1,3-SUBSTITUTED 2-AMINO-INDOLE DERIVATIVES AND ANALOGUES USEFUL IN THE TREATMENT OR PREVENTION OF DIABETES MELLITUS, OBESITY, AND INFLAMMATORY BOWEL DISEASE

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein Q, X.sup.4, X.sup.5, X.sup.6, X.sup.7, R.sup.1, R.sup.2, R.sup.3 and R.sup.8 are as defined in the specification, processes for the preparation of such compounds, pharmaceutical compositions containing them and the use of such compounds in therapy.

##STR00001##

Claims

1. A compound of formula (I): ##STR00211## or a pharmaceutically acceptable salt thereof, wherein Q represents —O—, —S—, —SO—, —SO.sub.2—, —SO.sub.2NR—, —SO.sub.2(CH.sub.2).sub.m— or —SO.sub.2O—; R represents a hydrogen atom or a C.sub.1-C.sub.6 alkyl group; m is 1 or 2; X.sup.4 represents N or CR.sup.4; X.sup.5 represents N or CR.sup.5; X.sup.6 represents N or CR.sup.6; X.sup.7 represents N or CR.sup.7; provided that one or two of X.sup.4, X.sup.5, X.sup.6 and X.sup.7 represents a nitrogen atom; R.sup.1 and R.sup.2 each independently represent a hydrogen atom or a C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl or C.sub.1-C.sub.6 alkoxycarbonyl group, each of which may be optionally substituted by at least one halogen atom; R.sup.3 represents a saturated or unsaturated 3- to 10-membered ring system which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur, wherein the 3- to 10-membered ring system is optionally substituted by at least one substituent independently selected from halogen, hydroxyl, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.3-C.sub.6 cycloalkylC.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxyC.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylC(O)NR.sup.14—, phenyl, (halo)phenylcarbonyl, phenoxy, benzyl, benzyloxycarbonyl and a saturated or unsaturated 4- to 6-membered heterocyclyl group, which heterocyclyl group is itself optionally substituted by at least one C.sub.1-C.sub.6 alkyl group, and when Q represents —SO.sub.2NR—, R.sup.3 may additionally represent a C.sub.1-C.sub.6 alkyl group optionally substituted by at least one substituent independently selected from halogen, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl, phenyl and a saturated or unsaturated 4- to 6-membered heterocyclyl group; R.sup.4, R.sup.5 and R.sup.6 each independently represent a hydrogen or a halogen atom, or a C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 haloalkyl, NR.sup.12R.sup.13, C.sub.3-C.sub.8 cycloalkyl or C.sub.5-C.sub.8 cycloalkenyl group; R.sup.7 represents a hydrogen or a halogen atom, hydroxyl, cyano, NR.sup.9R.sup.10, or a C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.5-C.sub.8 cycloalkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.8 cycloalkyloxy, benzyloxy, 3-to 11-membered saturated heterocyclyl, 3-to 11-membered saturated heterocyclyloxy, C.sub.6-C.sub.10 aryl or heteroaryl group, each of which may be optionally substituted by at least one substituent independently selected from halogen, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.8 cycloalkyl, phenyl and a saturated or unsaturated 4- to 6-membered heterocyclyl group wherein each C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.8 cycloalkyl, phenyl or saturated or unsaturated 4- to 6-membered heterocyclyl substituent group may itself be optionally substituted by at least one substituent independently selected from halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy and C.sub.3-C.sub.6 cycloalkyl; either R.sup.8 represents a saturated 3- to 8-membered ring system which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur, wherein the 3- to 8-membered ring system is optionally substituted by at least one substituent independently selected from halogen, hydroxyl and C.sub.1-C.sub.6 alkyl, or R.sup.8 represents a C.sub.1-C.sub.6 alkyl group optionally substituted by at least one substituent independently selected from phenyl and C.sub.3-C.sub.6 cycloalkyl, the cycloalkyl group itself being optionally substituted by at least one C.sub.1-C.sub.6 alkyl group; R.sup.9 and R.sup.10 each independently represent a hydrogen atom, or a C.sub.1-C.sub.6 alkyl or —(CH2).sub.p—R.sup.11 group, each of which may be optionally substituted by at least one substituent independently selected from halogen, C.sub.1-C.sub.3 alkyl and C.sub.1-C.sub.3 alkoxy; p is 0 or 1; R.sup.11 represents C.sub.3-C.sub.6 cycloalkyl, phenyl or a saturated or unsaturated 5- to 6-membered heterocyclyl group; and R.sup.12, R.sup.13 and R.sup.14 each independently represent a hydrogen atom or a C.sub.1-C.sub.6 alkyl group.

2. A compound according to claim 1, wherein X.sup.4 and X.sup.7 are N, X.sup.5 is CR.sup.5 and X.sup.6 is CR.sup.6.

3. A compound according to claim 1, wherein X.sup.4 and X.sup.6 are both N, X.sup.5 is CR.sup.5 and X.sup.7 is CR.sup.7.

4. A compound according to claim 1, wherein Q represents —SO.sub.2—.

5. A compound according to claim 1, wherein R.sup.1 and R.sup.2 are both hydrogen.

6. A compound according to claim 1, wherein R.sup.3 represents a saturated or unsaturated 3- to 10-membered ring system which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur, optionally substituted as defined in claim 1, wherein the ring system is selected from phenyl, thienyl, cyclopropyl, cyclohexyl, pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 1,4-oxazepanyl, azepanyl, thiomorpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydroisoindolyl, azabicyclo[3.2.1]octanyl and 2,3-dihydro-1,4-benzodioxinyl.

7. A compound according to claim 1, wherein R.sup.3 represents phenyl optionally substituted by one or two substituents independently selected from fluorine, chlorine, cyano, methyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy and C.sub.1-C.sub.3 alkoxy.

8. A compound according to claim 1, wherein R.sup.8 represents a saturated 4- to 7-membered ring system which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur, wherein the 4- to 7-membered ring system is optionally substituted by at least one substituent independently selected from halogen, hydroxyl and C.sub.1-C.sub.2 alkyl, or R.sup.8 represents a C.sub.1-C.sub.2 alkyl group optionally substituted by at least one substituent independently selected from phenyl and C.sub.3-C.sub.6 cycloalkyl, the cycloalkyl group itself being optionally substituted by at least one C.sub.1-C.sub.2 alkyl group.

9. A compound according to claim 1, wherein R.sup.8 represents a C.sub.4-C.sub.6 cycloalkyl group optionally substituted by at least one substituent independently selected from fluorine, hydroxyl and methyl.

10. A compound according to claim 1, selected from the group consisting of: 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cycloheptyl-7-[(4-methylbenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cycloheptyl-7-[(4-methylbenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclopentyl-7-[(4-methylbenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 7-[(4-chlorobenzene)sulfonyl]-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-[(4-fluorobenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-{[4-(propan-2-yloxy)benzene]sulfonyl}-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(thiophene-2-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[3,2-b]pyridin-2-amine, 1-cyclopentyl-3-[(4-methylbenzene)sulfonyl]-1H-pyrrolo[3,2-b]pyridin-2-amine, 1-cyclohexyl-3-[(4-methylbenzene)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-amine, 7-(cyclohexanesulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-(4,4-difluorocyclohexyl)-7-[(4-methoxybenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 1-(4,4-difluorocyclohexyl)-3-[(4-methoxybenzene)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-amine, 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-2-amine, 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-2-amine, 3-(benzenesulfonyl)-1-(4,4-difluorocyclohexyl)-1H-pyrrolo[2,3-b]pyridin-2-amine, 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine, 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-c]pyridin-2-amine, 3-(benzenesulfonyl)-1-(4,4-difluorocyclohexyl)-1H-pyrrolo[3,2-b]pyridin-2-amine, 1-(4,4-difluorocyclohexyl)-3-[(4-methoxybenzene)sulfonyl]-1H-pyrrolo[3,2-b]pyridin-2-amine, 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[3,2-c]pyridin-2-amine, methyl N-[7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-yl]carbamate, 3-(benzenesulfonyl)-1-(4,4-difluorocyclohexyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-amine, 7-(benzenesulfonyl)-5-cyclohexyl-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-6-amine, 5-(benzenesulfonyl)-3-chloro-7-cyclohexyl-7H-pyrrolo[2,3-c]pyridazin-6-amine, 5-(benzenesulfonyl)-7-cyclohexyl-7H-pyrrolo[2,3-c]pyridazin-6-amine, 7-(benzenesulfonyl)-5-(4,4-difluorocyclohexyl)-4-ethoxy-5H-pyrrolo[3,2-d]pyrimidin-6-amine, 7-(benzenesulfonyl)-4-(benzyloxy)-5-(4,4-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine, 6-amino-5-(4,4-difluorocyclohexyl)-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol, 7-(benzenesulfonyl)-4-chloro-5-(4,4-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine, 7-(benzenesulfonyl)-5-(4,4-difluorocyclohexyl)-4-N-methyl-5H-pyrrolo[3,2-d]pyrimidine-4,6-diamine, 7-(benzenesulfonyl)-5-cyclohexyl-4-N,4-N-dimethyl-5H-pyrrolo[3,2-d]pyrimidine-4,6-diamine, 7-(benzenesulfonyl)-5-cyclopentyl-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-6-amine, 3-(benzenesulfonyl)-1-cyclohexyl-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-amine, 6-amino-7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidine-carbonitrile, 5-cyclohexyl-7-(2-fluorobenzenesulfonyl)-4-methoxy-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine, 5-cyclohexyl-7-(3-fluorobenzenesulfonyl)-4-methoxy-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine, 7-(benzenesulfonyl)-4-methoxy-5-(oxan-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine, 6-amino-5-cyclohexyl-N-phenyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 6-amino-5-cyclohexyl-N-(pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 5-cyclobutyl-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-(2-methylcyclohexyl)-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-butyl-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-phenethyl-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 2-(6-amino-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)cyclohexanol, 5-(2-cyclopropylethyl)-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-(4,4-difluoro-cyclohexyl)-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-(2-cyclobutylethyl)-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 7-(phenylsulfonyl)-5-(tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-(3,3-dimethylbutyl)-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-((1R*,2R*,4S*)-bicyclo[2.2.1]heptan-2-yl)-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-(cyclopentylmethyl)-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-((1-ethyl cyclopropyl)-methyl)-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-((2,2-dimethylcyclopropyl)methyl)-7-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(piperidin-1-ylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(pyrrolidin-1-ylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 6-amino-5-cyclohexyl-N-propyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 6-amino-5-cyclohexyl-N-methyl-N-propyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 5-cyclohexyl-7-(morpholinosulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-((4-methylpiperidin-1-yl)sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-((4-methylpiperazin-1-yl)sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-((3-methoxyazetidin-1-yl)sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-((4-ethoxypiperidin-1-yl)sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-((4,4-dimethylpiperidin-1-yl)sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-((3-methylpyrrolidin-1-yl)sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-((2-methylpyrrolidin-1-yl)sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-((4,4-difluoropiperidin-1-yl)sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 6-amino-N-benzyl-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 6-amino-N,5-dicyclohexyl-N-methyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 5-cyclohexyl-7-(1,4-oxazepane-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(4-methoxypiperidine-1-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 6-amino-N-(cyclobutylmethyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 5-cyclohexyl-7-(3,3-dimethylpyrrolidine-1-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(2,6-dimethylmorpholine-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 7-(azepane-1-sulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(thiomorpholine-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, N-(1-{6-amino-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl}piperidin-4-yl)-N-methylacetamide, 6-amino-5-cyclohexyl-N-(oxetan-3-ylmethyl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 7-(4-benzylpiperidine-1-sulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine, 6-amino-5-cyclohexyl-N-(3,3,3-trifluoropropyl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 5-cyclohexyl-7-(4-phenylpiperidine-1-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 6-amino-5-cyclohexyl-N-(2-phenylethyl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 5-cyclohexyl-7-(4-phenoxypiperidine-1-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(3-phenylpyrrolidine-1-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-[4-(trifluoromethyl)piperidine-1-sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-[3-(methoxymethyl)pyrrolidine-1-sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 6-amino-5-cyclohexyl-N-(cyclopropylmethyl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 6-amino-5-cyclohexyl-N-(2-methoxyethyl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 5-cyclohexyl-7-(3-methoxypyrrolidine-1-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(3,3-dimethylpiperidine-1-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 1-{6-amino-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl}piperidin-4-ol, 5-cyclohexyl-7-(1,2,3,4-tetrahydroisoquinoline-2-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 6-amino-N-(butan-2-yl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 6-amino-5-cyclohexyl-N-(oxolan-2-ylmethyl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 5-cyclohexyl-7-(2,3-dihydro-1H-isoindole-2-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-{4-[(4-fluorophenyl)carbonyl]piperazine-1-sulfonyl}-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(3-phenoxyazetidine-1-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-[3-(piperidin-1-yl)azetidine-1-sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-[3-(1H-pyrazol-1-yl)azetidine-1-sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(3-methylpiperidine-1-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 6-amino-5-cyclohexyl-N-[2-(1,3-thiazol-2-yl)ethyl]-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide, 8-{6-amino-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl}-8-azabicyclo[3.2.1]octan-3-ol, 5-cyclohexyl-7-[4-(2,2,2-trifluoroethyl)-piperazine-1-sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, (1-{6-amino-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl}piperidin-4-yl)methanol, 5-cyclohexyl-7-[4-(cyclopropylmethoxy)piperidine-1-sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-[(4-methoxybenzene)-sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(cyclopropanesulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-[(3-fluorobenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-[(2-fluorobenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-[(3-methoxybenzene)-sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine, 4-{6-amino-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl}benzonitrile, 7-[(3-chloro-4-methoxybenzene)-sulfonyl]-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(6-methoxypyridine-3-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-{[4-(trifluoromethoxy)-benzene]sulfonyl}-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine, 5-cyclohexyl-7-{[4-(difluoromethoxy)-benzene]sulfonyl}-5H-pyrrolo[2,3-b]pyrazin-6-amine, and pharmaceutically acceptable salts of any one thereof.

11. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 which comprises (a) when NR.sup.1R.sup.2 represents NH.sub.2, reacting a compound of formula ##STR00212## wherein L.sup.1 represents a leaving group and X.sup.4, X.sup.5, X.sup.6, X.sup.7, Q and R.sup.3 are as defined in formula (I), with a compound of formula (III), H.sub.2NR.sup.8, or a salt thereof wherein R.sup.8 is as defined in formula (I); or (b) when NR.sup.1R.sup.2 represents NH.sub.2, reacting a compound of formula ##STR00213## wherein L.sup.2 represents a leaving group and X.sup.4, X.sup.5, X.sup.6, X.sup.7 and R.sup.8 are as defined in formula (I), with a compound of formula ##STR00214## wherein Q and R.sup.3 are as defined in formula (I); wherein any of compounds (II), (III), (IV) or (V) may optionally be protected; and optionally thereafter carrying out one or more of the following procedures: removing any protecting groups converting a compound of formula (I) into another compound of formula (I) forming a pharmaceutically acceptable salt.

12. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents.

13. (canceled)

14. A method for treating a condition whose development or symptoms are linked to GPR43 receptor activity, comprising administering a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

15. A method for treating obesity and/or diabetes, comprising administering a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

16. A method for treating inflammatory bowel disease, comprising administering a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

Description

EXPERIMENTAL

[0423] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated and at 300.3K unless otherwise stated; the chemical shifts (δ) are reported in parts per million. Spectra were recorded using a Bruker 400 AVANCE instrument fitted with a 5 mm BBFO probe with instrument controlled by Bruker TopSpin 2.1 software, or by a Bruker 400 AVANCE-III instrument fitted with a 5 mm BBFO probe with instrument controlled by Bruker TopSpin 3.0 software, or by a Bruker 300 MHz AVANCE II instrument fitted with a 5 mm DUL probe with instrument controlled by Bruker TopSpin 1.3 software.

[0424] Purity was assessed using one or more of the following: [0425] UPLC with UV (photodiode array) detection over a wide range of wavelengths, normally 220-450 nm, using a Waters Acquity UPLC system equipped with Acquity UPLC BEH or HSS C18 columns (2.1 mm id×50 mm long) operated at 50 or 60° C. Mobile phases typically consisted of acetonitrile or methanol mixed with water containing either 0.1% formic acid or 0.025% ammonia. Mass spectra were recorded with a Waters SQD single quadrupole mass spectrometer using atmospheric pressure ionisation. [0426] UPLC with UV (photodiode array) detection over a wide range of wavelengths, normally 200-500 nm, using a Waters Acquity H-Class UPLC system controlled by Empower-2 software. Mass spectra were recorded with a Waters SQD single quadrupole mass spectrometer using electro spray ionization. Mobile phase consisted of 5 mm Ammonium Acetate containing 0.1% formic acid in Water and Acetonitrile using Acquity UPLC BEH or HSS C18 columns (2.1 mm id×50 mm long). [0427] LCMS with UV (photodiode array) detection over a wide range of wavelengths, normally 200-500 nm and the detection was also proceed at wavelength 260 nm and 80 bandwidth, using Shimandzu Nexera LCMS-2020 system controlled by Lab Solution software. Mass spectra were recorded with a single quadrupole mass spectrometer using electro spray ionization. Mobile phase consisted of 20 mm Ammonium Acetate mixed with water and Methanol using Waters X-bridge column (C18, 5 μm, 4.6 mm id×150 mm). [0428] LCMS with UV (photodiode array) detection over a wide range of wavelengths, normally 200-500 nm, using Waters ZQ-2000 system controlled by Empower-1 software. Mass spectra were recorded with a Waters ZQ single quadrupole mass spectrometer using electro spray ionization. Mobile phases consisted of 0.1% Ammonia mixed with water and Acetonitrile using Waters X-bridge column (C18, 5 μm, 4.6 mm id×150 mm).

[0429] Compounds were purified using normal phase chromatography on silica, using Biotage or Isolute KP-Sil cartridges or Kinesis Telos Silica cartridges, or on basic silica, using Biotage or Isolute KP-NH cartridges, or by reverse phase chromatographic methods, using Biotage or Isolute KP-C18-HS cartridges or by SCX-2 catch-release cartridges, or by Preparative HPLC.

[0430] Preparative HPLC was performed using one or more of the following: [0431] Agilent Technologies 1100 Series system or a Waters autopurification LC/MS system typically using Waters 19 mm id×250 mm long C18 columns such as XBridge or SunFire 5 μm materials at room temperature. [0432] Shimadzu Preparative HPLC system typically using 19 mm id×150 mm long C18 columns 5 μm or 20 mm id×250 mm long C8 columns 5 μm materials at room temperature. Shimadzu Preparative HPLC system controlled by LC-Solution software.

[0433] Mobile phases typically consisted of acetonitrile or methanol mixed with water containing either 0.1% formic acid or 0.1% ammonia, unless stated otherwise.

[0434] Room temperature in the following examples means the temperature ranging from 20° C. to 25° C.

[0435] The abbreviations used in the specific examples have the following meanings: [0436] Ac acetyl [0437] aq aqueous [0438] Bn, Bzl benzyl [0439] BOC, Boc tert-butoxycarbonyl [0440] bp boiling point, [0441] br broad (spectral) [0442] Bu, n-Bu normal (primary) butyl [0443] t-Bu tert-butyl [0444] Bz benzoyl [0445] CBZ, Cbz benzyloxycarbonyl [0446] CD.sub.2Cl.sub.2 deuterated dichloromethane [0447] CDCl.sub.3 deuterated chloroform [0448] CHCl.sub.3 chloroform [0449] m-CPBA meta-chloroperoxybenzoic acid [0450] Cy cyclohexyl [0451] δ chemical shift in ppm downfield from tetramethylsilane [0452] d day(s); doublet (spectral); [0453] DCE 1,2-dichloroethane [0454] DCM dichloromethane [0455] DMAP 4-(N,N-dimethylamino)pyridine [0456] DME 1,2-dimethoxyethane [0457] DMF dimethylformamide [0458] DMSO dimethyl sulfoxide [0459] DMSO-d.sub.6 perdeuterated dimethyl sulfoxide [0460] DPPF 1,1′-bis(diphenylphosphanyl) ferrocene [0461] ES electrospray [0462] Et ethyl [0463] H-frit Biotage Phase Separator (Part #120-1908-F) [0464] h hour(s) [0465] HPLC high-performance liquid chromatography [0466] Hz hertz [0467] L litre(s) [0468] LDA lithium diisopropylamide [0469] μ micro [0470] m multiplet (spectral); metre(s); milli [0471] M molar (moles per litre); mega [0472] Me methyl [0473] mg milligram [0474] MgSO.sub.4 magnesium sulfate [0475] min minute(s); minimum [0476] mL millilitre [0477] mmol millimoles [0478] mmolar millimolar (millimoles per liter) [0479] mol mole(s); molecular (e.g. in mol. wt.) [0480] mp melting point [0481] Ms, mesyl methylsulfonyl [0482] MS mass spectrometry [0483] MTBE methyl tert-butyl ether [0484] MW molecular weight [0485] m/z mass-to-charge ratio [0486] NaHCO.sub.3 sodium bicarbonate; sodium hydrogen carbonate [0487] NaHMDS sodium hexamethyldisilazane [0488] nm nanometer(s) [0489] NMP N-methylpyrrolidone [0490] NMR nuclear magnetic resonance [0491] Pd(amphos).sub.2Cl.sub.2 Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) [0492] Ph phenyl [0493] PMB p-methoxybenzyl [0494] ppm part(s) per million [0495] Pr, n-Pr propan-1-yl [0496] iPr isopropyl [0497] q quartet (spectral) [0498] rt room temperature [0499] s singlet (spectral); second(s) [0500] Sat. saturated [0501] t triplet (spectral) [0502] t time; temperature in units of degrees Celsius (° C.) [0503] TEA triethylamine [0504] Tf, trifyl trifluoromethanesulfonyl [0505] TFA trifluoroacetic acid [0506] TFAA trifluoroacetic anhydride [0507] THF tetrahydrofuran [0508] THP tetrahydropyran-2-yl [0509] TMEDA N,N,N′,N′-tetramethyl-1,2-ethylenediamine [0510] Ts, tosyl para-toluenesulfonyl [0511] UV ultraviolet

1. Intermediates

[0512] ##STR00009##

Intermediate 1 2-(benzenesulfonyl)-2-(3-chloropyrzin-2-yl)acetonitrile

[0513] ##STR00010##

[0514] To a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 1.4 mL, 13 mmol) and 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 24 g, 13 mmol) in DMSO (8 mL) was added DBU (4.1 mL, 27 mmol). The reaction was subjected to microwave irradiation at 100° C. for 45 mins. The reaction mixture was diluted with water and brine and then extracted with ethyl acetate. The aqueous phase was extracted further with DCM. The combined organics were dried over MgSO.sub.4 and concentrated in vacuo. The crude product was loaded onto a plug of silica (10 g) and eluted using 0-100% EtOAc/petroleum ether. The product fractions were concentrated in vacuo to afford the title compound.

