken up in DCM (2 mL) and combined with 2-ethylpyrazole-3-carboxylic acid (10 mg, 0.06 mmol), in accordance with Procedure A, to give the title compound (mixture of diastereomers) (20 mg, 57%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.65 (s, 1H), 9.03-8.59 (m, 2H), 7.55-7.21 (m, 3H), 7.13 (t, J 7.7 Hz, 1H), 7.06-7.00 (m, 1H), 6.42-6.22 (m, 1H), 5.86-5.68 (m, 1H), 4.99 (t, J 8.6 Hz, 1H), 4.44 (q, J 7.1 Hz, 2H), 4.23-3.89 (m, 3H), 3.28-3.16 (m, 1H), 2.23 (d, J 13.9 Hz, 1H), 2.12-1.85 (m, 3H), 1.82-1.42 (m, 6H), 1.40-1.17 (m, 7H), 1.17-0.73 (m, 7H). LCMS (Method 6): [M+H].sup.+ m/z 589, RT 2.33

Example 101

(444) ##STR00109##

2-(2-{(S′)-[(2-Ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)-N,N-dimethylpiperidine-1-carboxamide (Trans Isomer)

(445) A mixture of Example 98 (36 mg, 0.06 mmol) in MeOH (2 mL) and 4M HCl in 1,4-dioxane (0.3 mL) was stirred at r.t. overnight. The reaction mixture was concentrated in vacuo, then dissolved in MeOH and flashed down an SCX column, eluting with a 7N solution of NH.sub.3 in MeOH. The residue was concentrated in vacuo, then taken up in DCM (1 mL). Triethylamine (9 μL, 0.06 mmol) and dimethylcarbamoyl chloride (6 μL, 0.06 mmol) were added. The reaction mixture was stirred for 1h at r.t., then further aliquots of triethylamine (3×9 μL) and dimethylcarbamoyl chloride (3×6 μL) were added over a 3 h period. The reaction mixture was left to stir overnight, then concentrated in vacuo.

(446) The residue was purified by reverse-phase HPLC to yield the title compound (mixture of diastereomers) (5 mg, 15%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.68-12.58 (s, 1H), 8.76-8.68 (s, 1H), 7.46 (d, J 2.0 Hz, 1H), 7.14-7.07 (m, 1H), 7.02-6.91 (m, 2H), 4.99-4.93 (m, 1H), 4.54-4.48 (m, 1H), 4.45 (q, J 7.0 Hz, 2H), 3.26-3.21 (m, 1H), 2.78 (d, J 1.5 Hz, 6H), 2.03-1.80 (m, 4H), 1.76-1.57 (m, 6H), 1.50-1.35 (m, 3H), 1.29-1.22 (m, 3H), 1.16-0.93 (m, 4H), 0.83 (d, J 6.5 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 538, RT 2.44 minutes.

Example 102

(447) ##STR00110##

N-[(S)-{5-[(2S)-2-(Dimethylcarbamoyl)piperidin-1-yl]-4-fluoro-1H-benzimidazol-2-yl}-(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(448) The title compound (30 mg, 13), a white solid, was prepared from Intermediate 157 (174 mg, 0.42 mmol) and 3-ethylisoxazole-4-carboxylic acid (75 mg, 0.51 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, CD.sub.3OD) 9.19 (s, 1H), 7.21 (d, J 8.7 Hz, 1H), 7.11 (dd, J 8.7, 7.3 Hz, 1H), 5.04 (d, J 8.3 Hz, 1H), 4.33 (dd, J 9.3, 3.3 Hz, 1H), 3.52-3.40 (m, 1H), 3.20 (s, 3H), 2.95-2.78 (m, 3H), 2.70 (s, 3H), 2.05-1.66 (m, 9H), 1.63-1.49 (m, 1H), 1.49-1.39 (m, 1H), 1.38-1.29 (m, 1H), 1.26-1.10 (m, 5H), 1.07-0.89 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 539, RT 2.30 minutes.

Example 103

(449) ##STR00111##

N-[(S)-{5-[2-(Dimethylamino)-2-oxoethyl]-4-fluoro-1H-benzimidazol-2-yl}(4-methyl-cyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(450) The title compound (9 mg, 7%), a white solid, was prepared from Intermediate 158 (102 mg, 0.29 mmol) and 3-ethylisoxazole-4-carboxylic acid (55 mg, 0.37 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, CD.sub.3OD) 9.20 (s, 1H), 7.30 (d, J 8.3 Hz, 1H), 7.11 (dd, J 8.3, 6.6 Hz, 1H), 5.07 (d, J 8.3 Hz, 1H), 3.94-3.86 (m, 2H), 3.16 (s, 3H), 2.99 (s, 3H), 2.90 (qd, J 7.6, 1.5 Hz, 2H), 2.08-1.93 (m, 2H), 1.84-1.75 (m, 1H), 1.75-1.66 (m, 1H), 1.49-1.40 (m, 1H), 1.40-1.28 (m, 1H), 1.28-1.08 (m, 5H), 1.03-0.92 (m, 2H), 0.91 (d, J 6.5 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 470, RT 2.05 minutes.

Example 104

(451) ##STR00112##

N-[(S)-{5-[2-(Dimethylcarbamoyl)phenyl]-4,6-difluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(452) The title compound (30 mg, 20%), a white solid, was prepared from Intermediate 161 (137 mg, 0.27 mmol) and 3-ethylisoxazole-4-carboxylic acid (39 mg, 0.28 mmol) in accordance with Procedure A, using DCM (5 mL) as solvent. δ.sub.H (373K, 400 MHz, DMSO-d.sub.6) 12.51 (s, 1H), 9.34 (s, 1H), 8.35 (s, 1H), 7.56-7.44 (m, 2H), 7.44-7.34 (m, 2H), 7.13 (d, J 9.5 Hz, 1H), 5.11 (t, J 7.1 Hz, 1H), 2.91-2.82 (m, 2H), 2.78 (s, 6H), 2.02 (dtt, J 11.5, 7.2, 3.6 Hz, 1H), 1.93-1.81 (m, 1H), 1.77-1.63 (m, 2H), 1.61-1.51 (m, 1H), 1.39-1.26 (m, 1H), 1.24-1.06 (m, 5H), 0.98-0.85 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 550.0, RT 2.42 minutes.

Example 105

(453) ##STR00113##

N-[(S)-{5-[2-(Dimethylcarbamoyl)phenyl]-4,6-difluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer)

(454) The title compound (31 mg, 21%), a white solid, was prepared from Intermediate 161 (137 mg, 0.27 mmol) and 2-ethylpyrazole-3-carboxylic acid (44 mg, 0.31 mmol) in accordance with Procedure A, using DCM (5 mL) as the solvent. δ.sub.H (400 MHz, DMSO-d6) 12.86 (s, 1H), 8.81 (s, 1H), 7.56-7.46 (m, 3H), 7.46-7.36 (m, 2H), 7.21 (s, 1H), 7.04 (d, J 2.0 Hz, 1H), 5.03 (t, J 8.6 Hz, 1H), 4.47 (qd, J 7.1, 1.4 Hz, 2H), 2.83-2.71 (m, 6H), 2.55 (s, 1H), 2.12-1.98 (m, 1H), 1.90 (d, J 12.8 Hz, 1H), 1.68 (dd, J 29.3, 12.7 Hz, 2H), 1.48-1.36 (m, 1H), 1.27 (td, J 7.1, 1.4 Hz, 4H), 1.20-0.98 (m, 2H), 0.98-0.77 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 549, RT 2.35 minutes.

Example 106

(455) ##STR00114##

N-(Cyclooctyl{4-fluoro-5-[2-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}methyl)-2-ethylpyrazole-3-carboxamide

(456) The title compound (2 mg, 6%), a white solid, was prepared from Intermediate 163 (31 mg, 0.064 mmol) and 4,4,5,5-tetramethyl-2-[2-(methylsulphonyl)phenyl]-1,3,2-dioxaborolane (23 mg, 0.08 mmol) in accordance with Procedure G. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.88 (s, 1H), 8.93 (s, 1H), 8.11 (d, J 7.9 Hz, 1H), 7.79-7.69 (m, 2H), 7.49-7.45 (m, 1H), 7.32 (s, 1H), 7.11 (s, 1H), 7.06-6.99 (m, 1H), 6.57-6.52 (m, 1H), 5.16-5.09 (m, 1H), 4.48 (q, J 7.5 Hz, 2H), 2.89 (s, 3H), 1.85-0.99 (m, 18H). LCMS (Method 6): [M+H].sup.+ m/z 552, RT 2.35 minutes.

Example 107

(457) ##STR00115##

N-(Cyclooctyl{4-fluoro-5-[3-(methanesulfonamido)phenyl]-1H-benzimidazol-2-yl}-methyl)-2-ethylpyrazole-3-carboxamide

(458) The title compound (3 mg, 8%), a white solid, was prepared from Intermediate 163 (31 mg, 0.06 mmol) and 3-(methylsulfonylamino)phenylboronic acid (16 mg, 0.08 mmol) in accordance with Procedure G. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.79 (s, 1H), 9.84 (s, 1H), 8.93 (d, J 8.7 Hz, 1H), 7.48 (d, J 2.0 Hz, 1H), 7.44-7.18 (m, 5H), 7.03 (d, J 2.1 Hz, 1H), 5.11 (t, J 8.9 Hz, 1H), 4.46 (q, J 7.1 Hz, 2H), 3.01 (s, 3H), 1.84-1.18 (m, 18H). LCMS (Method 6): [M+H].sup.+ m/z 567, RT 2.35 minutes.

Example 108

(459) ##STR00116##

N-[(S)-{5-[2-(Dimethylcarbamoyl)phenyl]-1H-imidazo[4,5-b]pyridin-2-yl}(4-methyl-cyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer)

(460) The title compound (14 mg, 32%), a white solid, was prepared from Intermediate 166 (38 mg, 0.086 mmol) and N,N-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (30 mg, 0.1 mmol) in accordance with Procedure G. δ.sub.H (400 MHz, DMSO-d) 13.04-12.64 (m, 1H), 8.94-8.76 (m, 1H), 8.05-7.87 (m, 1H), 7.77 (dd, J 7.7, 1.4 Hz, 1H), 7.55-7.35 (m, 4H), 7.31 (dd, J 7.4, 1.5 Hz, 1H), 7.04 (d, J=2.1 Hz, 1H), 5.06 (t, J 8.5 Hz, 1H), 4.45 (qd, J 7.2, 1.4 Hz, 2H), 2.87 (s, 3H), 2.62 (s, 3H), 2.12-2.01 (m, 1H), 1.91 (d, J 12.7 Hz, 1H), 1.71 (d, J 12.9 Hz, 1H), 1.63 (d, J 12.9 Hz, 1H), 1.44-1.35 (m, 1H), 1.35-1.19 (m, 4H), 1.18-1.01 (m, 2H), 0.99-0.74 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 514, RT 2.06 minutes.

Example 109

(461) ##STR00117##

N-(Cyclooctyl{6-[2-(dimethylcarbamoyl)phenyl]-4-methoxy-1H-imidazo[4,5-c]pyridin-2-yl}methyl)-2-methylpyrazole-3-carboxamide

(462) The title compound (18 mg, 12%), a white solid, was prepared from Intermediate 167 (130 mg, 0.27 mmol) and N,N-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (90 mg, 0.31 mmol) in accordance with Procedure G. δ.sub.H (400 MHz, DMSO-d.sub.6) 8.94 (d, J 8.8 Hz, 1H), 8.84 (s, 1H), 7.76 (dd, J 7.7, 1.3 Hz, 1H), 7.51-7.34 (m, 3H), 7.29 (dd, J 7.5, 1.4 Hz, 1H), 7.07 (d, J 2.1 Hz, 1H), 5.10 (t, J 8.7 Hz, 1H), 4.07-3.90 (m, 6H), 2.89 (s, 3H), 2.66 (s, 3H), 2.46-2.39 (m, 1H), 1.78-1.25 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 544, RT 2.25 minutes.

Example 110

(463) ##STR00118##

N-{Cyclooctyl[6-(3,6-dihydro-2H-pyran-4-yl)-7-fluoro-3H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(464) The title compound (5 mg, 17%), an off-white solid, was prepared from Intermediate 168 (60 mg, 0.06 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15 mg, 0.06 mmol) in accordance with Procedure G. H (300 MHz, DMSO-d.sub.6) 9.45 (s, 1H), 8.83 (s, 1H), 7.24 (d, J 8.3 Hz, 1H), 7.04 (t, J 7.6 Hz, 1H), 5.98 (s, 1H), 5.08 (t, J 8.5 Hz, 1H), 4.28-4.17 (m, 2H), 3.88-3.75 (m, 2H), 2.37 (s, 4H), 1.87-1.14 (m, 16H). LCMS (Method 6): [M+H].sup.+ m/z 467, RT 2.80 minutes.

Example 111

(465) ##STR00119##

N-{Cyclooctyl[4-fluoro-5-(piperidin-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(466) Intermediate 169 (463 mg, 0.59 mmol) was slurried in 4N HCl in 1,4-dioxane (5 mL, 20 mmol). The reaction mixture was stirred for 2 h, then concentrated in vacuo. The residue was dissolved in MeOH (2 mL) and eluted onto an Isolute SCX-2 cartridge (5 g), washing through with MeOH (20 mL). The material was released with a 4M solution of NH.sub.3 in MeOH (20 mL) and concentrated in vacuo. A portion (95 mg) of the recovered crude material was purified by preparative HPLC, and lyophilised, to give the title compound (49 mg, 18%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 9.45 (s, 1H), 8.95 (s, 1H), 7.39-7.16 (m, 1H), 7.14-6.97 (m, 1H), 5.08 (t, J 8.8 Hz, 1H), 3.19-2.87 (m, 4H), 2.72-2.54 (m, 2H), 2.45-2.29 (m, 4H), 1.88-1.14 (m, 18H). LCMS (Method 6): [M+H].sup.+ m/z 468, RT 1.79 minutes.

Example 112 (Method DD)

(467) ##STR00120##

N-{Cyclooctyl[4-fluoro-5-(piperazin-1-ylmethyl)-1H-benzimidazol-2-yl]methyl}-2-methylpyrazole-3-carboxamide

(468) To a solution of Example 33 (511 mg, 0.88 mmol) in DCM (5 mL) was added TFA (0.5 mL). The reaction mixture was stirred overnight, then concentrated in vacuo. The residue was loaded onto an SCX column in MeOH, eluting with a 7N solution of NH.sub.3 in MeOH. The residue was concentrated in vacuo to afford crude material (430 mg, quantitative). Purification of a portion (15 mg) of this material was carried out by preparative HPLC to give, after freeze-drying, the title compound (6 mg, 1%) as a white solid. δ.sub.H (400 MHz, CD.sub.3OD) 7.50 (d, J 2.2 Hz, 1H), 7.33 (d, J 8.3 Hz, 1H), 7.26 (dd, J 8.3, 6.4 Hz, 1H), 6.94 (d, J 2.2 Hz, 1H), 5.18 (d, J 8.7 Hz, 1H), 4.09 (s, 3H), 3.74 (d, J 1.8 Hz, 2H), 2.85 (t, J 5.1 Hz, 4H), 2.58-2.39 (m, 5H), 1.85-1.43 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 482, RT 1.70 minutes.

Example 113

(469) ##STR00121##

N-{Cyclooctyl[4-fluoro-5-(morpholin-3-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(470) The title compound (assumed 1:1 mixture of diastereomers) (4 mg, 17%), a white solid, was prepared from Example 43 (30 mg, 0.05 mmol) in accordance with Procedure DD. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.79 (s, 1H), 9.44 (s, 1H), 8.86 (s, 1H), 7.57-6.85 (m, 2H), 5.08 (t, J 8.7 Hz, 1H), 4.18 (d, J 9.9 Hz, 1H), 3.76 (d, J 10.9 Hz, 1H), 3.72-3.61 (m, 1H), 3.48 (td, J 10.5, 3.8 Hz, 1H), 3.23 (t, J 10.4 Hz, 1H), 2.92 (d, J 10.4 Hz, 2H), 2.73 (s, 1H), 2.36 (m, 4H), 1.93-1.11 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 470, RT 2.09 minutes.

Example 114

(471) ##STR00122##

N-{Cyclooctyl[4-fluoro-5-(1,4-oxazepan-3-yl)-1H-benzimidazol-2-yl]methyl}-3-methyl-isoxazole-4-carboxamide

(472) The title compound (assumed 1:1 mixture of diastereomers) (2 mg, 23%), a white solid, was prepared from Example 44 (18 mg, 0.02 mmol) in accordance with Procedure DD. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.92 (s, 1H), 9.46 (s, 1H), 8.94 (s, 1H), 7.30-7.12 (m, 2H), 5.07 (t, J 8.8 Hz, 1H), 4.28-4.13 (m, 1H), 3.98-3.62 (m, 3H), 3.40 (d, J 11.2 Hz, 1H), 3.18-2.98 (m, 1H), 2.84 (dt, J 13.7, 7.0 Hz, 1H), 2.36 (m, 4H), 1.87 (d, J 6.2 Hz, 2H), 1.79-1.17 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 484, RT 2.15 minutes.

Example 115

(473) ##STR00123##

N-[(S)-{5-[4-(Dimethylcarbamoyl)pyrrolidin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(474) The title compound (3 mg, 4%), a white solid, was prepared from Intermediate 172 (205 mg, 0.14 mmol) in accordance with Procedure DD, with purification by preparative HPLC. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.47 (s, 1H), 9.38 (d, J 1.0 Hz, 1H), 8.60 (d, J 9.5 Hz, 1H), 7.25-6.95 (m, 2H), 6.24 (s, 1H), 5.06 (d, J 8.4 Hz, 1H), 4.02-3.68 (m, 2H), 3.58-3.12 (m, 4H), 3.06-2.60 (m, 9H), 2.47-2.38 (m, 1H), 2.05-1.93 (m, 1H), 1.87 (d, J 13.0 Hz, 1H), 1.76-1.58 (m, 2H), 1.45 (d, J 13.0 Hz, 1H), 1.35-1.24 (m, 1H), 1.24-0.98 (m, 4H), 0.98-0.79 (m, 4H). LCMS (Method 6): [M+H].sup.+ m/z 525, RT 1.81 minutes.

Example 116 (Procedure EE)

(475) ##STR00124##

N-{Cyclooctyl[4-fluoro-5-(1-methylpiperidin-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(476) To a suspension of Example 111 (95 mg, 0.15 mmol) in THF (5 mL) was added formaldehyde (0.06 mL, 0.8 mmol). The reaction mixture was stirred at r.t. for 5 minutes, then sodium triacetoxyborohydride (67 mg, 0.30 mmol) was added. The reaction mixture was stirred overnight, then additional formaldehyde (0.06 mL, 0.8 mmol) was added. The mixture was stirred for 10 minutes, then further sodium triacetoxyborohydride (67 mg, 0.30 mmol) was added. The reaction mixture was quenched with saturated aqueous NaHCO.sub.3 solution (10 mL) and water (5 mL) and stirred for 5 minutes. The material was extracted with EtOAc (2×20 mL) and dried over Na.sub.2SO.sub.4, then filtered and concentrated in vacuo. Purification by preparative HPLC, followed by lyophilisation, gave the title compound (35 mg, 48%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.69 (s, 1H), 9.43 (s, 1H), 8.83 (d, J 8.7 Hz, 1H), 7.25 (d, J 8.3 Hz, 1H), 7.13-7.02 (m, 1H), 5.08 (t, J 8.5 Hz, 1H), 2.94-2.76 (m, 3H), 2.45-2.29 (m, 4H), 2.20 (s, 3H), 2.06-1.91 (m, 2H), 1.87-1.15 (m, 18H). LCMS (Method 6): [M+H].sup.+ m/z 482, RT 2.07 minutes.

Example 117

(477) ##STR00125##

N-(Cyclooctyl{4-fluoro-5-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-2-yl}-methyl)-2-methylpyrazole-3-carboxamide

(478) The title compound (19 mg, 18%), a white solid, was prepared from Example 112 (105 mg, 0.22 mmol) and formaldehyde in water (18.2 μL, 0.22 mmol, 36% by weight) in accordance with Procedure EE. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.96-12.65 (m, 1H), 8.95-8.77 (m, 1H), 7.46 (d, J 2.1 Hz, 1H), 7.40-7.20 (m, 1H), 7.16-7.09 (m, 1H), 7.07 (d, J 2.0 Hz, 1H), 5.07 (t, J 9.1 Hz, 1H), 4.02 (s, 3H), 3.62-3.52 (m, 2H), 2.45-2.22 (m, 8H), 2.12 (s, 3H), 1.75-1.28 (m, 15H). LCMS (Method 6): [M+H].sup.+ m/z 496, RT 1.73 minutes.

Example 118

(479) ##STR00126##

N-[Cyclooctyl(4-fluoro-5-{[4-(oxetan-3-yl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-2-methylpyrazole-3-carboxamide

(480) The title compound (2 mg, 2%), a white solid, was prepared from Example 112 (105 mg, 0.22 mmol) and 3-oxetanone (15 μL, 0.22 mmol) in accordance with Procedure EE. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.49 (s, 1H), 9.31 (s, 1H), 7.44 (d, J 2.1 Hz, 1H), 7.23-7.19 (m, 1H), 7.14-7.05 (m, 2H), 5.08 (t, J 8.8 Hz, 1H), 4.50 (t, J 6.5 Hz, 2H), 4.39 (t, J 6.1 Hz, 2H), 4.02 (s, 3H), 3.60 (s, 2H), 3.36 (q, J 6.5 Hz, 1H), 2.46-2.37 (m, 4H), 2.31-2.14 (m, 4H), 1.78-1.71 (m, 1H), 1.63-1.22 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 538, RT 1.97 minutes.

Example 119 (Procedure FF)

(481) ##STR00127##

N-{[5-(1-Acetylpiperidin-4-yl)-4-fluoro-1H-benzimidazol-2-yl](cyclooctyl)methyl}-3-methylisoxazole-4-carboxamide

(482) To a solution of Example 111 (95 mg, 0.15 mmol) and DIPEA (0.029 mL, 0.17 mmol) in DCM (3 mL) and THF (3 mL) at 0° C. was added acetyl chloride (0.011 mL, 0.15 mmol) in one portion. The reaction mixture was allowed to warm to r.t. Additional acetyl chloride (0.011 mL, 0.15 mmol) was added. The reaction mixture was stirred for a further 2 h, then concentrated in vacuo. The residue was dissolved in DCM (20 mL) and washed with saturated aqueous NaHCO.sub.3 solution (30 mL), then dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by preparative HPLC gave the title compound (29 mg, 38%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.63 (s, 1H), 9.43 (s, 1H), 8.83 (d, J 8.7 Hz, 1H), 7.25 (d, J 8.3 Hz, 1H), 7.15-6.99 (m, 1H), 5.08 (t, J 8.7 Hz, 1H), 4.65-4.44 (m, 1H), 4.08-3.82 (m, 1H), 3.24-3.07 (m, 2H), 2.69-2.55 (m, 1H), 2.45-2.31 (m, 4H), 2.04 (s, 3H), 1.86-1.11 (m, 18H). LCMS (Method 6): [M+H].sup.+ m/z 510, RT 2.13 minutes.

Example 120

(483) ##STR00128##

N-{[5-(4-Acetylmorpholin-3-yl)-4-fluoro-1H-benzimidazol-2-yl](cyclooctyl)methyl}-3-methylisoxazole-4-carboxamide

(484) The title compound (assumed 1:1 mixture of diasteromers) (6 mg, 820%), a white solid, was prepared from Example 113 (8 mg, 0.01 mmol) in accordance with Procedure FF. δ.sub.H (373K, 400 MHz, DMSO-d.sub.6) 12.36 (s, 1H), 9.34 (s, 1H), 8.34 (s, 1H), 7.32-7.23 (m, 2H), 5.50 (s, 1H), 5.16 (t, J 7.5 Hz, 1H), 4.19 (dt, J 11.9, 2.5 Hz, 1H), 4.02-3.91 (m, 2H), 3.87 (dd, J 11.9, 4.1 Hz, 1H), 3.57 (td, J 11.5, 3.4 Hz, 1H), 3.41-3.29 (m, 1H), 2.44-2.35 (m, 4H), 2.07-2.06 (m, 3H), 1.84-1.73 (m, 1H), 1.73-1.30 (m, 13H). LCMS (Method 6): [M+H].sup.+ m/z 512, RT 1.94 minutes.

Example 121 (Procedure GG)

(485) ##STR00129##

N-[{5-[(4-Acetylpiperazin-1-yl)methyl]-4-fluoro-1H-benzimidazol-2-yl}(cyclooctyl)-methyl]-2-methylpyrazole-3-carboxamide

(486) To a solution of Example 112 (105 mg, 0.22 mmol) in DCM (2 mL) were added triethylamine (30 μL, 0.22 mmol) and acetic anhydride (21 μL, 0.22 mmol). The reaction mixture was stirred at r.t. overnight, then concentrated in vacuo. The residue was purified by HPLC to yield the title compound (33 mg, 29%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 13.00-12.64 (m, 1H), 8.96-8.72 (m, 1H), 7.46 (d, J 2.0 Hz, 1H), 7.41-7.23 (m, 1H), 7.15 (t, J 7.3 Hz, 1H), 7.07 (d, J 2.0 Hz, 1H), 5.07 (t, J 8.8 Hz, 1H), 4.03 (s, 3H), 3.63 (s, 2H), 3.45-3.35 (m, 4H), 2.42-2.30 (m, 4H), 1.96 (s, 3H), 1.77-1.27 (m, 15H). LCMS (Method 6): [M+H].sup.+ m/z 524, RT 2.02 minutes.

Example 122

(487) ##STR00130##

N-[{5-[(4-Acetylpiperazin-1-yl)methyl]-1H-benzimidazol-2-yl}(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide

(488) The title compound (4 mg, 9%), a white solid, was prepared from Intermediate 174 (40 mg, 0.09 mmol) in accordance with Procedure GG. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.35 (d, J 8.6 Hz, 1H), 9.44 (d, J 0.6 Hz, 1H), 8.77 (d, J 6.6 Hz, 1H), 7.54-7.33 (m, 2H), 7.11 (t, J 9.0 Hz, 1H), 5.09 (t, J 8.6 Hz, 1H), 3.57 (s, 2H), 3.40 (s, 4H), 2.40-2.28 (m, 7H), 1.97 (s, 3H), 1.79-1.29 (m, 15H). LCMS (Method 6): [M+H].sup.+ m/z 507, RT 2.01 minutes.

Example 123

(489) ##STR00131##

N-[{6-[(4-Acetylpiperazin-1-yl)methyl]-4-methoxy-1H-imidazo[4,5-c]pyridin-2-yl}-(cyclooctyl)methyl]-2-methylpyrazole-3-carboxamide

(490) The title compound (2 mg, 4%), a white solid, was prepared from Intermediate 176 (53 mg, 0.11 mmol) in accordance with Procedure GG. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.94 (s, 1H), 8.61 (s, 1H), 7.45 (d, J 2.1 Hz, 1H), 7.02 (s, 1H), 6.73-6.60 (m, 1H), 5.03 (t, J 7.6 Hz, 1H), 4.03 (s, 3H), 3.91 (s, 3H), 3.55 (s, 2H), 3.49-3.36 (m, 4H), 2.48-2.39 (m, 4H), 2.39-2.35 (m, 1H), 1.97 (s, 3H), 1.77-1.26 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 537, RT 2.01 minutes.

Example 124

(491) ##STR00132##

N-[(5-{Acetyl[1-(methylsulfonyl)piperidin-4-yl]amino}-4-fluoro-1H-benzimidazol-2-yl)-(cyclooctyl)methyl]-3-methylisoxazole-4-carboxamide

(492) The title compound (25 mg, 25%), a white solid, was prepared from Example 32 (92 mg, 0.16 mmol) in accordance with Procedure GG. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.72 (s, 1H), 9.45-9.41 (m, 1H), 8.90-8.81 (m, 1H), 7.36 (d, J 8.4 Hz, 1H), 7.08 (t, J 7.7 Hz, 1H), 5.13 (td, J 8.7, 3.7 Hz, 1H), 4.58 (t, J 12.6 Hz, 1H), 3.55 (d, J 12.6 Hz, 2H), 2.89-2.75 (m, 5H), 2.46-2.34 (m, 4H), 2.00-1.24 (m, 21H). LCMS (Method 6): [M+H].sup.+ m/z 603, RT 2.21 minutes.

Example 125

(493) ##STR00133##

N-[(S)-(5-Cyano-4-fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methyl]-2-ethyl-pyrazole-3-carboxamide (Trans Isomer)

(494) The title compound (314 mg, 83%), a white solid, was prepared from Intermediate 177 (167 mg, 0.58 mmol) and 2-ethylpyrazole-3-carboxylic acid (105 mg, 0.71 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.21 (s, 1H), 8.74 (s, 1H), 7.47 (d, J 2.0 Hz, 1H), 7.45-7.33 (m, 2H), 7.02 (d, J 2.1 Hz, 1H), 5.04 (t, J 8.4 Hz, 1H), 4.45 (q, J 7.1 Hz, 2H), 2.04 (d, J 11.1 Hz, 2H), 1.85 (d, J 12.6 Hz, 1H), 1.69-1.55 (m, 2H), 1.41 (d, J 12.8 Hz, 1H), 1.25 (t, J 7.1 Hz, 3H), 1.18-0.96 (m, 3H), 0.94-0.76 (m, 4H). LCMS (Method 6): [M+H].sup.+ m/z 409, RT 2.23 minutes.

Examples 126 & 127

(495) ##STR00134##

N-{(S)-[5-(1-Acetamidoethyl)-4-fluoro-1H-benzimidazol-2-yl](4-methylcyclohexyl)-methyl}-2-ethylpyrazole-3-carboxamide (Trans Isomer) (Example 126)

N-{(S)-[5-(1-Acetamido-1-methylethyl)-4-fluoro-1H-benzimidazol-2-yl](4-methyl-cyclohexyl)methyl}-2-ethylpyrazole-3-carboxamide (Trans Isomer) (Example 127)

(496) To a solution of Example 125 (290 mg, 0.71 mmol) in anhydrous THF (5 mL) at −78° C. was added dropwise MeMgCl (3M in THF, 2.4 mL, 7.2 mmol). The reaction mixture was allowed to warm to r.t. over 1 h, then titanium(IV) isopropoxide (25.2 μL, 0.09 mmol) was added. The reaction mixture was stirred at r.t. overnight, then re-cooled to −78° C., and further MeMgCl (3M in THF, 2.4 mL, 7.2 mmol) was added. After further stirring at r.t. for 24 h, another aliquot of MeMgCl (3M in THF, 2.4 mL, 7.2 mmol) was added at −78° C. The reaction mixture was left another 24 h, then cooled to 0° C. MeOH (10 mL) was added dropwise, followed by the portionwise addition of NaBH.sub.4 (55 mg, 1.45 mmol). The reaction mixture was warmed to r.t. and stirred overnight, then quenched with water and concentrated in vacuo. The residue was partitioned between DCM and water. The organic layers were separated and washed with saturated aqueous NaHCO.sub.3 solution, then dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was flashed down an SCX column, eluting with a 7N solution of NH.sub.3 in MeOH, then concentrated in vacuo. The crude recovered material was purified further by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient). The recovered material was taken up in DCM (2 mL), with triethylamine (24 μL, 0.17 mmol) and acetic anhydride (16 μL, 0.17 mmol). The reaction mixture was stirred overnight, then concentrated in vacuo. The crude material was subject to purification using preparative HPLC, to yield the title compounds (Example 126, 16 mg, 20%; and Example 127, 2 mg, 2%) as white solids.

(497) Example 126: δ.sub.H (400 MHz, DMSO-d.sub.6) 13.00-12.50 (m, 1H), 8.95-8.65 (m, 1H), 8.33 (d, J 8.0 Hz, 1H), 7.47 (dd, J 2.1, 0.8 Hz, 1H), 7.24 (d, J 8.3 Hz, 1H), 7.17-7.08 (m, 1H), 7.06-7.00 (m, 1H), 5.28-5.25 (m, 1H), 4.97 (t, J 8.8 Hz, 1H), 4.49-4.38 (m, 2H), 2.04 (d, J 11.5 Hz, 1H), 1.90 (d, J 12.4 Hz, 1H), 1.81 (s, 3H), 1.70 (d, J 12.7 Hz, 1H), 1.61 (d, J 12.8 Hz, 1H), 1.48-1.15 (m, 8H), 1.14-0.97 (m, 2H), 0.96-0.72 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 469, RT 1.93 minutes.