[0515] .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 6.01 (s, 1H) 7.62-7.72 (m, 2H) 7.83-7.91 (m, 3H) 8.51-8.59 (m, 2H)

[0516] MS ES.sup.+: 294

##STR00011##

Intermediate a 2-(3-chloropyrazin-2-yl)-2-(4-methylbenzenesulfonyl)acetonitrile

[0517] ##STR00012##

[0518] To a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 360 μL, 3-4 mmol) and 2-(4-methylbenzenesulfonyl)acetonitrile (CAS 5697-44-9; 736 mg, 3.8 mmol) in acetonitrile (7 mL) was added DBU (620 μL, 4.1 mmol). The reaction was heated in a microwave at 80° C. for 30 min. The reaction mixture was evaporated to dryness and purified by column chromatography (C18-silica 0-30% Acetonitrile+0.05% NH.sub.3/Water+0.1% NH.sub.3) to afford the title compound.

[0519] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.46 (s, 3H) 7.00 (s, 1H) 7.50 (d, J=1 Hz, 2H) 7.62 (d, J=1 Hz, 2H) 8.64-8.75 (m, 2H)

[0520] MS ES.sup.+: 308

##STR00013##

Intermediate 3 2-(4-chlorobenzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile

[0521] ##STR00014##

[0522] To a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 156 μL, 1.50 mmol) and 2-(4-chlorophenylsulfonyl)acetonitrile (CAS 1851-09-8; 323 mg, 1.50 mmol) in DMF (1 mL) was added DBU (452 μL, 3.00 mmol). The reaction was heated in a microwave at 100° C. for 30 min. The reaction mixture was diluted with ammonium chloride solution, extracted with EtOAc/tetrahydrofuran (2:1), the combined organics dried (H frit) and evaporated to dryness. The crude product was purified by column chromatography silica (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.

[0523] MS ES.sup.+: 328

##STR00015##

Intermediate 4 2-(3-chloropyrazin-1-yl)-2-(4-fluorobenzenesulfonyl)acetonitrile

[0524] ##STR00016##

[0525] Prepared as described for 2-(4-chlorobenzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 3), to a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 156 μL, 1.50 mmol) and 2-(4-fluorophenylsulfonyl)acetonitrile (CAS 32083-66-2; 299 mg, 1.50 mmol) in DMF (1 mL) was added DBU (452 μL, 3.00 mmol).

[0526] The reaction was heated in a microwave at 100° C. for 30 min. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.

[0527] MS ES.sup.+: 312

##STR00017##

Intermediate 5 2-(3-chloropyrazin-2-yl)-2-[4-(propan-2-yloxy)benzenesulfonyl]acetonitrile

[0528] ##STR00018##

[0529] Prepared as described for 2-(4-Chlorobenzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 3), to a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 156 μL, 1.50 mmol) and 2-(4-isopropoxyphenylsulfonyl)acetonitrile (CAS 886499-39-4; 359 mg, 1.50 mmol) in DMF (1 mL) was added DBU (452 μL, 3.00 mmol). The reaction was then heated in a microwave at 100° C. for 30 min. The crude product was purified by column chromatography (silica, 0-40% EtOAc/petroleum ether) to afford the title compound.

[0530] MS ES.sup.+: 352

##STR00019##

Intermediate 6 2-(3-chloropyrazin-2-yl)-2-(thiophene-2-sulfonyl)acetonitrile

[0531] ##STR00020##

[0532] Prepared as described for 2-(4-chlorobenzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 3), to a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 156 μL 1.50 mmol) and 2-(thiophen-2-ylsulfonyl)acetonitrle (CAS 175137-62-9; 281 mg, 1.50 mmol) in DMF (1 mL) was added DBU (452 μL, 3.00 mmol). The reaction was heated in a microwave at 100° C. for 30 min then 125° C. for 30 min. The crude product was purified by column chromatography (C18-silica, 0-30% Acetonitrile+0.05% NH.sub.3/Water+0.1% NH.sub.3) to afford the title compound.

[0533] MS ES.sup.+: 300.

##STR00021##

Intermediate 7 2-bromo-N-cyclohexylpyridin-3-amine

[0534] ##STR00022##

[0535] To a stirred solution of cyclohexanone (CAS 108-94-1; 851 mg, 8.67 mmol) and 2-bromopyridin-3-amine (CAS 39856-58-1; 500 mg, 2.89 mmol) in DCM (8 mL) at 0° C. under N.sub.2 was added TiCl.sub.4 solution (1M in DCM, 3.18 mL, 3.18 mmol) dropwise. The reaction mixture was allowed to stir for 2 hours at rt and then cooled to 0° C. Sodium triacetoxyborohydride (1.8 g, 8.67 mmol) was added portionwise and then the reaction allowed to warm to rt and stirred over a weekend. The reaction mixture was quenched slowly into water and then extracted with DCM. The organic phase was separated and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-40% EtOAc/petroleum ether) to afford the title compound.

[0536] MS ES.sup.+: 255

##STR00023##

Intermediate 8 2-(4-methylbenzenesulfonyl)-2-(3-nitropyridin-2-yl)acetonitrile

[0537] ##STR00024##

[0538] To a stirred solution of potassium tert-butoxide (3.5 g, 32 mmol) in propan-2-ol (25 mL) at 0° C. was added 2-(4-methylbenzenesulfonyl)acetonitrile (CAS 5697-44-9; 3.69 g, 18 mmol) and the resulting mixture stirred for 30 min. 2-chloro-3-nitropyridine (CAS 5470-18-8; 2.5 g 15.8 mmol) was added and the reaction mixture stirred at 65° C. for 6 h. The reaction mixture was allowed to cool and concentrated in vacuo. The resulting residue was taken up in water and extracted with ethyl acetate. The organic phase was dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 25-30% EtOAc/hexane) to afford the title compound.

[0539] .sup.1H NMR (4 MHz, DMSO-d.sub.6) δ ppm 2.45 (s, 3H), 6.93 (s, 1H), 7.45-7.55 (m, 2H), 7.55-7.65 (m, 3H), 8.05-8.15 (m, 1H), 8.50-8.60 (m, 1H)

[0540] MS ES.sup.+: 318

Intermediate 9 2-amino-3-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridin-1-ol

[0541] ##STR00025##

[0542] A stirred suspension of 2-(4-methylbenzenesulfonyl)-2-(3-nitropyridin-2-yl)acetonitrile (Intermediate 8; 1.2 g, 11 mmol) and palladium on carbon (10% w/w) (60 mg, 0.55 mmol) in acetic acid (0.5 mL) and ethyl acetate (50 mL) was placed under an atmosphere of hydrogen. The reaction was stirred at rt for to h. The reaction was filtered and the filtrate concentrated in vacuo. The residue was taken up in water and neutralised with sat. aq. NaHCO.sub.3 solution and then extracted with ethyl acetate. The organics were dried (NaSO.sub.4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 2-5% MeOH/DCM) to afford the title compound.

[0543] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.30 (s, 3H), 6.90-7.00 (m, 1H), 7.10 (s, 2H), 7.25-7.35 (m, 2H), 7.35-7.45 (m, 1H), 7.85-7.95 (m, 2H), 8.05-8.15 (m, 1H), 11.50 (s, 1H)

[0544] MS ES.sup.+: 304

Intermediate 10 3-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridin-2-amine

[0545] ##STR00026##

[0546] A stirred suspension of 2-amino-3-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridin-1-ol (Intermediate 9; 400 mg) and palladium on carbon (10% w/w) (50 mg) in acetic acid (2 mL) and ethyl acetate (10 mL) was placed under an atmosphere of hydrogen at too psi. After 8 h the reaction was diluted with ethyl acetate and filtered. The filtrate was washed with sat. aq. NaHCO.sub.3 solution and the organic phase separated and dried (Na.sub.2SO.sub.4). The organic phase was concentrated in vacuo. The crude product was triturated with hexane and filtered to afford the title compound.

[0547] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.32 (s, 3H) 6.82-6.97 (m, 3H) 7.27-7.40 (m, 3H) 7.86-7.96 (m, 2H) 8.02-8.09 (m, 1H) MS ES.sup.+: 288

##STR00027##

Intermediate 11 2-(2-chloropyridin-3-yl)-2-(4-methylbenzenesulfonyl)acetonitrile

[0548] ##STR00028##

[0549] To a stirred solution of 2-chloro-3-iodopyridine (CAS 78607-36-0; 4.9 g, 20.5 mmol) in toluene(15 mL) was added potassium tert-butoxide (2.81 g, 25.0 mmol), Pd.sub.2dba.sub.3 (1.53 g, 1.70 mmol) and 2-(4-methylbenzenesulfonyl)acetonitrile (CAS 5697-44-9; 2.64 g, 14.6 mmol). The reaction was heated at 125° C. for 4 h. The reaction was poured onto ice and extracted with ethyl acetate. The organic phase was separated, dried and concentrated in vacuo. The crude product was purified by column chromatography (silica, 20-22% EtOAc/petroleum ether) to afford the title compound.

[0550] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.45 (s, 3H), 6.76 (s, 1H), 7.50-7.58 (m, 2H), 7.60-7.65 (m, 1H), 7.65-7.75 (m, 2H), 7.90-8.00 (m, 1H), 7.55-7.65 (m, 1H)

[0551] MS ES.sup.+: 307

##STR00029##

Intermediate 12 2-(3-chloropyrazin-2-yl)-2-(4-methoxybenzenesulfonyl)acetonitrle

[0552] ##STR00030##

[0553] A neat mixture of 2,3-dichloropyrazine (CAS 4858-85-9; 0.100 mL, 0.958 mmol), 2-((4-methoxyphenyl)sulfonyl)acetonitrile (CAS 132276-87-0; 220 mg, 0.958 mmol) and DBU (0.289 mL, 1.916 mmol) was heated to 85° C. for 1.5 h. The reaction mixture was treated with dilute citric acid and EtOAc. The phases were separated and the aqueous extracted with EtOAc. The combined organic extracts were then washed with dilute citric acid, water, sat. NaHCO.sub.3, sat. brine, dried (H-frit) and evaporated. The crude material was absorbed onto MgSO.sub.4 from DCM/MeOH and purified by column chromatography (silica, 0-40% EtOAc/petroleum ether) to afford the title compound. .sup.1H NMR (400 MHz, DCM-d.sub.2) δ ppm 3.96 (s, 3H) 5.99 (s, 1H) 7.10 (d, J=9 Hz, 2H) 7.76 (d, J=9 Hz, 2H) 8.49-8.60 (m, 2H)

[0554] MS ES.sup.+: 324

##STR00031##

Intermediate 13 2-(2-chloropyridin-3-yl)-2-(4-methoxybenzenesulfonyl)acetontrile

[0555] ##STR00032##

[0556] To a stirred degassed solution of Pd(Ph.sub.3P).sub.4 (0.058 g, 0.050 mmol) in anhydrous DME (1.5 mL) under an atmosphere of nitrogen was added a solution of 2-((4-methoxyphenyl)sulfonyl)acetonitrile (CAS 132276-87-0; 0.232 g, 1.10 mmol) and NaH (0.084 g, 2.10 mmol) in anhydrous DME (4 mL). The resulting mixture was stirred at room temperature for to min followed by the addition of 2-chloro-3-iodopyridine (CAS 78607-36-0; 00.239 g, 1 mmol). The reaction was heated in a microwave at 90° C. to 110° C. for 2.5 h. More Pd(Ph.sub.3P).sub.4 (0.029 g, 0.025 mmol) was added and the reaction heated in a microwave at 115° C. to 120° C. for 1.5 h. The solvent was removed under reduced pressure and the residue was diluted with water, neutralised with 2 M aq. HCl solution and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10-40% EtOAc/petroleum ether) to afford the title compound.

[0557] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3H) 5.72 (s, 1H) 7.03 (d, J=9 Hz, 2H) 7.33-7.45 (m, 1H) 7.74 (d, J=9 Hz, 2H) 7.89-7.99 (m, 1H) 8.41-8.55 (m, 1H) MS ES.sup.+: 323

##STR00033##

Intermediate 2-(benzenesulfonyl)-2-(2-chloropyridin-3-yl)acetonitrile

[0558] ##STR00034##

[0559] To a stirred degassed solution of Pd(Ph.sub.3P).sub.4 (0.116 g, 0.100 mmol) in anhydrous DME (1.5 mL) under an atmosphere of nitrogen was added a solution of 2-(phenylsulfonyl)acetonitrile (0.399 g, 2.20 mmol) and NaH (0.168 g, 4.20 mmol) in anhydrous DME (4 mL). The resulting mixture was stirred at room temperature for to min followed by the addition of 2-chloro-3-iodopyridine (0.479 g, 2.00 mmol). The reaction mixture was heated at 120° C. for 1.5 h. The solvent was removed under reduced pressure and the residue was diluted with water, neutralised with 2 M aq. HCl solution and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10-40% EtOAc/petroleum ether) to afford the title compound.

[0560] .sup.1H NMR (4 MHz, CHLOROFORM-d) δ ppm 5.73 (s, 1H) 7.36-7.45 (m, 1H) 7.56-7.71 (m, 2H) 7.76-7.86 (m, 1H) 7.87-7.94 (m, 2H) 7.95-8.03 (m, 1H) 8.45-8.60 (m, 1H)

[0561] MS ES.sup.+: 293

##STR00035##

Intermediate 15 N-cyclohexyl-5-iodopyrimidin-4-amine

[0562] ##STR00036##

[0563] A stirred suspension of cyclohexanamine (CAS 108-91-8; 0.114 mL, 0.998 mmol), 4-chloro-5-iodopyrimidine (CAS 63558-65-6; 200 mg, 0.832 mmol) and Cs.sub.2CO.sub.3 (407 mg, 1.248 mmol) in N-methyl-2-pyrrolidinone (2 mL) was heated in a microwave at 100° C. for 1 h. The reaction mixture was poured into water and extracted with EtOAc (×2). The combined extracts were washed with water, dilute citric acid, water, sat. NaHCO.sub.3, sat. brine, dried (H-frit) and evaporated. The crude product was then purified by column chromatography (silica, 0-20% EtOAc/petroleum ether) to afford the title compound. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21-1.37 (m, 3H) 1.39-1.54 (m, 2H) 1.63-1.73 (m, 1H) 1.73-1.85 (m, 2H) 1.99-2.12 (m, 2H) 3.96-4.10 (m, 1H) 5.19 (br. s., 1H) 8.44 (s, 1H) 8.46 (s, 1H)

[0564] MS ES.sup.+: 304

##STR00037##

Intermediate 16 4-chloro-N-cyclohexylpyrimidin-5-amine

[0565] ##STR00038##

[0566] To a stirred solution of 4-chloropyrimidin-5-amine (CAS 54660-78-5; 150 mg, 1.16 mmol) and cyclohexanone (CAS 108-94-1; 360 μL, 3.47 mmol) in DCM (5 mL) at 0° C. was added TiCl.sub.4 solution (1.0M in DCM, 1.27 mL, 1.27 mmol). The reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (736 mg, 3.47 mmol) was then added portionwise. Stirring at rt was maintained for 2 h. The reaction mixture was poured into water and extracted with EtOAc (×2). The combined organic extracts were washed with water, sat. NaHCO.sub.3, sat.brine, dried (H-frit) and evaporated. The crude product was purified by column chromatography (silica, 0-15% EtOAc/petroleum ether) to afford the title compound.

[0567] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21-152 (m, 5H) 1.62-1.96 (m, 3H) 1.99-2.17 (m, 2H) 3.29-3.47 (m, 1H) 4.11-4.27 (m, 1H) 8.06 (s, 1H) 8.33 (s, 1H)

[0568] MS ES.sup.+: 212

##STR00039##

Intermediate 17 N-cyclohexyl-4-iodopyridin-3-amine

[0569] ##STR00040##

[0570] To a stirred solution of cyclohexanone (CAS 108-94-1; 1.34 g, 13.6 mmol) and 4-iodopyridin-3-amine (CAS 105752-11-2; 1 g, 4.55 mmol) in DCM (15 mL) at 0° C. under N.sub.2 was added TiCl.sub.4 solution (1.0M in DCM, 5.00 mL, 5.00 mmol) dropwise. The reaction mixture was allowed to stir at rt for 2 hours and then sodium triacetoxyborohydride (2.89 g, 13.6 mmol) was added portionwise. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched slowly into water and then extracted with DCM. The organics were separated and concentrated. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.

[0571] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.07-1.49 (m, 4H) 1.56-1.76 (m, 4H) 1.89-1.97 (m, 2H) 3.42-3.53 (m, 1H) 4.28 (d, J=8 Hz, 1H) 7.48 (d, J=5 Hz, 1H) 7.65 (d, J=5 Hz, 1H) 7.90 (s, 1H)

[0572] MS ES.sup.+: 303

##STR00041##

Intermediate 18 2-bromo-N-(4,4-difluorocyclohexyl)pyridin-3-amine

[0573] ##STR00042##

[0574] Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 4,4-difluorocyclohexanone (CAS 22515-18-0; 2.33 g, 17.3 mmol) and 2-bromopyridin-3-amine (CAS 39856-58-1; 1 g, 5.78 mmol) in DCM (15 mL) at 0° C. under N.sub.2 was added TiCl.sub.4 solution (1M in DCM, 6.36 mL, 6.36 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (3.68 g, 17.3 mmol) was added portionwise and then the reaction stirred at room temperature for 72 h. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.

[0575] MS ES.sup.+: 291

##STR00043##

Intermediate 19 3-bromo-N-cyclohexylpyrldin-4-amine

[0576] ##STR00044##

[0577] A neat mixture of 3-bromo-4-fluoropyridine (200 mg 1.14 mmol) and cyclohexanamine (CAS 108-91-8; 650 μL, 5.68 mmol) was heated in a microwave at 120° C. for 45 min. The reaction mixture was dissolved in EtOAc and washed with water, brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.

[0578] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24-1.49 (m, 4H) 1.60-1.73 (m, 2H) 1.74-1.88 (m, 2H) 1.95-2.16 (m, 2H) 3.18-3.46 (m, 1H) 4.71 (br. s, 1H) 6.48 (d, J=6 Hz, 1H) 8.12 (d, J=6 Hz, 1H) 8.34 (s, 1H)

[0579] MS ES.sup.+: 255

##STR00045##

Intermediate 20 methyl N-[7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-yl]-N-(methoxycarbonyl)carbamate

[0580] ##STR00046##

[0581] To a stirred solution of 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine (Example 1; 0.135 g, 0.38 mmol) in anhydrous THF (5 mL) at −78° C. and under an atmosphere of nitrogen was added dropwise a solution of butyllithium (0.152 mL, 0.380 mmol) in hexanes (2.5 M). The resulting mixture was stirred at −78° C. for 10 min and then quenched at −78° C. by the addition of methyl carbonochloridate (0.294 ml, 3.80 mmol) and allowed to warm to room temperature. The reaction was partitioned between diethyl ether and water. The phases were separated and the aqueous extracted with diethyl ether. The combined organics were dried over MgSO.sub.4, filtered and concentrated in vacuo. Purification was performed by chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.

[0582] .sup.1H NMR (3 MHz, CHLOROFORM-d) δ ppm 1.18-1.48 (m, 3H) 1.65-1.99 (m, 5H) 2.40-2.67 (m, 2H) 3.76 (s, 6H) 4.04-4.29 (m, 1H) 7.39-7.65 (m, 3H) 8.07-8.25 (m, 2H) 8.38 (d, J=2 Hz, 1H) 8.66 (d, J=2 Hz, 1H)

[0583] MS ES.sup.+: 473

##STR00047##

Intermediate 21 3-bromo-((4,4-difluorocyclohexyl)amino)-6-methylpyridine 1-oxide

[0584] ##STR00048##

[0585] To a stirred solution of 3-bromo-2-chloro-6-methylpyridine 1-oxide (CAS 185017-76-9; 0.309 & 1.39 mmol) and difluorocyclohexanamine hydrochloride (CAS 675112-70-6; 0.309 g, 1.80 mmol) in NMP (3 mL) was added Cs.sub.2CO.sub.3 (1.22 g, 3.74 mmol) and the resulting mixture was heated at 110° C. to 140° C. for 6 h using a microwave reactor. The mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate (×2) The combined organics were washed with water, brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure.

[0586] The crude product was purified by column chromatography (silica, 20-100% EtOAc/petroleum ether) to afford the title compound.

[0587] MS ES.sup.+: 321

Intermediate 22 2-amino-1-(4,4-difluorocyclohexyl)-6-methyl-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide

[0588] ##STR00049##

[0589] To a stirred degassed solution of Pd(Ph.sub.3P).sub.4 (18 mg, 0.016 mmol) in anhydrous DME (1 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 62 mg, 0.343 mmol) and NaH, 60% dispersion in oil (26 mg, 0.654 mmol) in anhydrous DME (1 mL). The resulting mixture was stirred at room temperature for 10 min followed by addition of a solution of 3-bromo-2-((4,4-difluorocyclohexyl)amino)-6-methylpyridine 1-oxide (Intermediate 21; 1 mg, 0.311 mmol) in anhydrous DME (1 mL). The reaction mixture was heated at 120° C. for 1.5 h. The solvent was removed under reduced pressure and the residue was diluted with water, neutralised with 2 M aq. HCl solution and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) to afford the title compound.

[0590] MS ES.sup.+: 422

##STR00050##

Intermediate 23 4-chloro-N-cyclohexyl-6-methoxypyrimidin-5-amine

[0591] ##STR00051##

[0592] Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 4-chloro-6-methoxypyrimidin-5-amine (CAS 15846-19-2; 0.15 g, 0.940 mmol) and cyclohexanone (CAS 108-94-1; 0.294 ml, 2.82 mmol) in anhydrous DCM (5 mL) under an atmosphere of nitrogen at 0° C. was added TiCl.sub.4 solution (1M in DCM, 3.66 mL, 3.66 mmol). The reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (1.94 g, 9.15 mmol) was added portionwise and the reaction stirred at room temperature for 16 h. The crude product was purified by column chromatography (silica, 0-20% EtOAc/petroleum ether) to afford the title compound.

[0593] MS ES.sup.+: 242

##STR00052##

Intermediate 24 4-bromo-6-chloro-N-cyclohexylpyridazin-3-amine

[0594] ##STR00053##

[0595] To stirred solution of cyclohexanone (CAS 108-94-1; 1060 mg, 10.8 mmol) and 4-bromo-6-chloropyridazin-3-amine (CAS 446273-59-2; 750 mg, 3.60 mmol) in THF (10 mL) at 0° C. under N.sub.2 was added titanium isopropoxide (IV) (1.16 mL, 3.96 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (4580 mg, 21.6 mmol) was added portionwise and then the reaction allowed to stir at room temperature. The reaction was poured into water and extracted with DCM. The organics were separated and concentrated.

[0596] The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound. MS ES.sup.+: 292

##STR00054##

Intermediate 25 4-chloro-N-(4,4-difluorocyclohexyl)-6-ethoxypyrimidin-5-amine

[0597] ##STR00055##

[0598] Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to stirred solution of 4,4-difluorocyclohexanone (CAS 22515-18-0; 1480 mg, 11.1 mmol) and 4-chloro-6-ethoxypyrimidin-5-amine (CAS 63291-59-8; 960 mg, 5.53 mmol) in DCM (15 mL) at 0° C. under N.sub.2 was added TiCl.sub.4 solution (1M in DCM, 6.08 mL, 6.08 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (2340 mg, 11.06 mmol) was added portionwise and then the reaction allowed to stir at room temperature overnight. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.