(498) Example 127: δ.sub.H (400 MHz, CD.sub.3OD) 8.55 (s, 1H), 7.49 (d, J 2.1 Hz, 1H), 7.28-7.18 (m, 2H), 6.92 (d, J 2.1 Hz, 1H), 5.06 (d, J 8.6 Hz, 1H), 4.50 (qd, J 7.2, 2.8 Hz, 2H), 2.04-1.95 (m, 2H), 1.92 (s, 3H), 1.84-1.64 (m, 8H), 1.44-1.31 (m, 5H), 1.21-1.09 (m, 2H), 1.05-0.93 (m, 2H), 0.89 (d, J 6.5 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 483, RT 2.02 minutes.

Example 128 (Procedure HH)

(499) ##STR00135##

N-[Cyclooctyl(4-methoxy-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(500) To a solution of Intermediate 179 (25 mg, 0.05 mmol) in DCM (1 mL) were added triethylamine (7 μL, 0.05 mmol) and methanesulfonyl chloride (4 μL, 0.05 mmol). The reaction mixture was stirred at r.t. overnight, then concentrated in vacuo and subject to preparative HPLC purification, to give the title compound (7 mg, 24%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.66-12.24 (m, 1H), 9.44 (s, 1H), 8.91-8.57 (m, 1H), 7.16-6.88 (m, 1H), 6.76-6.55 (m, 1H), 5.16-4.94 (m, 1H), 3.90 (s, 3H), 3.57 (s, 2H), 3.23-3.00 (m, 4H), 2.87 (s, 3H), 2.50-2.44 (m, 4H), 2.40-2.24 (m, 4H), 1.81-1.26 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 573, RT 2.25 minutes.

Example 129

(501) ##STR00136##

N-[Cyclooctyl(4-fluoro-5-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)methyl]-2-methylpyrazole-3-carboxamide

(502) The title compound (39 mg, 32%), a white solid, was prepared from Example 112 (105 mg, 0.22 mmol) in accordance with Procedure HH. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.99-12.65 (m, 1H), 8.96-8.72 (m, 1H), 7.46 (d, J 2.0 Hz, 1H), 7.41-7.23 (m, 1H), 7.19-7.11 (m, 1H), 7.07 (d, J 2.1 Hz, 1H), 5.07 (t, J 9.0 Hz, 1H), 4.03 (s, 3H), 3.65 (s, 2H), 3.08 (d, J 5.4 Hz, 4H), 2.85 (s, 3H), 2.49-2.42 (m, 4H), 1.80-1.26 (m, 15H). LCMS (Method 6): [M+H].sup.+ m/z 560, RT 2.21 minutes.

Example 130

(503) ##STR00137##

N-[Cyclooctyl(5-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-benzimidazol-2-yl)-methyl]-3-methylisoxazole-4-carboxamide

(504) The title compound (6 mg, 13%), a white solid, was prepared from Intermediate 174 (40 mg, 0.09 mmol) in accordance with Procedure HH. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.40 (s, 1H), 9.44 (s, 1H), 8.80 (d, J 8.1 Hz, 1H), 7.58-7.28 (m, 2H), 7.11 (d, J 8.1 Hz, 1H), 5.09 (t, J 8.5 Hz, 1H), 3.59 (s, 2H), 3.09 (d, J 4.9 Hz, 4H), 2.86 (s, 3H), 2.46 (d, J 5.0 Hz, 4H), 2.37 (s, 3H), 1.83-1.19 (m, 15H). LCMS (Method 6): [M+H].sup.+ m/z 543, RT 2.20 minutes.

Example 131

(505) ##STR00138##

N-[Cyclooctyl(4-fluoro-5-{[1-(methylsulfonyl)piperidin-4-yl]methyl}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(506) The title compound (3 mg, 27%), a white solid, was prepared from Intermediate 181 (19 mg, 0.02 mmol) in accordance with Procedure HH. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.86-12.64 (m, 1H), 9.44 (s, 1H), 8.84-8.74 (m, 1H), 7.34-7.21 (m, 1H), 7.06-6.97 (m, 1H), 5.11-5.08 (m, 1H), 3.52 (d, J 11.7 Hz, 2H), 2.81 (s, 3H), 2.71-2.56 (m, 4H), 2.37-2.27 (m, 4H), 1.82-1.14 (m, 18H). LCMS (Method 6): [M+H].sup.+ m/z 560, RT 2.57 minutes.

Example 132

(507) ##STR00139##

N-[Cyclooctyl(4-fluoro-6-{[1-(methylsulfonyl)piperidin-4-yl]methyl}-1H-benzimidazol-2-yl)methyl]-3-methylisoxazole-4-carboxamide

(508) The title compound (12 mg, 10%), a white solid, was prepared from Intermediate 183 (100 mg, 0.21 mmol) in accordance with Procedure HH. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.61 (s, 1H), 9.43 (s, 1H), 8.82 (d, J 8.6 Hz, 1H), 7.09 (s, 1H), 6.82 (d, J 11.9 Hz, 1H), 5.08 (t, J 8.7 Hz, 1H), 3.52 (d, J 11.7 Hz, 2H), 2.82 (s, 3H), 2.62 (m, 4H), 2.37 (m, 4H), 1.80-1.12 (m, 19H). LCMS (Method 6): [M+H].sup.+ m/z 560, RT 2.64 minutes.

Example 133

(509) ##STR00140##

N-[Cyclooctyl(4-methoxy-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-imidazo-[4,5-c]pyridin-2-yl)methyl]-2-methylpyrazole-3-carboxamide

(510) The title compound (39 mg, 32%), a white solid, was prepared from Intermediate 176 (105 mg, 0.22 mmol) in accordance with Procedure HH. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.82 (s, 1H), 8.85 (s, 1H), 7.46 (d, J 2.1 Hz, 1H), 7.10 (s, 1H), 7.06 (d, J 2.1 Hz, 1H), 5.07 (t, J 8.4 Hz, 1H), 4.02 (s, 3H), 3.95 (s, 3H), 3.62 (s, 2H), 3.13 (t, J 4.9 Hz, 4H), 2.88 (s, 3H), 2.62-2.53 (m, 4H), 2.43-2.39 (m, 1H), 1.72-1.29 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 573, RT 2.19 minutes.

Example 134

(511) ##STR00141##

N-{Cyclooctyl[4-fluoro-5-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(512) The title compound (6 mg, 7%), a white solid, was prepared from Intermediate 168 (88 mg, 0.19 mmol) and potassium [(morpholin-4-yl)methyl]trifluoroborane (60 mg, 0.29 mmol) in accordance with Procedure R. δ.sub.H (300 MHz, DMSO-d.sub.6) 9.47 (s, 1H), 9.30 (d, J 8.9 Hz, 1H), 8.37 (s, 1H), 7.24 (d, J 8.3 Hz, 1H), 7.12 (dd, J 8.2, 6.4 Hz, 1H), 5.08 (t, J 9.0 Hz, 1H), 3.58 (d, J 1.6 Hz, 2H), 3.54 (t, J 4.6 Hz, 4H), 2.42-2.30 (m, 8H), 1.63-1.39 (m, 10H), 1.29-1.22 (m, 4H). LCMS (Method 6): [M+H].sup.+ m/z 484, RT 2.07 minutes.

Example 135

(513) ##STR00142##

N-{Cyclooctyl[4-fluoro-6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(514) The title compound (1 mg, 3%), a white solid, was prepared from Intermediate 184 (84 mg, 0.18 mmol) and potassium [(morpholin-4-yl)methyl]trifluoroborane (60 mg, 0.29 mmol) in accordance with Procedure MM. δ.sub.H (300 MHz, CD.sub.3OD) 9.18 (d, J 0.7 Hz, 1H), 7.32 (s, 1H), 7.02 (d, J 11.7 Hz, 1H), 5.14 (d, J 8.1 Hz, 1H), 3.69 (t, J 4.7 Hz, 4H), 3.61 (s, 2H), 2.51-2.44 (m, 4H), 2.42 (d, J 0.6 Hz, 3H), 2.10-2.02 (m, 1H), 1.76-1.43 (m, 14H). LCMS (Method 6): [M+H].sup.+ m/z 484, RT 2.13 minutes.

Example 136

(515) ##STR00143##

Methyl (2S)-1-[(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)-methyl}-4-fluoro-1H-benzimidazol-5-yl)methyl]pyrrolidine-2-carboxylate (Trans Isomer)

(516) The title compound (43 mg, 25%), a white solid, was prepared from Intermediate 185 (127 mg, 0.32 mmol) and 3-ethylisoxazole-4-carboxylic acid (58 mg, 0.41 mmol) in accordance with Procedure A, using DCM as solvent. δ.sub.H (500 MHz, DMSO-d.sub.6) 12.64 (br s, 1H), 9.41 (s, 1H), 8.82 (br s, 1H), 7.22 (br s, 1H), 7.15-7.07 (m, 1H), 5.02 (t, J 8.4 Hz, 1H), 3.90 (d, J 13.0 Hz, 1H), 3.76 (d, J 13.0 Hz, 1H), 3.57 (s, 3H), 3.24 (dd, J 8.9, 5.9 Hz, 1H), 2.91-2.77 (m, 3H), 2.39 (q, J 8.1 Hz, 1H), 2.07-1.92 (m, 2H), 1.88 (d, J 12.5 Hz, 1H), 1.84-1.74 (m, 1H), 1.74-1.65 (m, 3H), 1.65-1.58 (m, 1H), 1.40-1.22 (m, 2H), 1.15 (t, J 7.5 Hz, 3H), 1.12-1.00 (m, 2H), 0.95-0.78 (m, 5H). LCMS (Method 2): [M+H].sup.+ m/z 526, RT 2.11 minutes.

Example 137

(517) ##STR00144##

Methyl (2R)-1-[(2-{(S)-[(3-ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)-methyl}-4-fluoro-1H-benzimidazol-5-yl)methyl]pyrrolidine-2-carboxylate (Trans Isomer)

(518) The title compound (43 mg, 25%), a white solid, was prepared from Intermediate 186 (102 mg, 0.25 mmol) and 3-ethylisoxazole-4-carboxylic acid (47 mg, 0.33 mmol) in accordance with Procedure A, using DCM as solvent. δ.sub.H (500 MHz, DMSO-d.sub.6) 12.63 (br s, 1H), 9.41 (s, 1H), 8.81 (br s, 1H), 7.22 (br s, 1H), 7.15-7.07 (m, 1H), 5.02 (t, J 8.4 Hz, 1H), 3.90 (d, J 13.0 Hz, 1H), 3.76 (d, J 13.0 Hz, 1H), 3.57 (s, 3H), 3.25 (dd, J 8.9, 5.9 Hz, 1H), 2.90-2.75 (m, 3H), 2.39 (q, J 8.2 Hz, 1H), 2.10-1.93 (m, 2H), 1.92-1.84 (m, 1H), 1.84-1.58 (m, 5H), 1.41-1.22 (m, 2H), 1.15 (t, J 7.5 Hz, 3H), 1.12-0.99 (m, 2H), 0.95-0.78 (m, 5H). LCMS (Method 2): [M+H].sup.+ m/z 526, RT 2.11 minutes.

Example 138 (Procedure II)

(519) ##STR00145##

(2S)-1-[(2-{(S)-[(3-Ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)methyl]pyrrolidine-2-carboxylic Acid (Trans Isomer)

(520) LiOH.H.sub.2O (9.4 mg, 0.22 mmol) was added to a stirred solution of Example 136 (76 mg, 0.15 mmol) in 4:1 MeOH/water (3 mL). The mixture was stirred at 20° C. for 16 h. An additional portion of LiOH.H.sub.2O (9.4 mg, 0.22 mmol) was added, and stirring was continued at 20° C. for 48 h. The volatiles were removed in vacuo. The residue was diluted with water (30 mL), and the pH was adjusted to pH 4 with 1M aqueous HCl. The material was extracted successively with EtOAc (3×30 mL), then 2-methyltetrahydro-furan/EtOAc (1:1, 6×20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO.sub.4 and concentrated in vacuo. The resultant tan gum was purified by preparative HPLC to afford, after freeze-drying, the title compound (10.1 mg, 14%) as a white powder. δ.sub.H (500 MHz, DMSO-d.sub.6) 12.88 (br s, 1H), 9.43 (s, 1H), 8.94 (br s, 1H), 7.44-7.15 (m, 2H), 5.03 (t, J 8.5 Hz, 1H), 4.16 (d, J 13.0 Hz, 1H), 3.97 (d, J 13.2 Hz, 1H), 3.69-3.16 (obscured m, 1H), 3.12-3.04 (m, 1H), 2.88-2.76 (m, 2H), 2.66-2.58 (m, 1H), 2.15-2.04 (m, 1H), 1.99 (d, J 7.4 Hz, 1H), 1.93-1.82 (m, 2H), 1.81-1.56 (m, 4H), 1.41-1.21 (m, 2H), 1.15 (t, J 7.5 Hz, 3H), 1.11-0.99 (m, 2H), 0.95-0.75 (m, 5H). LCMS (Method 2): [M+H].sup.+ m/z 512, RT 2.32 minutes.

Example 139

(521) ##STR00146##

(2R)-1-[(2-{(S)-[(3-Ethylisoxazole-4-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)methyl]pyrrolidine-2-carboxylic Acid (Trans Isomer)

(522) The title compound (10 mg, 13%) was prepared from Example 137 (82 mg, 0.16 mmol) in accordance with Procedure II. δ.sub.H (500 MHz, DMSO-d.sub.6) 12.88 (br s, 1H), 9.43 (s, 1H), 8.94 (br s, 1H), 7.48-7.15 (m, 2H), 5.03 (t, J 8.5 Hz, 1H), 4.16 (d, J 13.1 Hz, 1H), 3.97 (d, J 13.1 Hz, 1H), 3.78-3.16 (obscured m, 1H), 3.12-3.05 (m, 1H), 2.88-2.76 (m, 2H), 2.67-2.57 (m, 1H), 2.09 (dq, J 12.5, 8.5 Hz, 1H), 2.03-1.94 (m, 1H), 1.92-1.82 (m, 2H), 1.80-1.57 (m, 4H), 1.40-1.22 (m, 2H), 1.15 (t, J 7.5 Hz, 3H), 1.11-1.00 (m, 2H), 0.94-0.77 (m, 5H). LCMS (Method 2): [M+H].sup.+ m/z 512, RT 2.32 minutes.

Example 140

(523) ##STR00147##

N-[(S)-(5-{[(2R)-2-(Dimethylcarbamoyl)pyrrolidin-1-yl]methyl}-4-fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(524) The title compound (30 mg, 47%), a white solid, was prepared from Example 139 (60 mg, 0.12 mmol) and dimethylamine hydrochloride (48 mg, 0.59 mmol) in accordance with Procedure A. δ.sub.H (500 MHz, DMSO-d.sub.6) 12.69 (br s, 1H), 9.41 (s, 1H), 8.82 (br s, 1H), 7.23 (br s, 1H), 7.17-7.05 (m, 1H), 5.01 (t, J 8.4 Hz, 1H), 3.84 (d, J 13.1 Hz, 1H), 3.64 (d, J 12.8 Hz, 1H), 3.45 (dd, J 8.5, 6.3 Hz, 1H), 2.98 (s, 3H), 2.91-2.76 (m, 6H), 2.31 (q, J 7.9 Hz, 1H), 2.11-1.92 (m, 2H), 1.88 (d, J 12.8 Hz, 1H), 1.76-1.58 (m, 5H), 1.40-1.22 (m, 2H), 1.15 (t, J 7.5 Hz, 3H), 1.18-0.99 (m, 2H), 0.94-0.78 (m, 5H). LCMS (Method 2): [M+H].sup.+ m/z 539, RT 2.04 minutes.

Example 141

(525) ##STR00148##

N-[{5-[2-(Dimethylcarbamoyl)phenyl]-4-fluoro-1H-benzimidazol-2-yl}(3,3-dimethyl-cyclohexyl)methyl]-3-methylisoxazole-4-carboxamide

(526) The title compound (1:1 mixture of diastereomers) (5.9 mg, 9%), a white solid, was prepared from Intermediate 117 (40 mg, 0.14 mmol) and Intermediate 34 (35 mg, 0.13 mmol) in accordance with Procedure Y. δ.sub.H (373K, 400 MHz, DMSO-d.sub.6) 12.42 (br s, 2H), 9.37 (s, 2H), 8.29 (s, 2H), 7.50-7.39 (m, 6H), 7.37-7.33 (m, 2H), 7.28-7.23 (m, 2H), 6.93 (t, J 6.8 Hz, 2H), 5.09 (t, J 7.2 Hz, 2H), 2.80-2.58 (br s, 12H), 2.41 (s, 6H), 2.33-2.22 (m, 2H), 1.89-0.92 (m, 16H), 0.93 (s, 6H), 0.89 (s, 3H), 0.88 (s, 3H). LCMS (Method 6): [M+H].sup.+ m/z 532, RT 2.25 minutes.

Example 142

(527) ##STR00149##

N-[{5-[2-(Dimethylcarbamoyl)phenyl]-4-fluoro-1H-benzimidazol-2-yl}(spiro[2.5]octan-7-yl)methyl]-3-ethylisoxazole-4-carboxamide

(528) The title compound (1:1 mixture of diastereomers) (3 mg, 4%), a white solid, was prepared from Intermediate 120 (41 mg, 0.14 mmol) and Intermediate 34 (35 mg, 0.13 mmol) in accordance with Procedure Y. δ.sub.H (373K, 400 MHz, DMSO-d.sub.6) 9.35 (s, 1H), 9.32 (s, 1H), 8.42-8.22 (s, 2H), 7.50-7.39 (m, 6H), 7.38-7.32 (m, 2H), 7.30-7.21 (m, 2H), 7.00-6.98 (m, 2H), 5.22-5.16 (m, 1H), 5.16-5.10 (m, 1H), 2.88 (ddd, J 7.8, 6.1, 2.0 Hz, 4H), 2.80-2.59 (v br s, 12H), 2.36-2.25 (m, 2H), 1.92-1.83 (m, 1H), 1.77-1.52 (m, 7H), 1.48-1.32 (m, 2H), 1.21 (td, J 7.5, 5.8 Hz, 6H), 1.14-1.04 (m, 2H), 0.91-0.79 (m, 4H), 0.31-0.16 (m, 7H), 0.16-0.10 (m, 1H). LCMS (Method 6): [M+H].sup.+ m/z 544, RT 2.34

Example 143

(529) ##STR00150##

N-[(3,3-Difluorocyclohexyl){5-[2-(dimethylcarbamoyl)phenyl]-4-fluoro-1H-benzimidazol-2-yl]methyl}-3-ethylisoxazole-4-carboxamide

(530) The title compound (1:1 mixture of diastereomers) (3.0 mg, 4%), a white solid, was prepared from Intermediate 123 (43 mg, 0.14 mmol) and Intermediate 34 (35 mg, 0.13 mmol) in accordance with Procedure Y. δ.sub.H (373K, 400 MHz, DMSO-d.sub.6) 9.38 (s, 2H), 8.28 (s, 2H), 7.48-7.22 (m, 8H), 7.21-7.12 (m, 2H), 6.77 (s, 2H), 5.21 (t, J 4.6 Hz, 2H), 2.97-2.87 (m, 4H), 2.80-2.67 (v br s, 6H), 2.67-2.56 (v br s, 6H), 2.49-2.35 (m, 2H), 2.22-1.04 (m, 16H), 1.24 (t, J 7.5 Hz, 6H). LCMS (Method 6): [M+H].sup.+ m/z 554, RT 2.09 minutes.

Example 144

(531) ##STR00151##

N-{[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](4-methylcyclohexyl)-methyl}-3-methylisoxazole-4-carboxamide

(532) The title compound (175 mg, quantitative), a white solid, was prepared from Intermediate 128 (137 mg, 0.39 mmol) and 3-methylisoxazole-4-carboxylic acid (51 mg, 0.4 mmol) in accordance with Procedure A. LCMS (Method 5): [M+H].sup.+ m/z 455, RT 1.38 minutes.

Examples 145 & 146

(533) ##STR00152##

N-{(S)-[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](4-methylcyclohexyl)-methyl}-3-methylisoxazole-4-carboxamide (Cis Isomer) (Example 145)

N-{(S)-[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](4-methylcyclohexyl)-methyl}-3-methylisoxazole-4-carboxamide (Trans Isomer) (Example 146)

(534) Example 144 was subject to preparative HPLC (Waters Prep 100-SQD2 equipped with a Lux Cellulose-4 250×21.2 mm, 5 μm column), flow rate 100 mL/min, column temperature 40° C., eluting with MeOH (+0.1% NH.sub.4OH) and food fresh grade liquid C02 (gradient of 5-15%) over 16 minutes, to yield, after freeze-drying, the title compounds (Example 145, 1.6 mg; Example 146, 2.0 mg) as white solids.

(535) Example 145: δ.sub.H (400 MHz, DMSO-d.sub.6) 13.00 (s, 1H), 9.45 (s, 1H), 8.87 (s, 1H), 7.27-7.13 (m, 1H), 7.07-6.91 (m, 1H), 5.28 (t, J 9.4 Hz, 1H), 3.96 (dd, J 11.3, 4.0 Hz, 2H), 3.53-3.43 (m, 2H), 3.20-3.10 (m, 1H), 2.36 (s, 3H), 2.27-2.17 (m, 1H), 1.86-1.72 (m, 2H), 1.69-1.06 (m, 11H), 0.91 (d, J 6.6 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 455, RT 2.23 minutes.

(536) Example 146: δ.sub.H (400 MHz, DMSO-d.sub.6) 12.81 (s, 1H), 9.46 (s, 1H), 8.86 (s, 1H), 7.24 (d, J 8.2 Hz, 1H), 7.05 (s, 1H), 5.01 (t, J 8.4 Hz, 1H), 3.96 (dd, J 11.3, 4.1 Hz, 2H), 3.53-3.43 (m, 2H), 3.24-3.08 (m, 1H), 2.36 (s, 3H), 2.03-1.92 (m, 1H), 1.92-1.57 (m, 7H), 1.40-1.17 (m, 2H), 1.16-0.97 (m, 2H), 0.96-0.77 (m, 2H), 0.85 (d, J 6.5 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 455, =2.24 minutes.

Example 147 (Procedure JJ)

(537) ##STR00153##

N-{Cycloheptyl[4-fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(538) To a solution of Intermediate 195 (103 mg, 0.29 mmol) in THF (2.5 mL) at −40° C. was added n-butyllithium (1.2M, 1.05 equiv.) dropwise over 5 minutes. The resulting dark yellow solution was stirred for 20 minutes at −40° C., then Intermediate 187 (134 mg, 0.58 mmol) in THF (2.5 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at −40° C. for 2 h, then warmed to r.t. and stirred for 1 h. Water (3 mL) was added, and the mixture was extracted with EtOAc (3×20 mL), then dried (MgSO.sub.4) and concentrated in vacuo. The crude residue was dissolved in MeOH (5 mL) at r.t., and 4N HCl in 1,4-dioxane (30.0 equiv.) was added. The mixture was stirred for 16 h, then concentrated in vacuo. The residue was purified by flash column chromatography, eluting with EtOAc/hexanes (50-100% gradient), then 10% MeOH in DCM. The resulting material was taken up in DMF (1 mL), and 3-methyl-4-isoxazolecarboxylic acid (1.05 equiv.), DIPEA (3.0 equiv.) and HATU (1.2 equiv.) were sequentially added at r.t. The reaction mixture was stirred for 16 h, then H.sub.2O (5 mL) and EtOAc (15 mL) were added. The layers were separated. The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×30 mL), then dried (MgSO.sub.4) and concentrated in vacuo. Purification by flash column chromatography, eluting with EtOAc/hexanes (30-100% gradient), followed by preparative HPLC, gave the title compound (9 mg, 31% overall) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.95-12.72 (m, 1H), 9.45 (s, 1H), 8.90-8.78 (m, 1H), 7.36-7.24 (m, 1H), 7.16-7.02 (m, 1H), 5.11 (t, J 8.5 Hz, 1H), 3.96 (dd, J 11.2, 3.7 Hz, 2H), 3.48 (td, J 11.6, 2.1 Hz, 2H), 3.24-2.94 (tt, J 11.8, 3.1 Hz, 1H), 2.36 (s, 3H), 2.34-2.23 (m, 1H), 1.91-1.15 (m, 16H). LCMS (Method 6): [M+H].sup.+ m/z 455, RT 2.20 minutes.

Example 148

(539) ##STR00154##

N-{Cyclohexyl[4-fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(540) The title compound (2 mg, 3%), a white solid, was prepared from Intermediate 195 (120 mg, 0.34 mmol), Intermediate 188 (148 mg, 0.68 mmol) and 3-methylisoxazole-4-carboxylic acid (25 mg, 0.19 mmol) in accordance with Procedure JJ. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.64 (s, 1H), 9.45 (s, 1H), 8.80 (s, 1H), 7.32-7.19 (m, 1H), 7.17-6.99 (m, 1H), 5.03 (t, J 8.5 Hz, 1H), 3.96 (dd, J 11.2, 4.0 Hz, 2H), 3.54-3.42 (m, 2H), 3.17 (tt, J 11.7, 3.5 Hz, 1H), 2.36 (s, 3H), 2.13-2.96 (m, 1H), 1.92-1.53 (m, 8H), 1.43-1.30 (m, 1H), 1.30-0.92 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 441, RT 2.20 minutes.

Example 149

(541) ##STR00155##

N-{Dispiro[2.0.24.13]heptan-7-yl[4-fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]methyl}-3-methylisoxazole-4-carboxamide

(542) The title compound (assumed mixture of diastereomers) (41 mg, 27%), a white solid, was prepared from Intermediate 195 (148 mg, 0.42 mmol), Intermediate 189 (189 mg, 0.84 mmol) and 3-methylisoxazole-4-carboxylic acid (25 mg, 0.19 mmol) in accordance with Procedure JJ. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.49 (s, 1H), 9.32 (s, 1H), 9.01 (s, 1H), 7.23 (s, 1H), 7.09 (t, J 7.7 Hz, 1H), 4.92 (t, J 8.5 Hz, 1H), 4.20-3.77 (m, 2H), 3.48 (t, J 11.8 Hz, 2H), 3.17 (t, J 12.2 Hz, 1H), 2.37 (s, 3H), 2.17 (d, J 9.9 Hz, 1H), 1.87-1.73 (m, 2H), 1.70-1.60 (m, 2H), 0.99-0.55 (m, 8H). LCMS (Method 6): [M+H].sup.+ m/z 451, RT 2.21 minutes.

Example 150

(543) ##STR00156##

N-{[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](norcaran-3-yl)methyl}-3-methylisoxazole-4-carboxamide

(544) The title compound (assumed mixture of diastereomers) (30 mg, 40%), a white solid, was prepared from Intermediate 195 (294 mg, 0.84 mmol), Intermediate 190 (382 mg, 1.68 mmol) and 3-methylisoxazole-4-carboxylic acid (22 mg, 0.17 mmol) in accordance with Procedure JJ. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.82-12.56 (m, 1H), 9.44 (s, 1H), 8.80-8.69 (m, 1H), 7.36-7.23 (m, 1H), 7.14-7.07 (m, 1H), 4.95-4.92 (m, 1H), 4.00-3.92 (m, 2H), 3.54-3.43 (m, 2H), 3.23-3.12 (m, 1H), 2.36 (s, 3H), 2.29-2.15 (m, 1H), 2.03-1.87 (m, 1H), 1.87-1.74 (m, 3H), 1.73-1.60 (m, 3H), 1.31-1.07 (m, 2H), 0.94-0.73 (m, 3H), 0.53 (td, J 8.8, 4.2 Hz, 1H), 0.05-0.03 (m, 1H). LCMS (Method 5): [M+H].sup.+ m/z 453, RT 1.09 minutes.

Example 151

(545) ##STR00157##

N-{[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](3-methylcyclohexyl)-methyl}-3-methylisoxazole-4-carboxamide

(546) The title compound (assumed mixture of diastereomers) (100 mg, 69%), a white solid, was prepared from Intermediate 195 (202 mg, 0.58 mmol), Intermediate 191 (264 mg, 1.15 mmol) and 3-methylisoxazole-4-carboxylic acid (43 mg, 0.33 mmol) in accordance with Procedure JJ. δ.sub.H (600 MHz, DMSO-d.sub.6) 12.92-12.69 (m, 1H), 9.43 (s, 1H), 8.87-8.74 (m, 1H), 7.37-7.25 (m, 1H), 7.14-7.07 (m, 1H), 5.24 (t, J 9.4 Hz, 1H), 3.96 (dd, J 11.7, 3.9 Hz, 2H), 3.48 (td, J 11.8, 2.1 Hz, 2H), 3.17 (tt, J 11.8, 3.7 Hz, 1H), 2.45-2.38 (m, 1H), 2.35 (s, 3H), 1.90-1.74 (m, 3H), 1.71-1.41 (m, 7H), 1.18-1.03 (m, 3H), 0.80 (d, J 6.8 Hz, 3H). LCMS (Method 5): [M+H].sup.+ m/z 455, RT 1.31 minutes.

Example 152

(547) ##STR00158##

N-{[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](norcaran-7-yl)methyl}-3-methylisoxazole-4-carboxamide

(548) The title compound (assumed mixture of diastereomers) (24 mg, 28%), a white solid, was prepared from Intermediate 195 (148 mg, 0.42 mmol), Intermediate 192 (192 mg, 0.84 mmol) and 3-methylisoxazole-4-carboxylic acid (26 mg, 0.20 mmol) in accordance with Procedure JJ. δ.sub.H (300 MHz, DMSO-d.sub.6) 12.59 (s, 1H), 9.43-9.40 (m, 1H), 9.14-9.02 (m, 1H), 7.26 (d, J 8.3 Hz, 1H), 7.09 (t, J 7.5 Hz, 1H), 5.10-4.63 (m, 1H), 3.96 (dd, J 11.3, 3.9 Hz, 2H), 3.49 (td, J 11.7, 2.1 Hz, 2H), 3.24-3.10 (m, 1H), 2.37-2.36 (m, 3H), 1.92-0.89 (m, 15H). LCMS (Method 6): [M+H].sup.+ m/z 453, RT 2.17 and 2.26 minutes (observable diastereomers).

Example 153

(549) ##STR00159##

N-{[4-Fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl](2-methylcyclohexyl)-methyl}-3-methylisoxazole-4-carboxamide

(550) The title compound (assumed mixture of diastereomers) (2 mg, 1%), a white solid, was prepared from Intermediate 195 (202 mg, 0.57 mmol), Intermediate 193 (264 mg, 1.15 mmol) and 3-methylisoxazole-4-carboxylic acid (12 mg, 0.09 mmol) in accordance with Procedure JJ. LCMS (Method 6): [M+H].sup.+ m/z 455, RT 2.18 minutes.

Example 154

(551) ##STR00160##

N-{(3,5-Dimethylcyclohexyl)[4-fluoro-5-(tetrahydropyran-4-yl)-1H-benzimidazol-2-yl]-methyl}-3-methylisoxazole-4-carboxamide

(552) The title compound (assumed mixture of diastereomers) (31 mg, 11%), a white solid, was prepared from Intermediate 195 (202 mg, 0.58 mmol), Intermediate 194 (281 mg, 1.15 mmol) and 3-methylisoxazole-4-carboxylic acid (47 mg, 0.37 mmol) in accordance with Procedure JJ. LCMS (Method 6): [M+H].sup.+ m/z 469.0, RT 2.55 minutes.

Example 155

(553) ##STR00161##

tert-Butyl 3-(4-fluoro-2-{(S)-(4-methylcyclohexyl)[(3-methylisoxazole-4-carbonyl)-amino]methyl}-1H-benzimidazol-5-yl)morpholine-4-carboxylate (Trans Isomer)

(554) The title compound (assumed mixture of diastereomers) (213 mg, 22%) was prepared from Intermediate 216 (300 mg, 0.67 mmol) and 3-methylisoxazole-4-carboxylic acid (81 mg, 0.67 mmol) in accordance with Procedure A, in DCM (12 mL) as solvent. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.74 (s, 1H), 9.46 (s, 1H), 8.82 (s, 1H), 7.25 (br s, 2H), 5.28 (d, J 2.8 Hz, 1H), 5.02 (t, J 8.4 Hz, 1H), 4.08 (d, J 11.8 Hz, 1H), 3.91 (dd, J 11.4, 3.7 Hz, 1H), 3.83 (dd, J 11.9, 4.1 Hz, 1H), 3.74 (app. d, J 11.9 Hz, 1H), 3.52 (td, J 11.5, 3.3 Hz, 1H), 3.32-3.32 (m, 1H), 2.36 (s, 3H), 2.04-1.94 (m, 1H), 1.94-1.85 (m, 1H), 1.75-1.66 (m, 1H), 1.66-1.57 (m, 1H), 1.41-1.22 (m, 2H), 1.34 (s, 9H), 1.14-0.98 (m, 2H), 0.96-0.78 (m, 2H), 0.85 (d, J 6.4 Hz, 3H). LCMS (Method 5): [M+H].sup.+ m/z 556, RT 1.39 minutes.