[0599] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.33-1.41 (m, 3H) 1.51-1.64 (m, 2H) 1.77-1.89 (m, 4H) 2.00-2.09 (m, 2H) 3.66-3.81 (m, 1H) 4.39-4.47 (m, 3H) 8.08 (s, 1H) MS ES.sup.+: 292

##STR00056##

Intermediate 26 4-(benzyloxy)-6-chloropyrimidin-5-amine

[0600] ##STR00057##

[0601] To a stirred solution of phenylmethanol (CAS 100-51-6; 791 mg, 7.32 mmol) in THF (10 mL) at 0° C. was added NaH, 60% dispersion in oil (0.305 g, 7.62 mmol) portionwise. The resulting suspension was allowed to stir for 15 minutes. 4,6-dichloropyrimidin-5-amine (CAS 5413-85-4; 1 g, 6.10 mmol) was then added slowly and the reaction allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water and extracted with DCM. The phases were separated and the organics concentrated in vacuo to afford the title compound.

[0602] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 5.45 (s, 2H) 5.49 (s, 2H) 7.31-7.36 (m, 1H) 7.38-7.44 (m, 2H) 7.47-7.52 (m, 2H) 7.92 (s, 1H) MS ES.sup.+: 236

Intermediate 27 4-(benzyloxy)-6-chloro-N-(4,4-difluorocyclohexyl)pyrimidin-5-amine

[0603] ##STR00058##

[0604] Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to stirred solution of 4,4-difluorocyclohexanone (CAS 22515-18-0; 1.59 g, 11.9 mmol) and 4-(benzyloxy)-6-chloropyrimidin-5-amine (Intermediate 26; 1.4 g, 5.94 mmol) in DCM (15 mL) at 0° C. under N.sub.2 was added TiCl.sub.4 solution (1M in DCM, 6.53 mL, 6.53 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (2.52 g, 11.9 mmol) was added portionwise and then the reaction allowed to stir at room temperature overnight. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.

[0605] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.74-1.82 (m, 2H) 1.89-1.98 (m, 2H) 2.26-2.39 (m, 2H) 2.40-2.46 (m, 2H) 3.64-3.78 (m, 1H) 4.47-4.53 (m, 1H) 5.47 (s, 2H) 7.30-7.46 (m, 3H) 7.46-7.54 (m, 2H) 8.12 (s, 1H)

[0606] MS ES.sup.+: 354

##STR00059##

Intermediate 28 6-chloro-5-N-cyclohexyl-4-N,4-N-dimethylpyrimidine-4,5-diamine

[0607] ##STR00060##

[0608] Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 6-chloro-N.sup.4,N.sup.4-dimethylpyrimidine-4,5-diamine (CAS 130623-81-3; 560 mg, 3.24 mmol) and cyclohexanone (CAS 108-94-1; 1.016 mL, 9.73 mmol) in anhydrous DCM (18 mL) under an atmosphere of N.sub.2 at 0° C. was added dropwise TiCl.sub.4 solution (1M in DCM, 3.66 mL, 3.66 mmol). The reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (1.94 g, 9.15 mmol) was added portionwise and the reaction stirred at room temperature for 16 h. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.

[0609] MS ES.sup.+: 255

##STR00061##

Intermediate 29 4-chloro-N-cyclopentyl-6-methoxypyrimidin-5-amine

[0610] ##STR00062##

[0611] Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 4-chloro-6-methoxypyrimidin-5-amine (CAS 15846-19-2; 200 mg, 1.25 mmol) and cyclopentanone (CAS 120-92-3; 0.33 mL, 3.76 mmol) in anhydrous DCM (6 mL) under an atmosphere of N.sub.2 at 0° C. was added dropwise TiCl.sub.4 solution (1M in DCM, 1.4 mL, 1.38 mmol). The reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (797 mg, 3.76 mmol) was added portionwise and the reaction stirred at room temperature for 16 h. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.

[0612] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33-1.53 (m, 2H) 1.55-1.82 (m, 4H) 1.83-2.00 (m, 2H) 3.73 (d, J=9 Hz, 1H) 4.04 (s, 3H) 4.18-4.42 (m, 1H) 8.08 (s, 1H) MS ES.sup.+: 228

##STR00063##

Intermediate 30 4-chloro-N-cyclohexyl-2-methoxypyridin-3-amine

[0613] ##STR00064##

[0614] Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 4-chloro-2-methoxypyridin-3-amine (CAS 934180-49-1; 250 mg, 1.58 mmol) and cyclohexanone (CAS 108-94-1; 309 mg, 3.15 mmol) in anhydrous DCM (10 mL) under an atmosphere of N.sub.2 at 0° C. was added dropwise TiCl.sub.4 solution (1M in DCM, 1.73 mL, 1.73 mmol). The reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (668 mg, 3.15 mmol) was added portionwise and the reaction stirred at room temperature overnight. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.

[0615] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.46-1.71 (m, 6H) 1.75-2.01 (m, 4H) 3.54-3.64 (m, 1H) 3.89 (s, 3H) 4.02-4.08 (m, 1H) 6.97 (d, J 6 Hz, 1H) 7.54 (d, J=6 Hz, 1H)

[0616] MS ES.sup.+: 241

##STR00065##

Intermediate 31 4-(benzyloxy)-6-chloro-N-cyclohexylpyrimidin-5-amine

[0617] ##STR00066##

[0618] Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a mixture of cyclohexanone (CAS 108-94-1; 2.68 g, 27.3 mmol) and 4-(benzyloxy)-6-chloropyrimidin-5-amine (Intermediate 26; 3.22 g, 13.66 mmol) in DCM (50 mL) at 0° C. under N.sub.2 was added dropwise TiCl.sub.4 solution (1M in DCM, 15 mL, 15 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (5.79 g, 27.3 mmol) was added portionwise and then the reaction allowed to stir at room temperature overnight. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.

[0619] MS ES.sup.+: 318

Intermediate 32 7-(benzenesulfonyl)-4-(benzyloxy)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine

[0620] ##STR00067##

[0621] To a stirred solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 1.96 g, 100.8 mmol) in DME (3 mL) at 0° C. was added NaH, 60% dispersion in oil (866 mg, 21.7 mmol). After to minutes the resulting suspension was added to a degassed solution of Pd(Ph.sub.3P).sub.4 (313 mg, 0.27 mmol) and Pd(amphos).sub.2Cl.sub.2 (192 mg, 0.271 mmol) in DME (2 mL). The resulting suspension was allowed to stir at room temperature for 20 minutes. 4-(benzyloxy)-6-chloro-N-cyclohexylpyrimidin-5-amine (Intermediate 31; 3.44 g, 10.8 mmol) was then added and the reaction mixture subjected to microwave irradiation at 120° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organics were dried over MgSO.sub.4 and concentrated. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.

[0622] MS ES.sup.+: 346

Intermediate 33 6-amino-5-cyclohexyl-7-(phenylsulfonyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one

[0623] ##STR00068##

[0624] A suspension of 7-(benzenesulfonyl)-4-(benzyloxy)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 32; 2.6 g, 5.62 mmol) and Pd/C (598 mg, 0.562 mmol) in MeOH (20 mL) was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through a pad of celite and the resulting filtrate concentrated. The crude product was purified by column chromatography (silica, o-10% MeOH/DCM) to afford the title compound.

[0625] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.33-1.96 (m, 9H) 2.41-2.55 (m, 2H) 7.47-7.62 (m, 4H) 7.63-7.70 (m, 2H) 7.83 (s, 1H) 8.04-8.11 (m, 2H)

[0626] MS ES.sup.+: 373

Intermediate 34 7-(benzenesulfonyl)-4-chloro-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine

[0627] ##STR00069##

[0628] A solution of 6-amino-5-cyclohexyl-7-(phenylsulfonyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (Intermediate 33; 2.1 g, 5.64 mmol) in POCl.sub.3 (8 mL, 86 mmol) was stirred at 80° C. overnight. The reaction mixture was allowed to cool and concentrated in vacuo. The crude residue was taken up in DCM and washed with water. The organics were separated and concentrated. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.

[0629] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.33-1.44 (m, 3H) 1.58-1.65 (m, 1H) 1.76-1.91 (m, 4H) 2.25-2.38 (m, 2H) 4.83-4.99 (m, 1H) 7.51-7.68 (m, 5H) 8.04-8.11 (m, 2H) 8.42 (s, 1H)

[0630] MS ES.sup.+: 391

##STR00070##

Intermediate 35 4-chloro-N-cyclohexyl-6-methoxy-2-methylpyrimidin-5-amine

[0631] ##STR00071##

[0632] Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of cyclohexanone (CAS 108-94-1; 565 mg, 5.76 mmol) and 4-chloro-6-methoxy-2-methylpyrimidin-5-amine (CAS 88474-31-1; 500 mg, 2.88 mmol) in DCM (10 mL) at 0° C. under N.sub.2 was added TiCl.sub.4 solution (1M in DCM, 3.17 ml, 3.17 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (1.22 g, 5.76 mmol) was added portionwise and then the reaction allowed to stir at room temperature overnight. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.

[0633] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.11-1.30 (m, 4H) 1.49-1.57 (m, 1H) 1.62-1.69 (m, 2H) 1.72-1.81 (m, 3H) 2.40 (s, 3H) 3.39-3.49 (m, 1H) 3.88-3.96 (m, 4H)

[0634] MS ES.sup.+: 256

##STR00072##

Intermediate 36 4-chloro-6-methoxy-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-amine

[0635] ##STR00073##

[0636] Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 4-chloro-6-methoxypyrimidin-5-amine (CAS 15846-19-2; 0.572 mL, 6.19 mmol) and oxan-4-one (CAS 29943-42-8; 0.33 mL, 3.76 mmol) in anhydrous DCM (6 mL) under an atmosphere of nitrogen at 0° C. was added dropwise TiCl.sub.4 solution (1M in DCM, 3.41 mL, 3.41 mmol). The reaction was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (1.31 g, 6.19 mmol) was added portionwise and the reaction stirred at room temperature over a weekend. The crude product was purified by column chromatography (silica, 50-100% EtOAc/petroleum ether) to afford the title compound.

[0637] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.40-1.53 (m, 2H) 1.69-1.77 (m, 2H) 3.26-3.35 (m, >2H due to overlap with water peak) 3.68-3.79 (m, 1H) 3.79-3.87 (m, 2H) 3.98 (s, 3H) 4.38 (d, J=10 Hz, 1H) 8.10 (s, 1H)

[0638] MS ES.sup.+: 244

##STR00074##

Intermediate 37 6-amino-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

[0639] ##STR00075##

[0640] A mixture of 2,3-dichloropyrazine (CAS 4858-85-9; 10 g, 67.1 mmol), cesium carbonate (24 g, 73.8 mmol) and malononitrile (CAS 109-77-3; 4.88 g, 73.8 mmol) in DMSO (150 mL) was stirred at 125° C. for 90 minutes then allowed to cool to rt. Cyclohexanamine (CAS 108-91-8; 150 mL, 1.31 mol) was added and the reaction mixture was stirred at 130° C. for 4 days. After cooling to rt, 2M sodium hydroxide solution (200 mL; 0.4 mol) was added and the mixture was stirred at 115° C. for 24 hr. After cooling the mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.

[0641] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.20-1.33 (m, 1H) 1.35-1.47 (m, 2H) 1.64-1.78 (m, 3H) 1.81-1.89 (m, 2H) 2.37-2.49 (m, 2H) 4.32-4.44 (m, 1H) 7.08 (br. s., 1H) 7.42 (br. s., 1H) 7.77-7.89 (m, 3H) 8.04 (d, J=3 Hz, 1H)

[0642] MS ES.sup.+: 260.

Intermediate 38 5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine formate

[0643] ##STR00076##

[0644] A solution of 6-amino-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (Intermediate 37; 13.9 g, 53.6 mmol) in 50% aqueous sulfuric acid (100 mL) was heated at 100° C. for 2 h. The reaction mixture was allowed to cool to rt then poured into water and then basified to pH to with 2M NaOH. The resulting mixture was extracted with DCM (×3) and the organic extracts were concentrated in vacuo. The crude product was purified by column chromatography (C18-silica 5-95% methanol/water+0.1% formic acid) to afford the title compound.

[0645] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.25-1.46 (m, 3H) 1.64-1.73 (m, 3H) 1.80-1.89 (m, 2H) 2.42-2.54 (m, 2H) 4.21-4.32 (m, 1H) 5.34 (s, 1H) 6.48 (br. s., 2H) 7.61 (d, J=3 Hz, 1H) 7.86 (d, J=3 Hz, 1H) 8.16 (s, 1H)

[0646] MS ES.sup.+: 217

Intermediate 3 2-{5-cyclohexyl-5-pyrrolo[2,3-b]pyrazin-6-yl}-2,3-dihydro-1H-isoindole-1,3-dione

[0647] ##STR00077##

[0648] A solution of 5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine formate (Intermediate 38; 5 g, 19.1 mmol) in DCM (0 mL) was treated with triethylamine (12.9 mL, 92 mmol) followed by phthaloyl dichloride (CAS 88-95-9; 4.93 g, 24.3 mmol). The reaction mixture was allowed to stir at rt for 3 hours then poured into water and extracted with DCM. The organic phase was separated and concentrated to yield the title compound, which was used without further purification.

[0649] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.00-1.09 (m, 2H) 1.16-1.41 (m, 3H) 1.58-1.65 (m, 1H) 1.73-1.86 (m, 4H) 4.22-4.32 (m, 1H) 6.84 (s, 1H) 7.96-8.02 (m, 2H) 8.04-8.10 (m, 2H) 8.37-8.41 (m, 1H) 8.48-8.54 (m, 1H)

Intermediate 40 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonic add

[0650] ##STR00078##

[0651] A solution of 2-{5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-yl}-2,3-dihydro-1H-isoindole-1,3-dione (Intermediate 39; 8.63 g, 24.9 mmol) and acetic anhydride (23.5 mL, 249 mmol) in dichloromethane (100 mL) was cooled to 0° C. then sulfuric acid (6.64 mL, 125 mmol) was added dropwise. After 2 h the reaction mixture was diluted with water and extracted with DCM. The organic phase was concentrated and then azeotroped with toluene to yield the title compound.

[0652] MS ES.sup.+: 427.

Intermediate 41 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl chloride

[0653] ##STR00079##

[0654] A solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonic acid (Intermediate 40; 10.63 g, 24.9 mmol) in phosphorus oxychloride (50 mL, 536 mmol) was treated with phosphorus pentachloride (5.42 g, 26.0 mmol) and heated to 80° C. for 1.5 h. The reaction mixture was slowly quenched into warm water. The aqueous mixture was allowed to cool to rt and extracted with DCM. The organic phase was concentrated to yield the title compound.

[0655] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.18-1.49 (m, 3H) 1.63-1.68 (m, 1H) 1.75-1.93 (m, 4H) 2.53-2.64 (m, 2H) 4.81 (s, 1H) 8.04-8.09 (m, 2H) 8.13-8.19 (m, 2H) 8.78 (d, J=2.27 Hz, 1H) 8.90 (d, J=2.53 Hz, 1H)

[0656] MS ES.sup.+: 445

Intermediate 42 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-phenyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide

[0657] ##STR00080##

[0658] To a stirred solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl chloride (Intermediate 41; 100 mg, 0.225 mmol) in THF (1 mL) was added DMAP (28 mg, 0.225 mmol) and aniline (CAS 62-53-3; 42 mg, 0.450 mmol) and the reaction mixture allowed to stir at room temperature overnight. The reaction mixture was diluted with water and extracted with DCM. The organics were separated and concentrated. The crude material was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound. .sup.1H NMR (40 MHz, DMSO-d.sub.6) δ ppm 1.19-1.28 (m, 1H) 1.30-1.47 (m, 2H) 1.56-1.69 (m, 1H) 1.72-1.81 (m, 3H) 2.40-2.48 (m, 3H) 4.52-4.65 (m, 1H) 6.84-6.93 (m, 1H) 6.96-6.70 (m, 2H) 7.06-7.12 (m, 2H) 8.01-8.10 (m, 2H) 8.11-8.17 (m, 2H) 8.57 (d, J=3 Hz, 1H) 8.69 (d, J=3 Hz, 1H) 10.67 (s, 1H)

[0659] MS ES.sup.+: 502

Intermediate 43 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide

[0660] ##STR00081##

[0661] To a stirred solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl chloride (Intermediate 41; 1 mg, 0.225 mmol) in THF (1 mL) was added DMAP (28 mg, 0.225 mmol) and pyridin-3-amine (CAS 462-08-8; 42 mg, 0.450 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with water and extracted with DCM. The crude material was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.

[0662] MS ES.sup.+: 503

##STR00082##

Intermediate 44 2-(5-cyclohexyl-7-((4-methoxyphenyl)sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)isoindoline-1,3-dione

[0663] ##STR00083##

[0664] A mixture of silver trifluoromethanesulfonate (45 mg, 0.173 mmol), 4-methoxybenzene-1-sulfonyl chloride (36 mg, 0.173 mmol) and 2-{5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-yl}-2,3-dihydro-1H-isoindole-1,3-dione (Intermediate 39; 30 mg, 0.087 mmol) in nitrobenzene (0.5 mL) was subjected to microwave heating to 120° C. for 40 minutes. The reaction mixture was partitioned between water and DCM then the organic phase was concentrated in vacuo and the residue was purified by column chromatography on silica (silica, 5-50% EtOAc/petroleum ether) to afford the title compound.

[0665] .sup.1H NMR (4 MHz, DMSO-d.sub.6) δ ppm 1.22-1.32 (m, 2H) 1.32-1.46 (m, 2H) 1.60-1.67 (m, 1H) 1.70-1.85 (m, 5H) 3.81 (s, 3H) 4.63-4.74 (m, 1H) 7.08-7.16 (m, 2H) 7.89-7.96 (m, 1H) 8.04-8.10 (m, 1H) 8.14-8.21 (m, 2H) 8.60 (d, J=2 Hz, 1H) 8.72 (d, J=2 Hz, 1H)

[0666] MS ES.sup.+: 517.

[0667] Intermediates 45 to 54 were prepared by analogous methods and the data are given in Table 1. Where reactions failed to proceed to completion, further sulfonyl chloride was added and the temperature was increased (up to 150° C.) as required. Conventional heating in a sealed tube could also be employed.

TABLE-US-00001 TABLE 1 Column chromatography MS Intermediate Name of compound Structure Sulfonyl chloride gradient ES+ 45 2-(5-cyclohexyl-7- (cyclopropylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- yl)isoindoline-1,3-dione [00084] Cyclopropanesulfonyl chloride (CAS 139631-62-2) 5-50% EtOAc/petrol 451 46 2-(5-cyclohexyl-7-((3- fluorophenyl)sulfonyl)- 5H-pyrrolo[2,3-b]pyrazin- 6-yl)isoindoline-1,3-dione [00085] 3-fluorobenzene-1- sulfonyl chloride (CAS 701-27-9) 5-50% EtOAc/petrol 505 47 2-(5-cyclohexyl-7-((2- fluorophenyl)sulfonyl)- 5H-pyrrolo[2,3-b]pyrazin- 6-yl)isoindoline-1,3-dione [00086] 2-fluorobenzene-1- sulfonyl chloride (CAS 2905-21-7) 5-50% EtOAc/petrol 505 48 2-(5-cyclohexyl-7-((3- methoxyphenyl)sulfonyl)- 5H-pyrrolo[2,3-b]pyrazin- 6-yl)isoindoline-1,3-dione [00087] 3-methoxybenzene-1- sulfonyl chloride (CAS 10130-74-2) 5-50% EtOAc/petrol 517 49 4-((5-cyclohexyl-6-(1,3- dioxoisoindolin-2-yl)-5H- pyrrolo[2,3-b]pyrazin-7- yl)sulfonyl)benzonitrile [00088] 4-cyanobenzene-1- sulfonyl chloride (CAS 49584-26-1) 5-50% EtOAc/petrol 512 50 2-(7-((3-chloro-4- methoxyphenyl)sulfonyl)- 5-cyclohexyl-5H- pyrrolo[2,3-b]pyrazin-6- yl)isoindoline-1,3-dione [00089] 3-chloro-4- methoxybenzene-1- sulfonyl chloride (CAS 22952-43-8) 5-70% EtOAc/petrol 551 51 2-(5-cyclohexyl-7-((6- methoxypridin-3- yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- yl)isoindoline-1,3-dione [00090] 6-methoxypyridine-3- sulfonyl chloride (CAS 312300-42-8) 5-75% EtOAc/petrol 518 52 2-(5-cyclohexyl-7-((4- (trifluoromethoxy)phenyl) sulfonyl)-5H-pyrrolo[2,3- b]pyrazin-6- yl)isoindoline-1,3-dione [00091] 4-(trifluoromethoxy) benzenesulfonyl chloride (CAS 94108-56-2) 5-80% EtOAc/petrol 571 53 2-(5-cyclohexyl-7-((2,3- ((2,3-dihydrobenzo[b][1,4] dioxin-6-yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- yl)isoindoline-1,3-dione [00092] 2,3-dihydrobenzo[b] [1,4]dioxine-6- sulfonyl chloride (CAS 63758-12-3) 5-40% EtOAc/petrol 545 54 2-(5-cyclohexyl-7-((4- (difluoromethoxy)phenyl) sulfonyl)-5H-pyrrolo[2,3- b]pyrazin-6- yl)isoindoline-1,3-dione [00093] 4-(difluoromethoxy) benzene-1-sulfonyl chloride (CAS 351003-34-4) 5-40% EtOAc/petrol 553

2. Final Compounds

Example 1 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine

[0668] ##STR00094##

[0669] To a stirred solution of 2-(benzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 1; 50 g, 170 mmol) and cyclohexanamine (CAS 108-91-8; 97 mL, 850-mmol) in DMSO (100 mL) was added triethylamine (26 mL, 190 mmol). The reaction was heated thermally at 170° C. for 48 h. More cyclohexanamine (97 mL, 850 mmol) and triethylamine (26 mL, 190 mmol) were added and the reaction heated thermally at 185° C. for 24 h. The reaction was allowed to cool and diluted with brine. The resulting mixture was extracted with ethyl acetate and the organics washed with water and then with water/brine (1:1). The organics were dried (MgSO.sub.4) and concentrated in vacuo. The crude product was loaded onto a plug of silica (10 g) and eluted using 0-50% EtOAc/petroleum ether. Product fractions were concentrated and this purification process repeated another 3 times. The product fractions were concentrated. The resulting residue was recrystallised from hot ethanol to afford the title compound.

[0670] .sup.1H NMR (40 MHz, DMSO-d.sub.6) δ ppm 1.20-1.29 (m, 1H) 1.33-1.48 (m, 2H) 1.62-1.76 (m, 3H) 1.77-1.88 (m, 2H) 2.39-2.48 (m, 2H) 4.33-4.47 (m, 1H) 7.52-7.64 (m, 5H) 7.86-7.91 (m, 1H) 8.01-8.07 (m, 2H) 8.07-8.12 (m, 1H)

[0671] MS ES.sup.+: 357

Example 2 5-cycloheptyl-7-[(4-methylbenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine

[0672] ##STR00095##

[0673] A neat mixture of 2-(3-chloropyrazin-2-yl)-2-(4-methylbenzenesulfonyl)acetonitrile (Intermediate 2; 109 mg, 0.35 mmol) and cycloheptanamine (CAS 5452-35-7; 1.13 mL, 8.85 mmol) was heated in a microwave at 170° C. for 1 h and 45 mins. The reaction mixture was evaporated and purified by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0674] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.40-1.75 (m, 8H), 2.32 (s, 3H), 2.35-2.47 (m, 2H) 2.95-3.07 (m, 2H) 4.45-4.60 (br. m., 1H) 7.33 (d, J=8 Hz, 2H) 7.54 (br. s., 2H) 7.82 (d, J=3 Hz, 1H) 7.91 (d, J=8 Hz, 2H) 8, (d, J=3 Hz, 1H)

[0675] MS ES.sup.+: 385

Example 3 5-cycloheptyl-7-[(4-methylbenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine

[0676] ##STR00096##

[0677] Prepared as described for 5-cycloheptyl-7-[(4-methylbenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine (Example 2), a neat mixture of 2-(3-chloropyrazin-2-yl)-2-(4-methylbenzenesulfonyl)acetonitrile (Intermediate 2; 109 mg, 0.35 mmol) and cyclohexanamine (CAS 108-91-8; 1.01 mL, 8.85 mmol) was heated in a microwave at 170° C. for 1 h and 45 mins. The reaction mixture was evaporated and purified by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0678] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.15-1.31 (m, 1H) 1.32-1.48 (m, 2H) 1.60-1.76 (m, 3H) 1.77-1.87 (m, 2H) 2.33 (s, 3H) 2.37-2.48 (m, 2H) 4.32-4.44 (m, 1H) 7.35 (d, J=8 Hz, 2H) 7.57 (s, 2H) 7.88 (d, J=3 Hz, 1H) 7.92 (d, J=8 Hz, 2H) 8.08 (d, J=3 Hz, 1H)

[0679] MS ES.sup.+: 371

Example 4 5-cyclopentyl-7-[(4-methylbenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine

[0680] ##STR00097##

[0681] Prepared as described for 5-cycloheptyl-7-[(4-methylbenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine (Example 2), a neat mixture of 2-(3-chloropyrazin-2-yl)-2-(4-methylbenzenesulfonyl)acetonitrile (Intermediate 2; 109 mg, 0.35 mmol) and cyclopentanamine (CAS 1003-03-8; 0.873 mL, 8.85 mmol) was heated in a microwave at 170° C. for 1 h and 45 mins. The reaction mixture was evaporated and purified by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0682] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.69-1.85 (m, 2H) 1.96-2.16 (m, 4H) 2.21-2.35 (m, 2H) 2.40 (s, 3H) 4.80-4.92 (m, 1H) 6.08 (br. &, 2H) 7.27-7.33 (m, 2H) 7.92 (d, J=3 Hz, 1H) 8.10 (d, J=8 Hz, 2H) 8.26 (d, J=3 Hz, 1H)

[0683] MS ES.sup.+: 357

Example 5 7-[(4-chlorobenzene)sulfonyl]-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine

[0684] ##STR00098##

[0685] A stirred solution of 2-(4-chlorophenylsulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 3; 218 mg 0.664 mmol) and cyclohexanamine (CAS 108-91-8; 228 μL, 1.99 mmol) in N-methyl-2-pyrrolidinone (1.3 mL) was heated in a microwave at 170° C. for 2 h. More cyclohexanamine (228 μL, 1.99 mmol) was then added and the reaction was heated in a microwave at 170° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with brine and water, dried (H frit) and evaporated to dryness. The crude product was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.

[0686] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24-1.54 (m, 3H) 1.74-1.83 (m, 1H) 1.84-1.93 (m, 2H) 1.93-2.01 (m, 2H) 2.29-2.46 (m, 2H) 4.17-4.33 (m, 1H) 6.14 (br. s., 2H) 7.46 (d, J=9 Hz, 2H) 7.95 (d, J=3 Hz, 1H) 8.16 (d, J=9 Hz, 2H) 8.25 (d, J=3 Hz, 1H)

[0687] MS ES.sup.+: 391

Example 6 5-cyclohexyl-7-[(4-fluorobenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine

[0688] ##STR00099##

[0689] A stirred solution of 2-(3-chloropyrazin-2-yl)-2-(4-fluorophenylsulfonyl)acetonitrile (Intermediate 4; 101 mg, 0.324 mmol) and cyclohexanamine (CAS 108-91-8; 111 μL, 0.972 mmol) in N-methyl-2-pyrrolidinone (650 μL) was heated in a microwave at 170° C. for 2 h. More cyclohexanamine (200 μL, 1.75 mmol) was added and the reaction heated in a microwave at 170° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with brine and water, dried (H fit) and evaporated to dryness. The crude product was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.

[0690] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 1.26-1.57 (m, 3H) 1.69-1.83 (m, 3H) 1.86-1.98 (m, 2H) 2.48-2.64 (m, 2H) 4.25-4.38 (m, 1H) 7.19-7.27 (m, 2H) 7.90 (d, J=3 Hz, 1H) 8.03 (d, J=3 Hz, 1H) 8.10-8.18 (m, 2H)

[0691] MS ES.sup.+: 375

Example 7 5-cyclohexyl-7-{[4-(propan-2-yloxy)benzene]sulfonyl}-5H-pyrrolo[2,3-b]pyrazin-6-amine

[0692] ##STR00100##

[0693] A stirred solution of 2-(3-chloropyrazin-2-yl)-2-(4-isopropoxyphenylsulfonyl)acetonitrile (Intermediate 5; 204 mg, 0.580 mmol) and cyclohexanamine (CAS 108-91-8; 199 μL, 1.74 mmol) in N-methyl-2-pyrrolidinone (1.1 mL) was heated in a microwave at 170° C. for 2 h. More cyclohexanamine (200 μL, 1.75 mmol) was added and the reaction heated in a microwave at 170° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with brine and water, dried (H frit) and evaporated to dryness. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.

[0694] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.25 (d, J=6 Hz, 6H) 1.32-1.48 (m, 2H) 1.62-1.76 (m, 3H) 1.77-1.87 (m, 2H) 2.36-2.49 (m, 3H) 4.32-4.44 (m, 1H) 4.62-4.73 (m, 1H) 7.03 (d, J=9 Hz, 2H) 7.54 (br. s, 2H) 7.88 (d, J=3 Hz, 1H) 7.94 (d, J=9 Hz, 2H) 8.08 (d, J=3 Hz, 1H)

[0695] MS ES.sup.+: 415

Example 8 5-cyclohexyl-7-(thiophene-2-sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-amine

[0696] ##STR00101##

[0697] A stirred solution of 2-(3-chloropyrazin-2-yl)-2-(thiophen-2-ylsulfonyl)acetonitrile (Intermediate 6; 74 mg, 0.247 mmol) and cyclohexanamine (CAS 108-91-8; 282 μl, 2.47 mmol) in DMSO (120 μL) was heated in a microwave at 170° C. for 2.5 h. The reaction mixture was diluted with DMSO and purified by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0698] .sup.1H NMR (4 MHz, METHANOL-d.sub.4) δ ppm 1.29-1.59 (m, 3H) 1.71-1.86 (m, 3H) 1.90-1.99 (m, 2H) 2.52-2.67 (m, 2H) 4.28-4.40 (m, 1H) 7.06-7.11 (m, 1H) 7.68-7.73 (m, 1H) 7.81-7.85 (m, 1H) 7.93 (d, J=3 Hz, 1H) 8.06 (d, J=3 Hz, 1H)

[0699] MS ES.sup.+: 363

Example 9 3-(benzenesulfonyl)-1-cyclohexyl-1H-[3,2-b]pyridin-2-amine

[0700] ##STR00102##

[0701] To a stirred solution of solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 555 mg, 3.07 mmol) in DME (3 mL) at 0° C. under a flow of N.sub.2 was added sodium hydride (60% dispersion in oil, 223 mg, 5.57 mmol) and the resulting suspension allowed to stir for to minutes. In a separate flask Pd(Ph.sub.3P).sub.4 (CAS 014221-01-3; 161 mg, 0.139 mmol) in DME (3 mL) was degassed with N.sub.2. The suspension of pre-formed sodium salt of 2-(benzenesulfonyl)acetonitrile was added to the second vessel. After stirring for a further 10 minutes 2-bromo-N-cyclohexylpyridin-3-amine (Intermediate 7; 711 mg, 2.79 mmol) was added and the reaction mixture subjected to microwave irradiation at 120° C. for 1.5 h. The reaction mixture was poured into water and extracted with ethyl acetate and then the organics washed with brine. The organics were dried over MgSO.sub.4 and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-500% EtOAc/DCM) to afford crude product. The crude product was triturated with hot IPA and then filtered and dried to afford the title compound.

[0702] .sup.1H NMR (400 MHz, DICHLOROMETHANE-d.sub.2) δ ppm 1.13-1.37 (m, 1H) 1.38-1.54 (m, 2H) 1.73-1.85 (m, 1H) 1.86-2.16 (m, 6H) 3.91-4.04 (m, 1H) 5.88 (br. s., 2H) 6.89-6.98 (m, 1H) 7.40-7.59 (m, 4H) 8.13-8.20 (m, 2H) 8.22-8.30 (m, 1H)

[0703] MS ES.sup.+: 356

Example 10 1-cyclopentyl-3-[(4-methylbenzene)sulfonyl]-1H-pyrrolo[3,2-b]pyridin-2-amine

[0704] ##STR00103##

[0705] To a stirred solution of 3-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridin-2-amine (Intermediate 10; 250 mg, 0.7 mmol) in DMF (10 mL) was added DBU (264 mg, 1.4 mmol) and cyclopentyl bromide (194 mg, 1.0 mmol). The reaction was heated in a sealed tube at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The organics were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 5-95% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0706] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.61-1.71 (m, 2H) 1.90-2.02 (m, 6H) 2.32 (s, 3H) 4.84-4.92 (m, 1H) 6.87-6.94 (m, 1H) 7.13 (s, 2H) 7.33 (d, J=8 Hz, 2H) 7.48-7.55 (m, 1H) 7.95 (d, J=8 Hz, 2H) 8.11-8.18 (m, 1H)

[0707] MS ES.sup.+: 356

Example 11 1-cyclohexyl-3-[(4-methylbenzene)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-amine

[0708] ##STR00104##

[0709] A stirred solution of 2-(2-chloropyridin-3-yl)-2-(4-methylbenzenesulfonyl)acetonitrile (Intermediate 11; 600 mg, 2.0 mmol), triethylamine (500 mg, 4.9 mmol) and cyclohexanamine (CAS 108-91-8; 2.43 g, 24.5 mmol) in DMSO (5 mL) was heated to 160° C. for 3 hours in a microwave. The reaction was poured onto ice and extracted with ethyl acetate. The organic phase was concentrated in vacuo. The resulting residue was purified by column chromatography (preparative HPLC, 5-95% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0710] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.20-1.33 (m, 2H) 1.34-1.48 (m, 3H) 1.60-1.71 (m, 3H) 1.78-1.87 (m, 2H) 2.33 (s, 3H) 4.29-4.40 (m, 1H) 6.96-7.09 (m, 3H) 7.32-7.36 (m, 2H) 7.70-7.74 (m, 1H) 7.80-7.85 (m, 2H) 7.92-7.98 (m, 1H)

[0711] MS ES.sup.+: 370

Example 12 7-(cyclohexanesulfonyl)-5-cyclohexyl-5-pyrrolo[2,3-b]pyrazin-6-amine

[0712] ##STR00105##

[0713] To a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 1.8 g, 12.1 mmol) and 2-(cyclohexanesulfonyl)acetonitrile (CAS 797036-54-5; 2.7 g, 14.4 mmol) in DMSO (2 mL) was added DBU (1.85 g, 12.1 mmol) and the reaction heated in a microwave to 130° C. for 3 h. To the resulting solution was added triethylamine (600 mg, 59 mmol) and cyclohexanamine (CAS 108-91-8; 6 g, 60.5 mmol) and the reaction heated in a microwave to 170° C. for 3 h. The reaction was poured onto ice and extracted with ethyl acetate. The organic phase was concentrated in vacuo. The resulting residue was purified by column chromatography (preparative HPLC, 5-95% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0714] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.04-1.30 (m, 4H) 1.33-1.49 (m, 4H) 1.55-1.63 (m, 1H) 1.66-1.80 (m, 5H) 1.80-1.98 (m, 4H) 2.39-2.49 (m, 2H) 3.09-3.24 (m, 1H) 4.32-4.44 (m, 1H) 7.31-7.43 (m, 2H) 7.91 (d, J=3 Hz, 1H) 8.09 (d, J=3 Hz, 1H)

[0715] MS ES.sup.+: 363

Example 13 5-(4,4-difluorocyclohexyl)-7-[(4-methoxybenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine

[0716] ##STR00106##

[0717] To a stirred solution of 2-(3-chloropyrazin-2-yl)-2-((4-methoxyphenyl)sulfonyl)acetonitrile (Intermediate 12; 136 mg, 0.420 mmol) and 4,4-difluorocyclohexanamine hydrochloride (CAS 675112-70-6; 433 mg, 2.52 mmol) in N-methyl-2-pyrrolidinone (2 mL) was added triethylamine (0.410 mL, 2.94 mmol). The reaction was then heated in a microwave to 180° C. for 2 h. The reaction mixture was partitioned between water and EtOAc. The phases were separated and the aqueous extracted with EtOAc. The combined organic extracts were then washed with water, dilute citric acid, water, sat. NaHCO.sub.3, sat. brine, dried (H-frit) and evaporated. The crude material was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.

[0718] .sup.1H NMR (400 MHz, DICHLOROMETHANE-d.sub.2) δ ppm 1.87-2.11 (m, 4H) 2.24-2.40 (m, 2H) 2.75-2.93 (m, 2H) 3.86 (s, 3H) 4.29-4.44 (m, 1H) 6.20 (br. s., 2H) 6.99 (d, J=9 Hz, 2H) 7.96 (d, J=3 Hz, 1H) 8.11 (d, J=9 Hz, 2H) 8.22 (d, J=3 Hz, 1H)

[0719] MS ES.sup.+: 423

Example 14 1-(4,4-difluorocyclohexyl)-3-[(4-methoxybenzene)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-amine

[0720] ##STR00107##

[0721] To a stirred solution of 2-(2-chloropyridin-3-yl)-2-((4-methoxyphenyl)sulfonyl)acetonitrile (Intermediate 13; 210 mg, 0.651 mmol) in N-methyl-2-pyrrolidinone (1 mL) was added a solution of 4,4-difluorocyclohexanamine hydrochloride (CAS 675112-70-6; 670 mg, 3.90 mmol) and triethylamine (0.635 mL, 4.55 mmol) in N-methyl-2-pyrrolidinone (2 mL) and the resulting mixture heated at 165-175° C. for 20 h. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate. The combined organics were washed with dilute citric acid, water, sat. aq. sodium bicarbonate solution and brine, dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-40% EtOAc/petroleum ether). Further purification was performed by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0722] .sup.1H NMR (4 MHz, CHLOROFORM-d) δ ppm 1.81-2.16 (m, 4H) 2.21-2.49 (m, 2H) 2.53-2.89 (m, 2H) 3.84 (8, 3H) 4.56-4.92 (m, 1H) 5.68 (br. s., 2H) 6.86-7.14 (m, 3H) 7.77-7.99 (m, 3H) 8.00-8.15 (m, 1H)

[0723] MS ES.sup.+: 422

Example 15 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-2-amine

[0724] ##STR00108##

[0725] To a stirred solution of 2-(2-chloropyridin-3-yl)-2-(phenylsulfonyl)acetonitrile (Intermediate 14; 100 mg, 0.342 mmol) in N-methyl-2-pyrrolidinone (1 mL) was added a solution of cyclohexanamine (CAS 108-91-8; 0.234 mL, 2.05 mmol) and triethylamine (0.048 mL, 0.342 mmol) in N-methyl-2-pyrrolidinone (1 mL) and the resulting mixture heated at 170° C. for 5 h using a microwave reactor. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate. The combined organics were washed with dilute citric acid, water, sat aq. sodium bicarbonate solution and brine, dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-40% EtOAc/petroleum ether). Further purification was performed by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0726] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.20-1.56 (m, 3H) 1.72-2.00 (m, 5H) 2.14-2.51 (m, 2H) 4.49 (br. s., 1H) 5.70 (br. s., 2H) 6.89-7.16 (m, 1H) 7.40-7.56 (m, 3H) 7.82-7.91 (m, 1H) 7.92-8.00 (m, 2H) 8.03-8.11 (m, 1H)

[0727] MS ES.sup.+: 356

Example 16 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-2-amine

[0728] ##STR00109##

[0729] A stirred solution of N-cyclohexyl-5-iodopyrimidin-4-amine (Intermediate 15; 139 mg, 0.459 mmol) and Pd(Ph.sub.3P).sub.4 (26.5 mg, 0.023 mmol) dry DME (2 mL) was degassed with N.sub.2. In a separate vial 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 91 mg, 0.504 mmol) was dissolved in dry DME (2 mL), degassed and cooled to 0° C. NaH, 60% dispersion in oil (36.7 mg, 0.917 mmol) was added and stirred 5 min. The solution of iodopyrimidine and Pd catalyst was then added via cannula, rinsing with further dry DME. The reaction mixture was then heated in a microwave at 110° C. for 1 h. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water, sat. brine, dried (H-frit) and evaporated. The crude material was then purified by column chromatography (silica, 0-40% EtOAc/petroleum ether) to afford the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.32-1.53 (m, 3H) 1.57-1.69 (m, 1H) 1.70-1.90 (m, 4H) 1.98-2.16 (m, 2H) 4.30-4.47 (m, 1H) 7.50-7.65 (m, 5H) 8.01-8.13 (m, 2H) 8.60 (s, 1H) 8.74 (s, 1H)

[0730] MS ES.sup.+: 357

Example 17 3-(benzenesulfonyl)-1-(4,4-difluorocyclohexyl)-1H-pyrrolo[2,3-b]pyridin-2-amine

[0731] ##STR00110##

[0732] Prepared as described for 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-2-amine (Example 15), a stirred solution of 2-(2-chloropyridin-3-yl)-2-(phenylsulfonyl)acetonitrile (Intermediate 14; 239 mg, 0.816 mmol), 4,4-difluorocyclohexanamine hydrochloride (CAS 675112-70-6; 662 mg, 4.90 mmol) and triethylamine (0.8 mL, 5.71 mmol) in N-methyl-2-pyrrolidinone (2. mL) was heated at 170° C. for 5 h using a microwave reactor. The crude product was purified by column chromatography (silica, 0-40% EtOAc/petroleum ether). Further purification was performed by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0733] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.82-2.14 (m, 4H) 2.17-2.46 (m, 2H) 2.58-2.87 (m, 2H) 4.49-4.90 (m, 1H) 5.76 (s, 2H) 6.97-7.14 (m, 1H) 7.39-7.63 (m, 3H) 7.76-7.93 (m, 1H) 7.97 (d, J=7 Hz, 2H) 8.04-8.14 (m, 1H)

[0734] MS ES.sup.+: 392

Example 19 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine

[0735] ##STR00111##

[0736] To a stirred degassed solution of 4-chloro-N-cyclohexylpyrimidin-5-amine (Intermediate 16; 209 mg, 0.987 mmol) in dry DME (2 mL) was added Pd(Ph.sub.3P).sub.4 (29 mg, 0.025 mmol) and Pd(amphos).sub.2Cl.sub.2 (18 mg, 0.025 mmol). In a separate vial, 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 197 mg, 1.09 mmol) was dissolved in dry DME (2 mL), degassed, cooled in ice and treated with NaH, 60% dispersion in oil (79 mg, 1.98 mmol). The second vial was stirred in ice for 5 min, then at rt for 5 min, under a gentle N.sub.2 stream. The solution of pyrimidine and Pd catalysts was then added via cannula, rinsing with further dry DME. The reaction heated in the microwave at 110° C. for 1 h. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water, sat. brine, dried (H-frit) and evaporated. The crude product was purified by column chromatography (silica, 50-90% EtOAc/petroleum ether) to afford the title compound.

[0737] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.32-1.53 (m, 3H) 1.57-1.69 (m, 1H) 1.70-1.90 (m, 4H) 1.98-2.16 (m, 2H) 4.30-4.47 (m, 1H) 7.50-7.65 (m, 5H) 8.01-8.13 (m, 2H) 8.60 (s, 1H) 8.74 (s, 1H)

[0738] MS ES.sup.+: 357

Example 20 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-]pyridin-2-amine

[0739] ##STR00112##

[0740] To a stirred solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 330 mg, 1.82 mmol) in DME (3 mL) at 0° C. under a flow of N.sub.2 was added NaH, 60% dispersion in oil (132 mg, 3.31 mmol) and the resulting suspension allowed to stir for 10 min. In a separate flask Pd(Ph.sub.3P).sub.4 (96 mg, 0.083 mmol) in DME (3 mL) was degassed. The solution in the first flask was added to the solution of Pd(Ph.sub.3P).sub.4 in DME. After stirring for a further to min N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17; 500 mg, 1.66 mmol) was added and the reaction mixture subjected to microwave irradiation at 120° C. for 1.5 h. The reaction mixture was poured into water and extracted with ethyl acetate and then the organics washed with brine. The organics were dried over MgSO.sub.4 and concentrated. The crude product was purified by column chromatography (basic silica, 0-20% EtOAc/petroleum ether). The resulting solid was recrystallised from hot IPA/water to afford the title compound.