Example 156 (Procedure KK)

(555) ##STR00162##

Methyl 3-(4-fluoro-2-{(S)-(4-methylcyclohexyl)[(3-methylisoxazole-4-carbonyl)amino]-methyl}-1H-benzimidazol-5-yl)morpholine-4-carboxylate (Trans Isomer)

(556) To a solution of Example 155 (0.16 mmol) in DCM (2 mL) was added TFA (0.9 mL). The reaction mixture was stirred overnight, then concentrated in vacuo. The residue was passed through an SCX column, eluting initially with MeOH, then with a 7N solution of NH.sub.3 in MeOH. The washings were concentrated in vacuo, and taken up in DCM (2 mL). Triethylamine (22 μL, 0.16 mmol), followed by methyl chloroformate (10 μL, 0.2 mmol), were added at r.t. The mixture was stirred overnight, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to give the title compound (assumed mixture of diastereomers) (50 mg, 60.8% overall). δ.sub.H (400 MHz, DMSO-d.sub.6) 12.73 (s, 1H), 9.45 (s, 1H), 8.79 (s, 1H), 7.25 (br s, 2H), 5.32 (d, J 3.4 Hz, 1H), 5.00 (t, J 8.4 Hz, 1H), 4.10 (d, J 11.9 Hz, 1H), 3.92 (dd, J 11.4, 3.4 Hz, 1H), 3.86 (dd, J 11.9, 4.1 Hz, 1H), 3.83-3.77 (m, 1H), 3.60 (s, 3H), 3.58-3.50 (m, 1H), 3.42-3.35 (m, 1H), 2.36 (s, 3H), 2.04-1.92 (m, 1H), 1.92-1.85 (m, 1H), 1.76-1.66 (m, 1H), 1.66-1.57 (m, 1H), 1.41-1.21 (m, 2H), 1.17-0.98 (m, 2H), 0.95-0.78 (m, 2H), 0.85 (d, J 6.4 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 514, RT 2.07 minutes.

Example 157

(557) ##STR00163##

N-[(S)-{4-Fluoro-5-[4-(methylsulfonyl)morpholin-3-yl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide (Trans Isomer)

(558) The title compound (assumed mixture of diastereomers) (22 mg, 52%), a white solid, was prepared from Example 155 (0.08 mmol) and methanesulfonyl chloride (10 μL, 0.1 mmol) in accordance with Procedure KK. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.73 (s, 1H), 9.45 (s, 1H), 8.79 (s, 1H), 7.55-7.42 (m, 1H), 7.38-7.20 (m, 1H), 5.06-4.98 (m, 2H), 4.02-3.86 (m, 3H), 3.72 (td, J 11.6, 10.5, 3.7 Hz, 1H), 3.54-3.39 (m, 2H), 2.74 (s, 3H), 2.36 (s, 3H), 2.05-1.93 (m, 1H), 1.93-1.84 (m, 1H), 1.75-1.66 (m, 1H), 1.66-1.57 (m, 1H), 1.42-1.19 (m, 3H), 1.17-0.98 (m, 2H), 0.96-0.78 (m, 1H), 0.85 (d, J 6.4 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 534, RT 1.97 minutes.

Example 158

(559) ##STR00164##

N-[(S)-{4-Fluoro-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-3-yl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide (Trans Isomer)

(560) To a solution of Example 155 (0.10 mmol) in DCM (2 mL) was added TFA (0.9 mL). The reaction mixture was stirred overnight, then concentrated in vacuo. The residue was passed through an SCX column, eluting initially with MeOH, then with a 7N solution of NH.sub.3 in MeOH. The washings were concentrated in vacuo, and taken up in EtOH (2 mL). Triethylamine (60 μL, 0.40 mmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (35 mg, 0.21 mmol) were added. The reaction mixture was heated in a sealed tube at 130° C. overnight. A further aliquot of triethylamine (60 μL, 0.40 mmol) was added, and the reaction mixture was heated a further 60 h. After cooling, the reaction mixture was concentrated in vacuo. The residue was re-dissolved in DCM (10 mL) and water (10 mL). The aqueous layer was further extracted with DCM (3×10 mL). The organic layers were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), then MeOH/DCM (0-10% gradient), followed by reverse-phase HPLC, gave the title compound (assumed mixture of diastereomers) (18 mg, 34%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.74 (s, 1H), 9.45 (s, 1H), 8.74 (s, 1H), 7.40-7.11 (m, 2H), 5.09 (t, J 3.8 Hz, 1H), 5.00 (t, J 8.4 Hz, 1H), 4.02-3.93 (m, 3H), 3.77 (unresolved t, J 10.3 Hz, 1H), 3.68-3.58 (m, 1H), 3.57-3.50 (m, 1H), 2.36 (s, 3H), 2.28 (s, 3H), 2.03-1.91 (m, 1H), 1.91-1.81 (m, 1H), 1.74-1.65 (m, 1H), 1.65-1.57 (m, 1H), 1.43-1.20 (m, 3H), 1.17-0.96 (m, 2H), 0.95-0.77 (m, 1H), 0.85 (d, J 6.4 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 538, RT 1.92 minutes.

Example 159

(561) ##STR00165##

N-Ethyl-3-(4-fluoro-2-{(S)-(4-methylcyclohexyl)[(3-methylisoxazole-4-carbonyl)amino]-methyl}-1H-benzimidazol-5-yl)morpholine-4-carboxamide (Trans Isomer)

(562) The title compound (assumed mixture of diastereomers) (25 mg, 34%), a white solid, was prepared from Example 155 (0.14 mmol) and ethyl isocyanate (33 μL, 0.41 mmol) in accordance with Procedure KK. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.72 (s, 1H), 9.46 (s, 1H), 8.81 (s, 1H), 7.30-7.16 (m, 1H), 7.10-6.99 (m, 1H), 6.51 (s, 1H), 5.31 (s, 1H), 5.00 (t, J 8.4 Hz, 1H), 4.11 (d, J 11.6 Hz, 1H), 3.87 (dd, J 10.5, 2.2 Hz, 1H), 3.80 (dd, J 11.7, 3.9 Hz, 1H), 3.72 (d, J 12.7 Hz, 1H), 3.49 (td, J 11.3, 3.2 Hz, 1H), 3.36-3.25 (m, 1H), 3.06-2.98 (m, 2H), 2.36 (s, 3H), 2.03-1.92 (m, 1H), 1.92-1.83 (m, 1H), 1.75-1.66 (m, 1H), 1.65-1.57 (m, 1H), 1.40-1.16 (m, 2H), 1.16-1.00 (m, 2H), 0.96 (t, J 7.1 Hz, 3H), 0.92-0.77 (m, 2H), 0.85 (d, J 6.4 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 527, RT 1.65 minutes.

Example 160

(563) ##STR00166##

tert-Butyl 3-{2-[(S)-acetamido(4-methylcyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}morpholine-4-carboxylate

(564) To a solution of Intermediate 216 (50 mg, 0.11 mmol) in THF (0.5 mL) at 0° C. was added DIPEA (21 μL, 0.12 mmol), followed by acetyl chloride (10 μL, 0.1 mmol). The reaction mixture was stirred, and allowed to warm to r.t. A 7N solution of NH.sub.3 in MeOH (0.5 mL) was added, and the reaction mixture was concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), then MeOH/DCM (0-10% gradient), followed by reverse-phase HPLC, gave the title compound (assumed mixture of diastereomers) (3 mg, 6%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.82-12.55 (m, 1H), 8.40-8.30 (m, 1H), 7.37-7.17 (m, 2H), 5.28 (d, J 3.7 Hz, 1H), 4.87 (t, J 8.3 Hz, 1H), 4.13-4.04 (m, 1H), 3.95-3.88 (m, 1H), 3.83 (dd, J 11.9, 4.1 Hz, 1H), 3.74 (d, J 13.3 Hz, 1H), 3.53 (td, J 11.5, 3.2 Hz, 1H), 3.36-3.24 (m, 1H), 1.89 (s, 3H), 1.89-1.73 (m, 2H), 1.72-1.56 (m, 2H), 1.39-1.13 (m, 2H), 1.34 (s, 9H), 1.11-0.95 (m, 1H), 0.93-0.76 (m, 2H), 0.84 (d, J 6.6 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 489, RT 1.93 minutes.

Example 161

(565) ##STR00167##

tert-Butyl 3-(2-{(S)-[(3-{[dimethyl(oxo)-λ.SUP.6.-sulfanylidene]amino}benzoyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)morpholine-4-carboxylate (Trans Isomer)

(566) The title compound (assumed mixture of diastereomers) (10 mg, 14%) was prepared from Intermediate 216 (50 mg, 0.11 mmol) and 3-{[dimethyl(oxo)-).sup.6-sulfanylidene]amino}benzoic acid (24 mg, 0.11 mmol) in accordance with Procedure A, in DCM (2 mL) as solvent. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.70 (s, 1H), 8.56 (s, 1H), 7.44-7.37 (m, 2H), 7.27 (t, J 8.0 Hz, 1H), 7.26-7.12 (v br m, 2H), 7.12-7.06 (m, 1H), 5.27 (d, J 2.6 Hz, 1H), 5.01 (t, J 8.1 Hz, 1H), 4.09 (d, J 11.8 Hz, 1H), 3.91 (d, J 10.9, 3.2 Hz, 1H), 3.82 (dd, J 11.9, 4.0 Hz, 1H), 3.74 (d, J 12.9 Hz, 1H), 3.51 (dt, J 11.5, 3.1 Hz, 1H), 3.41-3.26 (m, 1H), 3.23 (2×s, 6H), 2.10-1.93 (m, 1H), 1.93-1.77 (m, 1H), 1.74-1.53 (m, 2H), 1.48-0.75 (m, 6H), 1.34 (s, 9H), 0.84 (d, J 6.4 Hz, 3H). LCMS (Method 5): [M+H].sup.+ m/z 642, RT 1.33 minutes.

Example 162

(567) ##STR00168##

N-[(S)-{5-[3-(Dimethylcarbamoyl)pyrazin-2-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide (Trans Isomer)

(568) The title compound (32 mg, 67%), a white solid, was prepared from Intermediate 199 (41.1 mg, 0.09 mmol) and 3-methylisoxazole-4-carboxylic acid (24 mg, 0.19 mmol) in accordance with Procedure A, using DCM (3 mL) as solvent. δ.sub.H (400 MHz, DMSO-d6) 12.89 (s, 1H), 9.46 (s, 1H), 8.93-8.74 (m, 2H), 8.69 (d, J 2.5 Hz, 1H), 7.58-7.35 (m, 1H), 7.29 (t, J 7.4 Hz, 1H), 5.06 (t, J 8.5 Hz, 1H), 2.93 (s, 3H), 2.89 (s, 3H), 2.37 (s, 3H), 2.11-1.97 (m, 1H), 1.92 (d, J 12.9 Hz, 1H), 1.72 (d, J 12.6 Hz, 1H), 1.64 (d, J 12.7 Hz, 1H), 1.42 (d, J 12.6 Hz, 1H), 1.37-1.23 (m, 1H), 1.20-1.02 (m, 2H), 0.97-0.79 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 520, RT 1.77 minutes.

Example 163

(569) ##STR00169##

N-[(S)-{5-[4-(Dimethylcarbamoyl)-2-methylpyrimidin-5-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide (Trans Isomer)

(570) The title compound (3 mg, 46%), a white solid, was prepared from Intermediate 202 (5.6 mg, 0.01 mmol) and 3-methylisoxazole-4-carboxylic acid (5.3 mg, 0.04 mmol) in accordance with Procedure A, using DCM (3 mL) as solvent. δ.sub.H (400 MHz, CD.sub.3OD) 9.22 (s, 1H), 8.88 (d, J 1.2 Hz, 1H), 7.45 (d, J 8.4 Hz, 1H), 7.22 (dd, J 8.4, 6.6 Hz, 1H), 5.09 (d, J 8.3 Hz, 1H), 2.95 (s, 3H), 2.89 (s, 3H), 2.80 (s, 3H), 2.43 (s, 3H), 2.12-1.97 (m, 2H), 1.88-1.78 (m, 1H), 1.78-1.69 (m, 1H), 1.52-1.44 (m, 1H), 1.44-1.31 (m, 1H), 1.27-1.12 (m, 2H), 1.10-0.95 (m, 2H), 0.92 (d, J 6.5 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 534, RT 1.82 minutes.

Example 164

(571) ##STR00170##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide (Trans Isomer)

(572) The title compound (16 mg, 57%), a white solid, was prepared from Intermediate 204 (24.4 mg, 0.049 mmol) and 3-methylisoxazole-4-carboxylic acid (21.3 mg, 0.17 mmol) in accordance with Procedure A, using DCM (3 mL) as solvent. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.24-12.60 (m, 1H), 9.47 (s, 1H), 9.03-8.77 (m, 1H), 8.71 (d, J 4.8 Hz, 2H), 7.63 (d, J 5.0 Hz, 1H), 7.59-7.37 (m, 1H), 7.18 (dd, J 8.2, 6.7 Hz, 1H), 5.06 (t, J 8.5 Hz, 1H), 4.38 (dt, J 24.0, 12.5 Hz, 4H), 2.37 (s, 3H), 2.09-1.96 (m, 1H), 1.92 (d, J 12.7 Hz, 1H), 1.72 (d, J 12.7 Hz, 1H), 1.64 (d, J 12.6 Hz, 1H), 1.38 (d, J 12.8 Hz, 1H), 1.35-1.23 (m, 1H), 1.18-1.01 (m, 2H), 0.97-0.80 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 567, RT 2.00 minutes.

Example 165

(573) ##STR00171##

N-[(S)-{4-Fluoro-5-[4-(3-hydroxy-3-methylazetidine-1-carbonyl)pyridin-3-yl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide (Trans Isomer)

(574) The title compound (9 mg, 19%), a white solid, was prepared from Intermediate 206 (41.8 mg, 0.086 mmol) and 3-methylisoxazole-4-carboxylic acid (25.5 mg, 0.20 mmol) in accordance with Procedure A, using DCM (3 mL) as solvent. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.87 (s, 1H), 9.46 (s, 1H), 8.98-8.74 (m, 1H), 8.74-8.62 (m, 2H), 7.50 (d, J 5.0 Hz, 1H), 7.39 (d, J 8.3 Hz, 1H), 7.12 (t, J 7.0 Hz, 1H), 5.62 (d, J 1.9 Hz, 1H), 5.05 (t, J 8.4 Hz, 1H), 3.71-3.60 (m, 3H), 3.51 (t, J 7.5 Hz, 1H), 2.37 (d, J 1.2 Hz, 3H), 2.08-1.96 (m, 1H), 1.91 (d, J 12.9 Hz, 1H), 1.72 (d, J 12.6 Hz, 1H), 1.63 (d, J 12.7 Hz, 1H), 1.45-1.21 (m, 3H), 1.17-1.00 (m, 4H), 0.97-0.80 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 561, RT 1.69 minutes.

Examples 166 & 167

(575) ##STR00172##

N-[(S)-{5-[4-(Azetidine-1-carbonyl)pyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide (Trans Isomer) (Example 16)

N-[(S)-{5-[4-(3-Chloropropylcarbamoyl)pyridin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide (Trans Isomer) (Example 16)

(576) To the inseparable mixture of Intermediates 208 and 209 (90 mg, 0.20 mmol) in DCM (3 mL) were added HATU (90 mg, 0.23 mmol), 3-methylisoxazole-4-carboxylic acid (50 mg, 0.39 mmol) and DIPEA (0.10 mL, 0.58 mmol). The reaction mixture was stirred at r.t. for 3 h, then partitioned between DCM (10 mL) and water (10 mL). The organic layers were separated and concentrated in vacuo. The resulting brown oil was purified by preparative HPLC to yield the title compounds (Example 166, 15 mg, 15%; Example 167, 10 mg, 9%) as white solids.

(577) Example 166: δ.sub.H (400 MHz, DMSO-d.sub.6) 12.85 (d, J 2.2 Hz, 1H), 9.46 (s, 1H), 8.88 (d, J 8.5 Hz, 1H), 8.72-8.64 (m, 2H), 7.54-7.46 (m, 1H), 7.39 (d, J 8.3 Hz, 1H), 7.20-7.11 (m, 1H), 5.12-5.01 (m, 1H), 3.87 (t, J 7.9 Hz, 4H), 2.37 (s, 3H), 2.21-2.09 (m, 2H), 2.09-1.97 (m, 1H), 1.93 (d, J 9.7 Hz, 1H), 1.73 (d, J 12.8 Hz, 1H), 1.65 (d, J 12.9 Hz, 1H), 1.42 (d, J 12.5 Hz, 1H), 1.31 (br s, 1H), 1.19-1.03 (m, 2H), 0.97-0.83 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 531, RT 1.83 minutes.