[0741] .sup.1H NMR (400 MHz, DICHLOROMETHANE-d.sub.2) δ ppm 1.28-1.42 (m, 1H), 1.44-1.59 (m, 2H), 1.78-1.89 (m, 1H), 1.92-2.12 (m, 4H), 2.12-2.30 (m, 2H), 3.94-4.10 (m, 1H), 5.89 (br. s., 2H), 7.45-7.62 (m, 4H), 7.89-8.07 (m, 2H), 8.17-8.22 (m, 1H), 8.68 (s, 1H)

[0742] MS ES.sup.+: 356

Example 21 3-(benzenesulfonyl)-1-(4,4-difluorocyclohexyl)-1H-pyrrolo[3,2-b]pyridin-2-amine

[0743] ##STR00113##

[0744] Prepared as described for 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-c]pyridin-2-amine (Example 20), to a stirred solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 548 mg, 3.02 mmol) in DME (3 mL) at 0° C. under a flow of N.sub.2 was added NaH, 60% dispersion in oil (220 mg, 5.50 mmol) and the resulting suspension allowed to stir for to min. In a separate flask Pd(Ph.sub.3P).sub.4 (159 mg, 00.137 mmol) in DME (3 mL) was degassed. The solution in the first flask was added to the solution of Pd(Ph.sub.3P).sub.4 in DME. After stirring for a further to min, 2-bromo-N-(4,4-difluorocyclohexyl)pyridin-3-amine (Intermediate 18; 800 mg, 2.75 mmol) was added and the reaction mixture subjected to microwave irradiation at 120° C. for 1.5 h. The crude product was purified by column chromatography (basic silica, 0-50% DCM/EtOAc). The resulting solid was triturated with hot ethanol to afford the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.81-1.93 (m, 2H) 1.95-2.38 (m, 6H) 4.50-4.66 (m, 1H) 6.89-6.97 (m, 1H) 7.17 (s, 2H) 7.47-7.60 (m, 4H) 8.04-8.09 (m, 2H) 8.11-8.15 (m, 1H)

[0745] MS ES.sup.+: 392

Example 22 1-(4,4-difluorocyclohexyl)-3-[(4-methoxybenzene)sulfonyl]-1H-pyrrolo[3,2-b]pyridin-2-amine

[0746] ##STR00114##

[0747] Prepared as described for 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-c]pyridin-2-amine (Example 20), to a stirred solution of 2-((4-methoxyphenyl)sulfonyl)acetonitrile (CAS 132276-87-o; 638 mg, 3.02 mmol) in DME (4 mL) at 0° C. under a flow of N.sub.2 was added NaH, 60% dispersion in oil (2200 mg, 5.50 mmol) and the resulting suspension allowed to stir for 10 minutes. In a different flask Pd(Ph.sub.3P).sub.4 (159 mg, 0.137 mmol) in DME (4 mL) was degassed. The solution in the first flask was added to the solution of Pd(Ph.sub.3P).sub.4 in DME. After stirring for a further to minutes 2-bromo-N-(4,4-difluorocyclohexyl)pyridin-3-amine (Intermediate 18; 800 mg, 2.75 mmol) was added and the reaction mixture subjected to microwave irradiation at 120° C. for 1.5 h. The crude product was purified by column chromatography (basic silica, 0-100% DCM/EtOAc). The resulting solid was triturated with hot ethanol to afford the title compound.

[0748] .sup.1H NMR (400 MHz, DICHLOROMETHANE-d.sub.2) δ ppm 1.88-2.12 (m, 4H), 2.27-2.39 (m, 2H), 2.44-2.59 (m, 2H), 3.85 (s, 3H), 4.09-4.28 (m, 1H), 5.93 (s, 2H), 6.89-7.05 (m, 3H), 7.50-7.54 (m, 1H), 8.07-8.20 (m, 2H), 8.30-8.34 (m, 1H)

[0749] MS ES.sup.+: 422

Example 23 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[3,2-c]pyridin-2-amine

[0750] ##STR00115##

[0751] Prepared as described for 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-c]pyridin-2-amine (Example 20), to a stirred degassed solution Pd(Ph.sub.3P).sub.4 (73 mg, 0.063 mmol) in anhydrous DME (3 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 252 mg, 1.39 mmol) and NaH, 60% dispersion in oil (106 mg, 2.65 mmol) in anhydrous DME (4 mL). The resulting mixture was stirred at room temperature for 10 min followed by addition of a solution of 3-bromo-N-cyclohexylpyridin-4-amine (Intermediate 19; 322 mg, 1.262 mmol) in anhydrous DME (1 mL). The reaction mixture was heated at 120° C. for 1.5 h. Purification was carried out by column chromatography (silica, 0-100% EtOAc/petroleum ether). Further purification was performed by column chromatography (preparative HPLC, 20-600% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.

[0752] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19-1.55 (m, 3H) 1.76-2.29 (m, 7H) 3.82-4.19 (m, 1H) 5.75 (br. s, 2H) 7.20 (d, J=6 Hz, 1H) 7.38-7.62 (m, 3H) 7.88-8.09 (m, 2H) 8.23 (d, J=6 Hz, 1H) 8.92 (s, 1H)

[0753] MS ES.sup.+: 356

Example 24 methyl N-[7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-yl]carbamate

[0754] ##STR00116##

[0755] To a stirred solution of methyl N-[7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-yl]-N-(methoxycarbonyl)carbamate (Intermediate 20; 0.214 g, 0.453 mmol) in MeOH (7 mL) was added sodium methanolate (16 mg, 0.3 mmol) and the resulting mixture stirred at room temperature for 3 h. A further portion of sodium methoxide (10 mg, 0.19 mmol) was added and the reaction was stirred at room temperature for a further 2 h. The solvent was removed under reduced pressure. The residue was partitioned between DCM and water, passed through a phase separator and concentrated in vacuo. Purification was performed by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0756] .sup.1H NMR (4000 MHz, CHLOROFORM-d) δ ppm 1.27-1.46 (m, 3H) 1.66-2.05 (m, 5H) 2.47-2.73 (m, 2H) 3.89 (s, 3H) 4.09-4.28 (m, 1H) 7.37-7.64 (m, 3H) 8.05-8.21 (m, 2H) 8.27 (d, J=3 Hz, 2H) 8.52 (d, J=3 Hz, 1H)

[0757] MS ES.sup.+: 415

Example 25 3-(benzenesulfonyl)-1-(4,4-difluorocyclohexyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-amine

[0758] ##STR00117##

[0759] To a stirred solution 2-amino-1-(4,4-difluorocyclohexyl)-6-methyl-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (Intermediate 22; 65 mg, 0.154 mmol) in chloroform (2 mL) under an atmosphere of nitrogen was added trichlorophosphine (0.1 mL, 1.15 mmol). The resulting mixture was heated at reflux for 1 h. The mixture was partitioned between DCM and saturated NaHCO.sub.3. The phases were separated and the aqueous extracted with DCM. The combined organics were washed with saturated NaHCO.sub.3, dried over MgSO.sub.4 and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0760] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.76-2.19 (m, 4H) 2.22-2.41 (m, 2H) 2.52 (s, 3H) 2.58-2.81 (m, 2H) 4.58-4.87 (m, 1H) 5.57 (br. s, 2H) 6.91 (d, J=8 Hz, 1H) 7.36-7.60 (m, 3H) 7.76 (d, J=8 Hz, 1H) 7.86-8.07 (m, 2H)

[0761] MS ES.sup.+: 406

Example 26 7-(benzenesulfonyl)-5-cyclohexyl-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-6-amine

[0762] ##STR00118##

[0763] Prepared as described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a stirred degassed solution of Pd(Ph.sub.3P).sub.4 (14 mg, 0.013 mmol) and Pd(amphos).sub.2Cl.sub.2 (9 mg, 0.013 mmol) in anhydrous DME (1 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 100 mg, 0.550 mmol) and NaH, 60% dispersion in oil (44.0 mg, 1.100 mmol) in anhydrous DME (1 mL). The resulting mixture was stirred at room temperature for 10 min followed by addition of a solution of 4-chloro-N-cyclohexyl-6-methoxypyrimidin-5-amine (Intermediate 23; 121 mg, 0.5 mmol) in anhydrous DME (1 mL). The reaction mixture was heated at 120° C. for 1.5 h. The crude product was purified by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0764] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13-1.53 (m, 4H) 1.65-2.51 (m, 7H) 4.09 (s, 3H) 5.86 (br. s., 2H) 7.42-7.60 (m, 3H) 8.14-8.30 (m, 2H) 8.51 (s, 1H)

[0765] MS ES.sup.+: 387

Example 27 5-(benzenesulfonyl)-3-chloro-7-cyclohexyl-7H-pyrrolo[2,3-c]pyridazin-6-amine

[0766] ##STR00119##

[0767] Prepared as described for 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-c]pyridin-2-amine (Example 20), to a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 34 mg, 0.189 mmol) in DME (3 mL) at 0° C. was added NaH, 60% dispersion in oil (14 mg, 0.344 mmol). After 10 minutes the resulting suspension was added to a degassed solution of Pd(Ph.sub.3P).sub.4 (10 mg, 8.60 μmol) in DME (2 mL). The resulting suspension was allowed to stir at room temperature for 20 minutes. 4-bromo-6-chloro-N-cyclohexylpyridazin-3-amine (Intermediate 24; 50 mg, 0.172 mmol) was then added and the reaction mixture subjected to microwave irradiation at 120° C. for 2 h. Purification was carried out by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.

[0768] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.18-1.49 (m, 3H), 1.62-1.7 (m, 3H), 1.77-1.86 (m, 2H), 2.42-2.49 (m, 2H), 4.43 (br. s., 1H), 7.47 (s, 1H), 7.55-7.70 (m, 3H), 7.96 (br. s., 2H), 8.00-8.08 (m, 2H)

[0769] MS ES.sup.+: 391

Example 28 5-(benzenesulfonyl)-7-cyclohexyl-7H-pyrrolo[2,3-c]pyridazin-6-amine

[0770] ##STR00120##

[0771] A solution of 5-(benzenesulfonyl)-3-chloro-7-cyclohexyl-7H-pyrrolo[2,3-c]pyridazin-6-amine (Example 27; 31 mg, 0.079 mmol) in THF (2 mL) was passed through an H-Cube using a 10% Palladium on carbon cat-cart at 40° C. at ‘full H.sub.2’. The reactant was cycled through the H-Cube for 2 h at 1 mL/min. The product solution was then concentrated in vacuo. Purification was carried out by column chromatography (silica, 0-50% EtOAc/petroleum ether) followed by column chromatography (silica, 0-10% MeOH/DCM) and finally by trituration with diethyl ether to afford the title compound.

[0772] .sup.1H NMR (400 MHz, DICHLOROMETHANE-d.sub.2) δ ppm 1.25-1.44 (m, 3H), 1.62-1.71 (m, 1H), 1.75-1.98 (m, 4H), 2.34-2.48 (m, 2H), 4.32 (br. s., 1H), 6.13 (br. s, 2H), 7.31-7.55 (m, 4H), 7.78-7.89 (m, 2H), 8.57-8.67 (m, 1H)

[0773] MS ES.sup.+: 357

Example 29 7-(benzenesulfonyl)-5-(4,4-difluorocyclohexyl)-4-ethoxy-5H-pyrrolo[3,2-d]pyrimidin-6-amine

[0774] ##STR00121##

[0775] As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 373 mg, 2.06 mmol) in DME (3 mL) at 0° C. was added NaH, 60% dispersion in oil (165 mg, 4.11 mmol). After 10 min the resulting suspension was added to a degassed solution of Pd(Ph.sub.3P).sub.4 (59 mg, 0.051 mmol) and Pd(amphos).sub.2C.sub.2 (36 mg, 0.051 mmol) in DME (2 mL). The resulting suspension was allowed to stir at room temperature for 20 minutes. 4-chloro-N-(4,4-difluorocyclohexyl)-6-ethoxypyrimidin-5-amine (Intermediate 25; 6 mg, 2.06 mmol) was then added and the reaction mixture subjected to microwave irradiation at 120° C. for 2 b. Purification was carried out by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.

[0776] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.34-1.41 (m, 3H), 1.71-1.80 (m, 2H), 1.92-2.21 (m, 4H), 2.44-2.61 (m, 2H), 4.43-4.45 (m, 3H), 7.34 (br. s, 2H), 7.52-7.64 (m, 3H), 8.00-8.10 (nm, 2H), 8.30 (s, 1H)

[0777] MS ES.sup.+: 437

Example 30 7-(benzenesulfonyl)-4-(benzyloxy)-5-(4,4-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine

[0778] ##STR00122##

[0779] As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 512 mg, 2.83 mmol) in DME (3 mL) at 0° C. was added NaH, 60% dispersion in oil (226 mg, 5.65 mmol). After to min the resulting suspension was added to a degassed solution of Pd(Ph.sub.3P).sub.4 (0.082 g, 0.071 mmol) and Pd(amphos).sub.2Cl.sub.2 (0.050 g 0.071 mmol) in DME (2 mL). The resulting suspension was allowed to stir at room temperature for 20 minutes. 4-(benzyloxy)-6-chloro-N-(4,4-difluorocyclohexyl)pyrimidin-5-amine (Intermediate 27; 1 g, 2.83 mmol) was then added and the reaction mixture subjected to microwave irradiation at 120° C. for 2 h. Purification was carried out by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.

[0780] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.64-1.78 (m, 2H), 0.83-2.11 (m, 4H), 2.40-2.58 (m, 2H), 4.44-4.57 (m, 1H), 5.55 (s, 2H), 7.26-7.39 (m, 5H), 7.42-7.48 (m, 2H), 7.51-7.66 (m, 3H), 8.02-8.10 (m, 2H), 8.32 (s, 1H)

[0781] MS ES.sup.+: 499

Example 31 6-amino-5-(4,4-difluorocyclohexyl)-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol

[0782] ##STR00123##

[0783] A solution of 7-(benzenesulfonyl)-4-(benzyloxy)-5-(4,4-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 30; 420 mg, 0.842 mmol) in methanol (17 mL) was passed through an H-Cube using a palladium on carbon (10%) cat-cart at ‘full H.sub.2’ at room temperature at 1 mL/min. The product solution was concentrated and triturated with ethyl acetate to afford the title compound.

[0784] .sup.1H NMR (4 MHz, DMSO-d.sub.6) δ ppm 1.61-1.71 (m, 2H), 1.85-2.18 (m, 4H), 2.68-2.83 (m, 2H), 4.32-4.52 (m, 1H), 6.94 (s, 2H), 7.51-7.68 (m, 3H), 7.86 (s, 1H), 7.94-8.12 (m, 2H), 12.04 (br. s., 1H)

[0785] MS ES.sup.+: 409

Example 32 7-(benzenesulfonyl)-4-chloro-5-(4,4-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine

[0786] ##STR00124##

[0787] To a stirred suspension of 6-amino-7-(benzenesulfonyl)-5-(4,4-difluorocyclohexyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (Example 31; 75 mg, 0.184 mmol) in POCl.sub.3 (1 mL, 10.7 mmol) was heated at 80° C. overnight. The reaction was quenched slowly into warm water. The resulting solution was basified to pH.sub.12 with 2M NaOH. The resulting aqueous mixture was extracted with DCM. The organics were separated and concentrated. Trituration with diethyl ether afforded the title compound.

[0788] .sup.1H NMR (400 MHz, DICHLOROMETHANE-d.sub.2) δ ppm 1.86-2.23 (m, 4H), 2.27-2.68 (m, 4H), 5.41-5.73 (m, 1H), 6.28 (br. s., 2H), 7.35-7.73 (m, 3H), 8.05-8.32 (m, 2H), 8.56 (br. s., 1H)

[0789] MS ES.sup.+: 427

Example 33 7-(benzenesulfonyl)-5-(4,4-difluorocyclohexyl)-4-N-methyl-5H-pyrrolo[3,2-d]pyrimidine-4,6-diamine

[0790] ##STR00125##

[0791] A solution of 7-(benzenesulfonyl)-4-chloro-5-(4,4-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 32; 40 mg, 0.094 mmol) and methanamine, 2M in THF (0.234 mL, 0.469 mmol) in THF (1 mL) was subjected to microwave irradiation at 120-160° C. for a total of 7 h. The reaction mixture was concentrated in vacuo. To the crude product was added methanamine 2M in THF (2 ml). The solution was subjected to microwave irradiation for a further 2 h at 160° C. The reaction mixture was poured into sat. NaHCO.sub.3 and extracted with DCM. The organics were separated and concentrated to afford the title compound.

[0792] .sup.1H NMR (4 MHz, DMSO-d.sub.6) δ ppm 1.95-2.04 (m, 2H), 2.06-2.30 (m, 4H), 2.33-2.48 (m, 2H), 2.95 (d, J=5 Hz, 3H), 4.45-4.58 (m, 1H), 5.84-5.91 (m, 1H), 6.82 (s, 2H), 7.51-7.73 (m, 3H), 8.04-8.15 (m, 2H), 8.23 (s, 1H)

[0793] MS ES.sup.+: 422

Example 34 7-(benzenesulfonyl)-5-cyclohexyl-4-N,4-N-dimethyl-5H-pyrrolo[3,2-d]pyrimidine-4,6-diamine

[0794] ##STR00126##

[0795] As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a stirred degassed solution of Pd(Ph.sub.3P).sub.4 (28 mg, 0.024 mmol) and Pd(amphos).sub.2Cl.sub.2 (17 mg, 0.024 mmol) in anhydrous DME (3 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 261 mg, 1.44 mmol) and NaH, 60% dispersion in oil (115 mg, 2.89 mmol) in anhydrous DME (3 mL). The resulting mixture was stirred at room temperature for to min followed by addition of a solution of 6-chloro-5-N-cyclohexyl-4-N,4-N-dimethylpyrimidine-4,5-diamine (Intermediate 28; 245 mg, 0.962 mmol) in anhydrous DME (3 mL). The reaction mixture was heated at 125° C. for 20 h. The crude product was purified by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0796] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.03-2.10 (m, 10H) 2.89 (s, 6H) 4.67-4.92 (m, 1H) 6.01 (br. s., 2H) 7.39-7.63 (m, 3H) 8.11-8.32 (m, 2H) 8.53 (s, 1H)

[0797] MS ES.sup.+: 400

Example 35 7-(benzenesulfonyl)-5-cyclopentyl-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-6-amine

[0798] ##STR00127##

[0799] As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a stirred degassed solution of Pd(Ph.sub.3P).sub.4 (32 mg, 0.027 mmol) and Pd(amphos).sub.2Cl.sub.2 (19 mg, 0.027 mmol) in anhydrous DME (2 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 298 mg, 1.65 mmol) and NaH, 60% dispersion in oil (132 mg, 3.29 mmol) in anhydrous DME (2 mL). The resulting mixture was stirred at room temperature for to min followed by addition of a solution of 4-chloro-N-cyclopentyl-6-methoxypyrimidin-5-amine (Intermediate 29; 250 mg, 1.10 mmol) in anhydrous DME (2 mL). The reaction mixture was heated at 120° C. for 16 h. The crude product was purified by recrystallisation from DMSO/MeOH (1:1) to afford the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.46-1.73 (m, 2H) 1.80-2.05 (m, 6H) 3.98 (s, 3H) 4.70-5.01 (m, 1H) 7.25 (br. s, 2H) 7.42-7.72 (m, 3H) 7.94-8.13 (m, 2H) 8.33 (s, 1H)

[0800] MS ES.sup.+: 373

Example 36 3-(benzenesulfonyl)-1-cyclohexyl-7-methoxy-1-pyrrolo[2,3-c]pyridin-2-amine

[0801] ##STR00128##

[0802] As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a stirred degassed solution of Pd(Ph.sub.3P).sub.4 (23.64 mg, 0.0020 mmol) and Pd(amphos).sub.2Cl.sub.2 (19 mg, 0.027 mmol) in anhydrous DME (2 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 148 mg, 0.818 mmol) and NaH, 60% dispersion in oil (65.5 mg, 1.637 mmol) in anhydrous DME (3 mL). The resulting mixture was stirred at room temperature for to min followed by addition of a solution of 4-chloro-N-cyclohexyl-2-methoxypyridin-3-amine (Intermediate 30; 197 mg, 0.818 mmol) in anhydrous DME (1 mL). The reaction mixture was subjected to microwave irradiation at 120° C. for 2 h. Purification was carried out by column chromatography (C18-silica 5-95% methanol/water+0.1% ammonia) to afford the title compound.

[0803] .sup.1H NMR (4 MHz, DICHLOROMETHANE-d.sub.2) δ ppm 1.06-1.44 (m, 4H), 1.59-2.10 (m, 6H), 2.14-2.58 (m, 1H), 3.91 (s, 3H), 5.58 (br. s., 2H), 7.10 (d, J=5 Hz, 1H), 7.32-7.46 (m, 3H), 7.63 (d, J=5 Hz, 1H), 7.79-7.87 (m, 2H)

[0804] MS ES.sup.+: 386

Example 37 6-amino-7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidine-4-carbonitrile

[0805] ##STR00129##

[0806] A stirred suspension of dicyanozinc (CAS 557-21-1; 18 mg, 0.153 mmol), Pd(Ph.sub.3P).sub.4 (30 mg, 0.026 mmol) and 7-(benzenesulfonyl)-4-chloro-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 34; 100 mg, 0.256 mmol) in N,N-dimethylformamide (1 mL) was subjected to microwave irradiation at 150° C. for 30 minutes. The reaction mixture was poured into sat. NaHCO.sub.3 solution and extracted with ethyl acetate. The organics were washed with brine, dried over MgSO.sub.4 and concentrated to afford the title compound.

[0807] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.37-1.50 (m, 3H) 1.55-1.72 (m, 1H) 1.80-2.00 (m, 4H) 2.24-2.41 (m, 2H) 4.55-4.82 (m, 1H) 7.52-7.69 (m, 3H) 7.97 (br.s., 2H) 8.05-8.11 (m, 2H) 8.67 (s, 1H).

[0808] MS ES.sup.+: 382

Example 38 5-cyclohexyl-7-(2-fluorobenzenesulfonyl)-4-methoxy-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine

[0809] ##STR00130##

[0810] As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a solution of 2-(2-fluorobenzenesufonyl)acetonitrile (CAS 59849-52-4; 195 mg, 0.978 mmol) in DME (1 mL) was added NaH, 60% dispersion in oil (86 mg, 2.15 mmol). In a separate flask Pd(Ph.sub.3P).sub.4 (28 mg, 0.024 mmol), Pd(amphos).sub.2Cl.sub.2 (17 mg, 0.024 mmol) and 4-chloro-N-cyclohexyl-6-methoxy-2-methylpyrimidin-5-amine (Intermediate 35; 250 mg, 0.978 mmol) were stirred in DME (2 mL) and degassed. To the catalyst/substrate mixture was added the preformed sodium salt of 2-(2-fluorobenzenesulfonyl)acetonitrile and the reaction subjected to microwave irradiation at 130° C. for 2 h. Purification was carried out by column chromatography (silica, 0-10% MeOH/DCM) followed by trituration with ethyl acetate to afford the title compound.

[0811] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.21-1.31 (m, 1H) 1.36-1.49 (m, 2H) 1.63-1.70 (m, 3H) 1.79-1.88 (m, 2H) 2.12-2.24 (m, 2H) 2.35 (s, 3H) 3.97 (s, 3H) 4.28-4.48 (m, 1H) 7.17 (br. s., 2H) 7.27-7.34 (m, 1H) 7.36-7.42 (m, 1H) 7.60-7.70 (m, 1H) 8.01-8.07 (m, 1H)

[0812] MS ES.sup.+: 419

Example 39 5-cyclohexyl-7-(3-fluorobenzenesulfonyl)-4-methoxy-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine

[0813] ##STR00131##

[0814] As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a solution of 2-(3-fluorobenzenesulfonyl)acetonitrile (CAS 61081-29-6; 300 mg, 1.51 mmol) in dioxane (3 mL) was added NaH, 60% dispersion in oil (133 mg, 3.31 mmol). In a separate flask Pd(Ph.sub.3P).sub.4 (70 mg, 0.060 mmol), Pd(amphos).sub.2Cl.sub.2 (43 mg, 0.060 mmol) and 4-chloro-N-cyclohexyl-6-methoxy-2-methylpyrimidin-5-amine (Intermediate 35; 385 mg, 0.978 mmol) were stirred in dioxane (2 mL) and degassed. To the catalyst/substrate mixture was added the preformed sodium salt of 2-(3-fluorobenzenesulfonyl)acetonitrile and the reaction heated at reflux for 3 h. Purification was carried out by column chromatography (C18-silica 5-95% methanol/water+0.1% ammonia).

[0815] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.20-1.30 (m, 1H) 1.33-1.47 (m, 2H) 1.58-1.70 (m, 3H) 1.77-1.84 (m, 2H) 2.08-2.21 (m, 2H) 2.49 (s, 3H) 3.99 (s, 3H) 4.25-4.46 (m, 1H) 7.19 (br. s., 2H) 7.42-7.51 (m, 1H) 7.57-7.65 (m, 1H) 7.83-8.00 (m, 2H)

[0816] MS ES.sup.+: 419

Example 40 7-(benzenesulfonyl)-4-methoxy-5-(oxan-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine

[0817] ##STR00132##

[0818] A stirred solution of 4-chloro-6-methoxy-N-(oxan-4-yl)pyrimidin-5-amine (249 mg, 1.02 mmol), 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 204 mg, 1.12 mmol), Pd(Ph.sub.3P).sub.4 (59 mg, 0.051 mmol) and Pd(amphos).sub.2Cl.sub.2 (36 mg, 0.051 mmol) in Dioxane (5 mL) was degassed for 5 minutes. NaHMDS solution (2M in THF, 1.53 mL, 3.07 mmol) was added and the mixture was heated to reflux for 1.5 h. The mixture was partitioned between ethyl acetate and sat. aq. NaHCO.sub.3 then the organic phase was washed with brine and dried over MgSO.sub.4 and then concentrated in vacuo. Purification was carried out by column chromatography (silica, 0-100% EtOAc/Petrol then 0-10% MeOH/DCM). Further purification was carried out by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.

[0819] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.57-1.66 (m, 2H) 2.34-2.47 (m, 2H) 3.45 (t, J=11 Hz, 2H) 3.94-4.03 (m, 5H) 4.56-4.67 (m, 1H) 7.32 (br. s, 2H) 7.51-7.62 (m, 3H) 8.02-8.08 (m, 2H) 8.32 (s, 1H)

[0820] MS ES.sup.+: 389

Example 41 6-amino-5-cyclohexyl-N-phenyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide

[0821] ##STR00133##

[0822] To a solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-phenyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide (Intermediate 43; 46 mg, 0.092 mmol) in EtOH (1 mL) was added hydrazine monohydrate (13 μL, 0.275 mmol) and the reaction mixture stirred at reflux overnight. The reaction mixture was filtered and the resulting solid washed with methanol. The combined filtrates were concentrated in vacuo. Purification was carried out by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.

[0823] .sup.1H NMR (400 MHz, DICHLOROMETHANE-d.sub.2) δ ppm 1.21-1.49 (m, 4H) 1.67-1.82 (m, 2H) 1.84-1.97 (m, 2H) 2.23-2.39 (m, 2H) 4.04-4.18 (m, 1H) 5.77 (br. s., 2H) 6.97-7.07 (m, 3H) 7.10-7.20 (m, 2H) 7.32 (br. s., 1H) 7.90-7.97 (m, 1H) 8.14-8.22 (m, 1H)

[0824] MS ES.sup.+: 372

Example 42 6-amino-5-cyclohexyl-N-(pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide

[0825] ##STR00134##

[0826] To a solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide (Intermediate 43; 20 mg, 0.040 mmol) in EtOH (1 mL) was added hydrazine monohydrate (6 μL, 0.119 mmol) and the reaction mixture stirred at reflux overnight. The reaction mixture was filtered and the resulting solid washed with methanol. The combined filtrates were concentrated in vacuo. Purification was carried out by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound. .sup.1H NMR (4 MHz, DMSO-d.sub.6) δ ppm 1.20-129 (m, 1H) 1.33-1.50 (m, 2H) 0.61-1.73 (m, 3H) 1.75-1.88 (m, 2H) 2.35-2.48 (m, 2H) 4.30-4.43 (m, 1H) 7.12-7.22 (m, 1H) 7.36-7.47 (m, 3H) 7.84-7.93 (m, 1H) 8.02-8.13 (m, 2H) 8.21-8.8 (m, 1H) 10.42 (s, 1H)

[0827] MS ES.sup.+: 373

[0828] Examples 43 to 56 (see Table 2 following) were prepared according to one of the procedures 1, 2 or 3 described below.

Procedure 1

[0829] A solution of 2-(benzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 1; 100 mg, 0.34 mmol) in NMP (0.5 mL) was treated with a primary amine (0.68 mmol) and heated in the microwave at 170° C. for 1 h. Where the amine was used as a hydrochloride salt, triethylamine (0.095 mL, 0.68 mmol, 2 eq.) was included in the reaction. A further portion of each amine (1.14 mmol, 3 eq) was added and heating was repeated as before. The reaction mixtures were purified directly by preparative HPLC using one of the methods listed below.

Procedure 2

[0830] A solution of 2-(benzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 1; 110 mg, 0.326 mmol) in DMSO (1 mL) was treated with a primary amine (1.96 mmol, 6 eq.) and triethylamine (0.045 mL, 0.326 mmol) and heated to 180° C. for 3 h. The reaction mixtures were diluted with DMSO (2 mL), filtered and purified by preparative HPLC using one of the methods listed below.

Procedure 3

[0831] A solution of 2-(benzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 1; 70 mg, 0.238 mmol) in NMP (1.0 mL) was treated with a primary amine (1.43 mmol) and triethylamine (0.033 mL, 0.238 mmol) and heated in the microwave at 180° C. for 2.5 h. Where the amine used was a hydrochloride salt, triethylamine (0.196 mmol, 1.43 mmol) was included in the reaction. Samples were typically diluted with DMSO, filtered and purified by preparative HPLC using one of the methods listed below. If an aqueous workup was necessary, the reaction mixture was diluted with water and extracted with EtOAc). The combined extracts were washed with citric acid solution, water, sodium bicarbonate solution, water and brine then dried (H-frit) and evaporated, with the crude product then being purified by preparative HPLC using one of the methods listed below.

TABLE-US-00002 HPLC Gradient (acetonitrile/water Method (with 0.1% ammonia)) A  5-25% B  5-40% C 10-50% D 20-60% E 30-70% F 40-80% G 55-95%

TABLE-US-00003 TABLE 2 Syn- Purifi- thesis cation Ex. meth- meth- MS .sup.1H NMR data No. Compound name Structure Starting amine od od ES+ δ ppm 43 5-cyclobutyl-7- (phenylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- amine [00135] Cyclobutanamine (CAS 2516-34-9) 1 D 329 (400 MHz, DMSO-d.sub.6) 1.65-1.82 (m, 1 H) 1.84-1.95 (m, 1 H) 2.24-2.35 (m, 2 H) 3.05-3.22 (m, 2 H) 4.95-5.06 (m, 1 H) 7.50-7.62 (m, 5 H) 7.93 (d, J = 3 Hz, 1 H) 8.00-8.07 (m, 2 H) 8.13 (d, J = 3 Hz, 1 H) 44 5-(2-methylcyclohexyl)-7- (phenylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- amine [00136] 2-Methylcyclohexyl- amine, mixture of cis and trans (CAS 7003-32-9) 1 E 371 Mix of diastereoisomers in ~7:3 ratio (400 MHz, DMSO-d.sub.6) 0.49-0.62 (m, 2.1 H) 0.77-0.84 (m, 0.9 H) 1.26-1.57 (m, 3 H) 1.65-1.75 (m, 2 H) 1.77-1.91 (m, 2 H) 2.31-2.47 (m, 1 H) 2.62-2.71 (m, 1 H) 4.00-4.12 (m, 0.7 H) 4.39-4.50 (m, 0.3 H) 7.52-7.69 (m, 5 H) 7.84-7.90 (m, 1 H) 7.99-8.15 (m, 3 H) 45 5-butyl-7-5(phenylsulfonyl)- 5H-pyrrolo[2,3-b]pyrazin-6- amine [00137] Butan-1-amine (CAS 109-73-9) 2 D 331 (400 MHz, METHANOL-d.sub.4) 0.95 (t, J = 7 Hz, 3 H) 1.30-1.42 (m, 2 H) 1.67-1.78 (m, 2 H) 4.17 (t, J = 7 Hz, 2 H) 7.47-7.61 (m, 3 H) 7.92 (d, J = 3 Hz, 1 H) 8.04-8.15 (m, 3 H) 46 5-phenethyl-7- (phenylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- amine [00138] 2-phenylethanamine (CAS 64-04-0) 2 E.sup.Note 1 379 (400 MHz, METHANOL-d.sub.4) 3.05 (t, J = 7 Hz, 2 H) 4.42 (t, J = 7 Hz, 2 H) 6.97-7.11 (m, 5 H) 7.50-7.64 (m, 3 H) 7.83 (d, J = 3 Hz, 1 H) 8.02 (d, J = 3 Hz, 1 H) 8.07 (d, J = 8 Hz, 2 H) 47 2-(6-amino-7- (phenylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-5- yl)cyclohexanol [00139] 2-aminocyclohexanol (CAS 6850-38-0) 3 D 373 (400 MHz, DMSO-d.sub.6) 1.32-1.51 (m, 3 H) 1.61-1.73 (m, 2 H) 1.76-1.88 (m, 2 H) 4.09-4.17 (m, 1 H) 4.86 (d, J = 13 Hz, 1 H) 7.50-7.64 (m, 3 H) 7.89 (d, J = 3 Hz, 1 H) 8.00-8.09 (m, 2 H) 8.12 (d, J = 3 Hz, 1 H), further 1 H multiplet obscured by DMSO 48 5-(2-cyclopropylethyl)-7- (phenylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- amine [00140] 2-cyclopropyl- ethanamine (CAS 62893-54-3) 3 D 343 (400 MHz, DMSO-d.sub.6) −0.19-−0.12 (m, 2 H) 0.16-0.24 (m, 2 H) 0.55-0.67 (m, 1 H) 1.47-1.58 (m, 2 H) 4.15-4.25 (m, 2 H) 7.49-7.71 (m, 5 H) 7.88 (d, J = 3 Hz, 1 H) 7.99-8.06 (m, 2 H) 8.09 (d, J = 3 Hz, 1 H) 49 5-(4,4-difluoro-cyclohexyl)- 7-(phenylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- amine [00141] 4,4-difluoro- cyclohexanamine hydrochloride (CAS 675112-70-6) 3 C 393 (400 MHz, DICHLOROMETHANE-d.sub.2) 1.88-2.11 (m, 4 H) 2.25-2.39 (m, 2 H) 2.76-2.94 (m, 2 H) 4.29-4.45 (m, 1 H) 6.21 (br. s., 2 H) 7.47-7.63 (m, 3 H) 7.97 (d, J = 3 Hz, 1 H) 8.18 (d, J = 7 Hz, 2 H) 8.24 (d, J = 3 Hz, 1 H) 50 5-(2-cyclobutylethyl)-7- (phenylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- amine [00142] 2-cyclobutyl- ethanamine (CAS 60637-97-0) 3.sup.Note 2 E 357 (400 MHz, DMSO-d.sub.6) 1.46-1.58 (m, 2 H) 1.65-1.79 (m, 4 H) 1.80-1.91 (m, 2 H) 2.13-2.24 (m, 1 H) 4.05 (t, J = 7 Hz, 2 H) 7.51-7.71 (m, 5 H) 7.90 (d, J = 3 Hz, 1 H) 8.03 (d, J = 7 Hz, 2 H) 8.11 (d, J = 3 Hz, 1 H) 51 7-(phenylsulfonyl)-5- (tetrahydro-2H-pyran-3-yl)- 5H-pyrrolo[2,3-b]pyrazin-6- amine [00143] tetrahydro-2H-pyran- 3-amine hydrochloride (CAS 675112-58-0) 3.sup.Note 2 E 359 (400 MHz, DMSO-d.sub.6) 1.69-1.80 (m, 2 H) 1.84-1.94 (m, 1 H) 2.56-2.70 (m, 1 H) 3.36-3.45 (m, 1 H) 3.79-3.91 (m, 2 H) 4.26 (t, J = 10 Hz, 1 H) 4.52-4.62 (m, 1 H) 7.51-7.63 (m, 3 H) 7.71 (br. s., 2 H) 7.90 (d, J = 3 Hz, 1 H) 8.05 (d, J = 7 Hz, 2 H) 8.11 (d, J = 3 Hz, 1 H) 52 5-(3,3-dimethylbutyl)-7- (phenylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- amine [00144] 3,3-dimethylbutan-1- amine (CAS 15673-00-4) 3 E 359 (400 MHz, DMSO-d.sub.6) 0.95 (s, 9 H) 1.45-1.56 (m, 2 H) 4.09-4.19 (m, 2 H) 7.50-7.66 (m, 5 H) 7.92 (d, J = 3 Hz, 1 H) 8.01-8.07 (m, 2 H) 8.11 (d, J = 3 Hz, 1 H) 53 5-((1R*,2R*,4S*)- bicyclo[2.2.1]heptan-2-yl)-7- (phenylsulfonyl)-5H- pyrrolo[2,3-b)pyrazin-6- amine [00145] exo-2- aminonorbornane (CAS 7242-92-4, Sigma-Aldrich cat. no. 179604) 3 E 369 (400 MHz, DMSO-d.sub.6) 1.14-1.29 (m, 2 H) 1.43-1.59 (m, 3 H) 1.80-1.91 (m, 1 H) 2.29-2.42 (m, 2 H) 2.43-2.48 (m, 1 H) 2.60-2.67 (m, 1 H) 4.22-4.31 (m, 1 H) 7.45-7.64 (m, 5 H) 7.86 (d, J = 3 Hz, 1 H) 8.00-8.11 (m, 3 H) 54 5-(cyclopentylmethyl)-7- (phenylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- amine [00146] Cyclopentyl- methanamine (CAS 6053-81-2) 3 E 357 (400 MHz, DMSO-d.sub.6) 1.17-1.32 (m, 2 H) 1.39-1.69 (m, 6 H) 2.35-2.45 (m, 1 H) 4.08 (d, J = 8 Hz, 2 H) 7.51-7.61 (m, 3 H) 7.65 (br. s, 2 H) 7.89 (d, J = 3 Hz, 1 H) 8.01-8.07 (m, 2 H) 8.10 (d, J = 3 Hz, 1 H) 55 5-((1-ethylcyclopropyl)- methyl)-7-(phenylsulfonyl)- 5H-pyrrolo[2,3-b]pyrazin-6- amine [00147] (1-ethylcyclopropyl) methanamine (CAS 1177326-74-7) 3 E 357 (400 MHz, DMSO-d.sub.6) 0.27-0.34 (m, 2 H) 0.51-0.58 (m, 2 H) 0.79 (t, J = 7 Hz, 3 H) 1.26 (q, J = 7 Hz, 2 H) 4.17 (s, 2 H) 7.46-7.62 (m, 5 H) 7.91 (d, J = 3 Hz, 1 H) 7.99-8.07 (m, 2 H) 8.11 (d, J = 3 Hz, 1 H) 56 5-((2,2- dimethylcyclopropyl)methyl)- 7-(phenylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- amine [00148] (2,2- dimethylcyclopropyl) methanamine (CAS 725743-45-3) 3 E 357 (400 MHz, DMSO-d.sub.6) 0.30-0.40 (m, 2 H) 1.00 (s, 3 H) 1.02-1.11 (m, 1 H) 1.19 (s, 3 H) 3.94-4.05 (m, 1 H) 4.28-4.38 (m, 1 H) 7.51-7.70 (m, 5 H) 7.90 (d, J = 3.03 Hz, 1 H) 8.02-8.08 (m, 2 H) 8.11 (d, J = 3.03 Hz, 1 H) .sup.Note 1Followed by flash chromatography (12 g silica, 25-60% EtOAc/petrol) .sup.Note 2Aqueous workup

[0832] Examples 57 to 107 (see Table 3 following) were prepared according to one of the procedures 4 or 5 as described below.

Procedure 4

[0833] To a solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl chloride (Intermediate 41; 50 mg, 0.112 mmol) in THF (1 mL) was added triethylamine (0.089 mL, 0.635 mmol) and a primary or secondary amine (0.175 mmol). The reaction was stirred at rt for 3 hours and then ethanol (1 mL) and hydrazine monohydrate (0.635 mmol) were added. The reaction mixture was warmed to 80° C. and maintained at this temperature overnight. The reaction mixtures were filtered and concentrated. The residue was taken up in DCM and washed with water, then the organic phase was separated and concentrated and the resulting crude product was purified via prep HPLC using one of the methods listed below or column chromatography on silica.

Procedure 5

[0834] To a solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl chloride (Intermediate 41; 55 mg, 0.124 mmol) in THF (1 mL) was added triethylamine (0.052 mL, 0.371 mmol) and a primary or secondary amine (00.247 mmol). After 2 h at room temperature the mixture was diluted with water and extracted with DCM. The organic phase was concentrated, then ethanol (1 mL) and hydrazine monohydrate (0.018 mL, 0.371 mmol) were added and the reaction mixture was warmed to 70° C. for 3 h. The reaction mixture was filtered and concentrated and the residue was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether).

TABLE-US-00004 HPLC Gradient (acetonitrile/water Method (with 0.1% ammonia)) A  5-25% B  5-40% C 10-50% D 20-60% E 30-70% F 40-80% G 55-95%