(578) Example 167: δ.sub.H (400 MHz, DMSO-d.sub.6) 12.86 (s, 1H), 9.46 (s, 1H), 8.98-8.73 (m, 1H), 8.72-8.60 (m, 2H), 8.42 (s, 1H), 7.49 (d, J 5.0 Hz, 1H), 7.33 (d, J 8.1 Hz, 1H), 7.10 (s, 1H), 5.03 (t, J 8.5 Hz, 1H), 3.16 (q, J 6.3 Hz, 2H), 2.36 (s, 3H), 1.96-1.78 (m, 2H), 1.76-1.60 (m, 4H), 1.40 (d, J 12.6 Hz, 1H), 1.36-1.22 (m, 2H), 1.18-1.02 (m, 2H), 0.96-0.81 (m, 6H). LCMS (Method 6): [M+H].sup.+ m/z 567, RT 1.95 minutes.

Example 168

(579) ##STR00173##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)-1-oxidopyridin-1-ium-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide (Trans Isomer)

(580) To Example 164 (11 mg, 0.02 mmol) in DCM (1 mL) was added MCPBA (7.4 mg, 0.033 mmol). The reaction mixture was stirred at r.t. for 2 h, then further MCPBA (3.2 mg) was added. The reaction mixture was stirred at r.t. for 1 h. Saturated aqueous NaHCO.sub.3 solution (2 mL), water (1 mL) and DCM (2 mL) were added. The organic layer was further diluted with DCM (5 mL), then filtered through a phase separation frit, washing with water and DCM. The organic phase was concentrated in vacuo. The resulting yellow oil was purified by preparative HPLC to give the title compound (4 mg, 36%) as a colourless film. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.85 (s, 1H), 9.46 (s, 1H), 8.87 (d, J 8.4 Hz, 1H), 8.30 (d, J 6.2 Hz, 2H), 7.65 (d, J 6.7 Hz, 1H), 7.37 (d, J 8.3 Hz, 1H), 7.13 (t, J 7.5 Hz, 1H), 5.04 (t, J 8.4 Hz, 1H), 4.48-4.22 (m, 4H), 2.36 (s, 3H), 1.99 (dtt, J 11.7, 7.2, 3.4 Hz, 1H), 1.89 (dt, J 12.7, 3.1 Hz, 1H), 1.70 (dd, J 12.6, 3.2 Hz, 1H), 1.66-1.57 (m, 1H), 1.41-1.34 (m, 1H), 1.28 (dq, J 8.3, 4.2, 3.8 Hz, 1H), 1.08 (dqd, J 20.6, 12.7, 3.3 Hz, 2H), 0.95-0.77 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 583, RT 1.56 minutes.

Example 169

(581) ##STR00174##

3-Ethyl-N-[(S)-{4-fluoro-5-[4-(methylsulfonimidoyl)pyridin-3-yl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]isoxazole-4-carboxamide (Trans Isomer)

(582) Intermediate 211 (109 mg, 0.22 mmol), (diacetoxyiodo)benzene (175 mg, 0.54 mmol) and ammonium carbamate (35 mg, 0.45 mmol) were placed in a flask containing a stirrer bar, then MeOH (1 mL) was added. The reaction mixture was stirred at r.t. for 4 h, then concentrated in vacuo. The residue was purified by flash column chromatography, eluting with MeOH/EtOAc (0-20% gradient), then further purified using preparative HPLC, to give the title compound (19 mg, 16%). δ.sub.H (400 MHz, DMSO-d.sub.6) 12.88 (s, 1H), 9.43 (s, 1H), 8.91 (d, J 5.2 Hz, 1H), 8.85 (s, 1H), 8.65-8.59 (m, 1H), 8.06 (d, J 5.2 Hz, 1H), 7.37-7.31 (m, 1H), 7.21-7.13 (m, 1H), 5.07 (t, J 8.5 Hz, 1H), 4.50 (s, 1H), 2.92-2.74 (m, 5H), 2.02 (d, J 11.2 Hz, 1H), 1.93-1.87 (m, 1H), 1.71 (d, J 13.0 Hz, 1H), 1.64 (d, J 12.8 Hz, 1H), 1.47-1.38 (m, 1H), 1.34-1.25 (m, 1H), 1.19-1.01 (m, 5H), 0.97-0.79 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 539, RT 1.86 minutes.

Example 170

(583) ##STR00175##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyridin-3-yl]-1H-imidazo[4,5-b]pyridin-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer)

(584) The title compound (5 mg, 12%), a white solid, was prepared from Intermediate 212 (36 mg, 0.07 mmol) and 3,3-difluoroazetidine hydrochloride (16 mg, 0.16 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.88 (s, 1H), 9.11 (s, 1H), 8.81-8.61 (m, 2H), 7.98-7.84 (m, 1H), 7.68-7.56 (m, 1H), 7.48 (d, J 2.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.04-6.95 (m, 1H), 5.05 (t, J 8.0 Hz, 1H), 4.65-4.37 (m, 4H), 4.15-3.99 (m, 2H), 2.08-1.98 (m, 1H), 1.90-1.78 (m, 1H), 1.69 (d, J 13.2 Hz, 1H), 1.61 (d, J 12.7 Hz, 1H), 1.56-1.34 (m, 2H), 1.30-1.03 (m, 5H), 1.02-0.74 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 563, RT 1.73 minutes.

Examples 171 & 172

(585) ##STR00176##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)-1-oxidopyridin-3-yl]-1H-imidazo[4,5-b]-pyridin-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer) (Example 171)

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)-1-oxidopyridin-3-yl]-4-hydroxy-1H-imidazo[4,5-b]pyridin-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer) (Example 172)

(586) To a solution of Example 170 (43 mg, 0.08 mmol) in DCM (2 mL) was added MCPBA (13 mg, 0.08 mmol). The reaction mixture was stirred at r.t. overnight. Further MCPBA (13 mg, 0.08 mmol) was added. The reaction mixture was stirred for a further 24 h, then partitioned between DCM and saturated aqueous Na.sub.2CO.sub.3 solution. The organic layers were separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compounds (Example 171, 1 mg, 2%; and Example 172, 2 mg, 4%) as white solids.

(587) Example 171: δ.sub.H (400 MHz, CD.sub.3OD) 8.80 (d, J 1.7 Hz, 1H), 8.41 (dd, J 6.6, 1.8 Hz, 1H), 8.10 (d, J 8.3 Hz, 1H), 7.68 (dd, J 18.2, 7.4 Hz, 2H), 7.50 (d, J 2.1 Hz, 1H), 6.94 (d, J 2.2 Hz, 1H), 5.14 (d, J 8.6 Hz, 1H), 4.55-4.42 (m, 4H), 4.14 (t, J 11.9 Hz, 2H), 2.16-2.07 (m, 1H), 2.02 (dq, J 12.7, 3.6, 3.0 Hz, 1H), 1.80 (dt, J 13.0, 3.0 Hz, 1H), 1.70 (dt, J 13.2, 3.1 Hz, 1H), 1.46 (dt, J 12.7, 3.1 Hz, 1H), 1.33 (t, J 7.2 Hz, 3H), 1.25-1.12 (m, 2H), 1.10-0.80 (m, 6H). LCMS (Method 6): [M+H].sup.+ m/z 579, RT 1.54 minutes.

(588) Example 172: δ.sub.H (400 MHz, CD.sub.3OD) 8.53 (d, J 1.8 Hz, 1H), 8.40 (dd, J 6.6, 1.8 Hz, 1H), 7.78-7.65 (m, 2H), 7.50 (d, J 2.2 Hz, 1H), 7.26 (d, J 8.1 Hz, 1H), 6.94 (d, J 2.1 Hz, 1H), 5.23 (d, J 8.1 Hz, 1H), 4.69-4.63 (m, 2H), 4.54 (q, J 7.2 Hz, 2H), 4.49-4.39 (m, 2H), 1.99-1.88 (m, 2H), 1.75 (d, J 13.0 Hz, 1H), 1.66 (d, J 13.1 Hz, 1H), 1.48 (d, J 13.1 Hz, 1H), 1.36 (t, J 7.2 Hz, 3H), 1.27-1.11 (m, 3H), 1.00-0.83 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 595, RT 1.25 minutes.

Example 173

(589) ##STR00177##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)furan-3-yl]-1H-imidazo[4,5-b]pyridin-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide (Trans Isomer)

(590) The title compound (139 mg, quantitative), a white solid, was prepared from Intermediate 215 (120 mg, 0.26 mmol) and 3,3-difluoroazetidine hydrochloride (55 mg, 0.53 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.10 (s, 1H), 8.81 (s, 1H), 8.34 (d, J 1.0 Hz, 1H), 8.04-7.95 (m, 1H), 7.67 (d, J 8.3 Hz, 1H), 7.47 (d, J 2.1 Hz, 1H), 7.23 (d, J 0.9 Hz, 1H), 7.08 (d, J 2.1 Hz, 1H), 5.04 (t, J 8.4 Hz, 1H), 4.99-4.77 (m, 2H), 4.57-4.35 (m, 2H), 4.02 (d, J 7.9 Hz, 3H), 2.11-2.00 (m, 1H), 1.90 (d, J 12.8 Hz, 1H), 1.71 (d, J 12.8 Hz, 1H), 1.63 (d, J 12.9 Hz, 1H), 1.42 (d, J 12.7 Hz, 1H), 1.34-1.23 (m, 1H), 1.20-1.02 (m, 2H), 1.00-0.67 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 538, RT 1.77 minutes.

Example 174

(591) ##STR00178##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)tetrahydrofuran-3-yl]-1H-imidazo[4,5-b]-pyridin-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide (Trans Isomer

(592) To a solution of Example 173 (104 mg, 0.19 mmol) in MeOH (5 mL) was added 10% Pd/C (10 mg). The reaction mixture was stirred under an atmosphere of hydrogen for 4 days, then filtered through Celite®, and concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and charged again with 10% Pd/C (10 mg), then stirred under an atmosphere of hydrogen for 7 days. The reaction mixture was filtered through Celite®, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (1 mg, 1%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 7.94 (d, J 8.3 Hz, 1H), 7.57-7.40 (m, 2H), 6.94 (d, J 2.2 Hz, 1H), 5.14-5.02 (m, 2H), 4.67 (t, J 12.0 Hz, 2H), 4.31 (t, J 12.0 Hz, 2H), 4.22 (dd, J 8.5, 6.9 Hz, 1H), 4.15 (t, J 8.3 Hz, 1H), 4.06 (s, 3H), 3.43-3.35 (m, 1H), 2.71 (dddd, J 12.3, 8.2, 6.2, 1.8 Hz, 1H), 2.18 (dt, J 12.4, 9.4 Hz, 1H), 2.12-1.96 (m, 2H), 1.79 (dt, J 12.9, 3.0 Hz, 1H), 1.70 (dt, J 13.0, 3.0 Hz, 1H), 1.44 (d, J 13.0 Hz, 1H), 1.39-1.30 (m, 1H), 1.25-1.10 (m, 2H), 1.06-0.86 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 542, RT 1.59 minutes.

Example 175

(593) ##STR00179##

Ethyl 3-(4-fluoro-2-{(S)-(4-methylcyclohexyl)[(3-methylisoxazole-4-carbonyl)amino]-methyl}-1H-benzimidazol-5-yl)morpholine-4-carboxylate (Trans Isomer)

(594) The title compound (18 mg, 40%), a white solid, was prepared from Example 155 (40 mg, 0.08 mmol) and ethyl chloroformate (16 μL, 0.16 mmol) in accordance with Procedure KK. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.93 (v br s, 1H), 9.48 (s, 1H), 9.10 (br s, 1H), 7.34-7.21 (m, 2H), 5.34 (d, J 3.7 Hz, 1H), 5.01 (t, J 8.6 Hz, 1H), 4.12 (d, J 11.9 Hz, 1H), 4.04 (q, J 7.1 Hz, 2H), 3.93 (dd, J 11.5, 3.7 Hz, 1H), 3.86 (dd, J 12.0, 4.1 Hz, 1H), 3.79 (d, J 13.4, 2.1 Hz, 1H), 3.54 (td, J 11.6, 3.2 Hz, 1H), 3.37-3.27 (m, 1H), 2.35 (s, 3H), 2.04-1.94 (m, 1H), 1.92-1.84 (m, 1H), 1.75-1.66 (m, 1H), 1.66-1.57 (m, 1H), 1.37-1.21 (m, 2H), 1.14 (t, J 7.1 Hz, 3H), 1.16-0.96 (m, 2H), 0.96-0.75 (m, 2H), 0.85 (d, J 6.5 Hz, 3H). LCMS (Method 5): [M+H].sup.+ m/z 528, RT 1.29 minutes.

Example 176

(595) ##STR00180##

N-[(S)-Cyclopentyl{5-[4-(3,3-difluoroazetidine-1-carbonyl)tetrahydrofuran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-3-ethylisoxazole-4-carboxamide

(596) The title compound (11 mg, 17%), a white solid, was prepared from Intermediate 221 (56 mg, 0.12 mmol) and 3,3-difluoroazetidine hydrochloride (25 mg, 0.0.24 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.78 (s, 1H), 9.40 (s, 1H), 8.85 (s, 1H), 7.26-7.19 (m, 1H), 7.11-7.02 (m, 1H), 5.05 (t, J 8.8 Hz, 1H), 4.56 (q, J 12.1 Hz, 2H), 4.31-4.15 (m, 3H), 4.11 (t, J 7.9 Hz, 1H), 4.06-3.99 (m, 1H), 3.88 (dt, J 15.4, 7.8 Hz, 2H), 3.70 (t, J 8.1 Hz, 1H), 2.83 (qd, J 7.5, 2.7 Hz, 2H), 2.63-2.56 (m, 1H), 1.81-1.73 (m, 1H), 1.69-1.35 (m, 6H), 1.28-1.22 (m, 1H), 1.15 (t, J 7.5 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 546, RT 1.61 minutes.

Example 177

(597) ##STR00181##

N-[(S)-Cyclopentyl(4-fluoro-5-{4-[3-hydroxy-3-(trifluoromethyl)azetidine-1-carbonyl]-tetrahydrofuran-3-yl}-1H-benzimidazol-2-yl)methyl]-3-ethylisoxazole-4-carboxamide

(598) The title compound (11 mg, 16%), a white solid, was prepared from crude Intermediate 221 (56 mg, 0.12 mmol) and 3-(trifluoromethyl)azetidin-3-ol (35 mg, 0.24 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.68 (s, 1H), 9.38 (d, J 2.2 Hz, 1H), 8.96 (s, 1H), 7.42-7.24 (m, 2H), 7.21-7.12 (m, 1H), 5.08-4.99 (m, 1H), 4.40-3.63 (m, 10H), 3.30-3.27 (m, 1H), 2.83 (tt, J 9.1, 7.5, 5.5 Hz, 2H), 2.60 (m, 1H), 1.88-1.78 (m, 1H), 1.64-1.37 (m, 5H), 1.28-1.20 (m, 1H), 1.15 (td, J 7.5, 4.6 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 594, RT 1.55 minutes.

Example 178

(599) ##STR00182##

N-[(S)-Cyclopentyl{4-fluoro-5-[4-(3-hydroxyazetidine-1-carbonyl)tetrahydrofuran-3-yl]-1H-benzimidazol-2-yl}methyl]-3-ethylisoxazole-4-carboxamide

(600) The title compound (6 mg, 10%), a white solid, was prepared from crude Intermediate 221 (56 mg, 0.12 mmol) and azetidin-3-ol (20 mg, 0.26 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.72 (s, 1H), 9.39 (s, 1H), 8.93 (s, 1H), 7.31-7.21 (m, 1H), 7.18-7.09 (m, 1H), 5.67-5.54 (m, 1H), 5.09-5.01 (m, 1H), 4.41-4.06 (m, 4H), 4.01-3.85 (m, 2H), 3.77 (q, J 7.0, 6.1 Hz, 1H), 3.67 (q, J 7.8 Hz, 1H), 3.49 (ddd, J 24.7, 9.6, 4.5 Hz, 2H), 3.28-3.21 (m, 1H), 2.83 (qd, J 7.5, 3.0 Hz, 2H), 2.65-2.56 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.33 (m, 5H), 1.29-1.22 (m, 1H), 1.15 (t, J 7.5 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 526, RT 1.31 minutes.

Example 179

(601) ##STR00183##

N-[(S)-Cyclopentyl{4-fluoro-5-[4-(morpholine-4-carbonyl)tetrahydrofuran-3-yl]-1H-benzimidazol-2-yl}methyl]-3-ethylisoxazole-4-carboxamide

(602) The title compound (6 mg, 9%), a white solid, was prepared from crude Intermediate 221 (56 mg, 0.12 mmol) and morpholine (20 μL, 0.20 mmol) in accordance with Procedure A. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.69 (s, 1H), 9.39 (s, 1H), 8.97 (s, 1H), 7.25 (d, J 8.3 Hz, 1H), 7.18 (t, J 7.4 Hz, 1H), 5.03 (t, J 9.0 Hz, 1H), 4.21 (t, J 8.2 Hz, 1H), 4.15-4.01 (m, 2H), 3.84 (dd, J 8.3, 6.6 Hz, 1H), 3.70 (t, J 7.3 Hz, 1H), 3.63 (d, J 7.4 Hz, 1H), 3.57-3.13 (m, 9H), 2.82 (qd, J 7.4, 2.7 Hz, 2H), 2.65-2.57 (m, 1H), 1.86-1.78 (m, 1H), 1.65-1.35 (m, 5H), 1.27-1.21 (m, 1H), 1.15 (t, J 7.5 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 540, RT 1.46 minutes.

Example 180

(603) ##STR00184##

N-[(S)-Cyclopentyl{5-[4-(3,3-difluoroazetidine-1-carbonyl)tetrahydrofuran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-3-methylisoxazole-4-carboxamide

(604) The title compound (14 mg, 19% yield), a white solid, was prepared from crude Intermediate 222 (58 mg, 0.14 mmol) and 3-methylisoxazole-4-carboxylic acid (22 mg, 0.16 mmol) in accordance with Procedure A, in DCM (2 mL) as solvent. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.71 (s, 1H), 9.41 (s, 1H), 8.94 (s, 1H), 7.27 (d, J 8.3 Hz, 1H), 7.17 (t, J 7.4 Hz, 1H), 5.03 (t, J 8.9 Hz, 1H), 4.57 (q, J 12.0 Hz, 2H), 4.30-4.16 (m, 3H), 4.14-4.04 (m, 2H), 3.94 (q, J 7.8 Hz, 1H), 3.85 (dd, J 8.5, 6.9 Hz, 1H), 3.71 (t, J 8.0 Hz, 1H), 2.65-2.56 (m, 1H), 2.35 (s, 3H), 1.87-1.78 (m, 1H), 1.63-1.37 (m, 6H), 1.27-1.19 (m, 1H). LCMS (Method 6): [M+H].sup.+ m/z 532, RT 1.48 minutes.

Example 181

(605) ##STR00185##

3,3-Difluorocyclobutyl N-[(S)-cyclopentyl{5-[4-(3,3-difluoroazetidine-1-carbonyl)-tetrahydrofuran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}methyl]carbamate

(606) To a solution of 3,3-difluorocyclobutanol (20 mg, 0.18 mmol) in DCM (1 mL) were added triethylamine (40 μL, 0.3 mmol) and N,N′-disuccinimidyl carbonate (75 mg, 0.29 mmol). The reaction mixture was stirred at r.t. for 30 minutes, then a solution of Intermediate 222 (60 mg, 0.14 mmol) in DCM (1 mL) was added dropwise. After stirring for 80 minutes, the reaction mixture was partitioned between DCM and water. The organic layers were separated, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (12 mg, 15%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 7.35 (d, J 8.4 Hz, 1H), 7.26 (dd, J 8.4, 6.4 Hz, 1H), 4.64 (d, J 9.4 Hz, 1H), 4.48 (q, J 11.7 Hz, 2H), 4.32-4.20 (m, 3H), 4.04 (dt, J 11.7, 7.6 Hz, 2H), 3.94 (t, J 8.0 Hz, 1H), 3.86 (t, J 10.9 Hz, 1H), 3.38-3.33 (m, 1H), 2.95 (dtd, J 17.9, 13.3, 12.6, 6.6 Hz, 2H), 2.73-2.45 (m, 3H), 1.91 (dd, J 12.7, 5.8 Hz, 1H), 1.74-1.40 (m, 6H), 1.27 (d, J 11.9 Hz, 1H). LCMS (Method 6): [M+H].sup.+ m/z 557, RT 1.66 minutes.

Example 182

(607) ##STR00186##

N-[(S)-{5-[3-(3,3-Difluoroazetidine-1-carbonyl)-1H-pyrazol-4-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide (Trans Isomer

(608) The title compound (3 mg, 5%) was prepared from Intermediate 225 (50 mg, 0.10 mmol) and Intermediate 226 (35 mg, 0.13 mmol) in accordance with Procedure G. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.15 (s, 1H), 8.78 (s, 1H), 7.93 (s, 1H), 7.45 (d, J 2.1 Hz, 1H), 7.27-7.19 (m, 1H), 7.13-7.02 (m, 2H), 5.01 (t, J 8.4 Hz, 1H), 4.79-4.65 (m, 2H), 4.39 (t, J 12.6 Hz, 2H), 4.02 (s, 3H), 2.07-2.00 (m, 1H), 1.88 (d, J 12.7 Hz, 1H), 1.70 (d, J 12.7 Hz, 1H), 1.62 (d, J 12.8 Hz, 1H), 1.40 (d, J 12.5 Hz, 1H), 1.32-1.25 (m, 1H), 1.15-1.01 (m, 2H), 0.95-0.78 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 555, RT 1.68 minutes.

Example 183

(609) ##STR00187##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)-2-methylpyrimidin-5-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide (Trans Isomer

(610) The title compound (6 mg, 10%) was prepared from Intermediate 225 (50 mg, 0.10 mmol) and Intermediate 227 (35 mg, 0.12 mmol) in accordance with Procedure G. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.86 (s, 1H), 8.91-8.78 (m, 2H), 7.46 (d, J 2.1 Hz, 1H), 7.38 (d, J 8.2 Hz, 1H), 7.22-7.16 (m, 1H), 7.08 (d, J 2.1 Hz, 1H), 5.02 (t, J 8.6 Hz, 1H), 4.70 (t, J 12.3 Hz, 2H), 4.46 (t, J 12.4 Hz, 2H), 4.02 (s, 3H), 2.73 (s, 3H), 2.11-2.02 (m, 1H), 1.92 (d, J 12.8 Hz, 1H), 1.71 (d, J 12.7 Hz, 1H), 1.63 (d, J 12.8 Hz, 1H), 1.38 (d, J 12.7 Hz, 1H), 1.33-1.25 (m, 1H), 1.15-1.01 (m, 2H), 0.98-0.71 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 581, RT 1.85 minutes.

Example 184

(611) ##STR00188##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyrimidin-5-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide (Trans Isomer

(612) The title compound (11 mg, 19%) was prepared from Intermediate 225 (50 mg, 0.10 mmol) and Intermediate 228 (35 mg, 0.13 mmol) in accordance with Procedure G. δ.sub.H (400 MHz, DMSO-d.sub.6) 12.90 (s, 1H), 9.27 (s, 1H), 9.03 (s, 1H), 8.83 (s, 1H), 7.46 (d, J 2.1 Hz, 1H), 7.42-7.36 (m, 1H), 7.22-7.14 (m, 1H), 7.07 (d, J 2.1 Hz, 1H), 5.03 (t, J 8.5 Hz, 1H), 4.70 (t, J 12.2 Hz, 2H), 4.47 (t, J 12.4 Hz, 2H), 4.02 (s, 3H), 2.09-2.01 (m, 1H), 1.91 (d, J 12.6 Hz, 1H), 1.71 (d, J 12.8 Hz, 1H), 1.63 (d, J 12.9 Hz, 1H), 1.40 (d, J 12.6 Hz, 1H), 1.33-1.25 (m, 1H), 1.16-1.02 (m, 2H), 1.02-0.75 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 567, RT 1.78 minutes.

Example 185

(613) ##STR00189##

N-[(S)-(5-{[Dimethyl(oxo)-λ.SUP.6.-sulfanylidene]amino}-4-fluoro-1H-benzimidazol-2-yl)(4-methylcyclohexyl)methyl]-3-ethylisoxazole-4-carboxamide (Trans Isomer)

(614) TFA (0.75 mL, 10.1 mmol) was added to a solution of Intermediate 232 (90 mg, 0.16 mmol) in DCM (0.75 mL). The reaction mixture was stirred at 20° C. under air for 2 days, then partitioned between DCM (10 mL) and saturated aqueous Na.sub.2CO.sub.3 solution (10 mL). The phases were separated using a hydrophobic frit, and the aqueous phase was extracted with DCM (2×10 mL). The organic filtrate was concentrated in vacuo. The residue was dissolved in acetonitrile (1.5 mL). Aqueous NH.sub.3 (35%, 0.5 mL) was added, and the mixture was stirred at 20° C. under air for 30 minutes. The volatiles were removed in vacuo. The resultant tan powder was dissolved in DCM (2 mL) and adsorbed onto an SCX-2 column (2 g), which was eluted sequentially with DCM, MeOH and a 1M solution of ammonia in MeOH. The ammonia-MeOH fractions were combined and concentrated in vacuo. The resultant tan powder was dissolved in DCM (1 mL). A solution of 3-ethyl-isoxazole-4-carboxylic acid (41 mg, 0.29 mmol), HATU (116 mg, 0.31 mmol) and DIPEA (0.08 mL, 0.46 mmol) in DCM (1.0 mL), pre-mixed at 20° C. under N.sub.2 for 30 minutes, was added. The reaction mixture was stirred at 20° C. under nitrogen for 16 h, then diluted with DCM (10 mL), and quenched with saturated aqueous Na.sub.2CO.sub.3 solution (5 mL) and water (5 mL). The biphasic mixture was stirred at 20° C. for 30 minutes, then the organic phase was separated using a hydrophobic frit. The aqueous layer was extracted with DCM (2×10 mL), and the organic filtrate was concentrated in vacuo. The resultant orange viscous oil was separated by preparative HPLC to afford, after freeze-drying, the title compound (14.9 mg, 19%) as a white powder. δ.sub.H (353K, 250 MHz, DMSO-d.sub.6) 12.16 (br s, 1H), 9.33 (s, 1H), 8.38 (br s, 1H), 7.20-7.04 (m, 1H), 6.94 (dd, J 8.3, 7.7 Hz, 1H), 5.07 (t, J 7.5 Hz, 1H), 3.16 (s, 6H), 2.85 (q, J 7.5 Hz, 2H), 2.11-1.81 (m, 2H), 1.80-1.59 (m, 2H), 1.56-1.42 (m, 1H), 1.40-0.77 (m, 11H). uPLCMS (Method 9): [M+H].sup.+ m/z 476, RT 2.55 minutes.

Example 186

(615) ##STR00190##

3-(2-{(S′)-[(2-Ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-7-fluoro-3H-imidazo[4,5-c]pyridin-6-yl)-N,N-dimethylpyridine-4-carboxamide (Trans Isomer)

(616) DIPEA (58 μL, 0.33 mmol) was added to a stirred suspension of Intermediate 237 (53 mg, 0.13 mmol), 1-ethyl-1H-pyrazole-5-carboxylic acid (28 mg, 0.20 mmol) and HATU (82 mg, 0.22 mmol) in anhydrous DCM (1.8 mL). The mixture was stirred at 20° C. under N.sub.2 for 16 h, then diluted with DCM (10 mL) and quenched with saturated aqueous Na.sub.2CO.sub.3 solution (10 mL). The organic phase was separated using a hydrophobic frit, and the aqueous layer was extracted with DCM (2×10 mL). The organic filtrate was concentrated in vacuo. The resultant tan gum was separated by flash column chromatography, eluting with EtOAc/heptane (0-100% gradient). The resultant tan powder was combined with Intermediate 229 (45 mg, 0.23 mmol). The reagents were suspended in a mixture of 1,4-dioxane (0.6 mL) and a 2M aqueous Na.sub.2CO.sub.3 solution (0.2 mL, 0.40 mmol), and the suspension was sparged with N.sub.2 whilst sonicating for 5 minutes. Pd.sub.2(dba).sub.3 (2.6 mg, 2.84 μmol) and XPhos (2.7 mg, 5.66 μmol) were added, and the suspension was sparged with nitrogen whilst sonicating for 5 minutes. The reaction mixture was sealed under N.sub.2 and heated at 100° C. for 16 h. The mixture was re-treated four times with Intermediate 229 (45 mg, 0.23 mmol), twice with 2M aqueous sodium carbonate solution (0.2 mL, 0.40 mmol), and three times with Pd.sub.2(dba).sub.3 (2.6 mg, 2.84 μmol) and XPhos (2.7 mg, 5.66 μmol), whilst heating at 110° C. for 54 h. After cooling to r.t., the mixture was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO.sub.4 and concentrated in vacuo. The resultant brown viscous oil was purified by preparative HPLC to afford, after freeze-drying, the title compound (1.1 mg, 2%) as an off-white powder. δ.sub.H (500 MHz, CDCl.sub.3) 11.71 (br s, 1H), 9.11-8.88 (m, 1H), 8.73 (d, J 5.0 Hz, 1H), 8.62 (s, 0.5H), 8.05 (s, 0.5H), 7.55-7.08 (m, 3H), 6.75 (s, 0.5H), 6.58 (s, 0.5H), 5.32-4.89 (m, 1H), 4.76-4.44 (m, 2H), 3.39-2.81 (m, 6H), 1.97-1.85 (m, 1H), 1.82-1.14 (obs. m, 10H), 1.12-0.95 (m, 2H), 0.94-0.67 (m, 5H). uPLCMS (Method 9): [M+H].sup.+ m/z 533, RT 2.66 minutes.

Example 187

(617) ##STR00191##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)morpholin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-3-methylisoxazole-4-carboxamide (Trans Isomer)

(618) To a solution of Example 155 (0.17 mmol) in DCM (2 mL) was added TFA (0.9 mL). The reaction mixture was stirred overnight, then concentrated in vacuo. The residue was passed through an SCX column, eluting initially with MeOH, then with a 7N solution of NH.sub.3 in MeOH. The washings were concentrated in vacuo, then taken up in DCM (3 mL) and stirred with triethylamine (0.05 mL, 0.40 mmol) and Intermediate 230 (70.0 mg, 0.35 mmol). The reaction mixture was stirred at r.t. for 6 h, then additional triethylamine (0.05 mL, 0.40 mmol) and Intermediate 230 (70.0 mg, 0.35 mmol) were added. The reaction mixture was re-treated with triethylamine (0.05 mL, 0.40 mmol) and Intermediate 230 (70.0 mg, 0.35 mmol) on two further occasions at 17 h intervals. A 7N solution of NH.sub.3 in MeOH (1.5 mL) was added, and the mixture was stirred vigorously for 16 h, then concentrated in vacuo. The residue was subject to purification by flash column chromatography, eluting with EtOAc/hexanes (0-100% gradient) then MeOH/DCM (0-10% gradient), to furnish the title compound (mixture of diastereomers) (48 mg, 48%). δ.sub.H (400 MHz, DMSO-d.sub.6) 12.79 (s, 1H), 9.46 (s, 1H), 8.97 (s, 1H), 7.37-7.30 (m, 1H), 7.29-7.22 (m, 1H), 5.26 (s, 1H), 5.00 (t, J 8.7 Hz, 1H), 4.39 (q, J 12.5 Hz, 2H), 4.22 (q, J 12.2 Hz, 2H), 4.12 (unresolved dd, J 12.0, 1.2 Hz, 1H), 3.89-3.81 (m, 2H), 3.61-3.46 (m, 2H), 3.38-3.26 (m, 1H), 2.35 (s, 3H), 2.04-1.84 (m, 2H), 1.75-1.67 (m, 1H), 1.66-1.57 (m, 1H), 1.39-1.21 (m, 2H), 1.16-0.98 (m, 2H), 0.96-0.77 (m, 2H), 0.85 (d, J 6.4 Hz, 3H). LCMS (Method 6): [M+H].sup.+ m/z 575, RT 1.85 minutes.

Example 188

(619) ##STR00192##

N-[(S)-{2-[4-(3,3-difluoroazetidine-1-carbonyl)pyridin-3-yl]-7H-purin-8-yl}(4-methyl-cyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer)

(620) A sealed tube was charged with Intermediate 240 (52 mg, 0.09 mmol) and 3-boronopyridine-4-carboxylic acid (37 mg, 0.22 mmol) in 1,4-dioxane (0.6 mL) and 2M aqueous Na.sub.2CO.sub.3 solution (0.16 mL, 0.33 mmol). The suspension was sparged with N.sub.2 whilst sonicating for 5 minutes. Pd.sub.2(dba).sub.3 (2.6 mg, 0.003 mmol) and XPhos (2.2 mg, 0.004 mmol) were added, and the suspension was further sparged with N.sub.2 whilst sonicating for 5 minutes. The reaction mixture was sealed and heated at 100° C. for 18 h. The reaction mixture was re-treated four times with 3-boronopyridine-4-carboxylic acid (37 mg, 0.22 mmol), twice with 2M aqueous Na.sub.2CO.sub.3 solution (0.16 mL, 0.33 mol) and four times with Pd.sub.2(dba).sub.3 (2.6 mg, 0.003 mmol) and XPhos (2.2 mg, 0.004 mmol), whilst heating at 110° C. for 60 h. After cooling, the mixture was further diluted with 2M aqueous Na.sub.2CO.sub.3 solution (2 mL) and extracted with EtOAc (3×5 mL). The pH of the aqueous layer was adjusted to pH 4 using 6M aqueous HCl. The aqueous layer was extracted with 1:1 2-methyltetrahydrofuran/EtOAc (3×5 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, and the solvent was concentrated in vacuo. The resulting pink solid was purified by flash column chromatography (SNAP Ultra C18 12 g), eluting with water (+0.1% formic acid)/acetonitrile (10-100% gradient). The resulting off-white solid (5.7 mg) was suspended in DMF (1 mL). HATU (7.1 mg, 0.02 mmol) and DIPEA (10 μL, 0.06 mmol) were added, and the reaction mixture was stirred at 20° C. for 10 minutes. 3,3-Difluoroazetidine hydrochloride (1:1) (2.3 mg, 0.017 mmol) was added, and the reaction mixture was stirred for 18 h at 20° C. The reaction mixture was re-treated twice with HATU (10 mg, 0.026 mmol), DIPEA (10 μL, 0.06 mmol) and 3,3-difluoro-azetidine hydrochloride (1:1) (5 mg, 0.038 mmol), whilst stirring at 20° C. for 24 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford, after freeze-drying, the title compound (1.0 mg, 1%) as a white solid. δ.sub.H (500 MHz, CDCl.sub.3) 13.41 (br s, 1H), 10.17 (s, 1H), 9.08 (s, 1H), 8.88 (d, J 4.9 Hz, 1H), 7.49 (d, J 2.0 Hz, 1H), 7.43 (d, J 4.9 Hz, 1H), 6.97 (d, J 8.5 Hz, 1H), 6.65 (d, J 2.0 Hz, 1H), 5.33-5.22 (m, 1H), 4.68-4.62 (m, 2H), 4.59 (q, J 7.2 Hz, 2H), 4.36-4.29 (m, 2H), 2.24-2.18 (m, 1H), 1.98-1.89 (m, 1H), 1.82-1.75 (m, 1H), 1.75-1.69 (m, 2H), 1.43 (t, J 7.2 Hz, 3H), 1.34-1.30 (m, 1H), 1.24-1.14 (m, 2H), 1.02-0.93 (m, 2H), 0.88 (d, J 6.5 Hz, 3H). uPLCMS (Method 9): [M+H].sup.+ m/z 564, RT 2.97 minutes.

Example 189

(621) ##STR00193##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyridin-3-yl]-1H-imidazo[4,5-b]pyrazin-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer)

(622) A sealed tube was charged with Intermediate 241 (96 mg, 0.21 mmol), and 3-boronopyridine-4-carboxylic acid (93 mg, 0.5 mmol) in 1,4-dioxane (1 mL) and 2M aqueous sodium carbonate solution (0.37 mL, 0.73 mmol). The suspension was sparged with N.sub.2 whilst sonicating for 5 minutes. Pd.sub.2(dba).sub.3 (5.7 mg, 0.06 mmol) and XPhos (5.0 mg, 0.01 mmol) were added, and the suspension was sparged with N.sub.2 whilst sonicating for 5 minutes. The reaction mixture was sealed and heated at 100° C. for 18 h. The reaction mixture was re-treated four times with 3-boronopyridine-4-carboxylic acid (93 mg, 0.5 mmol), twice with 2M aqueous sodium carbonate solution (0.37 mL, 0.73 mmol), and four times with Pd.sub.2(dba).sub.3 (5.7 mg, 0.006 mmol) and XPhos (5.0 mg, 0.01 mmol), whilst heating at 110° C. for 60 h. After cooling, the mixture was diluted with 2M aqueous sodium carbonate solution (2 mL) and extracted with EtOAc (3×5 mL). The pH of the aqueous layer was adjusted to pH 4 using 6M HCl. The aqueous layer was extracted with 1:1 2-methyltetrahydrofuran/EtOAc (3×5 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, and the solvent was concentrated in vacuo. The resulting off-white solid was separated by flash column chromatography (SNAP Ultra C18 12 g), eluting with water (+0.1% formic acid)/acetonitrile (10-100% gradient). The resulting yellow solid (13 mg) was suspended in DMF (1 mL). HATU (16 mg, 0.042 mmol) and DIPEA (23 μL, 0.13 mmol) were added, and the reaction mixture was stirred at 20° C. for 10 minutes. 3,3-Difluoroazetidine hydrochloride (1:1) (5.1 mg, 0.039 mmol) was added, and the reaction mixture was stirred for 18 h at 20° C. The reaction mixture was re-treated twice with HATU (20 mg, 0.05 mmol), DIPEA (25 μL, 0.143 mmol) and 3,3-difluoroazetidine hydrochloride (1:1) (10 mg, 0.077 mmol), whilst stirring at 20° C. for 24 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford, after freeze-drying, the title compound (1.9 mg, 2%) as a cream solid. δ.sub.H (500 MHz, CD.sub.3OD) 9.25 (s, 1H), 8.90 (s, 1H), 8.84 (d, J 5.3 Hz, 1H), 7.80 (d, J 5.2 Hz, 1H), 7.51 (d, J 2.1 Hz, 1H), 6.95 (d, J 2.1 Hz, 1H), 5.15 (d, J 8.6 Hz, 1H), 4.60-4.54 (m, 2H), 4.52-4.46 (m, 2H), 4.39-4.29 (m, 2H), 2.19-2.10 (m, 1H), 2.08-2.01 (m, 1H), 1.85-1.78 (m, 1H), 1.75-1.69 (m, 1H), 1.54-1.45 (m, 1H), 1.40-1.35 (m, 1H), 1.32 (d, J 7.2 Hz, 3H), 1.27-1.19 (m, 2H), 1.09-0.94 (m, 2H), 0.90 (d, J 6.5 Hz, 3H). uPLCMS (Method 9): [M+H].sup.+ m/z 564, RT 2.91 minutes.

Example 190

(623) ##STR00194##

3-Ethyl-N-[(S)-{4-fluoro-5-[(2-oxopyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]isoxazole-4-carboxamide (Trans Isomer)

(624) The title compound (25 mg, 47%), a white solid, was prepared from Intermediate 246 (40 mg, 0.11 mmol) and 3-ethylisoxazole-4-carboxylic acid (19 mg, 0.14 mmol) in accordance with Procedure A, in DCM (2 mL) as solvent. δ.sub.H (500 MHz, DMSO-d.sub.6) 12.70 (br s, 1H), 9.41 (s, 1H), 8.82 (d, J 6.9 Hz, 1H), 7.27 (br s, 1H), 7.04 (dd, J 8.0, 6.8 Hz, 1H), 5.01 (t, J 8.5 Hz, 1H), 4.49 (s, 2H), 3.21 (t, J 7.0 Hz, 2H), 2.81 (qd, J 7.5, 3.6 Hz, 2H), 2.25 (t, J 8.1 Hz, 2H), 2.04-1.93 (m, 1H), 1.93-1.84 (m, 3H), 1.70 (d, J 12.4 Hz, 1H), 1.62 (d, J 12.8 Hz, 1H), 1.41-1.22 (m, 2H), 1.14 (t, J 7.5 Hz, 3H), 1.12-0.99 (m, 2H), 0.95-0.78 (m, 5H). uPLCMS (Method 9): [M+H].sup.+ m/z 482, RT 3.03 minutes.

Examples 191 & 192

(625) ##STR00195##

tert-Butyl 3-(3,3-difluoroazetidine-1-carbonyl)-4-(2-{(S)-[(2-ethylpyrazole-3-carbonyl-amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)-2,5-dihydro-pyrrole-1-carboxylate (Trans Isomer) (Example 191)

tert-Butyl 3-(3,3-difluoroazetidine-1-carbonyl)-4-(2-{(S)-[(2-ethylpyrazole-3-carbonyl)-amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-1-carboxylate (Trans Isomer) (Example 192)

(626) To a solution of Intermediate 249 (553 mg, 0.9 mmol) in EtOH (20 mL) was added 10% Pd/C (20 mg). The reaction mixture was stirred under an atmosphere of hydrogen for 1 week, then filtered through Celite®, washing with EtOAc. The filtrate was concentrated in vacuo. The material was redissolved in EtOH (20 mL), and 10% Pd/C (20 mg) was added. The reaction mixture was again stirred under an atmosphere of hydrogen for a further 2 days, then filtered through Celite®, washing with EtOAc. The filtrate was concentrated in vacuo. The crude material was purified by flash column chromatography, eluting with EtOAc/hexanes (0-100% gradient). The resulting white solid—30% O.sup.1-tert-butyl O.sup.3-ethyl 4-(2-{(S)-[(2-ethylpyrazole-3-carbonyl)amino](4-methylcyclohexyl)methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-1,3-dicarboxylate (assumed 1:1 mixture of cis isomers of reduced pyrrolidine moiety) and 70% unreduced inseparable Intermediate 249—was taken up in EtOH (4 mL) and treated with LiOH.H.sub.2O (10 mg, 0.40 mmol) in water (1 mL). The reaction mixture was stirred for 2 days, then concentrated in vacuo. The 70:30 mixture respectively of unreduced and reduced carboxylic acids was taken up in DMF (4 mL) and treated with DIPEA (0.36 mL, 2.10 mmol), followed by HATU (195 mg, 0.50 mmol). The reaction mixture was stirred at r.t. for 10 minutes, then 3,3-difluoroazetidine hydrochloride (85.0 mg, 0.80 mmol) was added. The reaction mixture was stirred at r.t. for 6 h, then partitioned between DCM and water. The organic layers were separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by reverse-phase HPLC to yield Example 192 (48 mg, 8% overall) and Example 193 (assumed 1:1 mixture of cis isomers of reduced pyrrolidine moiety) (57 mg, 9% overall) as white solids.

(627) Example 191: δ.sub.H (400 MHz, DMSO-d.sub.6) 12.77 (s, 1H), 8.87 (s, 1H), 7.48 (d, J 2.0 Hz, 1H), 7.39-7.29 (m, 1H), 7.13 (t, J 7.4 Hz, 1H), 7.04 (d, J 2.1 Hz, 1H), 5.02 (t, J 8.6 Hz, 1H), 4.53 (t, J 4.3 Hz, 2H), 4.48-4.35 (m, 4H), 4.31-4.15 (m, 2H), 4.07-3.88 (m, 2H), 2.06 (d, J 12.1 Hz, 1H), 1.90 (d, J 12.7 Hz, 1H), 1.70 (d, J 12.7 Hz, 1H), 1.61 (d, J 13.1 Hz, 1H), 1.44 (d, J 3.3 Hz, 9H), 1.37-1.22 (m, 5H), 1.05 (dtd, J 24.5, 12.2, 3.3 Hz, 2H), 0.95-0.78 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 670, RT 2.22 minutes.

(628) Example 192: δ.sub.H (400 MHz, DMSO-d.sub.6) 12.74 (s, 1H), 8.83 (s, 1H), 7.47 (d, J 2.0 Hz, 1H), 7.32-7.24 (m, 1H), 7.17 (t, J 7.4 Hz, 1H), 7.03 (t, J 1.8 Hz, 1H), 4.99 (t, J 8.5 Hz, 1H), 4.63 (q, J 12.2 Hz, 1H), 4.44 (q, J 7.1 Hz, 2H), 4.30-4.03 (m, 3H), 3.93-3.80 (m, 2H), 3.75 (t, J 8.9 Hz, 2H), 3.38 (d, J 8.7 Hz, 2H), 2.07-1.98 (m, 1H), 1.89 (d, J 12.6 Hz, 1H), 1.70 (d, J 12.7 Hz, 1H), 1.60 (d, J 12.6 Hz, 1H), 1.41 (d, J 11.2 Hz, 9H), 1.35-1.20 (m, 5H), 1.13-0.97 (m, 2H), 0.94-0.76 (m, 5H). LCMS (Method 6): [M+H].sup.+ m/z 672, RT 2.18 minutes.

Example 193

(629) ##STR00196##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyrrolidin-3-yl]-4-fluoro-1H-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-ethylpyrazole-3-carboxamide (Trans Isomer)

(630) Example 192 (53 mg, 0.10 mmol) was dissolved in DCM (1 mL, 15.6 mmol), and 4M HCl in 1,4-dioxane (0.1 mL, 0.40 mmol) was added. The reaction mixture was stirred at r.t. for 16 h, then flashed down an SCX column, eluting with a 7N solution of NH.sub.3 in MeOH, to give the title compound (1:1 mixture of cis isomers of pyrrolidine moiety) (45 mg, quantitative) as an off-white solid. δ.sub.H (400 MHz, CD.sub.3OD) 7.50 (d, J 2.1 Hz, 1H), 7.37 (d, J 8.4 Hz, 1H), 7.26 (dd, J 8.4, 6.4 Hz, 1H), 6.92 (q, J 2.0, 1.5 Hz, 1H), 5.07 (dd, J 8.7, 2.6 Hz, 1H), 4.55-4.38 (m, 3H), 4.32-4.12 (m, 2H), 3.84 (q, J 8.8 Hz, 1H), 3.70-3.58 (m, 1H), 3.49-3.42 (m, 1H), 3.39-3.23 (m, 2H), 3.19 (dd, J 8.6, 6.6 Hz, 1H), 3.08 (t, J 10.5 Hz, 1H), 2.08-1.96 (m, 2H), 1.82-1.75 (m, 1H), 1.69 (d, J 13.0 Hz, 1H), 1.44-1.30 (m, 5H), 1.26-1.13 (m, 2H), 1.06-0.86 (m, 5H). LCMS (Method 5): [M+H].sup.+ m/z 572, RT 1.14 minutes.

Examples 194 & 195

(631) ##STR00197##

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)pyridin-3-yl]-4-fluoro-1-methyl-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide (Trans Isomer) (Example 194)

N-[(S)-{6-[4-(3,3-Difluoroazetidine-1-carbonyl)pyridin-3-yl]-7-fluoro-1-methyl-benzimidazol-2-yl}(4-methylcyclohexyl)methyl]-2-methylpyrazole-3-carboxamide (Trans Isomer) (Example 195)

(632) To Intermediate 250 (mixture of isomers, 140 mg, 0.30 mmol), under nitrogen, were added bis(pinacolato)diboron (92 mg, 0.36 mmol), Pd(dppf)Cl.sub.2.DCM (13 mg, 0.016 mmol), potassium acetate (90 mg, 0.92 mmol) and 1,4-dioxane (3 mL). The mixture was degassed and placed under nitrogen, then heated at 100° C. with stirring for 18 h. (3-Bromopyridin-4-yl)(3,3-difluoroazetidin-1-yl)methanone (75% purity, 132 mg, 0.35 mmol) and saturated aqueous sodium carbonate solution (1 mL) were added. The mixture was heated at 100° C. overnight, then partitioned between EtOAc and brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by chromatography (silica, 0-100% EtOAc in isohexane) to give the title compounds (1:1 mixture) (5.0 mg, 5.7%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 9.06 (dd, J 24.9, 8.2 Hz, 1H), 8.78-8.65 (m, 2H), 7.64 (d, J 4.9 Hz, 1H), 7.53 (dd, J 8.4, 4.0 Hz, 1H), 7.45 (dd, J 2.2, 1.1 Hz, 1H), 7.24 (ddd, J 18.7, 8.2, 6.9 Hz, 1H), 7.08 (t, J 2.2 Hz, 1H), 5.11 (t, J 9.1 Hz, 1H), 4.41 (dq, J 25.0, 12.7, 12.1 Hz, 4H), 4.03 (3 s, 4.5H, 3-NMe), 3.96 (s, 1.5H, 1-NMe), 2.33-2.14 (m, 1H), 2.04 (m, 1H), 1.75 (m, 1H), 1.62 (m, 1H), 1.47-0.69 (m, 9H). LCMS (pH 10): [M+H].sup.+ 580.4, RT 1.90 and 1.93 minutes (97% purity, ˜1:1).