TABLE-US-00005 TABLE 3 Syn- thesis Ex. meth- Purification MS .sup.1H NMR data No. Name of compound Structure Starting amine od method ES+ δ ppm  57 5-cyclohexyl-7- (piperidin-1- ylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00149] Piperidine (CAS 110-89- 4) 2 0-100% ethyl acetate/petrol 364 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.32-1.57 (m, 5 H) 1.59-1.71 (m, 4 H) 1.74-1.84 (m, 1 H) 1.87-2.07 (m, 4 H) 2.38-2.55 (m, 2 H) 3.08-3.29 (m, 4 H) 4.19-4.39 (m, 1 H) 5.97 (br. s., 2 H) 7.89-7.98 (m, 1 H) 8.14-8.23 (m, 1 H)  58 5-cyclohexyl-7- (pyrrolidin-1- ylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00150] Pyrrolidine (CAS 123-75- 1) 1 0-100% ethyl acetate/petrol 350 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.29-1.57 (m, 4 H) 1.73-1.84 (m, 4 H) 1.87-2.04 (m, 4 H) 2.37-2.56 (m, 2 H) 3.39-3.52 (m, 4 H) 4.23-4.38 (m, 1 H) 6.01 (br. s., 2 H) 7.94 (d, J = 3 Hz, 1 H) 8.18 (d, J = 3 Hz, 1 H)  59 6-amino-5-cyclohexyl- N-propyl-5H- pyrrolo[2,3- b]pyrazine-7- sulfonamide [00151] Propan-1- amine (CAS 107-10- 8) 1 0-100% ethyl acetate/petrol 338 (400 MHz, DMSO-d.sub.6) 0.74 (t, J = 7 Hz, 3 H) 1.18-1.47 (m, 5 H) 1.66-1.76 (m, 3 H) 1.80-1.89 (m, 2 H) 2.42-2.57 (m, 2 H) 2.70-2.79 (m, 2 H) 4.31-4.44 (m, 1 H) 7.14 (t, J = 6 Hz, 1 H) 7.21 (s, 2 H) 7.88 (d, J = 3 Hz, 1 H) 8.08 (d, J = 3 Hz, 1 H)  60 6-amino-5-cyclohexyl- N-methyl-N-propyl- 5H-pyrrolo[2,3- b]pyrazine-7- sulfonamide [00152] N- methylpropan- 1-amine (CAS 627-35- 0) 1 0-100% ethyl acetate/petrol 352 (400 MHz, DICHLOROMETHANE- d.sub.2) 0.94 (t, J = 7 Hz, 3 H) 1.33-1.65 (m, 5 H) 1.76-1.84 (m, 1 H) 1.88-2.06 (m, 4 H) 2.38-2.51 (m, 2 H) 2.84 (s, 3 H) 3.09-3.17 (m, 2 H) 4.23-4.36 (m, 1 H) 6.00 (br. s., 2 H) 7.95 (d, J = 3 Hz, 1 H) 8.18 (d, J = 3 Hz, 1 H)  61 5-cyclohexyl-7- (morpholinosulfonyl)- 5H-pyrrolo[2,3- b]pyrazin-6-amine [00153] Morpholine (CAS 110-91- 8) 1 0-100% ethyl acetate/petrol 366 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.33-1.59 (m, 3 H) 1.77-1.85 (m, 1 H) 1.88-2.06 (m, 4 H) 2.38-2.57 (m, 2 H) 3.14-3.27 (m, 4 H) 3.70-3.81 (m, 4 H) 4.22-4.40 (m, 1 H) 6.02 (br. s., 2 H) 7.97 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H)  62 5-cyclohexyl-7-((4- methylpiperidin-1- yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00154] 4-methyl- piperidine (CAS 626-58- 4) 1 0-100% ethyl acetate/petrol 378 (400 MHz, DICHLOROMETHANE- d.sub.2) 0.81-0.97 (m, 3 H) 1.24-1.57 (m, 6 H) 1.64-1.73 (m, 2 H) 1.76-1.84 (m, 1 H) 1.89-2.05 (m, 4 H) 2.38-2.50 (m, 2 H) 2.52-2.62 (m, 2 H) 3.76-3.85 (m, 2 H) 4.20-4.39 (m, 1 H) 6.00 (br. s., 2 H) 7.95 (d, J = 3 Hz, 1 H) 8.18 (d, J = 3 Hz, 1 H)  63 5-cyclohexyl-7-((4- methylpiperazin-1- yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00155] 1-methyl- piperazine (CAS 109-01- 3) 1 0-100% ethyl acetate/petrol 379 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.35-1.57 (m, 3 H) 1.76-1.85 (m, 1 H) 1.89-2.03 (m, 4 H) 2.25 (s, 3 H) 2.37-2.57 (m, 6 H) 3.17-3.30 (m, 4 H) 4.22-4.34 (m, 1 H) 5.92 (br. s., 2H) 7.95 (d, J = 3 Hz, 1 H) 8.18 (d, J = 3 Hz, 1 H)  64 5-cyclohexyl-7-((3- methoxyazetidin-1- yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00156] 3-metboxy- azetidine (CAS 110925- 17-2) 1 0-100% ethyl acetate/petrol 366 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.33-1.58 (m, 3 H) 1.76-1.84 (m, 1 H) 1.90-2.04 (m, 4 H) 2.40-2.55 (m, 2 H) 3.14 (s, 3 H) 3.82-3.90 (m, 2 H) 4.00-4.06 (m, 1 H) 4.07-4.14 (m, 2 H) 4.25-4.38 (m, 1 H) 6.09 (br. s., 2 H) 7.99 (d, J = 3 Hz, 1 H) 8.22 (d, J = 3 Hz, 1 H)  65 5-cyclohexyl-7-((4- ethoxypiperidin-1- yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00157] 4-ethoxy- piperidine (CAS 1122-86- 7) 1 0-100% ethyl acetate/petrol 408 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.05-1.15 (m, 3 H) 1.26-1.51 (m, 3 H) 1.57-1.66 (m, 2 H) 1.75-1.83 (m, 1 H) 1.84-1.98 (m, 6 H) 2.38-2.53 (m, 2 H) 2.96-3.05 (m, 2 H) 3.28-3.37 (m, 1 H) 3.37-3.48 (m, 4 H) 4.26 (br. s., 1 H) 6.01 (br. s., 2 H) 7.92 (d, J = 3 Hz, 1 H) 8.14 (d, J = 3 Hz, 1 H)  66 5-cyclohexyl-7-((4,4- dimethylpiperidin-1- yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00158] 4,4-dimethyl- piperidine hydrochloride (CAS 38646- 68-3) 1 0-100% ethyl acetate/petrol 392 (400 MHz, DICHLOROMETHANE- d.sub.2) 0.88 (s, 6 H) 1.32-1.56 (m, 7 H) 1.76-1.84 (m, 1 H) 1.89-2.03 (m, 4 H) 2.39-2.53 (m, 2 H) 3.16-3.26 (m, 4 H) 4.23-4.36 (m, 1 H) 5.99 (br. s., 2 H) 7.95 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H)  67 5-cyclohexyl-7-((3- methylpyrrolidin-1- yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00159] 3-methyl- pyrrolidine (CAS 34375- 89-8) 1 0-100% ethyl acetate/petrol 364 (400 MHz, DICHLOROMETHANE- d.sub.2) 0.95 (d, J = 7 Hz, 3 H) 1.34-1.57 (m, 4 H) 1.77-1.85 (m, 1 H) 1.88-2.04 (m, 5 H) 2.08-2.22 (m, 1 H) 2.39-2.54 (m, 2 H) 2.90-2.98 (m, 1 H) 3.39-3.49 (m, 1 H) 3.59-3.73 (m, 2 H) 4.24-4.39 (m, 1 H) 6.05 (br. s., 2 H) 7.95 (d, J = 3 Hz, 1 H) 8.18 (d, J = 3 Hz, 1H)  68 5-cyclohexyl-7-((2- methylpyrrolidin-1- yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00160] 2-methyl- pyrrolidine (CAS) 1 0-100% ethyl acetate/petrol 364 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.32 (d, J = 7 Hz, 3 H) 1.35-1.63 (m, 5 H) 1.69-1.87 (m, 3 H) 1.89-2.04 (m, 4 H) 2.37-2.51 (m, 2 H) 3.39-3.55 (m, 2 H) 4.18-4.36 (m, 2 H) 6.03 (br. s., 2 H) 7.94 (d, J = 3 Hz, 1 H) 8.18 (d, J = 3 Hz, 1 H)  69 5-cyclohexyl-7-((4,4- difluoropiperidin-1- yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00161] 4,4-difluoro- piperidine (CAS 21987- 29-1) 1 0-100% ethyl acetate/petrol 400 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.34-1.56 (m, 3 H) 1.77-1.84 (m, 1 H) 1.89-2.02 (m, 4 H) 2.04-2.17 (m, 4 H) 2.39-2.54 (m, 2 H) 3.37-3.48 (m, 4 H) 4.21-4.38 (m, 1 H) 6.02 (br. s., 2 H) 7.93-8.01 (m, 1 H) 8.15-8.23 (m, 1 H)  70 6-amino-N-benzyl-5- cyclohexyl-5H- pyrrolo[2,3- b]pyrazine-7- sulfonamide [00162] Benzylamine (CAS 100-46- 9) 1 0-100% ethyl acetate/petrol 386 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.33-1.55 (m, 3 H) 1.75-1.85 (m, 1 H) 1.86-2.06 (m, 4 H) 2.33-2.51 (m, 2 H) 4.10 (d, J = 7 Hz, 2 H) 4.18-4.28 (m, 1 H) 5.51 (t, J = 6 Hz, 1 H) 5.87 (br. s., 2 H) 7.12-7.22 (m, 5 H) 7.95 (d, J = 3 Hz, 1 H) 8.15 (d, J = 3 Hz, 1 H)  71 6-amino-N,5- dicyclohexyl-N- methyl-5H- pyrrolo[2,3- b]pyrazine-7- sulfonamide [00163] N-methyl- cyclohexan- amine (CAS 100-60- 7) 1 0-100% ethyl acetate/petrol 392 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.00-1.11 (m, 1 H) 1.27-1.65 (m, 10 H) 1.68-1.83 (m, 3 H) 1.86-2.05 (m, 4 H) 2.38-2.54 (m, 2 H) 2.83 (s, 3 H) 3.83-3.94 (m, 1 H) 4.21-4.35 (m, 1 H) 5.97 (br. s., 2 H) 7.93 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H)  72 5-cyclohexyl-7-(1,4- oxazepane-4-sulfonyl)- 5H-pyrrolo[2,3- b]pyrazin-6-amine [00164] 1,4-oxazepane hydrochloride (CAS 178312- 62-4) 1 0-100% ethyl acetate/petrol 380 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.33-1.55 (m, 3 H) 1.76-1.86 (m, 1 H) 1.89-2.04 (m, 6 H) 2.37-2.53 (m, 2 H) 3.51-3.61 (m, 4 H) 3.71-3.80 (m, 4 H) 4.20-4.36 (m, 1 H) 5.94 (br. s., 2 H) 7.95 (d, J = 3 Hz, 1 H) 8.18 (d, J = 3 Hz, 1 H)  73 5-cyclohexyl-7-(4- methoxypiperidine-1- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00165] 4-methoxy- piperidine (CAS 4045-24- 3) 1 0-100% ethyl acetate/petrol 394 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.35-1.55 (m, 3 H) 1.64-1.73 (m, 2 H) 1.77-1.84 (m, 1 H) 1.87-2.04 (m, 6 H) 2.39-2.54 (m, 2 H) 3.05-3.13 (m, 2 H) 3.18-3.30 (m, 4 H) 3.36-3.45 (m, 2 H) 4.20-4.38 (m, 1 H) 5.98 (br. s., 2 H) 7.96 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H)  74 6-amino-N- (cyclobutylmethyl)-5- cyclohexyl-5H- pyrrolo[2,3- b]pyrazine-7- sulfonamide [00166] Cyclobutyl- methanamine hydrochloride (CAS 5454-82- 0) 1 0-100% ethyl acetate/petrol 364 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.35-1.55 (m, 3 H) 1.57-1.68 (m, 2 H) 1.75-2.05 (m, 9 H) 2.39-2.54 (m, 3 H) 2.82-2.91 (m, 2 H) 4.21-4.34 (m, 1 H) 5.04 (t, J = 6 Hz, 1 H) 5.88 (br. s., 2 H) 7.98 (d, J = 3 Hz, 1 H) 8.18 (d, J = 3 Hz, 1 H)  75 5-cyclohexyl-7-(3,3- dimethylpyrrrolidine- 1-sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00167] 3,3-Dimethyl- pyrrolidine (CAS 3437-30- 7) 1 0-100% ethyl acetate/petrol 378 (400 MHz, DICHLOROMETHANE- d.sub.2) 0.97 (s, 6 H) 1.33-1.53 (m, 3 H) 1.58 (t, J = 7 Hz, 2 H) 1.77-1.85 (m, 1 H) 1.90-2.04 (m, 4 H) 2.38-2.53 (m, 2 H) 3.18 (s, 2 H) 3.61 (t, J = 7 Hz, 2 H) 4.24-4.35 (m, 1 H) 5.96 (br. s., 2 H) 7.95 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H)  76 5-cyclohexyl-7-(2,6- dimethylmorpholine-4- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00168] 2,6-dimethyl- morpholine (mixture of stereoisomers; CAS 141-91-3) 1 0-100% ethyl acetate/petrol 394 Mixture of diasteroisomers in ~4:1 ratio. (400 MHz, DICHLOROMETHANE- d.sub.2) 1.11-1.16 (m, 4.5 H) 1.21-1.27 (m, 1.5 H) 1.35-1.58 (m, 3 H) 1.77-1.85 (m, 1 H) 1.89-2.07 (m, 4 H) 2.28-2.39 (m, 1.6 H) 2.41-2.53 (m, 2 H) 2.85-2.95 (m, 0.4 H) 3.20-3.28 (m, 0.4 H) 3.59-3.65 (m, 1.6 H) 3.67-3.75 (m, 1.6 H) 4.01-4.11 (m, 0.4 H) 4.23-4.36 (m, 1 H) 5.96 (br. s., 2 H) 7.92-8.01 (m, 1 H) 8.16-8.23 (m, 1 H)  77 7-(azepane-1- sulfonyl)-5- cyclohexyl-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00169] Azepane (CAS 111-49- 9) 1 0-100% ethyl acetate/petrol 378 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.33-1.57 (m, 3 H) 1.58-1.64 (m, 4 H) 1.69-1.84 (m, 5 H) 1.88-2.04 (m, 4 H) 2.36-2.51 (m, 2 H) 3.37-3.46 (m, 4 H) 4.22-4.34 (m, 1 H) 5.92 (br. s., 2 H) 7.94 (d, J = 3 Hz, 1 H) 8.18 (d, J = 3 Hz, 1 H)  78 5-cyclohexyl-7- (thiomorpholine-4- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00170] Thio- morpholine (CAS 123-90- 0) 1 E 382 (400 MHz, DMSO-d.sub.6) 1.21-1.33 (m, 1 H) 1.35-1.50 (m, 2 H) 1.64-1.78 (m, 3 H) 1.81-1.90 (m, 2 H) 2.43-2.56 (m, 2 H) 2.61-2.70 (m, 4 H) 3.32-3.40 (m, 4 H) 4.35-4.47 (m, 1 H) 7.32 (s, 2 H) 7.91 (d, J = 3 Hz, 1 H) 8.08 (d, J = 3 Hz, 1 H)  79 N-(1-{6-amino-5- cyclohexyl-5H- pyrrolo[2,3- b]pyrazine-7- sulfonyl}piperidin-4- yl)-N-methylacetamide [00171] N-methyl-N- (piperidin-4- yl)acetamide (CAS 83180- 55-6) 1 D 435 (400 MHz, DMSO-d.sub.6) 1.24-1.33 (m, 1 H) 1.36-1.49 (m, 3 H) 1.56-1.79 (m, 6 H) 1.81-1.88 (m, 2 H) 1.90-1.97 (m, 3 H) 2.52-2.61 (m, 4 H) 2.63-2.72 (m, 2 H) 3.53-3.68 (m, 1 H) 3.75-3.85 (m, 2 H) 4.10-4.22 (m, 1 H) 4.36-4.47 (m, 1 H) 7.25-7.37 (m, 2 H) 7.86-7.94 (m, 1 H) 8.06-8.13 (m, 1 H)  80 6-amino-5-cyclohexyl- N-(oxetan-3-ylmethyl)- 5H-pyrrolo[2,3- b]pyrazine-7- sulfonamide [00172] Oxetan-3-yl- methanamine (CAS 6246-05- 5) 1 D 366 (400 MHz, DMSO-d.sub.6) 1.23-1.33 (m, 1 H) 1.35-1.50 (m, 2 H) 1.66-1.78 (m, 3 H) 1.82-1.90 (m, 2 H) 2.43-2.57 (m, 2 H) 2.89-3.03 (m, 1 H) 3.05-3.12 (m, 2 H) 4.12-4.19 (m, 2 H) 4.34-4.43 (m, 1 H) 4.45-4.51 (m, 2 H) 7.23 (s, 2 H) 7.38 (t, J = 6 Hz, 1 H) 7.90 (d, J = 3 Hz, 1 H) 8.09 (d, J = 3 Hz, 1 H)  81 7-(4-benzylpiperidine- 1-sulfonyl)-5- cyclohexyl-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00173] 4-benzyl- piperidine (CAS 31252- 42-3) 1 F 454 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.29-1.56 (m, 5 H) 1.67-1.73 (m, 2 H) 1.77-1.84 (m, 1 H) 1.87-1.94 (m, 2 H) 1.95-2.05 (m, 3 H) 2.37-2.59 (m, 6 H) 3.76-3.86 (m, 2 H) 4.22-4.34 (m, 1 H) 5.91 (s, 2 H) 7.08-7.15 (m, 2 H) 7.15-7.22 (m, 1 H) 7.24-7.31 (m, 2 H) 7.94 (d, J = 3 Hz, 1 H) 8.17 (d, J = 3 Hz, 1 H)  82 6-amino-5-cyclohexyl- N-(3,3,3- trifluoropropyl)-5H- pyrrolo[2,3- b]pyrazine-7- sulfonamide [00174] 3,3,3-trifluoro- propan-1- amine (CAS 460-39- 9) 1 E 392 (400 MHz, DMSO-d.sub.6) 1.23-1.32 (m, 1 H) 1.34-1.49 (m, 2 H) 1.65-1.78 (m, 3 H) 1.81-1.90 (m, 2 H) 2.34-2.55 (m, 4 H) 3.05-3.13 (m, 2 H) 4.33-4.45 (m, 1 H) 7.26 (s, 2 H) 7.36-7.44 (m, 1 H) 7.90 (d, J = 3 Hz, 1 H) 8.08 (d, J = 3 Hz, 1 H)  83 5-cyclohexyl-7-(4- phenylpiperidine-1- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00175] 4-phenyl- piperidine (CAS 771-99- 3) 1 F 440 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.34-1.58 (m, 3 H) 1.77-2.07 (m, 9 H) 2.39-2.56 (m, 3 H) 2.68-2.78 (m, 2 H) 3.92-4.07 (m, 2 H) 4.25-4.37 (m, 1 H) 5.96 (s, 2 H) 7.15-7.25 (m, 3 H) 7.28-7.34 (m, 2 H) 7.98 (d, J = 3 Hz, 1 H) 8.22 (d, J = 3 Hz, 1 H)  84 6-amino-5-cyclohexyl- N-(2-phenylethyl)-5H- pyrrolo[2,3- b]pyrazine-7- sulfonamide [00176] 2-phenyl- ethanamine (CAS 64-04-0) 1 F 400 (400 MHz, DMSO-d.sub.6) 1.21-1.32 (m, 1 H) 1.35-1.49 (m, 2 H) 1.64-1.77 (m, 3 H) 1.80-1.90 (m, 2 H) 2.43-2.55 (m, 2 H) 2.61-2.69 (m, 2 H) 3.01-3.09 (m, 2 H) 4.32-4.44 (m, 1 H) 7.04-7.16 (m, 3 H) 7.17-7.26 (m, 5 H) 7.88 (d, J = 3 Hz, 1 H) 8.06 (d, J = 3 Hz, 1 H)  85 5-cyclohexyl-7-(4- phenoxypiperidine-1- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00177] 4-phenoxy- piperidine (CAS 3202-33- 3) 1 F 456 (400 MHz, DMSO-d.sub.6) 1.25-1.33 (m, 1 H) 1.36-1.50 (m, 2 H) 1.56-1.79 (m, 5 H) 1.83-1.90 (m, 2 H) 1.94-2.04 (m, 2 H) 2.46-2.58 (m, 2 H) 2.85-2.96 (m, 2 H) 3.44-3.53 (m, 2 H) 4.35-4.48 (m, 2 H) 6.82-6.91 (m, 3 H) 7.17-7.24 (m, 2 H) 7.31 (s, 2 H) 7.91 (d, J = 3 Hz, 1 H) 8.10 (d, J = 3 Hz, 1 H)  86 5-cyclohexyl-7-(3- phenylpyrrolidine-1- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00178] 3-phenyl- pyrrolidine (CAS 936-44- 7) 1 F 426 (400 MHz, DMSO-d.sub.6) 1.22-1.35 (m, 1 H) 1.35-1.51 (m, 2 H) 1.66-1.79 (m, 4 H) 1.82-1.93 (m, 2 H) 2.03-2.13 (m, 1 H) 2.46-2.57 (m, 2 H) 3.13-3.28 (m, 2 H) 3.33-3.43 (m, 1 H) 3.61-3.70 (m, 1 H) 3.89-3.98 (m, 1 H) 4.36-4.51 (m, 1 H) 7.04-7.13 (m, 2 H) 7.14-7.28 (m, 3 H) 7.31 (s, 2 H) 7.92 (d, J = 3 Hz, 1 H) 8.11 (d, J = 3 Hz, 1 H)  87 5-cyclohexyl-7-[4- (trifluoromethyl) piperidine-1-sulfonyl]- 5H-pyrrolo[2,3- b]pyrazin-6-amine [00179] 4-(trifluoro- methyl)- piperidine (CAS 657-36- 3) 1 F 432 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.34-1.54 (m, 3 H) 1.66-1.75 (m, 2 H) 1.77-1.86 (m, 1 H) 1.89-2.11 (m, 7 H) 2.39-2.52 (m, 2 H) 2.60-2.70 (m, 2 H) 3.93-4.03 (m, 2 H) 4.24-4.35 (m, 1 H) 5.94 (br. s., 2 H) 7.97 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H)  88 5-cyclohexyl-7-[3- (methoxyrnethyl) pyrrolidine-1- sulfonyl]-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00180] 3-(methoxy- methyl)- pyrrolidine (CAS 936940- 38-4) 1 E 394 (400 MHz, DMSO-d.sub.6) 1.24-1.33 (m, 1 H) 1.36-1.50 (m, 3 H) 1.65-1.80 (m, 4 H) 1.81-1.90 (m, 2 H) 2.20-2.30 (m, 1 H) 2.43-2.56 (m, 2 H) 2.95-3.13 (m, 6 H) 3.23-3.29 (m, 1 H) 3.38-3.50 (m, 2 H) 4.34-4.45 (m, 1 H) 7.29 (s, 2 H) 7.90 (d, J = 3 Hz, 1 H) 8.08 (d, J = 3 Hz, 1 H)  89 6-amino-5-cyclohexyl- N- (cyclopropylmethyl)- 5H-pyrrolo[2,3- b]pyrazine-7- sulfonamide [00181] Cyclopropyl- methanamine (CAS 2516-47- 4) 1 E 350 (400 MHz, DMSO-d.sub.6) −0.03-0.05 (m, 2 H) 0.20-0.29 (m, 2 H) 0.72-0.80 (m, 1 H) 1.22-1.31 (m, 1 H) 1.34-1.47 (m, 2 H) 1.62-1.74 (m, 3 H) 1.78-1.90 (m, 2 H) 2.40-2.52 (m, 2 H) 2.67-2.73 (m, 2 H) 4.31-4.43 (m, 1 H) 7.11-7.24 (m, 3 H) 7.86 (d, J = 3 Hz, 1 H) 8.06 (d, J = 3 Hz, 1 H)  90 6-amino-5-cyclohexyl- N-(2-methoxyethyl)- 5H-pyrrolo[2,3- b]pyrazine-7- sulfonamide [00182] 2-methoxy- ethanamine (CAS 109-85- 3) 1 D 354 (400 MHz, DMSO-d.sub.6) 1.24-1.34 (m, 1 H) 1.36-1.49 (m, 2 H) 1.66-1.78 (m, 3 H) 1.81-1.90 (m, 2 H) 2.44-2.56 (m, 2 H) 2.95-3.03 (m, 2 H) 3.11 (s, 3 H) 3.25-3.30 (m, 2 H) 4.34-4.44 (m, 1 H) 7.06-7.13 (m, 1 H) 7.21 (s, 2 H) 7.89 (d, J = 3 Hz, 1 H) 8.08 (d, J = 3 Hz, 1 H)  91 5-cyclohexyl-7-(3- methoxypyrrolidine-1- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00183] 3-methoxy- pyrrolidine (CAS 62848- 20-8) 1 E 380 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.34-1.44 (m, 1 H) 1.46-1.60 (m, 2 H) 1.78-1.84 (m, 1 H) 1.86-2.03 (m, 6 H) 2.39-2.55 (m, 2 H) 3.14 (s, 3 H) 3.45-3.63 (m, 4 H) 3.83-3.91 (m, 1 H) 4.31-4.44 (m, 1 H) 6.22-6.45 (m, 2 H) 7.97 (d, J = 3 Hz, 1 H) 8.18 (d, J = 3 Hz, 1 H)  92 5-cyclohexyl-7-(3,3- dimethylpiperidine-1- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00184] 3,3-dimethyl- piperidine (CAS 1193-12- 0) 1 F 392 (400 MHz, DICHLOROMETHANE- d.sub.2) 0.99 (s, 6 H) 1.22-1.28 (m, 2 H) 1.35-1.55 (m, 3 H) 1.66-1.73 (m, 2 H) 1.77-1.86 (m, 1 H) 1.89-2.04 (m, 4 H) 2.37-2.54 (m, 2 H) 2.82 (s, 2 H) 3.09-3.19 (m, 2 H) 4.19-4.35 (m, 1 H) 5.91 (br. s., 2 H) 7.95 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H)  93 1-{6-amino-5- cyclohexyl-5H- pyrrolo[2,3- b]pyrazine-7- sulfonyl}piperidin-4-ol [00185] piperidin-4-ol (CAS 5382-16- 1) 1 D 380 (400 MHz, DMSO-d.sub.6) 1.22-1.33 (m, 1 H) 1.35-1.48 (m, 4 H) 1.68-1.78 (m, 5 H) 1.80-1.91 (m, 2 H) 2.43-2.56 (m, 2 H) 2.77-2.87 (m, 2 H) 3.27-3.37 (m, 2 H) 3.47-3.56 (m, 1 H) 4.34-4.45 (m, 1 H) 4.59 (d, J = 4 Hz, 1 H) 7.27 (s, 2 H) 7.89 (d, J = 3 Hz, 1 H) 8.08 (d, J = 3 Hz, 1 H)  94 5-cyclohexyl-7- (1,2,3,4- tetrahydroisoquinoline- 2-sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00186] 1,2,3,4- tetrahydro- isoquinoline (CAS 91-21-4) 1 F 412 (400 MHz, DMSO-d.sub.6) 1.19-1.32 (m, 1 H) 1.35-1.48 (m, 2 H) 1.65-1.77 (m, 3 H) 1.79-1.90 (m, 2 H) 2.39-2.48 (m, 2 H) 2.80-2.88 (m, 2 H) 3.40-3.47 (m, 2 H) 4.31-4.43 (m, 3 H) 6.99-7.14 (m, 4 H) 7.35 (s, 2 H) 7.85 (d, J = 3 Hz, 1 H) 8.05 (d, J = 3 Hz, 1 H)  95 6-amino-N-(butan-2- yl)-5-cyclohexyl-5H- pyrrrolo[2,3- b]pyrazine-7- sulfonamide [00187] butan-2-amine (CAS 13952- 84-6) 1 E 352 (400 MHz, DMSO-d.sub.6) 0.64 (t, J = 7 Hz, 3 H) 0.88 (d, J = 7 Hz, 3 H) 1.21-1.33 (m, 3 H) 1.36-1.49 (m, 2 H) 1.65-1.77 (m, 3 H) 1.80-1.92 (m, 2 H) 2.44-2.57 (m, 2 H) 3.08-3.19 (m, 1 H) 4.31-4.44 (m, 1 H) 7.02-7.11 (m, 1 H) 7.19 (s, 2 H) 7.88 (d, J = 3 Hz, 1 H) 8.08 (d, J = 3 Hz, 1 H)  96 6-amino-5-cyclohexyl- N-(oxolan-2- ylmethyl)-5H- pyrrolo[2,3- b]pyrazine-7- sulfonamide [00188] (tetrahydro- furan-2-yl)- methanamine (CAS 4795-29- 3) 1 E 380 (400 MHz, DMSO-d.sub.6) 1.23-1.33 (m, 1 H) 1.36-1.55 (m, 3 H) 1.64-1.91 (m, 8 H) 2.42-2.54 (m, 2 H) 2.77-2.94 (m, 2 H) 3.46-3.56 (m, 1 H) 3.57-3.67 (m, 1 H) 3.73-3.86 (m, 1 H) 4.31-4.46 (m, 1 H) 7.07-7.15 (m, 1 H) 7.20 (s, 2 H) 7.89 (d, J = 3 Hz, 1 H) 8.08 (d, J = 3 Hz, 1 H)  97 5-cyclohexyl-7-(2,3- dihydro-1H-isoindole- 2-sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00189] Isoindoline (CAS 496-12- 8) 1 F 398 (400 MHz, DMSO-d.sub.6) 1.19-1.31 (m, 1 H) 1.34-1.47 (m, 2 H) 1.61-1.78 (m, 3 H) 1.78-1.89 (m, 2 H) 2.38-2.48 (m, 2 H) 4.30-4.44 (m, 1 H) 4.73 (s, 4 H) 7.13-7.26 (m, 4 H) 7.38 (s, 2 H) 7.82-7.85 (m, 1 H) 7.99-8.06 (m, 1 H)  98 5-cyclohexyl-7-{4-[(4- fluorophenyl)carbonyl] piperazine-1-sulfonyl}- 5H-pyrrolo[2,3- b]pyrazin-6-amine [00190] (4- fluorophenyl) (piperazin-1- yl)methanone (CAS 102391- 98-0) 1 E 487 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.35-1.57 (m, 3 H) 1.78-1.87 (m, 1 H) 1.91-2.06 (m, 4 H) 2.39-2.53 (m, 2 H) 3.21-3.34 (m, 4 H) 3.55-3.85 (m, 4 H) 4.23-4.35 (m, 1 H) 5.95 (br. s., 2 H) 7.08-7.18 (m, 2 H) 7.33-740 (m, 2 H) 7.98 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H)  99 5-cyclohexyl-7-(3- phenoxyazetidine-1- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00191] 3-phenoxy- azetidine (CAS 76263- 18-8 1 F 428 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.35-1.56 (m, 3 H) 1.77-1.85 (m, 1 H) 1.92-2.06 (m, 4 H) 2.41-2.56 (m, 2 H) 4.06-4.16 (m, 2 H) 4.25-4.34 (m, 1 H) 4.36-4.41 (m, 2 H) 4.75-4.83 (m, 1 H) 6.00 (br. s., 2 H) 6.55-6.60 (m, 2 H) 6.93-7.01 (m, 1 H) 7.21-7.29 (m, 2 H) 7.99 (d, J = 3 Hz, 1 H) 8.18 (d, J = 3 Hz, 1 H) 100 5-cyclohexyl-7-[3- (piperidin-1- yl)azetidine-1- sulfonyl]-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00192] 1-(azetidin-3- yl)piperidine (CAS 138022- 86-3) 1 E 419 (400 MHz, DMSO-d.sub.6) 1.13-1.34 (m, 7 H) 1.37-1.52 (m, 2 H) 1.65-1.80 (m, 3 H) 1.83-1.97 (m, 6 H) 2.54-2.60 (m, 2 H) 2.84-2.95 (m, 1 H) 3.69-3.76 (m, 2 H) 3.76-3.83 (m, 2 H) 4.37-4.50 (m, 1 H) 7.32 (s, 2 H) 7.93 (d, J = 3 Hz, 1 H) 8.11 (d, J = 3 Hz, 1 H) 101 5-cyclohexyl-7-[3-(1H- pyrazol-1-yl)azetidine- 1-sulfonyl]-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00193] 1-(azetidin-3- yl)-1H- pyrazole (CAS 1107627-16-6) 1 E 402 (400 MHz, DMSO-d.sub.6) 1.24-1.35 (m, 1 H) 1.37-1.52 (m, 2 H) 1.65-1.94 (m, 5 H) 2.53-2.62 (m, 2 H) 4.22 (d, J = 7 Hz, 4 H) 4.38-4.51 (m, 1 H) 4.97-5.09 (m, 1 H) 6.06-6.14 (m, 1 H) 7.11-7.19 (m, 1 H) 7.35 (s, 2 H) 7.46-7.56 (m, 1 H) 7.91 (d, J = 3 Hz, 1 H) 8.05 (d, J = 3 Hz, 1 H) 102 5-cyclohexyl-7-(3- methylpiperidine-1- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00194] 3-methyl- piperidine (CAS 626-56- 2) 1 F 378 (400 MHz, DICHLOROMETHANE- d.sub.2) 0.80-0.98 (m, 4 H) 1.33-1.67 (m, 4 H) 1.68-1.86 (m, 4 H) 1.90-2.05 (m, 4 H) 2.18-2.29 (m, 1 H) 2.40-2.54 (m, 2 H) 2.54-2.63 (m, 1 H) 3.64-3.77 (m, 2 H) 4.24-4.38 (m, 1 H) 6.00 (br. s., 2 H) 7.95 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H) 103 6-amino-5-cyclohexyl- N-[2-(1,3-thiazol-2- yl)ethyl]-5H- pyrrolo[2,3- b]pyrazine-7- sulfonamide [00195] 2-(thiazol-2- yl)-ethanamine (CAS 18453- 07-1) 1 D 407 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.29-1.56 (m, 3 H) 1.76-1.85 (m, 1 H) 1.89-2.04 (m, 4 H) 2.38-2.54 (m, 2 H) 3.17-3.26 (m, 2 H) 3.34-3.46 (m, 2 H) 4.19-4.35 (m, 1 H) 5.82-6.05 (m, 3 H) 7.20 (d, J = 3 Hz, 1 H) 7.64 (d, J = 3 Hz, 1 H) 7.95 (d, J = 3 Hz, 1 H) 8.12 (d, J = 3 Hz, 1 H) 104 8-{6-amino-5- cyclohexyl-5H- pyrrolo[2,3- b]pyrazine-7- sulfonyl}-8- azabicyclo[3.2.1]octan- 3-ol [00196] 8-azabicyclo- [3.2.1]octan-3- ol 1 D 406 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.33-1.58 (m, 6 H) 1.76-1.85 (m, 3 H) 1.86-1.94 (m, 2 H) 1.95-2.05 (m, 4 H) 2.17-2.25 (m, 2 H) 2.37-2.53 (m, 2 H) 4.05-4.15 (m, 1 H) 4.24-4.40 (m, 3 H) 5.96 (br. s., 2 H) 7.95 (d, J = 3 Hz, 1 H) 8.22 (d, J = 3 Hz, 1 H) 105 5-cyclohexyl-7-[4- (2,2,2-trifluoroethyl)- piperazine-1-sulfonyl]- 5H-pyrrolo[2,3- b]pyrazin-6-amine [00197] 1-(2,2,2- trifluoroethyl)- piperazine (CAS 13349- 90-1) 1 Reverse phase C18 5-95% water (+0.05% NH.sub.3)/MeOH 447 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.34-1.55 (m, 3 H) 1.78-1.86 (m, 1 H) 1.89-2.05 (m, 4 H) 2.39-2.52 (m, 2 H) 2.73-2.83 (m, 4 H) 2.94-3.05 (m, 2 H) 3.19-3.31 (m, 4 H) 4.23-4.37 (m, 1 H) 5.94 (br. s., 2 H) 7.97 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H) 106 (1-{6-amino-5- cyclohexyl-5H- pyrrolo[2,3- b]pyrazine-7- sulfonyl}piperidin-4- yl)methanol [00198] piperidin-4-yl- methanol (CAS 6457-49- 4) 1 Reverse phase C18 5-95% water (+0.05% NH.sub.3)/MeOH 394 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.31-1.52 (m, 6 H) 1.77-1.84 (m, 3 H) 1.90-2.04 (m, 4 H) 2.38-2.53 (m, 2 H) 2.56-2.66 (m, 3 H) 3.42-3.51 (m, 2 H) 3.83-3.91 (m, 2 H) 4.23-4.35 (m, 1 H) 5.92 (br. s., 2 H) 7.95 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H) 107 5-cyclohexyl-7-[4- (cyclopropylmethoxy) piperidine-1-sulfonyl]- 5H-pyrrolo[2,3- b]pyrazin-6-amine [00199] 4- (cyclopropyl- methoxy)- piperidine (CAS 865106- 51-0) 1 Reverse phase C18 5-95% water (+0.05% NH.sub.3)/MeOH 434 (400 MHz, DICHLOROMETHANE- d.sub.2) −0.05-0.07 (m, 2 H) 0.27-0.37 (m, 2 H) 0.77-0.90 (m, 1 H) 1.21-1.44 (m, 3 H) 1.50-1.59 (m, 2 H) 1.65-1.72 (m, 1 H) 1.74-1.90 (m, 6 H) 2.25-2.39 (m, 2 H) 2.87-2.94 (m, 2 H) 3.06-3.12 (m, 2 H) 3.20-3.29 (m, 1 H) 3.30-3.41 (m, 2 H) 4.12-4.25 (m, 1 H) 5.78-5.97 (m, 2 H) 7.84 (d, J = 3 Hz, 1 H) 8.06 (d, J = 3 Hz, 1 H)

[0835] Examples 108 to 118 (see Table 4 following) were prepared using the general procedure 6 described below.

Procedure 6

[0836] A solution of 2-(5-cyclohexyl-7-((4-methoxyphenyl)sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)isoindoline-1,3-dione (Intermediate 44; 56 mg, 0.108 mmol) and hydrazine monohydrate (11 μL, 0.22 mmol) in ethanol (1 mL) was stirred at 70° C. in a sealed tube for 1 h. The mixture was allowed to cool then (except where noted otherwise) diluted with DCM and filtered. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography on silica with the indicated eluent, or by preparative reverse phase HPLC as indicated in the table to afford the title compound.

TABLE-US-00006 TABLE Reverse phase preparative HPLC methods Gradient (acetonitrile/water Method (with 0.1% ammonia unless indicated)) A  5-25% B  5-40% C 10-50% D 20-60% E 30-70% F 40-80% G 55-95% H 30-70% (0.1% formic acid)

TABLE-US-00007 TABLE 4 Ex- Puri- am- fication MS .sup.1H NMR ple Compound Name Structure Starting material Method ES+ data δ ppm 108 5-cyclohexyl-7-[(4- methoxybenzene)- sulfonyl]-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00200] 2-(5-cyclohexyl-7-((4- methoxyphenyl)sulfonyl)- 5H-pyrrolo[2,3-b]pyrazin- 6-yl)isoindoline-1,3-dione (Intermediate 44) 0-100% ethyl acetate/ petrol 387 (400 MHz, METHANOL-d.sub.4) 1.32- 1.43 (m, 1 H) 1.45-1.57 (m, 2 H) 1.73- 1.83 (m, 3 H) 1.89-1.98 (m, 2 H) 2.52-2.64 (m, 2 H) 3.84 (s, 3 H) 4.27- 4.39 (m, 1 H) 6.99-7.06 (m, 2 H) 7.90 (d, J = 3 Hz, 1 H) 8.00-8.07 (m, 3 H) 109 5-cyclohexyl-7- (cyclopropanesulfonyl)- 5H-pyrrolo[2,3- b]pyrazin-6-amine [00201] 2-(5-cyclohexyl-7- (cyclopropylsulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- yl)isoindoline-1,3-dione (Intermediate 45) 0-100% ethyl acetate/ petrol 321 (400 MHz, DICHLOROMETHANE- d.sub.2) 0.81-0.89 (m, 2 H) 1.20-1.46 (m, 5 H) 1.65-1.74 (m, 1 H) 1.78- 1.93 (m, 4 H) 2.25-2.43 (m, 2 H) 2.67-2.78 (m, 1 H) 4.09-4.23 (m, 1 H) 5.89 (br. s., 2 H) 7.82-7.89 (m, 1 H) 8.06-8.12 (m, 1 H) 110 5-cyclohexyl-7-[(3- fluorobenzene)sulfonyl]- 5H-pyrrolo[2,3- b]pyrazin-6-amine [00202] 2-(5-cyclohexyl-7-((3- fluorophenyl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- yl)isoindoline-1,3-dione (Intermediate 46) 0-100% ethyl acetate/ petrol 375 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.17-1.41 (m, 3 H) 1.61-1.70 (m, 1 H) 1.71-1.89 (m, 4 H) 2.23-2.39 (m, 2 H) 4.05-4.21 (m, 1 H) 6.13 (br. s., 2 H) 7.09-7.19 (m, 1 H) 7.34- 7.42 (m, 1 H) 7.74-7.91 (m, 3 H) 8.06-8.13 (m, 1 H) 111 5-cyclohexyl-7-[(2- fluorobenzene)sulfonyl]- 5H-pyrrolo[2,3- b]pyrazin-6-amine [00203] 2-(5-cyclohexyl-7-((2- fluorophenyl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- yl)isoindoline-1,3-dione (Intermediate 47) 0-100% ethyl acetate/ petrol 375 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.16-1.47 (m, 3 H) 1.64-1.72 (m, 1 H) 1.76-1.94 (m, 4 H) 2.25-2.46 (m, 2 H) 4.09-4.26 (m, 1 H) 6.17 (br. s., 2 H) 6.95-7.05 (m, 1 H) 7.19- 7.30 (m, 1 H) 7.40-7.50 (m, 1 H) 7.76-7.83 (m, 1 H)7.94-8.01 (m, 1 H) 8.07-8.14 (m, 1 H) 112 5-cyclohexyl-7-[(3- methoxybenzene)- sulfonyl]-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00204] 2-(5-cyclohexyl-7-((3- methoxyphenyl)sulfonyl)- 5H-pyrrolo[2,3-b]pyrazin- 6-yl)isoindoline-1,3-dione (Intermediate 48) H 387 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.27-1.56 (m, 3 H) 1.75-1.81 (m, 1 H) 1.83-2.02 (m, 4 H) 2.35-2.49 (m, 2 H) 3.87 (s, 3 H) 4.20-4.31 (m, 1 H) 6.21 (br. s., 2 H) 7.05-7.12 (m, 1 H) 7.36-7.45 (m, 1 H) 7.69-7.73 (m, 1 H) 7.78-7.83 (m, 1 H) 7.95 (d, J = 3 Hz, 1 H) 8.22 (d, J = 3 Hz, 1 H) 113 4-{6-amino-5- cyclohexyl-5H- pyrrolo[2,3-b]pyrazine- 7-sulfonyl}benzonitrile [00205] 4-((5-cyclohexyl-6-(1,3- dioxoisoindolin-2-yl)-5H- pyrrolo[2,3-b]pyrazin-7- yl)sulfonyl)benzonitrile (Intermediate 49) H 382 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.32-1.53 (m, 3 H) 1.76-1.83 (m, 1 H) 1.85-1.93 (m, 2 H) 1.94-2.05 (m, 2 H) 2.36-2.49 (m, 2 H) 4.18- 4.32 (m, 1 H) 6.20 (br. s., 2 H) 7.77- 7.84 (m, 2 H) 7.97 (d, J = 3 Hz, 1 H) 8.22 (d, J = 3 Hz, 1 H) 8.27-8.35 (m, 2 H) 114 7-[(3-chloro-4- methoxybenzene)- sulfonyl]-5-cyclohexyl- 5H-pyrrolo[2,3- b]pyrazin-6-amine [00206] 2-(7-((3-chloro-4- methoxyphenyl)sulfonyl)-5- cyclohexyl-5H-pyrrolo[2,3- b]pyrazin-6-yl)isoindoline- 1,3-dione (Intermediate 50) Note 1 421 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.32-1.56 (m, 3 H) 1.73-2.02 (m, 5 H) 2.34-2.51 (m, 2 H) 3.95 (s, 3 H) 4.19-4.35 (m, 1 H) 6.26 (br. s., 2 H) 7.04 (d, J = 9 Hz, 1 H) 7.95 (d, J = 3 Hz, 1 H) 8.09-8.17 (m, 2 H) 8.20 (d, J = 3 Hz, 1 H) 115 5-cyclohexyl-7-(6- methoxypyridine-3- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00207] 2-(5-cyclohexyl-7-((6- methoxypyridin-3- yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- yl)isoindoline-1,3-dione (Intermediate 51) 0-4% methanol/ DCM 388 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.28-1.55 (m, 3 H) 1.79 (d, J = 12 Hz, 1 H) 1.85-2.03 (m, 4 H) 2.36- 2.52 (m, 2 H) 3.58 (s, 3 H) 4.19-4.33 (m, 1 H) 6.18 (br. s., 2 H) 6.47 (d, J = 10 Hz, 1 H) 7.82-7.90 (m, 1 H) 7.96 (d, J = 3 Hz, 1 H) 8.19 (d, J = 3 Hz, 1 H) 8.41 (d, J = 3 Hz, 1 H) 116 5-cyclohexyl-7-{[4- (trifluoromethoxy)- benzene]sulfonyl}-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00208] 2-(5-cyclohexyl-7-((4- (trifluoromethoxy)phenyl) sulfonyl)-5H-pyrrolo[2,3- b]pyrazin-6-yl)isoindoline- 1,3-dione (Intermediate 52) F 441 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.25-1.51 (m, 3 H) 1.71-2.01 (m, 5 H) 2.30-2.48 (m, 2 H) 4.12-4.33 (m, 1 H) 6.15 (br. s., 2 H) 7.31 (d, J = 8 Hz, 2 H) 7.92 (d, J = 3 Hz, 1 H) 8.13- 8.28 (m, 3 H) 117 5-cyclohexyl-7-(2,3- dihydro-1,4- benzodioxine-6- sulfonyl)-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00209] 2-(5-cyclohexyl-7-((2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)sulfonyl)-5H- pyrrolo[2,3-b]pyrazin-6- yl)isoindoline-1,3-dione (Intermediate 53) E 415 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.24-1.51 (m, 3 H) 1.71-1.80 (m, 1 H) 1.81-1.99 (m, 4 H) 2.30-2.46 (m, 2 H) 4.15-4.30 (m, 5 H) 6.12 (br. s., 2 H) 6.91 (d, J = 8 Hz, 1 H) 7.58- 7.65 (m, 2 H) 7.90 (d, J = 3 Hz, 1 H) 8.17 (d, J = 3 Hz, 1 H) 118 5-cyclohexyl-7-{[4- (difluoromethoxy)- benzene]sulfonyl}-5H- pyrrolo[2,3-b]pyrazin- 6-amine [00210] 2-(5-cyclohexyl-7-((4- (difluoromethoxy)phenyl)- sulfonyl)-5H-pyrrolo[2,3- b]pyrazin-6-yl)isoindoline- 1,3-dione (Intermediate 54) Note 2 443 (400 MHz, DICHLOROMETHANE- d.sub.2) 1.26-1.52 (m, 3 H) 1.71-2.00 (m, 5 H) 2.27-2.47 (m, 2 H) 4.12-4.32 (m, 1 H) 6.19 (br. s., 2 H) 6.59 (t, J = 74 Hz, 1 H) 7.19 (d, J = 9 Hz, 2 H) 7.92 (d, J = 3 Hz, 1 H) 8.14-8.23 (m, 3 H) Note 1 Alternative workup: The mixture was filtered and the precipitate was washed with ethanol. The filtrate was diluted with ether then concentrated in vacuo and the crude material was purified by column chromatography (silica, 10-55% EtOAc/petroleum ether gradient) to afford the title compound. Note 2 Alternative workup: The reaction mixture was evaporated and the residue was dissolved in ethyl acetate then washed with dilute NaOH(aq), water, and saturated brine. The organic phase was dried (H-frit) and concentrated to afford the title compound.

3. Biological Efficacy of Compounds of the Invention

Screening Protocol:

Ca-Flux Functional Assay: Determination of Agonist/Positive Allosteric Modulator (PAM) Activity

[0837] GPR43 agonist/PAM activity was determined by measuring changes in intracellular calcium levels using a Ca.sup.2+ sensitive fluorescent dye. The changes in fluorescent signal were monitored by FLIPR (manufactured by Molecular Devices). GPR43 mediated increases in intracellular Ca.sup.2+ concentration were readily detected upon activation with sodium acetate. Prior to the assay (24 hours), CHO-K1 Gα16 cells stably expressing human GPR43 were-seeded in cell culture medium in black, clear-bottom 384-well plates (Corning Inc) and grown overnight at 37° C., 5% CO.sub.2. On the day of the assay, cell culture media was removed and cells were loaded with Calcium 5 Dye (Molecular Devices) diluted in HBSS containing 25 mM HEPES, 2.5 mM Probenecid, 0.1% BSA for 1 hour at 37° C., 5% CO.sub.2. 10 point half log concentration response curves of sodium acetate from 10 mM were conducted prior to the testing of compounds to calculate the sodium acetate concentration that produces 20% of the maximal response (EC.sub.20). Test compounds (at to point half log concentration response curves from 10 μM) were added in the presence of sodium acetate to achieve a final concentration that produces approximately 20% maximal response as calculated from the previous experiment. The changes in fluorescent signal were monitored by FLIPR upon addition of the compound/EC.sub.20 sodium acetate mix. The EC.sub.50 values were determined from ten point concentration response curves. Curves were generated using the average of two wells for each data point.

[0838] The above assay detects both GPR43 receptor agonists and positive allosteric modulators of the GPR43 receptor, without distinguishing between the two. Activity in either regard is useful in the treatment of conditions associated with GPR43 receptor activity.

Results:

[0839]

TABLE-US-00008 Compound Mean Compound Mean Compound Mean of Example EC.sub.50 of Example EC.sub.50 of Example EC.sub.50 No. (nM) No. (nM) No. (nM) 1 261 2 218 3 122 4 908 5 195 6 301 7 172 8 118 9 1249 10 2298 11 753 12 671 13 129 14 138 15 381 16 337 17 559 19 1775 20 2359 21 282 22 167 23 1052 24 2586 25 1099 26 79 27 277 28 707 29 31 30 199 31 6936 32 689 33 2722 34 5985 35 1861 36 245 37 468 38 169 39 657 40 7377 41 585 42 2296 43 6985 44 1075 45 2892 46 5257 47 6486 48 3261 49 211 50 760 51 5998 52 822 53 275 54 1536 55 7169 56 1305 57 259 58 2235 59 792 60 1408 61 4316 62 303 63 7946 64 7131 65 210 66 327 67 830 68 1465 69 547 70 3276 71 8378 72 1795 73 488 74 321 75 1187 76 1528 77 290 78 337 79 5968 80 6066 81 1253 82 821 83 931 84 3288 85 1060 86 1715 87 1553 88 3145 89 658 90 6184 91 8352 92 440 93 5697 94 308 95 334 96 1955 97 173 98 2812 99 1551 100 3931 101 7031 102 258 103 471 104 3077 105 647 106 3052 107 320 108 78 109 2902 110 343 111 209 112 295 113 486 114 206 115 4564 116 1082 117 124 118 177

[0840] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the present invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims.