NOVEL MODIFIED MACROCYCLIC COMPOUNDS

Abstract

The present invention relates to novel modified macrocyclic compounds of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I).

Claims

1. A compound of formula (I) ##STR00298## wherein A represents a bivalent moiety selected from the group consisting of S, S(O), S(O).sub.2, S(O)(NR.sup.5); G, E represent, independently from each other, a bivalent moiety selected from the group consisting of O, N(R.sup.A), CH.sub.2, CH(C.sub.1-C.sub.6-alkyl)-, S, S(O), S(O).sub.2, with the proviso that at least one of said bivalent moieties G and E is different from O; L represents a C.sub.2-C.sub.8-alkylene moiety, wherein said moiety is optionally substituted with (i) one substituent selected from hydroxy, NR.sup.6R.sup.7, C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-, C.sub.3-C.sub.4-cycloalkyl-, hydroxy-C.sub.1-C.sub.3-alkyl, (CH.sub.2)NR.sup.6R.sup.7, and/or (ii) one or two or three or four substituents, identically or differently, selected from halogen and C.sub.1-C.sub.3-alkyl-, or wherein one carbon atom of said C.sub.2-C.sub.8-alkylene moiety forms a three- or four-membered ring together with a bivalent moiety to which it is attached, wherein said bivalent moiety is selected from CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, CH.sub.2OCH.sub.2; X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N; R.sup.2 represents a group selected from C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.6-alkynyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, heteroaryl-, phenyl-C.sub.1-C.sub.3-alkyl- and heteroaryl-C.sub.1-C.sub.3-alkyl-, wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.3-fluoroalkoxy-, NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, OP(O)(OH).sub.2, C(O)OH, C(O)NH.sub.2; R.sup.2 represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.3, R.sup.4 represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.5 represents a group selected from a hydrogen atom, cyano, C(O)R.sup.8, C(O)OR.sup.8, S(O).sub.2R.sup.8, C(O)NR.sup.6R.sup.7, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, heteroaryl-, wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl- or heteroaryl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.6, R.sup.7 represent, independently from each other, a group selected from a hydrogen atom, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- and heteroaryl-, wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- or heteroaryl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-, or R.sup.6 and R.sup.7, together with the nitrogen atom they are attached to, form a cyclic amine; R.sup.8 represents a group selected from C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.3-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- and heteroaryl-, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-, R.sup.A represents a hydrogen atom or a C.sub.1-C.sub.6-alkyl-group, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

2. The compound of formula (I) according to claim 1, wherein A represents a bivalent moiety selected from the group consisting of S, S(O), S(O).sub.2, S(O)(NR.sup.5); G, E each represent, independently from each other, a bivalent moiety selected from the group consisting of O, N(R.sup.A), CH.sub.2, CH(C.sub.1-C.sub.3-alkyl)-, S, S(O).sub.2, with the proviso that at least one of said bivalent moieties G and E is different from O; L represents a C.sub.2-C.sub.5-alkylene moiety, wherein said moiety is optionally substituted with (i) one substituent selected from hydroxy, C.sub.3-C.sub.4-cycloalkyl-, hydroxy-C.sub.1-C.sub.3-alkyl-, (CH.sub.2)NR.sup.6R.sup.7, and/or (ii) one or two or three additional substituents, identically or differently, selected from a fluorine atom and a C.sub.1-C.sub.3-alkyl-group; X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N; R.sup.1 represents a group selected from C.sub.1-C.sub.6-alkyl- and C.sub.3-C.sub.5-cycloalkyl-, wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C.sub.1-C.sub.3-alkyl-, fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.3-alkoxy-, C.sub.1-C.sub.2-fluoroalkoxy-, NH.sub.2, alkylamino-, dialkylamino-, cyclic amines, OP(O)(OH).sub.2, C(O)OH, C(O)NH.sub.2; R.sup.2 represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, cyano, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-, fluoro-C.sub.1-C.sub.2-alkyl-; R.sup.3, R.sup.4 represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, cyano C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-, fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.5 represents a group selected from a hydrogen atom, cyano, C(O)R.sup.8, C(O)OR.sup.8, S(O).sub.2R.sup.8, C(O)NR.sup.6R.sup.7, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, phenyl-, wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl- or phenyl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, NH.sub.2, alkylamino-, dialkylamino-, cyclic amines, fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.6, R.sup.7 represent, independently from each other, a group selected from a hydrogen atom, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, phenyl- and benzyl-, wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, phenyl- or benzyl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, NH.sub.2, alkylamino-, dialkylamino-, cyclic amines, fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-, or R.sup.6 and R.sup.7, together with the nitrogen atom they are attached to, form a cyclic amine; R.sup.8 represents a group selected from C.sub.1-C.sub.6-alkyl-, fluoro-C.sub.1-C.sub.3-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, phenyl- and benzyl-, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, NH.sub.2, alkylamino-, dialkylamino-, cyclic amines, fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.A represents a hydrogen atom or a C.sub.1-C.sub.3-alkyl-group, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

3. The compound of formula (I) according to claim 1, wherein A represents a bivalent moiety selected from the group consisting of S, S(O), S(O).sub.2, S(O)(NR.sup.5); E represents a bivalent moiety selected from the group consisting of O, N(R.sup.A), CH.sub.2, CH(C.sub.1-C.sub.3-alkyl)-, S; G represents a bivalent moiety selected from the group consisting of O, N(R.sup.A), CH.sub.2, CH(C.sub.1-C.sub.3-alkyl)-, S, S(O).sub.2; with the proviso that at least one of said bivalent moieties G and E is different from O; L represents a C.sub.2-C.sub.5-alkylene moiety, wherein said moiety is optionally substituted with (i) one substituent selected from C.sub.3-C.sub.4-cycloalkyl- and hydroxymethyl-, and/or (ii) one or two additional substituents, identically or differently, selected from C.sub.1-C.sub.2-alkyl-, X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N; R.sup.1 represents a group selected from C.sub.1-C.sub.4-alkyl- and C.sub.3-C.sub.5-cycloalkyl-, wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, a fluorine atom, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-, NH.sub.2, C(O)OH; R.sup.2 represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-; R.sup.3 represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-, trifluoromethoxy-; R.sup.4 represents a hydrogen atom or a fluorine atom; R.sup.5 represents a group selected from a hydrogen atom, cyano, C(O)R.sup.8, C(O)OR.sup.8, S(O).sub.2R.sup.8, C(O)NR.sup.6R.sup.7, C.sub.1-C.sub.4-alkyl-, wherein said C.sub.1-C.sub.4-alkyl-group is optionally substituted with one substituent selected from the group consisting of a fluorine atom, hydroxy, cyano, C.sub.1-C.sub.3-alkoxy-, NH.sub.2, alkylamino-, dialkylamino-, cyclic amines; R.sup.6, R.sup.7 represent, independently from each other, a group selected from a hydrogen atom, C.sub.1-C.sub.4-alkyl- and C.sub.3-C.sub.5-cycloalkyl-, wherein said C.sub.1-C.sub.4-alkyl- or C.sub.3-C.sub.5-cycloalkyl-group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-, NH.sub.2, alkylamino-, dialkylamino-, cyclic amines, or R.sup.6 and R.sup.7, together with the nitrogen atom they are attached to, form a cyclic amine; R.sup.8 represents a group selected from C.sub.1-C.sub.6-alkyl-, fluoro-C.sub.1-C.sub.3-alkyl-, C.sub.3-C.sub.5-cycloalkyl- and benzyl-, wherein said group is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-, NH.sub.2, R.sup.A represents a hydrogen atom or a C.sub.1-C.sub.3-alkyl-group, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

4. The compound of formula (I) according to claim 1, wherein A represents a bivalent moiety selected from the group consisting of S, S(O), S(O)(NR.sup.5); E represents a bivalent moiety selected from the group consisting of O, N(R.sup.A), CH.sub.2; G represents a bivalent moiety selected from the group consisting of O, N(R.sup.A), CH.sub.2, S; with the proviso that at least one of said bivalent moieties G and E is different from O; L represents a C.sub.2-C.sub.5-alkylene moiety; X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N; R.sup.1 represents a C.sub.1-C.sub.4-alkyl-group, wherein said group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, C.sub.1-C.sub.2-alkoxy-, NH.sub.2, C(O)OH; R.sup.2 represents a hydrogen atom or a fluorine atom; R.sup.3 represents a group selected from a hydrogen atom, a fluorine atom and a methoxy-group; R.sup.4 represents a hydrogen atom; R.sup.5 represents a group selected from a hydrogen atom, cyano, C(O)R.sup.8, C(O)OR.sup.8, C.sub.1-C.sub.4-alkyl-, wherein said C.sub.1-C.sub.4-alkyl-group is optionally substituted with one substituent selected from the group consisting of hydroxy, cyano, C.sub.1-C.sub.3-alkoxy-, NH.sub.2, alkylamino-, dialkylamino-; R.sup.8 represents a group selected from C.sub.1-C.sub.6-alkyl-, fluoro-C.sub.1-C.sub.3-alkyl- and benzyl-; R.sup.A represents a hydrogen atom, a methyl- or an ethyl-group, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

5. The compound of formula (I) according to claim 1, wherein L represents a C.sub.3-C.sub.4-alkylene moiety, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

6. The compound of formula (I) according to claim 1, wherein A represents a bivalent moiety S(O)(NR.sup.5); E represents a bivalent moiety selected from the group consisting of O, N(R.sup.A); G represents a bivalent moiety selected from the group consisting of O, N(H); with the proviso that at least one of said bivalent moieties G and E is different from O; R.sup.5 represents a hydrogen atom; R.sup.A represents a hydrogen atom or a methyl-group, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

7. The compound of formula (I) according to claim 1, wherein A represents a bivalent moiety selected from the group consisting of S, S(O), S(O)(NR.sup.5); E represents a bivalent moiety selected from the group consisting of O, N(R.sup.A); G represents a bivalent moiety selected from the group consisting of O, CH.sub.2, S; with the proviso that at least one of said bivalent moieties G and E is different from O; L represents a C.sub.3-C.sub.5-alkylene moiety; X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N; R.sup.1 represents a C.sub.1-C.sub.3-alkyl-group; R.sup.2 represents a hydrogen atom or a fluorine atom; R.sup.3 represents a group selected from a hydrogen atom, a fluorine atom and a methoxy-group; R.sup.4 represents a hydrogen atom; R.sup.5 represents a group selected from a hydrogen atom, cyano, C(O)R.sup.8, C(O)OR.sup.8, C.sub.1-C.sub.3-alkyl-; R.sup.8 represents a group selected from C.sub.1-C.sub.4-alkyl-, trifluoromethyl- and benzyl-; R.sup.A represents a hydrogen atom or a methyl-group, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

8. The compound of formula (I) according to claim 1, wherein A represents a bivalent moiety selected from the group consisting of S, S(O), S(O)(NR.sup.5); E represents a bivalent moiety selected from the group consisting of O, N(R.sup.A); G represents a bivalent moiety selected from the group consisting of O, CH.sub.2; with the proviso that at least one of said bivalent moieties G and E is different from O; L represents a C.sub.3-C.sub.4-alkylene moiety; X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N; R.sup.1 represents a methyl-group; R.sup.2 represents a hydrogen atom; R.sup.3 represents a hydrogen atom or a fluorine atom; R.sup.4 represents a hydrogen atom; R.sup.5 represents a group selected from a hydrogen atom, C(O)OR.sup.8; R.sup.8 represents a group selected from tert-butyl- and benzyl-; R.sup.A represents a hydrogen atom or a methyl-group, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

9. The compound of formula (I) according to claim 1, wherein R.sup.3 represents a fluorine atom, and R.sup.4 represents a hydrogen atom, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

10. The compound of formula (I) according to claim 1, wherein A represents a bivalent moiety S(O)(NR.sup.5); E represents a bivalent moiety selected from the group consisting of O, N(R.sup.A); G represents a bivalent moiety selected from the group consisting of O, N(H); with the proviso that at least one of said bivalent moieties G and E is different from O; L represents a C.sub.3-C.sub.4-alkylene moiety; X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N; R.sup.1 represents a methyl-group; R.sup.2 represents a hydrogen atom; R.sup.3 represents a hydrogen atom or a fluorine atom; R.sup.4 represents a hydrogen atom; R.sup.5 represents a hydrogen atom; R.sup.A represents a hydrogen atom or a methyl-group, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

11. The compound according to claim 1, which is selected from 15,19-difluoro-8-[(methylsulfanyl)methyl]-2,3,4,5-tetrahydro-11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzoxatriazacyclooctadecine; (rac)-benzyl [{[16,20-difluoro-3,4,5,6-tetrahydro-2H,12H-11,7-(azeno)-13,17-(metheno)-1,6,12,14-benzoxatriazacyclononadecin-9-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate; (rac)-16,20-difluoro-9-[(S-methylsulfonimidoyl)methyl]-3,4,5,6-tetrahydro-2H,12H-11,7-(azeno)-13,17-(metheno)-1,6,12,14-benzoxatriazacyclononadecine; 2,18-difluoro-94(methylsulfanyl)methyl]-13,14,15,16-tetrahydro-6H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclooctadecine; (rac)-2,18-difluoro-9-[(methylsulfinyl)methyl]-13,14,15,16-tetrahydro-6H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclooctadecine; (rac)-tert-butyl [{[16,20-difluoro-6-methyl-3,4,5,6-tetrahydro-2H,12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzoxatriazacyclononadecin-9-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate; (rac)-tert-butyl [{[15,19-difluoro-2,3,4,5-tetrahydro-11H-10,6-(azeno)-16,12-(metheno)-1,5,11,13-benzoxatriazacyclooctadecin-8-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate; (rac)-15,19-difluoro-8-[(S-methylsulfonimidoyl)methyl]-2,3,4,5-tetrahydro-11H-10,6-(azeno)-16,12-(metheno)-1,5,11,13-benzoxatriazacyclooctadecine; (rac)-tert-butyl [{[17,21-difluoro-2,3,4,5,6,7-hexahydro-13H-12,8-(azeno)-14,18-(metheno)-1,7,13,15-benzoxatriazacycloicosin-10-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate; (rac)-17,21-difluoro-10-[(S-methylsulfonimidoyl)methyl]-2,3,4,5,6,7-hexahydro-13H-12,8-(azeno)-14,18-(metheno)-1,7,13,15-benzoxatriazacycloicosine (rac)-16,20-difluoro-6-methyl-9-[(S-methylsulfonimidoyl)methyl]-3,4,5,6-tetrahydro-2H-7,11-(azeno)-17,13-(metheno)-1,6,12,14-benzoxatriazacyclononadecine 8,16,20-trifluoro-6-methyl-9-[(methylsulfanyl)methyl]-3,4,5,6-tetrahydro-2H,12H-11,7-(azeno)-13,17-(metheno)-1,6,12,14-benzoxatriazacyclononadecine (rac)-tert-butyl [{[15,19-difluoro-1,2,3,4-tetrahydro-16,12-(azeno)-6,10-(metheno)-5,1,11,13-benzoxatriazacyclooctadecin-8(11H)-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate; (rac)-15,19-difluoro-8-[(S-methylsulfonimidoyl)methyl]-1,2,3,4-tetrahydro-16,12-(azeno)-6,10-(metheno)-5,1,11,13-benzoxatriazacyclooctadecine; (rac)-tert-butyl [{[16,20-difluoro-2,3,4,5-tetrahydro-1H,12H-13,17-(azeno)-11,7-(metheno)-6,1,12,14-benzoxatriazacyclononadecin-9-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate; (rac)-16,20-difluoro-9-[(S-methylsulfonimidoyl)methyl]-2,3,4,5-tetrahydro-1H-17,13-(azeno)-7,11-(metheno)-6,1,12,14-benzoxatriazacyclononadecine; (rac)-16,20-difluoro-6-methyl-9-[(S-methylsulfonimidoyl)methyl]-1,2,3,4,5,6-hexahydro-12H-17,13-(azeno)-11,7-(metheno)-1,6,12,14-benzotetraazacyclononadecine; salt with formic acid; 2,19-difluoro-9-[(methylsulfanyl)methyl]-14,15,16,17-tetrahydro-6H,13H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclononadecine; (rac)-2,19-difluoro-9-[(methylsulfinyl)methyl]-14,15,16,17-tetrahydro-6H,13H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclononadecine; (rac)-2,19-difluoro-9-[(S-methylsulfonimidoyl)methyl]-14,15,16,17-tetrahydro-6H,13H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclononadecine; (rac)-tert-butyl [{[16,20-difluoro-2,3,4,5-tetrahydro-12H-17,13-(azeno)-11,7-(metheno)-6,1,12,14-benzoxathiadiazacyclononadecin-9-yl[methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate; (rac)-16,20-difluoro-9-[(S-methylsulfonimidoyl)methyl]-2,3,4,5-tetrahydro-12H-17,13-(azeno)-11,7-(metheno)-6,1,12,14-benzoxathiadiazacyclononadecine; (rac)-16,20-difluoro-6-methyl-9-[(S-methylsulfonimidoyl)methyl]-3,4,5,6-tetrahydro-2H,12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzoxatriazacyclononadecine; (rac)-tert-butyl [{[16,20-difluoro-3,4,5,6-tetrahydro-2H,12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzoxatriazacyclononadecin-9-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate; (rac)-16,20-difluoro-9-[(S-methylsulfonimidoyl)methyl]-3,4,5,6-tetrahydro-2H,12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzoxatriazacyclononadecine; and an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

12. (canceled)

13. A method for treating and/or prophylaxis of hyper-proliferative disorders, virally induced infectious diseases and/or of cardiovascular diseases in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of formula (I) according to claim 1 to the subject.

14-15. (canceled)

16. A method for treating and/or prophylaxis of lung carcinomas, prostate carcinomas, cervical carcinomas, colorectal carcinomas, melanomas, ovarian carcinomas or leukemias in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of formula (I) according to claim 1 to the subject.

17. A method for treating and/or prophylaxis of non-small cell lung carcinomas, hormone-independent human prostate carcinomas, multidrug-resistant human cervical carcinomas or human acute myeloid leukemias in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of formula (I) according to claim 1 to the subject.

18. A pharmaceutical combination comprising the compound according to claim 1 in combination with at least one or more further active ingredients.

19. A method for treating and/or prophylaxis of hyper-proliferative disorders, virally induced infectious diseases and/or of cardiovascular diseases in a subject in need thereof, comprising administering a therapeutically effective amount of the pharmaceutical combination according to claim 18 to the subject.

20. A method for treating and/or prophylaxis of lung carcinomas, prostate carcinomas, cervical carcinomas, colorectal carcinomas, melanomas, ovarian carcinomas or leukemias in a subject in need thereof, comprising administering a therapeutically effective amount of the pharmaceutical combination according to claim 18 to the subject.

21. A pharmaceutical composition comprising the compound according to claim 1 in combination with an inert, nontoxic, pharmaceutically suitable adjuvant.

22. A method for treating and/or prophylaxis of hyper-proliferative disorders, virally induced infectious diseases and/or of cardiovascular diseases in a subject in need thereof, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 21 to the subject.

23. A method for treating and/or prophylaxis of lung carcinomas, prostate carcinomas, cervical carcinomas, colorectal carcinomas, melanomas ovarian carcinomas or leukemias in a subject in need thereof, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 21 to the subject.

24. A compound of formula (44) ##STR00299## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and L are as defined according to claim 1 for the compound of formula (I), or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

25. A compound of formula (34) ##STR00300## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.A and L are as defined according to claim 1 for the compound of formula (I), or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

26. A process for the preparation of a compound of formula (45), in which process a compound of the formula (44), in which R.sup.1, R.sup.2, R.sup.3, R.sup.4 and L are as defined for the compound of formula (I) according to claim 1, ##STR00301## is reacted in an intramolecular Palladium-catalyzed CN cross-coupling reaction, ##STR00302## to give a compound of the formula (45), and in which process the resulting compound is optionally, if appropriate, converted with the corresponding (i) solvents and/or (ii) bases or acids to the solvates, salts and/or solvates of the salts thereof.

27. A process for the preparation of a compound of formula (35), in which process a compound of the formula (34), in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.A and L are as defined for the compound of formula (I) according to claim 1, ##STR00303## is reacted in an intramolecular Palladium-catalyzed CN cross-coupling reaction, ##STR00304## to give a compound of the formula (35), and in which process the resulting compound is optionally, if appropriate, converted with the corresponding (i) solvents and/or (ii) bases or acids to the solvates, salts and/or solvates of the salts thereof.

Description

PREPARATIVE EXAMPLES

[1044] Syntheses of Compounds

[1045] The syntheses of the macrocyclic compounds of formula (I) according to the present invention are preferably carried out according to the general synthetic sequences as shown in Schemes 1a, 1b, 1c, 1d, 2, 3a, 3b, 3c, 3d, 3e, 4a, 4b, 4c, 5, 6a, 6b, 6c, 6d, 6e, 6f, 6g, 7a, 7b, 7c, 8a, 8b, 8c, 9a, 9b, 9c, 9d, 9e and 9f.

[1046] In addition to said routes described below, also other routes may be used to synthesise the target compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis. The order of transformations exemplified in the following Schemes is therefore not intended to be limiting, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences. In addition, modification of any of the substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4 and/or R.sup.5 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metallation, metal catalysed coupling reactions, substitution or other reactions known to a person skilled in the art. These transformations include those which introduce a functionality allowing for further interconversion of substituents. Appropriate protective groups and their introduction and cleavage are well-known to a person skilled in the art (see for example T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 4.sup.th edition, Wiley 2006). Specific examples are described in the subsequent paragraphs. Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a one-pot reaction, as it is well-known to a person skilled in the art.

[1047] The geometry of the sulfinyl and sulfoximine moiety renders some of the compounds of the general formula (I) chiral. Separation of racemic sulfoxides and sulfoximines into their enantiomers can be achieved by methods known to the person skilled in the art, preferably by means of preparative HPLC on chiral stationary phase.

[1048] The syntheses of the pyridine derivatives of formulae (11), (15), (15a) and (15b), all of them constituting subsets of the general formula (I) according to the present invention, are preferably carried out according to the general synthetic sequences as shown in Schemes 1a, 1b, 1c and 1d.

[1049] Schemes 1a, 1b and 1c, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined for the compound of general formula (I) according to the present invention, outline the preparation of pyridine-based macrocyclic compounds of of formulae (11) and (15), from 2-chloro-5-fluoro-4-iodopyridine (1; CAS #884494-49-9).

[1050] As outlined in Scheme 1a, said starting material (1) can be reacted with a boronic acid derivative of formula (2), in which R.sup.3 and R.sup.4 are as defined for the compound of general formula (I), to give a compound of formula (3). The boronic acid derivative (2) may be a boronic acid (RH) or an ester of the boronic acid, e.g. its isopropyl ester (RCH(CH.sub.3).sub.2), or an ester derived from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (RRC(CH.sub.3).sub.2C(CH.sub.3).sub.2).

[1051] Said coupling reaction can be catalyzed by palladium catalysts, e.g. by Pd(0) catalysts such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh.sub.3).sub.4], tris(dibenzylideneacetone)di-palladium(0) [Pd.sub.2(dba).sub.3], or by Pd(II) catalysts such as dichlorobis(triphenylphosphine)-palladium(II) [Pd(PPh.sub.3).sub.2Cl.sub.2], palladium(II) acetate and triphenylphosphine or by [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride.

[1052] The reaction is preferably carried out in a mixture of a solvent such as 1,2-dimethoxyethane, dioxane, DMF, THF, or isopropanol with water and in the presence of a base such as potassium carbonate, sodium bicarbonate or potassium phosphate.

[1053] (review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein).

[1054] The reaction is performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1055] In the second step, a compound of formula (3) can be converted to a compound of formula (4). This reaction can be carried out by a Palladium-catalyzed CN cross-coupling reaction (for a review on CN cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in Metal-Catalyzed Cross-Coupling Reactions, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004).

[1056] Preferred is the herein described use of lithium bis(trimethylsilyl)amide, tris(dibenzylideneacetone)dipalladium(0) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl in THF. The reactions are preferably run under an atmosphere of argon for 3-24 hours at a temperature of 40 C. to 80 C. in an oil bath.

[1057] In the third step, a compound of formula (4) can be converted to a compound of formula (5), by means of cleaving the methyl ether present in compounds of formula (4).

[1058] Preferred is the herein described use of boron tribromide in DCM. The reactions are preferably run for 1 to 24 hours at 0 C. to room temperature.

[1059] In the fourth step, a compound of formula (5) can be coupled with a compound of formula (6), in which L is as defined for the compound of general formula (I), and in which LG.sup.1 is a leaving group such as chloro, bromo, iodo, C.sub.1-C.sub.4-alkyl-S(O).sub.2O, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or para-toluenesulfonyloxy-, preferably bromo, to give a compound of formula (7). This reaction is carried out preferentially in the presence of an inorganic base such as potassium carbonate in MeCN at 80 C. in a sealed vessel and reaction times of 3 to 24 hours.

[1060] Compounds of the formula (6) are well known to the person skilled in the art and widely commercially available.

##STR00057## ##STR00058##

[1061] In the fifth step, and as shown in Scheme 1b, a compound of formula (7) can be coupled with a compound of formula (8), in which R.sup.1 and R.sup.2 are as defined for the compound of general formula (I), to give a compound of formula (9). This reaction can be carried out by a Palladium-catalyzed CN cross-coupling reaction (for a review on CN cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in Metal-Catalyzed Cross-Coupling Reactions, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004).

[1062] Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably potassium phosphate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent, preferably a mixture of toluene and NMP, as a solvent. The reactions are preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 130 C. in a microwave oven or in an oil bath.

[1063] Compounds of the formula (8) can be prepared as outlined in Scheme 2, infra.

[1064] In the sixth step, a compound of formula (9) can be converted to a compound of formula (10). This deprotection is preferably run using an aqueous solution of hydrazine in an aliphatic alcohol of the formula C.sub.1-C.sub.4-alkyl-OH, preferably MeOH or EtOH, as a solvent, at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. Optionally, a cyclic ether such as tetrahydrofuran, tetrahydropyran or 1,4 dioxane can be added as co-solvent in order to support complete dissolution of the starting material. The reaction is preferably completed after 1 to 36 hours of reaction time. (P. G. M. Wuts, T. W. Green, Protective Groups in Organic Synthesis, 4.sup.th Edition, John Wiley & Sons, Hoboken, USA, 2006).

[1065] In the seventh step, a compound of formula (10) can be converted to a macrocyclic compound of formula (11). This cyclization reaction can be carried out by an intramolecular Palladium-catalyzed CN cross-coupling reaction (for a review on CN cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in Metal-Catalyzed Cross-Coupling Reactions, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004).

[1066] Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably potassium phosphate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent, preferably a mixture of toluene and NMP, as a solvent. The reactions are preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 130 C. in a microwave oven or in an oil bath.

##STR00059## ##STR00060##

[1067] As outlined in Scheme 1c, a compound of formula (7), in which R.sup.3, R.sup.4 and L are as defined for the compound of general formula (I), can also be converted to a compound of formula (12). This deprotection is preferably run using an aqueous solution of hydrazine in an aliphatic alcohol of the formula C.sub.1-C.sub.4-alkyl-OH, preferably MeOH or EtOH, as a solvent, at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. Optionally, a cyclic ether such as tetrahydrofuran, tetrahydropyran or 1,4 dioxane can be added as co-solvent in order to support complete dissolution of the starting material. The reaction is preferably completed after 1 to 36 hours of reaction time. (P. G. M. Wuts, T. W. Green, Protective Groups in Organic Synthesis, 4.sup.th Edition, John Wiley & Sons, Hoboken, USA, 2006).

[1068] In the next step, a compound of formula (12) can be coupled with a compound of formula (13), in which R.sup.1, R.sup.2 and R.sup.5 are as defined for the compound of general formula (I), to give a compound of formula (14). This reaction is preferentially carried out in the presence of an organic or inorganic base, such as pyridine which is optionally substituted on, two or three times, identically or differently, with C.sub.1-C.sub.3-alkyl-, such as lutidine, or an aliphatic amine of the formula (C.sub.1-C.sub.3-alkyl-).sub.3N or an alkali carbonate, preferentially N,N-diisopropylethylamine in a dipolar aprotic solvent such as a carboxamide based solvent or dimethyl sulfoxide, preferably NMP. The reactions are preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 160 C. in a microwave oven or in an oil bath.

[1069] Compounds of the formula (13) can be prepared as outlined in Scheme 2, infra.

[1070] Subsequently, a compound of formula (14) can be converted to a macrocyclic compound of formula (15). This cyclization reaction can be carried out by an intramolecular Palladium-catalyzed CN cross-coupling reaction (for a review on CN cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in Metal-Catalyzed Cross-Coupling Reactions, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004).

[1071] Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably potassium phosphate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent, preferably a mixture of toluene and NMP, as a solvent. The reactions are preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 130 C. in a microwave oven or in an oil bath. In case the R.sup.5 group present in the compound formula (15) is a protective group, such as trifluoroacetyl-(C(O)CF.sub.3), tert-butoxycarbonyl-(C(O)OC(CH.sub.3).sub.3; also referred to herein as Boc), or benzyloxycarbonyl-(C(O)OCH.sub.2Ph), R.sup.5 can be readily converted into a hydrogen atom, using methods well known to the person skilled in the art.

##STR00061## ##STR00062##

[1072] As outlined in Scheme 1d, N-unprotected sulfoximines of formula (15a) (R.sup.5H) may be further converted into N-functionalized derivatives of formula (15b). There are multiple methods for the preparation of N-functionalized sulfoximines by functionalization of the nitrogen of the sulfoximine group:

[1073] Alkylation: see for example: a) U. Lcking et al, US 2007/0232632; b) C. R. Johnson, J. Org. Chem. 1993, 58, 1922; c) C. Bolm et al, Synthesis 2009, 10, 1601.

[1074] Acylation: see for example: a) C. Bolm et al, Chem. Europ. J. 2004, 10, 2942; b) C. Bolm et al, Synthesis 2002, 7, 879; c) C. Bolm et al, Chem. Eur. J. 2001, 7, 1118.

[1075] Arylation: see for example: a) C. Bolm et al, Tet. Lett. 1998, 39, 5731; b) C. Bolm et al., J. Org. Chem. 2000, 65, 169; c) C. Bolm et al, Synthesis 2000, 7, 911; d) C. Bolm et al, J. Org. Chem. 2005, 70, 2346;

[1076] e) U. Lcking et al, WO2007/71455.

[1077] Reaction with isocyanates: see for example: a) V. J. Bauer et al, J. Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al, J. Am. Chem. Soc. 1970, 92, 6594; c) S. Allenmark et al, Acta Chem. Scand. Ser. B 1983, 325; d) U. Lcking et al, US2007/0191393.

[1078] Reaction with sulfonylchlorides: see for example: a) D. J. Cram et al, J. Am. Chem. Soc. 1970, 92, 7369; b) C. R. Johnson et al, J. Org. Chem. 1978, 43, 4136; c) A. C. Barnes, J. Med. Chem. 1979, 22, 418; d) D. Craig et al, Tet. 1995, 51, 6071; e) U. Lcking et al, US2007/191393.

[1079] Reaction with chloroformiates: see for example: a) P. B. Kirby et al, DE2129678; b) D. J. Cram et al, J. Am. Chem. Soc. 1974, 96, 2183; c) P. Stoss et al, Chem. Ber. 1978, 111, 1453; d) U. Lcking et al, WO2005/37800.

[1080] Reaction with bromocyane: see for example: a) D. T. Sauer et al, Inorganic Chemistry 1972, 11, 238; b) C. Bolm et al, Org. Lett. 2007, 9, 2951; c) U. Lcking et al, WO 2011/29537.

##STR00063##

[1081] Compounds of the formula (8), in which R.sup.1 and R.sup.2 are as defined for the compound of general formula (I) and compounds of the formula (13), in which R.sup.1, R.sup.2 and R.sup.5 are as defined for the compound of general formula (I), can be prepared according to Scheme 2, starting e.g. from a 2,6-dichloroisonicotinic acid derivative of formula (16), in which R.sup.2 is as defined for the compound of general formula (I), which can be reduced to the corresponding pyridinemethanol of formula (17), by means of reduction. Preferred is the herein described use of sulfanediyldimethane-borane (1:1 complex) in tetrahydrofuran. Derivatives of isonicotinic acid of formula (16), and esters thereof, are well known to the person skilled in the art, and are often commercially available.

[1082] In a second step, a pyridinemethanol of formula (17) can be reacted to give a compound of formula (18), in which LG.sup.2 represents a leaving group such as chloro, bromo, iodo, C.sub.1-C.sub.4-alkyl-S(O).sub.2O, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or para-toluenesulfonyloxy-. Such conversions are well known to the person skilled in the art; preferred is the herein described use of methanesulfonyl chloride in the presence of triethylamine as a base, in dichloromethane as a solvent, to give a compound of formula (18) in which LG.sup.2 represents methanesulfonyloxy-, or the herein described use of thionyl chloride in the presence of pyridine as a base, in toluene as a solvent, to give a compound of formula (18) in which LG.sup.2 represents chloro.

[1083] In a third step, a compound of formula (18) can be reacted with a thiol (or a salt of said thiol) of the formula R.sup.1SH, in which R.sup.1 is as defined for the compound of general formula (I), to give a thioether derivative of formula (8). Thiols of the formula R.sup.1SH, and salts thereof, are well known to the person skilled in the art and are commercially available in considerable variety.

[1084] Oxidation of a thioether of formula (8) can be used to obtain the corresponding sulfoxide of formula (19). The oxidation can be performed analogously to known processes (see for example: (a) M. H. Ali et al, Synthesis 1997, 764; (b) M. C. Carreno, Chem. Rev. 1995, 95, 1717; (c) I. Patel et al, Org. Proc. Res. Dev. 2002, 6, 225; (d) N. Khiar et al, Chem. Rev. 2003, 103, 3651). Preferred is the herein described use of periodic acid and iron(III)chloride.

[1085] Rhodium-catalyzed imination of a sulfoxide of formula (19) can be used to prepare the corresponding sulfoximines of formula (13) (see for example: a) Bolm et al, Org. Lett. 2004, 6, 1305; b) Bull et al, J. Org. Chem. 2015, 80, 6391). In this type of reaction, R.sup.5 preferably represents a C(O)R.sup.8 or C(O)OR.sup.8 group, in which R.sup.8 is as defined for the compound of general formula (I); more preferably, R.sup.5 represents a group selected from trifluoroacetyl-(C(O)CF.sub.3), tert-butoxycarbonyl-(C(O)OC(CH.sub.3).sub.3), and, as described herein, benzyloxycarbonyl-(C(O)OCH.sub.2Ph).

##STR00064##

[1086] The syntheses of pyridine derivatives of formulae (25), (26), (27), (27a) and (28), all of them constituting further subsets of the general formula (I) according to the present invention, are preferably carried out according to the general synthetic sequences as shown in Schemes 3a, 3b, 3c, 3d and 3e.

[1087] As outlined in Scheme 3a, a compound of formula (5, prepared as described above; see Scheme 1a), in which R.sup.3 and R.sup.4 are as defined for the compound of general formula (I), can be converted into a triflate compound of formula (20), in which OTf represents OS(O).sub.2CF.sub.3, in the first step. This reaction is carried out preferentially using N-phenyl trifluoromethanesulfonimide and a base, preferentially trimethylamine, in solvents such as DCM at temperatures from room temperature to reflux and reaction times from 1 to 24 hours.

[1088] In a second step, a compound of formula (20) can be coupled with an alkyne of formula (21), in which L represents a C.sub.1-C.sub.7-alkylene group featuring one carbon atom less as compared to the corresponding group L in formula (23), to give a compound of formula (22). Said coupling reaction, also known as Sonogashira coupling, is catalyzed by palladium catalysts, e.g. by Pd(0) catalysts such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh.sub.3).sub.4], tris(dibenzylideneacetone)di-palladium(0) [Pd.sub.2(dba).sub.3], or by Pd(II) catalysts such as dichlorobis(triphenylphosphine)-palladium(II) [Pd(PPh.sub.3).sub.2Cl.sub.2], also being referred herein to as bis(triphenylphosphino)palladium(II) chloride, or by palladium(II) acetate and triphenylphosphine or by [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride. The reaction is promoted by a copper(I) salt such as copper(I) iodide.

[1089] The reaction is preferably carried out in a solvent such as 1,2-dimethoxyethane, dioxane, DMF, THF and in the presence of a base such as triethylamine, DIPEA or diisopropylamine. The reaction is performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. The reaction is preferably completed after 1 to 36 hours of reaction time. (For a review on the Sonogashira reaction, see: R. Chinchilla, C. Najera, Chem. Rev. 2007, 107, 874-922)

[1090] Compounds of formula (21) are well known to the person skilled in the art and are widely commercially available.

[1091] In a third step, a compound of formula (22) can be hydrogenated to give a compound of formula (23). This reaction is preferentially run in the presence of a hydrogenation catalyst such as palladium on activated charcoal under positive pressure of hydrogen (1 to 50 bar) and solvents such as MeOH, EtOH or THF. (For an overview on heterogeneous catalytic hydrogenation, see: S. Nishimura, Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis, Wiley-VCH, Weinheim, 2001).

##STR00065##

[1092] In a fourth step and as shown in Scheme 3b, a compound of formula (23) can be coupled with a compound of formula (8, see Scheme 2), in which R.sup.1 and R.sup.2 are as defined for the compound of general formula (I), to provide a compound of formula (24). This coupling is preferentially carried out in the presence of a base such as alkali carbonates, alkali phosphates, alkali hydrides or organic bases such as alkali tert-butoxides or amines. The reaction is preferentially run in solvents such as diethylether, methyl-tert-butyl ether, cyclopentylmethyl ether, THF, DMF, DME, NMP or DMSO at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent.

##STR00066##

[1093] In a fifth step and as shown in Scheme 3c, a compound of formula (24) is converted to a macrocyclic compound of formula (25). This cyclization reaction can be carried out by an intramolecular Palladium-catalyzed CN cross-coupling reaction (for a review on CN cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in Metal-Catalyzed Cross-Coupling Reactions, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004).

[1094] Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably potassium phosphate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent, preferably a mixture of toluene and NMP, as a solvent. The reactions are preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 130 C. in a microwave oven or in an oil bath.

##STR00067##

[1095] As outlined in Scheme 3d, oxidation of a thioether of formula (25) can be used to obtain the corresponding sulfoxide of formula (26). The oxidation can be performed analogously to known processes (see for example: (a) M. H. Ali et al, Synthesis 1997, 764; (b) M. C. Carreno, Chem. Rev. 1995, 95, 1717; (c) I. Patel et al, Org. Proc. Res. Dev. 2002, 6, 225; (d) N. Khiar et al, Chem. Rev. 2003, 103, 3651).

[1096] Preferred is the herein described use of periodic acid and iron(III) chloride.

[1097] Imination of a sulfoxide of formula (26) gives the corresponding unsubstituted sulfoximine of formula (27). Preferred is the well-known use of sodium azide and sulfuric acid in trichloromethane or DCM at 45 C. (see for example: a) H. R. Bentley et al, J. Chem. Soc. 1952, 1572; b) C. R. Johnson et al, J. Am. Chem. Soc. 1970, 92, 6594; c) Satzinger et al, Angew. Chem. 1971, 83, 83).

[1098] Furthermore, thioethers of formula (25) can also be oxidized to the corresponding sulfones of formula (28). The oxidation can be prepared analogously to known processes (see for example: Sammond et al; Bioorg. Med. Chem. Lett. 2005, 15, 3519).

##STR00068##

[1099] N-unprotected sulfoximines of formula (27) (R.sup.5H) may be further converted into N-functionalized derivatives of formula (27a), as shown in Scheme 3e. There are multiple methods for the preparation of N-functionalized sulfoximines by functionalization of the nitrogen of the sulfoximine group; for details see the references listed in context of the conversion of N-unprotected sulfoximines of formula (15a) (R.sup.5H) into N-functionalized derivatives of formula (15b)/Scheme 1c.

##STR00069##

[1100] The syntheses of the pyrimidine derivatives of formula (35), (35a) and (35b), constituting further subsets of the general formula (I) according to the present invention, are preferably carried out according to the general synthetic sequences as shown in Schemes 4a, 4b and 4c.

[1101] Schemes 4a, 4b and 4c, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.A and L are as defined for the compound of general formula (I) according to the present invention, outline the preparation of pyrimidine compounds of the general formula (I) from 2,4-dichloro-5-fluoropyrimidine (CAS #2927-71-1, 29). As shown in Scheme 4a, said starting material (29) can be reacted with a boronic acid derivative of formula (2) to give a compound of formula (30). The boronic acid derivative (2) may be a boronic acid (RH) or an ester of the boronic acid, e.g. its isopropyl ester (RCH(CH.sub.3).sub.2), or an ester derived from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (RRC(CH.sub.3).sub.2-C(CH.sub.3).sub.2). Boronic acids and their esters are commercially available and well-known to the person skilled in the art; see e.g. D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein.

[1102] The coupling reaction can be catalyzed by Pd catalysts, e.g. by Pd(0) catalysts such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh.sub.3).sub.4], tris(dibenzylideneacetone)di-palladium(0) [Pd.sub.2(dba).sub.3], or by Pd(II) catalysts such as dichlorobis(triphenylphosphine)-palladium(II) [Pd(PPh.sub.3).sub.2Cl.sub.2], palladium(II) acetate and triphenylphosphine or by [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride [Pd(dppf)Cl.sub.2].

[1103] The reaction is preferably carried out in a mixture of a solvent such as 1,2-dimethoxyethane, dioxane, DMF, THF, or isopropanol with water and in the presence of a base such as aqueous potassium carbonate, aqueous sodium bicarbonate or potassium phosphate. The reaction is performed at temperatures ranging from room temperature (=20 C.) to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. (review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein). The reaction is preferably completed after 1 to 36 hours of reaction time.

[1104] In the second step, a compound of formula (30) is converted to a compound of formula (31), by means of cleaving the methyl ether present in the compound of formula (30). Preferred is the herein described use of boron tribromide in DCM. The reactions are preferably run for 1 to 24 hours at 0 C. to room temperature.

[1105] In the third step, a compound of formula (31) is coupled with a compound of formula (32) to give a compound of formula (33). This reaction can be carried out by a Mitsunobu reaction (see for example: a) K. C. K. Swamy et al, Chem. Rev. 2009, 109, 2551). Compounds of the formula (32) can be prepared as outlined in Scheme 5, infra

##STR00070##

[1106] As outlined in Scheme 4b, a compound of formula (33), wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, L and R.sup.A are as defined for the compound of general formula (I) according to the present invention, can be reduced to give an aniline of formula (34). The reduction can be prepared analogously to known processes (see for example: (a) Sammond et al; Bioorg. Med. Chem. Lett. 2005, 15, 3519; (b) R. C. Larock, Comprehensive Organic Transformations, VCH, New York, 1989, 411-415). Preferred is the herein described use of hydrogen gas in the presence of commercial catalysts containing platinum and vanadium on carbon, preferably on activated carbon, in a suitable solvent such as an aliphatic alcohol of the formula C.sub.1-C.sub.3-alkyl-OH, optionally containing a cyclic ether such as tetrahydrofuran or 1,4-dioxane as co-solvent, preferably in methanol or a mixture of methanol and tetrahydrofuran. Alternatively, titanium(III)chloride in a mixture of aqueous hydrochloric acid and tetrahydrofuran can be used.

[1107] The resulting compounds of formula (34) can be converted to a macrocyclic compound of formula (35). This cyclization reaction can be carried out by an intramolecular Palladium-catalyzed CN cross-coupling reaction (for a review on CN cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in Metal-Catalyzed Cross-Coupling Reactions, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably potassium phosphate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent, preferably a mixture of toluene and NMP, as a solvent. The reactions are preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 130 C. in a microwave oven or in an oil bath.

[1108] Finally, the tert-butoxycarbonyl-group attached to the sulfoximine nitrogen can be cleaved under acidic conditions to give unprotected sulfoximines of formula (35a) (see for example: J. A. Bull, J. Org. Chem. 2015, 80, 6391). Preferred is the herein described use of an acid, preferably trifluoroacetic acid in dichloromethane as a solvent.

##STR00071## ##STR00072##

[1109] Scheme 4c, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.A and L are as defined for the compound of general formula (I) according to the present invention, outlines the preparation of an N-substituted sulfoximine compound of the formula (35b) from an N-unsubstituted sulfoximine compound of the formula (35a).

[1110] An N-unprotected sulfoximine of formula (35a) (R.sup.5H) may be reacted to to give an N-functionalized derivative of formula (35b). Formulae (35a) and (35b) both constitute further subsets of the general formula (I). There are multiple methods known for the preparation of N-functionalized sulfoximines by functionalization of the nitrogen of the sulfoximine group; for details see the references listed in context of the conversion of N-unprotected sulfoximines of formula (15a) (R.sup.5H) into N-functionalized derivatives of formula (15b)/Scheme 1c.

##STR00073##

[1111] Compounds of the formula (32), in which R.sup.1 and R.sup.2 are as defined for the compound of general formula (I) according to the present invention, can be prepared according to Scheme 5, starting e.g. from a sulfoxide derivative of the formula (36), in which R.sup.1 and R.sup.2 are as defined for the compound of general formula (I) according to the present invention, which are reacted to give a Boc-protected sulfoximine compound of formula (37) (see for example: J. A. Bull, J. Org. Chem. 2015, 80, 6391).

[1112] In a second step, a compound of formula (37) is reacted with an amine of the formula HO-L-NHR.sup.A, in which L and R.sup.A are as defined for the compound of general formula (I) according to the present invention to give compounds of the formula (32). Sulfoxide derivatives of formula (36) and methods for their preparation are known to the person skilled in the art (see e.g. WO 2013037894).

##STR00074##

[1113] The syntheses of pyrimidine derivatives of formulae (45). (45a) and (45b), all of them constituting further subsets of the general formula (I) according to the present invention, can be preferably carried out according to the general synthetic sequences as shown in Schemes 6a, 6b, 6c, 6d and 6e.

##STR00075## ##STR00076##

[1114] In a first step, pyrimidine of formula (29) can be reacted with a boronic acid derivative of formula (38), in which R.sup.3 and R.sup.4 are as defined for the compound of general formula (I), to give a compound of formula (39). The boronic acid derivative (38) may be a boronic acid (RH) or an ester of the boronic acid, e.g. its isopropyl ester (RCH(CH.sub.3).sub.2), or an ester derived from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (RRC(CH.sub.3).sub.2C(CH.sub.3).sub.2).

[1115] Said coupling reaction can be catalyzed by palladium catalysts, e.g. by Pd(0) catalysts such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh.sub.3).sub.4], tris(dibenzylideneacetone)di-palladium(0) [Pd.sub.2(dba).sub.3], or by Pd(II) catalysts such as dichlorobis(triphenylphosphine)-palladium(II) [Pd(PPh.sub.3).sub.2Cl.sub.2], palladium(II) acetate and triphenylphosphine or by [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride.

[1116] The reaction can be preferably carried out in a mixture of a solvent such as 1,2-dimethoxyethane, dioxane, DMF, THF, or isopropanol with water and in the presence of a base such as potassium carbonate, sodium bicarbonate or potassium phosphate. (review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein).

[1117] The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1118] In a second step, the compounds of formula (39) can be reacted with 2-nitrobenzenesulfonyl chloride (NsCl) to give compounds of the formula (40). This reaction can be carried out in the presence of an organic base, preferably pyridine, and catalytic amounts of 4-dimethylaminopyridine in solvents such as dichloromethane. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1119] In a third step, compounds of the formula (40), in which Ns represents a 2-nitrobenzenesulfonyl group, can be reacted with with an alcohol of formula (41), in which R.sup.1, R.sup.2 and L are as defined for the compound of the general formula (I) and which can be prepared according to Scheme 6e, in the presence of a tertiary phosphine, such as triphenylphosphine, and a dialkyl diazodicarboxylate (known as Mitsunobu reaction, see for example: K. C. K. Swamy et al, Chem. Rev. 2009, 109, 2551), to yield compounds of formula (42). Preferred is the use of diisopropyl azodicarboxylate and triphenylphosphine as coupling reagent in a solvent such as dichloromethane or THF. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

##STR00077##

[1120] As outlined in Scheme 6b, compounds of the formula (42), in which R.sup.1, R.sup.2, R.sup.3, R.sup.4 and L are as defined for the compound of the general formula (I), and in which Ns represents a 2-nitrobenzenesulfonyl group, can be reacted with thiophenol to yield compounds of the formula (43). This reaction can be carried out in the presence of an organic or an inorganic base, such as cesium carbonate and preferably in a carboxamide based solvent, such as DMF or NMP. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1121] Subsequently, the resulting compounds of formula (43) can be reduced to give aniline derivatives of formula (44). The reduction can be performed analogously to known processes (see for example: (a) Sammond et al; Bioorg. Med. Chem. Lett. 2005, 15, 3519; (b) R. C. Larock, Comprehensive Organic Transformations, VCH, New York, 1989, 411-415). Preferred is the herein described use of platinum and vanadium on activated carbon under an atmosphere of hydrogen gas in a solvent mixture of methanol and THF. (For an overview on heterogeneous catalytic hydrogenation, see: S. Nishimura, Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis, Wiley-VCH, Weinheim, 2001).

##STR00078## ##STR00079##

[1122] The resulting compounds of formula (44) can be converted to macrocyclic compounds of formula (45) (Scheme 6c). This cyclization reaction can be carried out by an intramolecular Palladium-catalyzed CN cross-coupling reaction (see above, e.g. Scheme 1b).

[1123] Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably potassium phosphate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent, preferably a mixture of toluene and NMP, as a solvent. The reactions are preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 130 C. in a microwave oven or in an oil bath.

[1124] Finally, the tert-butoxycarbonyl-group attached to the sulfoximine nitrogen can be cleaved under acidic conditions to give unprotected sulfoximines of formula (45a) (see for example: J. A. Bull, J. Org. Chem. 2015, 80, 6391). Preferred is the herein described use of an acid, preferably trifluoroacetic acid in dichloromethane as a solvent.

[1125] Scheme 6d, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and L are as defined for the compound of general formula (I) according to the present invention, outlines the preparation of N-substituted sulfoximine compounds of the formula (45b) from N-unsubstituted sulfoximine compounds of the formula (45a).

##STR00080##

[1126] N-Unprotected sulfoximines of formula (45a) (R.sup.5H) may be reacted to give N-functionalized derivatives of formula (45b). Formulae (45a) and (45b) both constitute further subsets of the general formula (I). There are multiple methods known for the preparation of N-functionalized sulfoximines by functionalization of the nitrogen of the sulfoximine group; for details see the references listed in context of the conversion of N-unprotected sulfoximines of formula (15a) (R.sup.5H) into N-functionalized derivatives of formula (15b)/Scheme 1c.

[1127] Compounds of the formula (41) can be obtained as outlined in Scheme 6e. In a first step, a thioether derivative of formula (46), in which R.sup.1 and R.sup.2 are as defined for the compound of general formula (I), can be reacted with a carboxylic ester of formula (47), in which R.sup.E represents a C.sub.1-C.sub.4-alkyl group, and

[1128] LG.sup.3 represents a leaving group such as chloro, bromo, iodo, C.sub.1-C.sub.4-alkyl-S(O).sub.2O, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or para-toluenesulfonyloxy-, and in which L represents a C.sub.1-C.sub.5-alkylene group featuring one carbon atom less as compared to the corresponding group L in formula (41), L in turn being as defined for the the compound of general formula (I), in the presence of a base, such as an alkali carbonate, preferably potassium carbonate, in N,N-dimethylformamide (DMF) as a solvent, to give a compound of formula (48). Compounds of the formula (46) are known to the person skilled in the art and described in literature (see e.g. WO 2015/155197).

##STR00081## ##STR00082##

[1129] In a second step, oxidation of a thioether of formula (48) can be used to obtain the corresponding sulfoxide of formula (49). The oxidation can be performed analogously to known processes as outlined above (e.g. as discussed in context of Scheme 3d, conversion of compounds of formula (25) into compounds of formula (26)). Preferred is the herein described use of periodic acid and iron(III)chloride. In a third step, Rhodium-catalyzed imination of a sulfoxide of formula (49) can be used to prepare the corresponding sulfoximines of formula (50) (see for example: a) Bolm et al, Org. Lett. 2004, 6, 1305; b) Bull et al, J. Org. Chem. 2015, 80, 6391). This type of reaction can be also performed with R.sup.5 groups different from tert-butoxycarbonyl-(C(O)OC(CH.sub.3).sub.3) as shown here, R.sup.5 optionally representing a C(O)R.sup.8 or C(O)OR.sup.8 group, in which R.sup.8 is as defined for the compound of general formula (I); more specifically, R.sup.5 may represent a group such as trifluoroacetyl-(C(O)CF.sub.3), or benzyloxycarbonyl-(C(O)OCH.sub.2Ph).

[1130] In a fourth step, an ester of the formula (50) can be reduced using a reducing agent such as lithium aluminium hydride or di-iso-butylaluminiumhydride (DIBAL), in an ether, preferably tetrahydrofuran, as a solvent, to give compound of the formula (41) which can be further elaborated e.g. as shown in Scheme 6a.

##STR00083## ##STR00084##

[1131] Alternatively, macrocycles of the formula (45) can be obtained as outlined in Schemes 6f and 6g.

[1132] In a first step, phenol derivatives of the formula (51), in which R.sup.1 and R.sup.2 are as defined for the compound of general formula (I), can be reacted with a compound of formula (6), in which L is as defined for the compound of general formula (I), and in which LG.sup.1 is a leaving group such as chloro, bromo, iodo, C.sub.1-C.sub.4-alkyl-S(O).sub.2O, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or para-toluenesulfonyloxy-, preferably bromo, to give compounds of formula (52). This reaction can be carried out preferentially in the presence of an inorganic base such as potassium carbonate in a carboxamide solvent such as DMF or NMP. The reaction can be preferably carried out at temperatures ranging from room temperature (=20 C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1133] Phenols of the formula (51) are well known to the person skilled in the art and literature known.

[1134] Compounds of the formula (6) are well known to the person skilled in the art and widely commercially available.

[1135] In a next step, oxidation of thioethers of formula (52) can be used to obtain the corresponding sulfoxides of formula (53). The oxidation can be performed analogously to known processes as outlined above (e.g. as discussed in context of Scheme 3d, conversion of compounds of formula (25) into compounds of formula (26)). Preferred is the herein described use of periodic acid and iron(III)chloride.

[1136] Rhodium-catalyzed imination of sulfoxides of formula (53) can be used to prepare the corresponding sulfoximines of formula (54) (see for example: a) Bolm et al, Org. Lett. 2004, 6, 1305; b) Bull et al, J. Org. Chem. 2015, 80, 6391). This type of reaction can be also performed with R.sup.5 groups different from tert-butoxycarbonyl-(C(O)OC(CH.sub.3).sub.3) as shown here, R.sup.5 optionally representing a C(O)R.sup.8 or C(O)OR.sup.8 group, in which R.sup.8 is as defined for the compound of general formula (I); more specifically, R.sup.5 may represent a group such as trifluoroacetyl-(C(O)CF.sub.3), or benzyloxycarbonyl-(C(O)OCH.sub.2Ph).

[1137] Subsequently, compounds of formula (54) can be reduced to give aniline derivatives of formula (55). This conversion can be accomplished according to known methods, e.g. as discussed in context of Scheme 6b, conversion of compounds of formula (43) into compounds of formula (44). Preferred is the herein described use of platinum and vanadium on activated carbon under an atmosphere of hydrogen gas in a solvent mixture of methanol and THF.

##STR00085## ##STR00086##

[1138] In a next step, anilines of the formula (55) can be reacted with 2-chloro pyrimidines of the formula (56), in which R.sup.3 and R.sup.4 are as defined for the compound of general formula (I), to give compounds of formula (57). Said 2-chloro pyrimidines of formula (56) are well known to the person skilled in the art and are often commercially available, or can be prepared according to known methods, e.g. as discussed in context of Scheme 1a.

[1139] This reaction can be carried out by an intermolecular Palladium-catalyzed CN cross-coupling reaction (for a review on CN cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in Metal-Catalyzed Cross-Coupling Reactions, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably potassium phosphate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent or an ethereal solvent such as 1,4-dioxane, preferably a mixture of toluene and NMP, as a solvent. The reactions can be preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 130 C. in a microwave oven or in an oil bath.

[1140] Said compounds of formula (57) can be further converted to free amino compounds of formula (58). This deprotection reaction can be preferably run using an aqueous solution of hydrazine in an aliphatic alcohol of the formula C.sub.1-C.sub.4-alkyl-OH, preferably MeOH or EtOH, as a solvent, at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. Optionally, a cyclic ether such as tetrahydrofuran, tetrahydropyran or 1,4 dioxane can be added as co-solvent in order to support complete dissolution of the starting material. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1141] Finally, the macrocyclic compounds of formula (45) can be obtained by an intramolecular nucleophilic displacement. The reaction can be carried out by treating amine compounds of the formula (58) in the presence of an organic base such as triethylamine, ethyldiisopropylamine or 2,6-lutidine in polar solvents such as DMSO. The reaction can be preferably carried out at temperatures ranging from 120 C. to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1142] Schemes 7a, b and c outline the synthesis of compounds of the formulae (66), (66a) and (66b), all of them constituting further subsets of the general formula (I) according to the present invention.

[1143] In a first step, compounds of the formula (59), in which L and R.sup.A are as defined for the compound of general formula (I), and which are known to the person skilled in the art and are typically commercially available, can be reacted with phthalimide in the presence of a tertiary phosphine, such as triphenylphosphine, and a dialkyl diazodicarboxylate (known as Mitsunobu reaction, see for example: K. C. K. Swamy et al, Chem. Rev. 2009, 109, 2551), to yield compounds of formula (60). Preferred is the use of diisopropyl azodicarboxylate and triphenylphosphine as coupling reagent in a solvent such as dichloromethane or THF. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1144] In a second step, the tert-butoxycarbonyl group in compounds of formula (60) can be cleaved off to yield compounds of formula (61). This reaction can be carried out in the presence of a Brnstedt acid, preferably trifluoroacetic acid or hydrochloric acid, in dichloromethane. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

##STR00087## ##STR00088##

[1145] In a third step, compounds of the structure (37), in which R.sup.1 and R.sup.2 are as defined for the compound of general formula (I) and the synthesis of which is outlined above in Scheme 5, can be reacted with amines of formula (61) to yield compounds of formula (62). This conversion can be preferably carried out in the presence of an organic base such as triethylamine and in DMSO. The reaction can be preferably carried out at temperatures ranging from 120 C. to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1146] In a fourth step, compounds of formula (62) can be reduced to give aniline derivatives of formula (63). This conversion can be accomplished according to known methods, e.g. as discussed in context of Scheme 6b, conversion of compounds of formula (43) into compounds of formula (44). Preferred is the herein described use of platinum and vanadium on activated carbon under an atmosphere of hydrogen gas in a solvent mixture of methanol and THF.

##STR00089## ##STR00090##

[1147] In a next step, anilines of the formula (63) can be reacted with a 2-chloro pyrimidine of the formula (56) (see also Scheme 6g), to give compounds of formula (64). This coupling reaction can be carried out by an intermolecular Palladium-catalyzed CN cross-coupling reaction (for a review on CN cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in Metal-Catalyzed Cross-Coupling Reactions, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably potassium phosphate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent or an ethereal solvent such as 1,4-dioxane, as a solvent. The reactions can be preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 130 C. in a microwave oven or in an oil bath.

[1148] The resulting compounds of formula (64) can be further converted to compounds of formula (65). This deprotection reaction can be preferably run using an aqueous solution of hydrazine in an aliphatic alcohol of the formula C.sub.1-C.sub.4-alkyl-OH, preferably MeOH or EtOH, as a solvent, at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. Optionally, a cyclic ether such as tetrahydrofuran, tetrahydropyran or 1,4 dioxane can be added as co-solvent in order to support complete dissolution of the starting material. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1149] Subsequently, macrocyclic compounds of formula (66) can be obtained by an intramolecular nucleophilic displacement. The reaction is carried out by treating amine compounds of the formula (65) in the presence of an organic base such as triethylamine, ethyldiisopropylamine or 2,6-lutidine in polar solvents such as DMSO. The reaction can be preferably carried out at temperatures ranging from 120 C. to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1150] Finally, the tert-butoxycarbonyl-group attached to the sulfoximine nitrogen in compounds of formula (66) can be cleaved under acidic conditions to give unprotected sulfoximines of formula (66a) (see for example: J. A. Bull, J. Org. Chem. 2015, 80, 6391). Preferred is the herein described use of an acid, preferably trifluoroacetic acid in dichloromethane as a solvent. Optionally, said unprotected sulfoximines of formula (66a) can be converted into N-substituted sulfoximine compounds of the formula (66b). Formulae (66a) and (66b) both constitute further subsets of the general formula (I). There are multiple methods known for the preparation of N-functionalized sulfoximines by functionalization of the nitrogen of the sulfoximine group; for details see the references listed in context of the conversion of N-unprotected sulfoximines of formula (15a) (R.sup.5H) into N-functionalized derivatives of formula (15b)/Scheme 1c.

##STR00091## ##STR00092##

[1151] Schemes 8a, b and c outline the synthesis of thioether compounds of the formulae (72), (72a) and (72b), all of them constituting further subsets of the general formula (I) according to the present invention.

[1152] As outlined in Scheme 8a, thiol derivatives of formula (67), in which R.sup.3 and R.sup.4 are as defined for the compound of the general formula (I), can be reacted with an alcohol of formula (41) (see also Scheme 6e), in which R.sup.1, R.sup.2 and L are as defined for the compound of the general formula (I), in the presence of a tertiary phosphine, such as triphenylphosphine, and a dialkyl diazodicarboxylate (known as Mitsunobu reaction, see for example: K. C. K. Swamy et al, Chem. Rev. 2009, 109, 2551), to yield compounds of formula (68). Thiol derivatives of formula (67) are known to the person skilled in the art and are commercially available in certain cases. Preferred is the use of diisopropyl azodicarboxylate and triphenylphosphine as coupling reagent in as solvent such as dichloromethane or THF. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

##STR00093## ##STR00094##

[1153] In a second step, compounds of formula (68) can be reacted with 4,4,4,4,5,5,5,5-octamethyl-2,2-bi-1,3,2-dioxaborolane in the presence of a palladium catalyst, preferentially dichlorobis(tricyclohexylphosphine)palladium(II), and an organic or an inorganic base, preferentially potassium acetate, to access compounds of formula (69), in which the two groups R together form a group C(CH.sub.3).sub.2C(CH.sub.3).sub.2). The reaction can be preferably carried out in an ethereal solvent such as THF or 1,4-dioxane at temperatures from temperatures ranging from room temperature (=20 C.) to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. The reaction is preferably completed after 1 to 36 hours of reaction time.

[1154] In a third step, said boronic acid derivatives of formula (69) can be reacted with 2-chloro-5-fluoro-4-iodopyrimidine (CAS #884494-49-9) to give compounds of the formula (70).

[1155] Said reaction can be catalyzed by Pd catalysts, e.g. by Pd(0) catalysts such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh.sub.3).sub.4], tris(dibenzylideneacetone)di-palladium(0) [Pd.sub.2(dba).sub.3], or by Pd(II) catalysts such as dichlorobis(triphenylphosphine)-palladium(II) [Pd(PPh.sub.3).sub.2Cl.sub.2], palladium(II) acetate and triphenylphosphine or by [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride [Pd(dppf)Cl.sub.2].

[1156] The reaction can be preferably carried out in a mixture of a solvent such as 1,2-dimethoxyethane, dioxane, DMF, THF, or isopropanol with water and in the presence of a base such as aqueous potassium carbonate, aqueous sodium bicarbonate or potassium phosphate.

[1157] The reaction can be performed at temperatures ranging from room temperature (=20 C.) to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point using pressure tubes and a microwave oven. The reaction is preferably completed after 1 to 36 hours of reaction time. (review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein).

[1158] As outlined in Scheme 8b, compounds of formula (70) can be reduced to give aniline derivatives of formula (71) analogously to known processes. This conversion can be accomplished according to known methods, e.g. as discussed in context of Scheme 6b, conversion of compounds of formula (43) into compounds of formula (44). Preferred is the herein described use of platinum and vanadium on activated carbon under an atmosphere of hydrogen gas in a solvent mixture of methanol and THF.

##STR00095## ##STR00096##

[1159] The resulting compounds of formula (71) can be converted to macrocyclic compounds of formula (72). This cyclization reaction can be carried out by an intramolecular Palladium-catalyzed CN cross-coupling reaction (for a review on CN cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in Metal-Catalyzed Cross-Coupling Reactions, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably potassium phosphate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent, preferably a mixture of toluene and NMP, as a solvent. The reactions can be preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 130 C. in a microwave oven or in an oil bath.

[1160] Finally, the tert-butoxycarbonyl-group attached to the sulfoximine nitrogen present in compounds of formula (72) can be cleaved under acidic conditions to give unprotected sulfoximines of formula (72a) (see for example: J. A. Bull, J. Org. Chem. 2015, 80, 6391). Preferred is the herein described use of an acid, preferably trifluoroacetic acid in dichloromethane as a solvent. Optionally, said unprotected sulfoximines of formula (66a) can be converted into N-substituted sulfoximine compounds of the formula (72b).

##STR00097##

[1161] Formulae (72a) and (72b) both constitute further subsets of the general formula (I). There are multiple methods known for the preparation of N-functionalized sulfoximines by functionalization of the nitrogen of the sulfoximine group; for details see the references listed in context of the conversion of N-unprotected sulfoximines of formula (15a) (R.sup.5H) into N-functionalized derivatives of formula (15b)/Scheme 1c.

[1162] Schemes 9a, 9b, 9c, 9d and 9e outline an additional synthesis route to compounds of the formula (34a), constituting a subset of formula (34) (in that NR.sup.A as of the formula (34) is NH in formula (34a)), described in context of Scheme 4b.

[1163] In a first step, benzylic alcohols of formula (73), in which R.sup.2 is as defined as for the compound of general formula (I), can be converted into the corresponding thioethers of formula (74) by reaction with a halogenating agent, preferably thionyl chloride, in a solvent such as dichloromethane, followed by reaction with a thiol of formula R.sup.1SH or a salt therof, in which R.sup.1 is as defined for the compound of general formula (I), in a solvent such as acetone. Benzylic alcohols of formula (73) as well as thiols of formula R.sup.1SH, and their salts, are known to the person skilled in the art and are commercially available in many cases.

[1164] In a second step, said thioethers of formula (74) can be reacted with 2-nitrobenzenesulfonyl chloride (NsCl) to give compounds of the formula (75). This reaction can be carried out in the presence of an organic base, preferably pyridine, and, optionally, catalytic amounts of 4-dimethylaminopyridine, in solvents such as dichloromethane. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

##STR00098##

[1165] In a third step, the resulting compounds of formula (75), in which R.sup.1 and R.sup.2 are as defined for the compound of general formula (I), and in which Ns represents a 2-nitrobenzenesulfonyl group, can be reacted with compounds of formula (76), in which R.sup.3, R.sup.4 and L are as defined as for the compound of general formula (I), in the presence of a tertiary phosphine, such as triphenylphosphine, and a dialkyl diazodicarboxylate (known as Mitsunobu reaction, see for example: K. C. K. Swamy et al, Chem. Rev. 2009, 109, 2551), to yield compounds of formula (77). Preferred is the use of diisopropyl azodicarboxylate and triphenylphosphine as coupling reagent in a solvent such as dichloromethane or THF. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time. Compounds of formula (76) can be prepared according to Scheme 9f.

##STR00099##

[1166] In a fourth step, oxidation of thioethers of formula (77) can be used to obtain the corresponding sulfoxides of formula (78). The oxidation can be performed analogously to known processes as outlined above (e.g. as discussed in context of Scheme 3d, conversion of compounds of formula (25) into compounds of formula (26)). Preferred is the herein described use of periodic acid and iron(III)chloride. Rhodium-catalyzed imination of sulfoxides of formula (78) can be used to prepare the corresponding sulfoximines of formula (79) (see for example: a) Bolm et al, Org. Lett. 2004, 6, 1305; b) Bull et al, J. Org. Chem. 2015, 80, 6391). This type of reaction can be also performed with R.sup.5 groups different from tert-butoxycarbonyl-(C(O)OC(CH.sub.3).sub.3) as shown here, R.sup.5 optionally representing a C(O)R.sup.8 or C(O)OR.sup.8 group, in which R.sup.8 is as defined for the compound of general formula (I); more specifically, R.sup.5 may represent a group such as trifluoroacetyl-(C(O)CF.sub.3), or benzyloxycarbonyl-(C(O)OCH.sub.2Ph).

##STR00100##

[1167] In a fifth step, and as outlined in Scheme 6d, compounds of the formula (79), in which R.sup.1, R.sup.2, R.sup.3, R.sup.4 and L are as defined for the compound of the general formula (I), and in which Ns represents a 2-nitrobenzenesulfonyl group, can be reacted with thiophenol to yield compounds of the formula (80). This reaction can be carried out in the presence of an organic or an inorganic base, such as cesium carbonate and preferably in a carboxamide based solvent, such as DMF or NMP. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time. Subsequently, compounds of formula (80) can be reduced to give aniline derivatives of formula (34a). which constitutes a subset of formula (34). This conversion can be accomplished according to known methods, e.g. as discussed in context of Scheme 6b, conversion of compounds of formula (43) into compounds of formula (44). Preferred is the herein described use of platinum and vanadium on activated carbon under an atmosphere of hydrogen gas in methanol as a solvent.

##STR00101##

[1168] Scheme 9e, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and L are as defined for the compound of general formula (I) according to the present invention, outlines preparation of macrocyclic sulfoximines of formulae (35c), (35d) and (35e), representing subsets of formulae (35), (35a) and (35b), respectively, in analogy to the corresponding conversions discussed in the context of Schemes 4b and 4c.

##STR00102## ##STR00103##

[1169] According to Scheme 9f, compounds of formula (31), in which R.sup.3 and R.sup.4 are as defined for the compound of general formula (I) and which are described in context of Scheme 4a, can be reacted with compounds of formula (81), in L is as defined for the compound of general formula (I), and in which PG.sup.1 represents a protective group for a hydroxy group, preferably tert-butyldimethylsilyl-, in the presence of a tertiary phosphine, such as triphenylphosphine, and a dialkyl diazodicarboxylate (known as Mitsunobu reaction, see for example: K. C. K. Swamy et al, Chem. Rev. 2009, 109, 2551), to yield compounds of formula (82). Preferred is the use of diisopropyl azodicarboxylate and triphenylphosphine as coupling reagent in a solvent such as dichloromethane or THF. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20 C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time

[1170] The protective group PG.sup.1 can subsequently be removed using methods known to the person skilled in the art, such as reaction with aqueous hydrochloric acid or tetrabutylammonium fluoride in case PG.sup.1 represents a tert-butyldimethylsilyl-group. Protective groups for a hydroxy group, and methods for their introduction as well for their removal, are well known to the person skilled in the art, see e.g. P. G. M. Wuts, T. W. Green, Protective Groups in Organic Synthesis, 4.sup.th Edition, John Wiley & Sons, Hoboken, USA, 2006.

##STR00104##

[1171] Abbreviations used in the description of the chemistry and in the Examples that follow are:

[1172] br. (broad, .sup.1H NMR signal); CDCl.sub.3 (deuterated chloroform); cHex (cyclohexane); DCE (dichloroethane); d (doublet, .sup.1H NMR signal); DCM (dichloromethane); DIPEA (di-iso-propylethylamine); DMAP (4-N,N-dimethylaminopyridine), DME (1,2-dimethoxyethane), DMF (NN-dimethylformamide); DMSO (dimethyl sulfoxide); ES (electrospray); EtOAc (ethyl acetate); EtOH (ethanol); h (hour(s)); .sup.1H NMR (proton nuclear magnetic resonance spectroscopy); HPLC (High Performance Liquid Chromatography), iPrOH (iso-propanol); m (multiplet, .sup.1H NMR signal); mCPBA (meta-chloroperoxybenzoic acid), MeCN (acetonitrile), MeOH (methanol); min (minute(s)); MS (mass spectrometry); MTBE (methyl tert-butyl ether); NMP (N-Methylpyrrolidin-2-one); NMR (nuclear magnetic resonance); Pd(dppf)Cl.sub.2 ([1,1-bis(diphenylphosphino)ferrocene]dichloro palladium(II) complex with dichloromethane); q (quartet, .sup.1H NMR signal); quin (quintet, .sup.1H NMR signal); rac (racemic); RT (room temperature); s (singlet, .sup.1H NMR signal); sat. aq. (saturated aqueous); SiO.sub.2 (silica gel); t (triplet, .sup.1H NMR signal); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran); UPLC (Ultra-High Performance Liquid Chromatography), UV (ultraviolet), wt-% (percent by weight).

[1173] .sup.1H-NMR Spectra

[1174] .sup.1H-NMR signals are specified with their multiplicity/combined multiplicities as apparent from the spectrum; possible higher-order effects are not considered. Chemical shifts of the signals (6) are specified as ppm (parts per million).

[1175] Chemical Naming:

[1176] Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.

[1177] Salt Stoichiometry:

[1178] In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.

[1179] Unless specified otherwise, suffixes to chemical names or structural formulae such as hydrochloride, trifluoroacetate, sodium salt, or x HCl, x CF.sub.3COOH, x Na.sup.+, for example, are to be understood as not a stoichiometric specification, but solely as a salt form.

[1180] This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition.

[1181] Preparative HPLC Methods:

[1182] Autopurifier: Acidic Conditions

TABLE-US-00001 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1 vol-% HCOOH (99%) B = MeCN Gradient: 0.00-0.50 min 5% B, 25 mL/min 0.51-5.50 min 10-100% B, 70 mL/min 5.51-6.50 min 100% B, 70 mL/min Temperature: RT Solution: max. 250 mg/max. 2.5 mL DMSO or DMF Injection: 1 2.5 ml Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

[1183] Autopurifier: Basic Conditions

TABLE-US-00002 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% vol-% aqueous NH.sub.3 (32%) B = MeCN Gradient: 0.00-0.50 min 5% B, 25 mL/min 0.51-5.50 min 10-100% B, 70 mL/min 5.51-6.50 min 100% B, 70 mL/min Temperature: RT Solution: max. 250 mg/max. 2.5 mL DMSO or DMF Injection: 1 2.5 ml Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

[1184] General Methods for LC-MS Analysis

[1185] Method a:

[1186] Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 m, 502.1 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 C.; DAD scan: 210-400 nm.

[1187] Method b:

[1188] Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 m, 502.1 mm; eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 C.; DAD scan: 210-400 nm.

Example 1

15,19-Difluoro-8-[(methylsulfanyl)methyl]-2,3,4,5-tetrahydro-11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzoxatriazacyclooctadecine

[1189] ##STR00105##

[1190] Preparation of Intermediate 1.1:

2-Chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridine

[1191] ##STR00106##

[1192] A batch with 2-chloro-5-fluoro-4-iodopyridine (1000 mg, 3.88 mmol, APAC Pharmaceutical, LLC), (4-fluoro-2-methoxyphenyl)boronic acid (660 mg, 3.88 mmol, Aldrich Chemical Company Inc.) and tetrakis(triphenylphosphin)palladium(0) (449 mg, 0.38 mmol) in 1,2-dimethoxyethane (10.0 mL) and an aqueous 2 M solution of potassium carbonate (5.8 mL) was degassed using argon. The batch was stirred under an atmosphere of argon for 4 h at 100 C. After cooling, the batch was diluted with ethyl acetate and THF and washed with a saturated aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (hexane to hexane/ethyl acetate 50%) to give the desired title compound (947 mg, 3.70 mmol).

[1193] .sup.1H NMR (400 MHz, CDCl.sub.3, 295 K) /ppm=8.27 (m, 1H), 7.33 (m, 1H), 7.24 (m, 1H), 6.75 (m, 2H), 3.83 (s, 3H).

[1194] Preparation of Intermediate 1.2:

5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-amine

[1195] ##STR00107##

[1196] A solution of lithium bis(trimethylsilyl)amide in THF (1M, 20.5 mL, 20.5 mmol, Aldrich Chemical Company Inc.) was added to a mixture of 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridine (2.50 g, 9.78 mmol, see Intermediate 1.1), tris(dibenzylideneacetone)dipalladium (0) (0.18 g, 0.20 mmol, Aldrich Chemical Company Inc.) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (0.19 g, 0.39 mmol, Aldrich Chemical Company Inc.) in THF (16.3 mL) under an atmosphere of argon at room temperature. The mixture was stirred at 60 C. for 6 h. The mixture was cooled to 40 C. and water (10 ml) was added. The mixture was slowly warmed to room temperature under stirring, solid sodium chloride was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 60%) to give the desired title compound (2.04 g, 8.64 mmol).

[1197] .sup.1H NMR (400 MHz, CDCl.sub.3, 295 K) /ppm=7.95 (1H), 7.20 (1H), 6.72 (2H), 6.46 (1H), 4.33 (2H), 3.61 (3H).

[1198] Preparation of Intermediate 1.3:

2-(2-Amino-5-fluoropyridin-4-yl)-5-fluorophenol

[1199] ##STR00108##

[1200] A solution of boron tribromide in DCM (1M, 47.1 mL, 47.1 mmol, Aldrich Chemical Company Inc.) was added dropwise to a stirred solution of 5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-amine (2.00 g, 8.47 mmol) in DCM (205 mL) at 0 C. The mixture was slowly warmed to room temperature while stirring overnight. The mixture was cautiously diluted with an aqueous solution of sodium bicarbonate under stirring at 0 C. and stirred at room temperature for 1 h. A saturated aqueous solution of sodium chloride was added and the mixture was extracted with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated to give the crude title compound (1.92 g) that was used without further purification.

[1201] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=10.21 (1H), 7.84 (1H), 7.19 (1H), 6.71 (2H), 6.39 (1H), 5.80 (2H).

[1202] Preparation of Intermediate 1.4:

2-{3-[2-(2-Amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]propyl}-1H-isoindol-1,3(2H)-dione

[1203] ##STR00109##

[1204] A suspension of 2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenol (700 mg, 3.15 mmol), 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione (1.01 g, 3.78 mmol) and potassium carbonate (870 mg, 6.30 mmol) in MeCN (14 mL) in a sealed tube was heated to 80 C. and stirred for 16 h. The mixture was cooled to room temperature and the reaction was stopped by the addition of water (20 mL). The mixture was extracted with ethyl acetate (320 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered and concentrated to obtain the title compound (1.3 g, 90% pure) which was used without further purification in the next step.

[1205] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.94-2.00 (2H), 3.63-3.70 (2H), 4.04-4.11 (2H), 5.81 (2H), 6.39 (1H), 6.83-6.92 (1H), 6.96-7.04 (1H), 7.28 (1H), 7.77-7.92 (5H).

[1206] Preparation of Intermediate 1.5:

(2,6-Dichloropyridin-4-yl)methanol

[1207] ##STR00110##

[1208] To a stirred solution 2,6-dichloroisonicotinic acid (10.0 g, 52.1 mmol) in THF (300 mL) at 0 C. was added a solution of sulfanediyldimethane-borane (1:1) (16.0 g, 210.5 mmol) in THF. The mixture was allowed to react at room temperature overnight. Then, MeOH (22 mL) was cautiously added to the stirred mixture while cooling with an ice bath. The reaction mixture was diluted with ethyl acetate (300 mL), washed with an aqueous sodium hydroxide solution (1N, 100 mL) and saturated aqueous sodium chloride solution. The organic layer was concentrated and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate=7:1 to 3:1) to give the desired title compound (8.3 g, 46.6 mmol).

[1209] .sup.1H NMR (300 MHz, CDCl.sub.3, 295 K) /ppm=7.25 (2H), 4.72 (2H), 2.24 (1H).

[1210] Preparation of Intermediate 1.6:

(2,6-Dichloropyridin-4-yl)methyl methanesulfonate

[1211] ##STR00111##

[1212] (2,6-Dichloropyridin-4-yl)methanol (1.0 g, 5.62 mmol) was dissolved in DCM (20 mL) and triethyl amine (1.0 g, 9.88 mmol) was added. The resulting mixture was cooled to 0 C. and methanesulfonyl chloride (0.9 g, 7.89 mmol) was added. The mixture was stirred at room temperature for 1 h. By adding an aqueous hydrogen chloride solution (1N), the pH value of the mixture was adjusted to 3, before it was extracted three times with ethyl acetate. The combined organic layers were concentrated to give the crude title compound (1.4 g) that was used without further purification.

[1213] Preparation of Intermediate 1.7:

2,6-Dichloro-4-[(methylsulfanyl)methyl]pyridine

[1214] ##STR00112##

[1215] (2,6-Dichloropyridin-4-yl)methyl methanesulfonate (1.40 g, 5.47 mmol) was dissolved in THF (20 mL) and a mixture of sodium thiomethoxide and sodium hydroxide (wt 1/1, 0.70 g, 5 mmol, supplied by Shanghai DEMO Medical Tech Co., Ltd) was added. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (10 mL) and extracted three times with ethyl acetate. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate=6:1 to 3:1) to give the desired product (0.54 g, 2.60 mmol).

[1216] .sup.1H NMR (300 MHz, CDCl.sub.3, 295 K) /ppm=7.18 (2H), 3.55 (2H), 1.98 (3H).

[1217] Preparation of Intermediate 1.8:

2-(3-{2-[2-({6-Chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}amino)-5-fluoropyridin-4-yl]-5-fluorophenoxy}propyl)-1H-isoindol-1,3(2H)-dione

[1218] ##STR00113##

[1219] To a degassed suspension of 2-{3-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]propyl}-1H-isoindol-1,3(2H)-dione (435 mg, 90% pure, 956 mol; see Intermediate 1.4), 2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine (199 mg, 956 mol), potassium phosphate (1.01 g, 4.78 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (91.2 mg, 191 mol) in toluene (8.7 mL) and NMP (0.87 mL) was added chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (158 mg, 191 mol) and the mixture was heated to 130 C. overnight. Additional 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (46 mg, 95 mol) and chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (79 mg, 95 mol) was added and the mixture was stirred for an additional 2 h at 130 C. The mixture was cooled to room temperature and stopped by the addition of water (50 mL) and extracted with ethyl acetate (350 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, filtered (Whatman-filter) and concentrated. The residue was redissolved in diethylether and the solution was washed with brine, dried (Whatman filter) and concentrated. The organic layer was dried (Whatman filter) and concentrated. The crude product was combined with a second reaction batch carried out analogously as described above. The two reaction batches were combined and purified by flash column chromatography (hexanes/ethyl acetate to ethyl acetate/MeOH) to yield the title compound (750 mg, 80% pure), which was contaminated by catalyst impurities and used without further purification in the next step.

[1220] Preparation of Intermediate 1.9:

4-[2-(3-Aminopropoxy)-4-fluorophenyl]-N-{6-chlor-4-[(methylsulfanyl)methyl]pyridin-2-yl}-5-fluoropyridin-2-amine

[1221] ##STR00114##

[1222] To a suspension of 2-(3-{2-[2-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}amino)-5-fluoropyridin-4-yl]-5-fluorophenoxy}propyl)-1H-isoindol-1,3(2H)-dione (400 mg, 80% pure, 0.54 mmol) in EtOH (20 mL) was added an aqueous solution of hydrazine (35 wt-%, 290 l, 3.2 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to 5 C., the precipitate was filtered off and the filtrate was concentrated. Purification by flash column chromatography on silica gel (DCM/MeOH) yielded the title compound (116 mg, 0.23 mmol).

[1223] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.65-1.80 (2H), 2.01 (3H), 2.58 (2H), 3.24-3.53 (2H), 3.68 (2H), 4.06-4.15 (2H), 6.89-6.98 (2H), 7.05-7.16 (1H), 7.35 (1H), 7.54 (1H), 7.72-7.90 (2H), 8.03-8.13 (1H), 8.27 (1H), 10.16 (1H).

Example 1

Preparation of the End Product

[1224] To a degassed suspension of 4-[2-(3-aminopropoxy)-4-fluorophenyl]-N-{6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}-5-fluoropyridin-2-amine (60 mg, 0.133 mmol), potassium phosphate (141 mg, 0.665 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (12.7 mg, 27 mol) in toluene (9.9 mL) and NMP (1.2 mL) was added chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (22 mg, 27 mol) and the mixture was heated in a sealed tube to 130 C. overnight. Additional 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (12.7 mg, 27 mol) and chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (22 mg, 27 mol) was added and the mixture was heated to 130 C. over night. The mixture was diluted with saturated aqueous sodium chloride solution (60 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (Whatman filter) and concentrated. The crude product was combined with a second reaction batch carried out analogously as described above, but with 50 mg (0.111 mmol) of 4-[2-(3-aminopropoxy)-4-fluorophenyl]-N-{6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}-5-fluoropyridin-2-amine and reaction at 110 C. Sequential purification by flash column chromatography on silica gel (hexanes/ethyl acetate) and preparative HPLC (autopurifier: acidic conditions) yielded the title compound (5.5 mg, 0.01 mmol).

[1225] 1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.81-1.91 (2H), 2.00 (3H), 3.43 (4H), 4.04-4.13 (2H), 5.83-5.88 (1H), 6.05-6.10 (1H), 6.73-6.81 (1H), 6.83-6.92 (1H), 7.05 (1H), 7.54 (1H), 8.24 (1H), 8.91 (1H), 9.24 (1H).

Example 2

(rac)-Benzyl[{[16,20-difluoro-3,4,5,6-tetrahydro-2H,12H-11,7-(azeno)-13,17-(metheno)-1,6,12,14-benzoxatriazacyclononadecin-9-yl]methyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1226] ##STR00115##

[1227] Preparation of Intermediate 2.1:

(rac)-2,6-Dichloro-4-[(methylsulfinyl)methyl]pyridine

[1228] ##STR00116##

[1229] Iron(III)chloride (0.11 g, 0.7 mmol) was added to a mixture of 2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine (5.00 g, 24.0 mmol; see Intermediate 1.7) in acetonitrile (57 mL) and the batch was stirred at room temperature for 10 minutes. The batch was cooled to 0 C. and periodic acid (5.86 g, 25.7 mmol) was added under stirring in one portion. After 90 min at 0 C., the mixture was added to a stirred solution of sodium thiosulfate pentahydrate (33.4 g, 134.5 mmol) in ice water (306 mL). The batch was saturated with solid sodium chloride and extracted twice with THF. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate) to give the desired title compound (4.83 g, 21.6 mmol).

[1230] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=4.01 (d, 1H), 4.25 (d, 1H), 7.51 (s, 2H).

[1231] Preparation of Intermediate 2.2:

(rac)-Benzyl{[(2,6-dichloropyridin-4-yl)methyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1232] ##STR00117##

[1233] To a suspension of (rac)-2,6-dichloro-4-[(methylsulfinyl)methyl]pyridine (1000 mg, 4.46 mmol), benzyl carbamate (1349 mg, 8.92 mmol), magnesium oxide (719 mg, 17.85 mmol) and rhodium(II) acetate dimer (49 mg, 0.11 mmol) in DCM (44 mL) was added iodobenzene diacetate (2.16 g, 6.69 mmol) at room temperature. The batch was stirred for 18 h at room temperature. The volume of the reaction mixture was reduced to about 10 ml and the mixture was purified by column chromatography on silica gel (hexane/ethyl acetate 0 to 75%) to give the desired title compound (960 mg, 2.6 mmol).

[1234] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=3.32 (s, 3H), 5.02 (m, 4H), 7.22-7.49 (m, 5H), 7.59 (s, 2H).

[1235] Preparation of Intermediate 2.3:

2-{4-[2-(2-Amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]butyl}-1H-isoindole-1,3(2H)-dione

[1236] ##STR00118##

[1237] A suspension of 2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenol (500 mg, 2.25 mmol; see Intermediate 1.3), 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione (762 mg, 2.70 mmol) and potassium carbonate (622 mg, 4.50 mmol) in MeCN (14 mL) in a sealed tube was heated to 80 C. and stirred for 16 h. The mixture was cooled to room temperature and the reaction was stopped by the addition of water (20 mL). The mixture was extracted with ethyl acetate (320 mL). The combined organic layers were washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated to obtain the crude product (1095 mg) which was used without further purification.

[1238] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) =1.59-1.67 (4H), 3.51-3.67 (2H), 4.03 (2H), 5.81 (2H), 6.34 (1H), 6.85 (1H), 7.02 (1H), 7.26 (1H), 7.78-7.89 (m, 5H).

[1239] Preparation of Intermediate 2.4:

4-[2-(4-Aminobutoxy)-4-fluorophenyl]-5-fluoropyridin-2-amine

[1240] ##STR00119##

[1241] To a suspension of 2-{4-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]butyl}-1H-isoindole-1,3(2H)-dione (2190 mg, 85% pure, 4.40 mmol) in EtOH (93 mL) was added a solution of hydrazine in water (35 wt-%, 2.4 mL, 26.4 mmol) and the mixture was heated to reflux for 150 min. The mixture was cooled to 5 C., the precipitate was filtered off and the filtrate was concentrated. Purification by flash column chromatography on silica gel (hexane/ethyl acetate 1:4 to 0:1 followed by ethyl acetate/methanol 4:1) yielded the title compound (1070 mg, 3.57 mmol).

[1242] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.30-1.45 (4H), 1.58-1.67 (2H), 3.96-4.05 (2H), 5.85 (2H), 6.36 (1H), 6.85 (1H), 7.02 (1H), 7.04 (1H), 7.26 (1H), 7.86 (1H).

[1243] Preparation of Intermediate 2.5:

(rac)-Benzyl[{[2-({4-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]butyl}amino)-6-chloropyridin-4-yl]methyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1244] ##STR00120##

[1245] N,N-Diisopropylethylamine (0.36 mL, 2.05 mmol) was added to a suspension of 4-[2-(4-aminobutoxy)-4-fluorophenyl]-5-fluoropyridin-2-amine (200 mg, 0.68 mmol) and benzyl {[(2,6-dichloropyridin-4-yl)methyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (509 mg; see Intermediate 2.2) in NMP (26.8 mL) and the mixture was stirred at 130 C. for 90 min After cooling, the mixture was diluted with water and extracted with ethyl acetate (350 mL). The combined organic phases were washed with aqueous saturated sodium chloride solution, dried (Whatman filter) and concentrated. The residue was purified by column chromatography on silica gel (hexane to ethyl acetate) to give the desired title compound (92 mg, 0.11 mmol).

[1246] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.51-1.62 (2H), 1.63-1.75 (2H), 3.17 (2H), 3.25 (3H), 4.02 (2H), 4.75 (2H), 5.03 (2H), 5.83 (2H), 6.36 (1H), 6.42-6.49 (1H), 6.49-6.57 (1H), 6.85 (1H), 7.03 (1H), 7.16-7.23 (1H), 7.19-7.38 (6H), 7.75-7.95 (1H).

Example 2

Preparation of the End Product

[1247] To a degassed suspension of (rac)-benzyl [{[2-({4-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]butyl}amino)-6-chloropyridin-4-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (270 mg, 0.43 mmol), potassium phosphate (455 mg, 2.14 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (41 mg, 0.09 mmol) in toluene (44 mL) and NMP (6 mL) was added chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (71 mg, 0.09 mmol) and the mixture was heated in a sealed tube to 130 C. for 6 h. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (360 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (Whatman filter) and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 1:4 to 0:1) to give the desired product (26 mg, 0.04 mmol).

[1248] 1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.69-1.90 (4H), 3.13-3.30 (5H), 4.08-4.22 (2H), 4.50-4.76 (2H), 4.90-5.17 (2H), 5.89-6.01 (1H), 6.01-6.20 (1H), 6.78-6.95 (2H), 7.01-7.14 (1H), 7.27-7.48 (6H), 8.17-8.43 (2H), 9.30-9.60 (1H).

Example 3

[1249] (rac)-16,20-Difluoro-9-[(S-methylsulfonimidoyl)methyl]-3,4,5,6-tetrahydro-2H,12H-11,7-(azeno)-13,17-(metheno)-1,6,12,14-benzoxatriazacyclononadecine

##STR00121##

[1250] To a degassed suspension of (rac)-benzyl [{[2-({4-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]butyl}amino)-6-chloropyridin-4-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (Intermediate 2.5, 90 mg, 0.14 mmol), potassium phosphate (152 mg, 0.714 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (13.6 mg, 0.029 mmol) in toluene (14.8 mL) and NMP (1.9 mL) was added chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (23 mg, 0.029 mmol) and the mixture was heated in a sealed tube to 130 C. overnight. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (360 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (Whatman filter) and concentrated. The residue was sequentially purified by column chromatography on silica gel (hexane/ethyl acetate, then ethyl acetate/MeOH), followed by preparative HPLC to give the desired title compound (1.2 mg, 2.6 mol).

[1251] HPLC Purification:

[1252] Instrument: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO,

[1253] DAD 2996, ELSD 2424, SQD; Column: YMC Triart C18 5 m 10030 mm;

[1254] Eluent A: water+0.1 vol-% formic acid (99%); Eluent B: acetonitrile;

[1255] Gradient: 0.00-0.50 min 40% B (25.fwdarw.70 mL/min), 0.51-5.50 min 40-60% B (70 mL/min);

[1256] Detection: DAD scan, 210-400 nm.

[1257] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295K) /ppm=1.72-1.88 (4H), 2.87 (3H), 3.15-3.26 (2H), 3.59 (1H), 4.03-4.20 (4H), 5.91 (1H), 6.07 (1H), 6.76 (1H), 6.82-6.90 (1H), 7.09 (1H), 7.31 (1H), 8.26 (1H), 8.33 (1H), 9.33 (1H).

Example 4

2,18-Difluoro-9-[(methylsulfanyl)methyl]-13,14,15,16-tetrahydro-6H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclooctadecine

[1258] ##STR00122##

[1259] Preparation of Intermediate 4.1

2-(2-Amino-5-fluoropyridin-4-yl)-5-fluorophenyl trifluormethansulfonate

[1260] ##STR00123##

[1261] To a solution of 2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenol (500 mg, 2.25 mmol; see Intermediate 1.3) in DCM (22 mL) was sequentially added triethylamine (380 l, 2.7 mmol) and N-phenyl trifluoromethanesulfonimide (1.21 g, 3.38 mmol) and the mixture was heated to reflux for 2 h. The mixture was cooled to room temperature and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate) to yield the title compound. Such material was contaminated by N-phenyl trifluoromethanesulfonimide byproducts and was used without further purification.

[1262] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295K) /ppm=6.10 (2H), 6.46 (1H), 7.56 (1H), 7.67-7.78 (2H), 8.01 (1H).

[1263] Preparation of Intermediate 4.2

4-[2-(2-Amino-5-fluoropyridin-4-yl)-5-fluorophenyl]but-3-yn-1-ol

[1264] ##STR00124##

[1265] To a mixture of crude 2-(2-Amino-5-fluoropyridin-4-yl)-5-fluorophenyl-trifluormethansulfonate (1.24 g), but-3-yn-1-ol (294 mg, 4.20 mmol), triethylamine (980 l, 7.0 mmol) and copper(I) iodide (133 mg, 700 mol) in DMF was added bis(triphenylphosphino)palladium(II) chloride (246 mg, 350 mol) and the mixture was heated to 110 C. overnight. The mixture was cooled to room temperature, filtered over a pad of Celite and concentrated. The residue was dissolved in ethyl acetate (250 mL) and water (100 mL) and the layers were separated. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried (Whatman filter) and concentrated. The crude product was purified by column chromatography on silica gel, hexanes/ethyl acetate to ethyl acetate/MeOH) to yield the title compound (473 mg, 1.55 mmol).

[1266] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295K) /ppm=2.42 (2H), 3.42 (2H), 4.80-4.87 (1H), 5.92 (2H), 6.44 (1H), 7.28-7.33 (1H), 7.35-7.44 (2H), 7.92 (1H).

[1267] Preparation of Intermediate 4.3

4-[2-(2-Amino-5-fluoropyridin-4-yl)-5-fluorophenyl]butan-1-ol

[1268] ##STR00125##

[1269] To a solution of 4-[2-(2-Amino-5-fluoropyridin-4-yl)-5-fluorophenyl]but-3-yn-1-ol (473 mg, 1.72 mmol) in MeOH (15 mL) in an autoclave was added palladium on charcoal (91.7 mg, 10 wt-% Pd, 86.2 mol) and the mixture was reacted with an atmosphere of hydrogen (20 bar H.sub.2) for 3 h. The hydrogen atmosphere was replaced by argon and reaction control indicated incomplete conversion. Additional palladium on charcoal (120 mg, 10 wt-% Pd, 113 mol) was added and the mixture was hydrogenated (20 bar H.sub.2) for an additional 2.5 h. The hydrogen atmosphere was replaced by argon, the mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated to yield the title compound (432 mg, 1.40 mmol).

[1270] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295K) /ppm=1.24-1.34 (3H), 1.45 (2H), 3.24-3.31 (2H), 4.33 (1H), 5.94 (2H), 6.29 (1H), 7.09-7.16 (1H), 7.18-7.28 (2H), 7.92 (1H). Two protons are overlayed by residual DMSO.

[1271] Preparation of Intermediate 4.4

4-{2-[4-({6-Chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)butyl]-4-fluorophenyl}-5-fluoropyridin-2-amine

[1272] ##STR00126##

[1273] To a solution of 4-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenyl]butan-1-ol (382 mg, 1.37 mmol) in THF (10 mL) at 0 C. was added sodium hydride (82.3 mg, 60 wt-% in mineral oil, 2.06 mmol). The mixture was allowed to warm to room temperature and stirred for 30 min Then, 2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine (428 mg, 2.06 mmol, see Intermediate 1.7) was added and the mixture was heated to 90 C. for 2 h and subsequently cooled to room temperature. The mixture was carefully concentrated and the residue was dissolved in ethyl acetate (50 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (350 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried by filtering over a Whatman filter and concentrated. The crude product was purified by column chromatography on silica gel (hexanes/ethyl acetate) to yield the desired title compound (304 mg, 0.64 mmol).

[1274] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295K) /ppm=1.52-1.62 (4H), 1.93-1.93 (1H), 1.95 (3H), 3.65 (2H), 4.08-4.16 (2H), 5.93 (2H), 6.31 (1H), 6.68 (1H), 7.02 (1H), 7.09-7.15 (1H), 7.20-7.28 (2H), 7.89 (1H). Two protons are overlayed by residual DMSO.

Example 4

Preparation of the End Product

[1275] To a solution of 4-{2-[4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)butyl]-4-fluorophenyl}-5-fluoropyridin-2-amine (254 mg, 565 mol) in toluene (57 mL) and NMP (6.9 mL) was sequentially added potassium phosphate (599 mg, 2.82 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (26.9 mg, 56.5 mol) and chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (46.7 mg, 56.5 mol). The suspension was degassed and heated to 130 C. overnight. The mixture was allowed to cool to room temperature and filtered. The filtrate was partitioned between ethyl acetate (170 mL) and saturated aqueous sodium chloride solution (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2170 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (Whatman filter) and concentrated. The residue was combined with a reaction batch carried out analogously as described above but with 50 mg of 4-{2-[4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)butyl]-4-fluorophenyl}-5-fluoropyridin-2-amine (111 mol). The residue was partitioned between diethyl ether and saturated aqueous sodium chloride solution, the layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were dried and concentrated. The residue was dissolved in DMSO (8 mL) and water (1 mL). The resulting suspension was filtered and the filtrate was subjected to preparative HPLC to yield the title compound (82 mg, 0.19 mmol).

[1276] HPLC Purification:

[1277] Instrument: Pump: LABOMATIC HD-5000; Manual injection valve: Rheodyne 3725i038; Detector: Knauer AZURA UVD 2.15; Collector: LABOMATIC LABOCOL Vario-4000; Column: Chromatorex RP C-18 10 m, 12530 mm;

[1278] Eluent A: water+0.1 vol-% formic acid (99%); Eluent B: acetonitrile;

[1279] Gradient: 0.00-0.50 min 65% B (60 mL/min), 0.50-10.00 min 65-100% B (60 mL/min), 10.00-10.10 min 65-100% B (60 mL/min), 10.10-12.00 min 100% B (60 mL/min);

[1280] Detection: UV 269 nm.

[1281] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.81 (4H), 1.98 (3H), 2.61-2.86 (2H), 3.56 (2H), 3.91-4.89 (2H), 6.16 (1H), 6.41 (1H), 7.12 (1H), 7.29-7.43 (2H), 7.54 (1H), 8.32 (1H), 9.70 (1H).

Example 5

(rac)-2,18-Difluoro-9-[(methylsulfinyl)methyl]-13,14,15,16-tetrahydro-6H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclooctadecine

[1282] ##STR00127##

[1283] To a solution of 2,18-difluoro-9-[(methylsulfanyl)methyl]-13,14,15,16-tetrahydro-6H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclooctadecine (60.0 mg, 145 mol, see Example 4) in MeCN (4.4 mL) at 0 C. was added iron(III) chloride (2.35 mg, 14.5 mol) and the mixture was stirred for 10 min Then, periodic acid (99.2 mg, 435 mol) was added and the mixture was stirred for 2 h. Additional iron(III) chloride (2.35 mg, 14.5 mol) and periodic acid (99.2 mg, 435 mol) was added and the mixture was stirred for 1 h. The reaction was stopped by pouring onto ice and saturated aqueous sodium thiosulfate (15 mL) was added. The mixture was stirred for 10 min and the product was extracted with ethyl acetate (235 mL). The combined organic layers were washed with a saturated solution of aqueous sodium chloride, dried (Whatman filter) and concentrated. The residue was combined with the crude material of a second reaction batch carried out analogously as described above, but with 20 mg of 2,18-difluoro-9-[(methylsulfanyl)methyl]-13,14,15,16-tetrahydro-6H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclooctadecine (48 mol). The crude material was purified by preparative HPLC to yield the title compound (17.2 mg, 0.04 mmol).

[1284] HPLC Purification:

[1285] Instrument: Pump: LABOMATIC HD-5000; Manual injection valve: Rheodyne 3725i038; Detector: Knauer AZURA UVD 2.15; Collector: LABOMATIC LABOCOL Vario-4000; Column: Chromatorex

[1286] RP C-18 10 m, 12530 mm;

[1287] Eluent A: water+0.1 vol-% formic acid (99%); Eluent B: acetonitrile;

[1288] Gradient: 0.00-1.00 min 30% B (60 mL/min), 1.00-10.00 min 35-70% B (60 mL/min), 10.00-10.10 min 70-100% B (60 mL/min), 10.10-12.53 min 100% B (60 mL/min);

[1289] Detection: UV 269 nm.

[1290] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.82 (4H), 2.55 (3H), 2.65-2.81 (2H), 3.84 (1H), 4.03 (1H), 4.09-5.05 (2H), 6.17 (1H), 6.39 (1H), 7.13 (1H), 7.31-7.45 (2H), 7.56 (1H), 8.34 (1H), 9.80 (1H)

Example 6

(rac)-tert-butyl[{[16,20-difluoro-6-methyl-3,4,5,6-tetrahydro-2H,12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzoxatriazacyclononadecin-9-yl]methyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1291] ##STR00128##

[1292] Preparation of Intermediate 6.1:

2-Chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine

[1293] ##STR00129##

[1294] A batch with 2,4-dichloro-5-fluoropyrimidine (200 mg; 1.20 mmol; Aldrich Chemical Company Inc.), (4-fluoro-2-methoxyphenyl)boronic acid (224 mg; 1.31 mmol; Aldrich Chemical Company Inc.) and tetrakis(triphenylphosphin)palladium(0) (138 mg; 0.12 mmol) in 1,2-dimethoxyethane (3.6 ml) and an aqueous 2M solution of potassium carbonate (1.8 ml) was degassed using argon. The batch was stirred under an atmosphere of argon for 16 hours at 90 C. After cooling the batch was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (hexane/ethyl acetate 1:1) to give the desired title compound (106 mg; 0.41 mmol).

[1295] .sup.1H NMR (400 MHz, CDCl.sub.3, 295 K) /ppm=8.47 (1H), 7.51 (1H), 6.82 (1H), 6.73 (1H), 3.85 (3H).

[1296] Preparation of Intermediate 6.2:

2-(2-Chloro-5-fluoropyrimidin-4-yl)-5-fluorophenol

[1297] ##STR00130##

[1298] A solution of boron tribromide in DCM (1M; 43.3 mL; 43.3 mmol; Aldrich Chemical Company Inc.) was added dropwise to a stirred solution of 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (2.00 g; 7.79 mmol) in DCM (189 mL) at 0 C. The mixture was slowly warmed to room temperature while stirring overnight. The mixture was cautiously diluted with an aqueous solution of sodium bicarbonate under stirring at 0 C. and stirred at room temperature for 1 hour. Solid sodium chloride was added and the mixture filtered using a Whatman filter. The organic layer was concentrated to give the crude title compound (1.85 g) that was used without further purification.

[1299] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=10.80 (1H), 8.90 (1H), 7.50 (1H), 6.83 (1H), 6.78 (1H)

[1300] Preparation of Intermediate 6.3:

1-Fluoro-3-[(methylsulfanyl)methyl]-5-nitrobenzene

[1301] ##STR00131##

[1302] Intermediate 6.3 was prepared as described in WO 2013/037894 (Intermediate 9.1, page 94)

[1303] .sup.1H NMR (400 MHz, CDCl.sub.3, 295 K) /ppm=8.00 (m, 1H), 7.82 (m, 1H), 7.44 (m, 1H), 3.74 (s, 2H), 2.03 (s, 3H).

[1304] Preparation of Intermediate 6.4:

(rac)-1-Fluoro-3-[(methylsulfinyl)methyl]-5-nitrobenzene

[1305] ##STR00132##

[1306] Intermediate 6.4 was prepared as described in WO 2013/037894 (Intermediate 9.2, page 94)

[1307] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=8.06 (m, 2H), 7.63 (m, 1H), 4.32 (d, 1H), 4.08 (d, 1H), 2.45 (s, 3H).

[1308] Preparation of Intermediate 6.5:

(rac)-tert-butyl[(3-fluoro-5-nitrobenzyl)(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1309] ##STR00133##

[1310] To a suspension of (rac)-1-fluoro-3-[(methylsulfinyl)methyl]-5-nitrobenzene (834 mg; 3.84 mmol), tert-butyl carbamate (675 mg; 5.76 mmol), magnesium oxide (619 mg; 15.36 mmol) and rhodium(II)-acetate dimer (85 mg; 0.19 mmol) in DCM (38 mL) was added iodobenzene diacetate (1855 mg; 5.76 mmol) at room temperature. The batch was stirred for 16 hours at room temperature and additional 2 hours at 40 C. After cooling, the batch was filtered and concentrated. The residue was purified by chromatography (hexane to hexane/ethyl acetate 45%) to give the desired title compound (998 mg; 3.00 mmol).

[1311] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.29-1.42 (9H), 3.17-3.25 (3H), 5.04-5.13 (2H), 7.75 (1H), 8.18-8.23 (2H).

[1312] Preparation of Intermediate 6.6:

(rac)-tert-butyl[{3-[(4-hydroxybutyl)(methyl)amino]-5-nitrobenzyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1313] ##STR00134##

[1314] A mixture of (rac)-tert-butyl [(3-fluoro-5-nitrobenzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (200 mg; 0.60 mmol) and 4-(methylamino)butan-1-ol (186 mg; 1.81 mmol) in NMP (2.0 mL) was stirred at 100 C. overnight. The mixture was stirred for additional 2 h at 110 C. After cooling, the mixture was diluted with ethyl acetate and washed twice with water and once with an aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 0:1) followed by preparative HPLC to give the title compound (95 mg; 0.23 mmol).

[1315] HPLC Purification:

[1316] Instrument: Pump: LABOMATIC HD-5000; Manual injection valve: Rheodyne 3725i038; Detector: Knauer AZURA UVD 2.15; Collector: LABOMATIC LABOCOL Vario-4000; Column: Chromatorex RP C-18 10 m, 12530 mm;

[1317] Eluent A: water+0.1 vol-% formic acid (99%); Eluent B: acetonitrile;

[1318] Gradient: 0.00-0.50 min 15% B (150 mL/min), 0.50-6.00 min 15-55% B (150 mL/min), 6.00-6.10 min 55-100% B (150 mL/min), 6.10-8.00 min 100% B (150 mL/min).

[1319] Detection: UV 254 nm.

[1320] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.37-1.59 (13H), 2.98 (3H), 3.11-3.18 (3H), 3.36-3.48 (4H), 4.44 (1H), 4.87-4.98 (2H), 7.17 (1H), 7.39 (1H), 7.47 (1H).

[1321] Preparation of Intermediate 6.7:

(rac)-tert-butyl N-[[3-[4-[2-(2-chloro-5-fluoro-pyrimidin-4-yl)-5-fluoro-phenoxy]butyl-methyl-amino]-5-nitro-phenyl]methyl-methyl-oxo-.SUP.6.-sulfanylidene]carbamate

[1322] ##STR00135##

[1323] A solution of diisopropyl azodicarboxylate (16 mg; 79 mol) in DCM (0.2 mL) was added dropwise to a mixture of (rac)-tert-butyl [{3-[(4-hydroxybutyl)(methyl)amino]-5-nitrobenzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (30 mg; 72 mol), 2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenol (19 mg; 79 mol) and triphenylphosphine (21 mg; 79 mol) in DCM (0.3 mL) at 0 C. and the batch was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (26 mg; 40 mol).

[1324] HPLC Purification:

[1325] Instrument: Pump: LABOMATIC HD-5000; Manual injection valve: Rheodyne 3725i038; Detector: Knauer AZURA UVD 2.15; Collector: LABOMATIC LABOCOL Vario-4000; Column: Chromatorex RP C-18 10 m, 12530 mm;

[1326] Eluent A: water+0.1 vol-% formic acid (99%); Eluent B: acetonitrile;

[1327] Gradient: 0.00-0.50 min 65% B (150 mL/min), 0.50-6.00 min 65-100% B (150 mL/min), 6.00-8.00 min 100% B (150 mL/min);

[1328] Detection: UV 254 nm.

[1329] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.37 (9H), 1.51-1.71 (4H), 2.95 (3H), 3.12 (3H), 3.36-3.45 (2H), 4.11 (2H), 4.85-4.96 (2H), 6.97 (1H), 7.12-7.18 (2H), 7.36 (1H), 7.49 (1H), 7.50-7.55 (1H), 8.80 (1H).

[1330] Preparation of Intermediate 6.8:

(rac)-tert-butyl[{3-amino-5-[{4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}(methyl)amino]benzyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1331] ##STR00136##

[1332] Platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder, 10 mg) was added to a solution of (rac)-tert-butyl N-[[3-[4-[2-(2-chloro-5-fluoro-pyrimidin-4-yl)-5-fluoro-phenoxy]butyl-methyl-amino]-5-nitro-phenyl]methyl-methyl-oxo-.sup.6-sulfanylidene]carbamate (25 mg; 39 mol) in methanol (5 mL) and the mixture was stirred for 10 min at room temperature under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated to give the crude title compound (17 mg) that was used without further purification.

[1333] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.31-1.40 (9H), 1.41-1.67 (4H), 2.65-2.83 (3H), 3.04 (3H), 3.14-3.28 (2H), 4.08 (2H), 4.46-4.62 (2H), 4.95 (2H), 5.91-5.99 (3H), 6.97 (1H), 7.15 (1H), 7.53 (1H), 8.84 (1H).

Example 6

Preparation of the End Product

[1334] A mixture of crude (rac)-tert-butyl[{3-amino-5-[{4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}(methyl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (17.0 mg), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (4.6 mg; 5.6 mol; ABCR GmbH & CO. KG) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (2.7 mg; 5.6 mol; Aldrich Chemical Company Inc.) and potassium phosphate (29.6 mg; 139 mol) in toluene (2.0 ml) and NMP (0.2 mL) was stirred under an atmosphere of argon at 110 C. in a closed vessel for 4 hours. After cooling, the batch was diluted with aqueous sodium chloride solution and extracted with ethyl acetate/THF. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the title compound (11.0 mg; 20 mol).

[1335] HPLC Purification:

[1336] Instrument: Waters Autopurificationsystem; Column: Waters XBridge C18 5 10030 mm;

[1337] Eluent A: H.sub.2O+0.1 vol % formic acid (99%), Eluent B: MeCN;

[1338] Gradient: 0.00-0.50 min 25% B (25.fwdarw.70 mL/min), 0.51-5.50 min 50-70% B (70 mL/min), DAD scan: 210-400 nm

[1339] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.38 (9H), 1.67 (2H), 1.82 (2H), 2.89 (3H), 3.10 (3H), 3.22-3.31 (m, 2H), 4.19-4.27 (2H), 4.61-4.69 (2H), 6.25 (1H), 6.42 (1H), 6.86 (1H), 7.13 (1H), 7.33-7.39 (1H), 7.71 (1H), 8.62 (1H), 9.56 (1H).

Example 7

(rac)-tert-butyl[{[15,19-difluoro-2,3,4,5-tetrahydro-11H-10,6-(azeno)-16,12-(metheno)-1,5,11,13-benzoxatriazacyclooctadecin-8-yl]methyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1340] ##STR00137##

[1341] Preparation of Intermediate 7.1:

4-[2-(3-aminopropoxy)-4-fluorophenyl]-5-fluoropyridin-2-amine

[1342] ##STR00138##

[1343] To a solution of 2-{3-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]propyl}-1H-isoindole-1,3(2H)-dione (see Intermediate 1.4; 2.01 g, 90% purity) in ethanol (100 mL) was added aqueous hydrazine (2.4 mL, 35% purity) and the mixture was heated to reflux for 3 h. The mixture was cooled to 5 C., filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, ethyl acetate/methanol) to yield the title compound (1.14 g, 95% purity).

[1344] LC-MS (Method a): R.sub.t=0.53 min; MS (ESIpos): m/z=280 [M+H].sup.+

[1345] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.62-1.72 (m, 2H), 2.54-2.59 (m, 2H), 3.13-3.19 (m, 2H), 4.02-4.08 (m, 2H), 5.78-5.89 (m, 2H), 6.33-6.39 (m, 1H), 6.81-6.87 (m, 1H), 7.01-7.08 (m, 1H), 7.20-7.28 (m, 1H), 7.82-7.88 (m, 1H).

[1346] Preparation of Intermediate 7.2:

(rac)-tert-butyl{[(2,6-dichloropyridin-4-yl)methyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1347] ##STR00139##

[1348] To a suspension of (rac)-2,6-dichloro-4-[(methylsulfinyl)methyl]pyridine (see Intermediate 2.1; 6.00 g), tert-butyl carbamate (4.70 g), magnesium oxide (4.32 g) and rhodium(II)acetate dimer (296 mg) in dichloromethane (270 ml) was added portionwise iodobenzene diacetate (12.9 g) and the mixture was stirred at room temperature for 15 h and subsequently at 40 C. for 3 h. The mixture was allowed to cool to room temperature, filtered over a pad of Celite and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (7.33 g, 97% purity).

[1349] LC-MS (Method a): R.sub.t=1.10 min; MS (ESIpos): m/z=339 [M+H].sup.+

[1350] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.38-1.42 (m, 9H), 3.20-3.26 (m, 3H), 4.96-5.04 (m, 2H), 7.55-7.61 (m, 2H).

[1351] Preparation of Intermediate 7.3:

(rac)-tert-butyl[{[2-({3-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]propyl}amino)-6-chloropyridin-4-yl]methyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1352] ##STR00140##

[1353] A solution of 4-[2-(3-aminopropoxy)-4-fluorophenyl]-5-fluoropyridin-2-amine (580 mg, 2.08 mmol), (rac)-tert-butyl {[(2,6-dichloropyridin-4-yl)methyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (587 mg) and 2,6-lutidine (600 L) in DMSO (19 mL) was heated to 130 C. for 3 h and subsequently to 150 C. for 1.5 h. The mixture was allowed to cool to room temperature, diluted with water (100 mL) and extracted three times with ethyl acetate (60 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (233 mg, 90% purity).

[1354] LC-MS (Method a): R.sub.t=1.17 min; MS (ESIpos): m/z=582 [M+H].sup.+.sup.1H NMR (400 MHz, DMSO-d.sub.6, 22 C.) /ppm=1.38 (s, 9H), 1.81-1.93 (m, 2H), 3.14-3.18 (m, 3H), 3.20-3.29 (m, 2H), 4.05-4.13 (m, 2H), 4.66-4.78 (m, 2H), 5.78-5.90 (m, 2H), 6.36-6.39 (m, 1H), 6.40-6.44 (m, 1H), 6.50-6.53 (m, 1H), 6.79-6.92 (m, 1H), 7.01-7.10 (m, 1H), 7.19-7.25 (m, 1H), 7.25-7.31 (m, 1H), 7.84-7.90 (m, 1H).

Example 7

Preparation of the End Product

[1355] A degassed suspension of rac-tert-butyl [{[2-({3-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]propyl}amino)-6-chloropyridin-4-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (220 mg), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (31.3 mg), 2-(dicyclohexylphosphino)-2,4,6-tri-iso-propyl-1,1-biphenyl (18.0 mg) and potassium phosphate (401 mg) in toluene (36 mL) and N-methylpyrrolidone (4.6 mL) was heated at 130 C. for 5.5 h and subsequently at 110 C. for 12 h. The mixture was allowed to cool to room temperature, diluted with water (100 mL) and extracted three times with ethyl acetate (50 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol yielded the title compound (145 mg, 84% purity). A pure sample was obtained by preparative HPLC.

[1356] HPLC Purification:

[1357] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBridge C18 5 10030 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml/min; temperature: 25 C.; DAD scan: 210-400 nm.

[1358] LC-MS (Method a): R.sub.t=1.31 min; MS (ESIpos): m/z=546 [M+H].sup.+

[1359] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.38 (s, 9H), 1.82-1.94 (m, 2H), 3.21 (s, 3H), 3.41 (br s, 2H), 4.03-4.13 (m, 2H), 4.47-4.65 (m, 2H), 5.93 (d, 1H), 6.10-6.18 (m, 1H), 6.83-6.96 (m, 2H), 7.05 (dd, 1H), 7.54 (dd, 1H), 8.26 (d, 1H), 8.83-8.92 (m, 1H), 9.35-9.43 (m, 1H).

Example 8

(rac)-15,19-difluoro-8-[(S-methylsulfonimidoyl)methyl]-2,3,4,5-tetrahydro-11H-10,6-(azeno)-16,12-(metheno)-1,5,11,13-benzoxatriazacyclooctadecine

[1360] ##STR00141##

[1361] To a solution of (rac)-tert-butyl [{[15,19-difluoro-2,3,4,5-tetrahydro-11H-10,6-(azeno)-16,12-(metheno)-1,5,11,13-benzoxatriazacyclooctadecin-8-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (90.0 mg) in dichloromethane (900 L) was added trifluoroacetic acid (410 L) and the mixture was stirred for 2 h. The pH value of the reaction mixture was adjusted to pH>7 by the addition of saturated aqueous sodium bicarbonate solution (5 mL). The mixture was combined with a second reaction batch carried out as described above but with 20 mg of (rac)-tert-butyl [{[15,19-difluoro-2,3,4,5-tetrahydro-11H-10,6-(azeno)-16,12-(metheno)-1,5,11,13-benzoxatriazacyclooctadecin-8-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate The mixture was extracted three times with dichloromethane (25 mL each), the combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by preparative HPLC to yield the title compound (38 mg, 99% purity).

[1362] HPLC Purification:

[1363] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBridge C18 5 10030 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml/min; temperature: 25 C.; DAD scan: 210-400 nm.

[1364] LC-MS (Method a): R.sub.t=1.07 min; MS (ESIpos): m/z=446 [M+H].sup.+

[1365] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm 1.83-1.96 (m, 2H), 2.88 (s, 3H), 3.37-3.47 (m, 2H), 3.55-3.62 (m, 1H), 4.05-4.20 (m, 4H), 5.86-5.95 (m, 1H), 6.06-6.15 (m, 1H), 6.83-6.92 (m, 2H), 7.02-7.09 (m, 1H), 7.48-7.60 (m, 1H), 8.23-8.29 (m, 1H), 8.88-8.91 (m, 1H), 9.31 (s, 1H).

Example 9

(rac)-tert-butyl[{[17,21-difluoro-2,3,4,5,6,7-hexahydro-13H-12,8-(azeno)-14,18-(metheno)-1,7,13,15-benzoxatriazacycloicosin-10-yl]methyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1366] ##STR00142##

[1367] Preparation of Intermediate 9.1:

2-{5-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]pentyl}-1H-isoindole-1,3(2H)-dione

[1368] ##STR00143##

[1369] To a suspension of 2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenol (see Intermediate 1.3; 2.00 g) and 2-(5-bromopentyl)-1H-isoindole-1,3(2H)-dione (3.20 g) in acetonitrile (57 ml) was added potassium carbonate (2.49 g) and the mixture was heated to 80 C. for 22 h. The mixture was allowed to cool to room temperature, diluted with water (150 mL) and extracted three times with ethyl acetate (100 mL each). The combined organic layers were washed with saturated aqueous sodium chloride, dried and concentrated to yield the title compound (4.58 g, 82% purity) that was used without further purification.

[1370] LC-MS (Method a): R.sub.t=1.11 min; MS (ESIpos): m/z=438 [M+H].sup.+

[1371] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.27-1.35 (m, 2H), 1.55-1.67 (m, 4H), 3.52-3.61 (m, 2H), 3.93-4.01 (m, 2H), 5.74-5.92 (m, 2H), 6.28-6.37 (m, 1H), 6.80-6.91 (m, 1H), 6.97-7.04 (m, 1H), 7.20-7.28 (m, 1H), 7.62-7.69 (m, 1H), 7.80-7.90 (m, 4H).

[1372] Preparation of Intermediate 9.2:

4-{2-[(5-aminopentyl)oxy]-4-fluorophenyl}-5-fluoropyridin-2-amine

[1373] ##STR00144##

[1374] To a suspension of 2-{5-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]pentyl}-1H-isoindole-1,3(2H)-dione (4.58 g, 82% purity) in ethanol (220 mL) was added aqueous hydrazine (4.7 mL, 35% purity) and the mixture was heated to reflux for 3.5 h. The mixture was cooled to 5 C., filtered and concentrated. The residue was treated with dichloromethane and the resulting suspension was filtered. The filtrate was treated with ethanol, cooled to 0 C. and filtered. The combined filter cakes were purified by flash column chromatography (silica gel, ethyl acetate/methanol) to yield the title compound (1.53 g, 95% purity).

[1375] LC-MS (Method a): R.sub.t=0.65 min; MS (ESIpos): m/z=308 [M+H].sup.+

[1376] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.27-1.37 (m, 4H), 1.56-1.64 (m, 2H), 3.14-3.19 (m, 2H), 3.96-4.02 (m, 2H), 5.79-5.93 (m, 2H), 6.34-6.41 (m, 1H), 6.79-6.88 (m, 1H), 6.98-7.07 (m, 1H), 7.20-7.30 (m, 1H), 7.82-7.87 (m, 1H) (one methylene group obscured).

[1377] Preparation of Intermediate 9.3:

(rac)-tert-butyl[{[2-({5-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]pentyl}amino)-6-chloropyridin-4-yl]methyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1378] ##STR00145##

[1379] A solution of 4-{2-[(5-aminopentyl)oxy]-4-fluorophenyl}-5-fluoropyridin-2-amine (1.60 g, 70% purity), (rac)-tert-butyl {[(2,6-dichloropyridin-4-yl)methyl]s(methyl)oxido-.sup.6-sulfanylidene}carbamate (see Intermediate 7.2; 1.03 g) and 2,6-lutidine (1.1 mL) in DMSO (37 mL) was heated to 130 C. for 2.5 h. The mixture was allowed to cool to room temperature, diluted with water (150 mL) and extracted three times with ethyl acetate (70 mL each). The combined organic layers were washed with saturated aqueous sodium chloride, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (623 mg, 95% purity).

[1380] LC-MS (Method a): R.sub.t=1.23 min; MS (ESIpos): m/z=610 [M+H].sup.+

[1381] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.31-1.41 (m, 11H), 1.44-1.54 (m, 2H), 1.58-1.69 (m, 2H), 3.10-3.19 (m, 5H), 3.97-4.02 (m, 2H), 4.68-4.79 (m, 2H), 5.79-5.86 (m, 2H), 6.32-6.39 (m, 1H), 6.41-6.46 (m, 1H), 6.47-6.53 (m, 1H), 6.82-6.91 (m, 1H), 6.97-7.07 (m, 1H), 7.13-7.20 (m, 1H), 7.24-7.29 (m, 1H), 7.83-7.87 (m, 1H).

Example 9

Preparation of the End Product

[1382] A degassed suspension of (rac)-tert-butyl [{[2-({5-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]pentyl}amino)-6-chloropyridin-4-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (310 mg), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (84.0 mg), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (84.0 mg) and potassium phosphate (539 mg) in toluene (31 mL) and N-methylpyrrolidone (3.1 mL) was heated at 130 C. for 18 h. Additional portions of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (84.0 mg) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (84.0 mg) were added, and the mixture was stirred for an additional 7 h at 130 C. The mixture was allowed to cool to room temperature, diluted with water (100 mL) and extracted three times with ethyl acetate (50 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was sequentially purified by flash column chromatography (silica gel, dichloromethane/methanol) followed by preparative HPLC to yield the title compound (78 mg, 99% purity).

[1383] HPLC Purification:

[1384] Instrument: pump: Labomatic HD-5000, head HDK 280, low pressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 m, 12530 mm; solvent A: water+0.1 vol-% formic acid, solvent B: acetonitrile; gradient: 0.00-0.50 min 40% B (150 ml/min), 0.50-6.00 min 40-80% B (150 ml/min), 6.00-6.10 min 80-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); detection: UV 279 nm.

[1385] LC-MS (Method a): R.sub.t=1.36 min; MS (ESIpos): m/z=574 [M+H].sup.+

[1386] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.35-1.41 (m, 11H), 1.43-1.49 (m, 2H), 1.59-1.70 (m, 2H), 3.10-3.17 (m, 2H), 3.17-3.23 (m, 3H), 4.13-4.20 (m, 2H), 4.50-4.62 (m, 2H), 5.89-5.95 (m, 1H), 6.10-6.16 (m, 1H), 6.67-6.74 (m, 1H), 6.84-6.93 (m, 1H), 7.12-7.18 (m, 1H), 7.24-7.33 (m, 1H), 8.17-8.28 (m, 2H), 9.38 (s, 1H).

Example 10

(rac)-17,21-difluoro-10-[(S-methylsulfonimidoyl)methyl]-2,3,4,5,6,7-hexahydro-13H-12,8-(azeno)-14,18-(metheno)-1,7,13,15-benzoxatriazacycloicosine

[1387] ##STR00146##

[1388] To a solution of (rac)-tert-butyl [{[17,21-difluoro-2,3,4,5,6,7-hexahydro-13H-12,8-(azeno)-14,18-(metheno)-1,7,13,15-benzoxatriazacycloicosin-10-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (75.0 mg) in dichloromethane (25 mL) was added trifluoroacetic acid (250 L) and the mixture was stirred for 4 h. The pH value of the reaction mixture was adjusted to pH>7 by the addition of saturated aqueous sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane (20 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by preparative HPLC to yield the title compound (32 mg, 99% purity).

[1389] HPLC Purification:

[1390] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBridge C18 5 10030 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml/min; temperature: 25 C.; DAD scan: 210-400 nm.

[1391] LC-MS (Method a): R.sub.t=1.11 min; MS (ESIpos): m/z=474 [M+H].sup.+

[1392] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.32-1.41 (m, 2H), 1.41-1.52 (m, 2H), 1.61-1.69 (m, 2H), 2.82-2.91 (m, 3H), 3.06-3.20 (m, 2H), 3.56-3.62 (m, 1H), 4.03-4.12 (m, 1H), 4.12-4.20 (m, 3H), 5.79-5.97 (m, 1H), 6.10-6.17 (m, 1H), 6.55-6.66 (m, 1H), 6.81-6.92 (m, 1H), 7.11-7.19 (m, 1H), 7.25-7.34 (m, 1H), 8.18-8.26 (m, 2H), 9.25-9.34 (m, 1H).

Example 11

(rac)-16,20-difluoro-6-methyl-9-[(S-methylsulfonimidoyl)methyl]-3,4,5,6-tetrahydro-2H-7,11-(azeno)-17,13-(metheno)-1,6,12,14-benzoxatriazacyclononadecine

[1393] ##STR00147##

[1394] Preparation of Intermediate 11.1:

(rac)-tert-butyl[({2-chloro-6-[(4-hydroxybutyl)(methyl)amino]pyridin-4-yl}methyl)(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1395] ##STR00148##

[1396] To a solution of (rac)-tert-butyl {[(2,6-dichloropyridin-4-yl)methyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (see Intermediate 7.2; 1.00 g) and 4-(methylamino)butan-1-ol (365 mg) in DMSO (35 mL) was added 2,6-lutidine (1.0 mL) and the mixture was heated at 130 C. for 4.5 h. The mixture was allowed to cool to room temperature, diluted with water (150 mL) and extracted three times with ethyl acetate (70 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to yield the title compound (539 mg, 99% purity).

[1397] LC-MS (Method a): R.sub.t=1.07 min; MS (ESIneg): m/z=404 [MH].sup.

[1398] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.35-1.45 (m, 11H), 1.50-1.59 (m, 2H), 2.93-3.01 (m, 3H), 3.12-3.17 (m, 3H), 3.37-3.43 (m, 2H), 3.44-3.49 (m, 2H), 4.39-4.44 (m, 1H), 4.72-4.87 (m, 2H), 6.54-6.60 (m, 1H), 6.60-6.65 (m, 1H).

[1399] Preparation of Intermediate 11.2

(rac)-tert-butyl[({2-[{4-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]butyl}(methyl)amino]-6-chloropyridin-4-yl}methyl)(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1400] ##STR00149##

[1401] To a suspension of (rac)-tert-butyl [({2-chloro-6-[(4-hydroxybutyl)(methyl)amino]pyridin-4-yl}methyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (350 mg), 2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenol (see Intermediate 1.3; 160 mg) and triphenylphospine (283 mg) in dichloromethane (5 mL) was added a solution of diisoproyl azodicarboxylate (210 l) in dichloromethane (1 mL), and the mixture was stirred for 18 h at room temperature. Additional portions of 2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenol (80 mg), triphenylphosphine (141 mg) and diisoproyl azodicarboxylate (105 l) were added, and the mixture was stirred for an additional 4 h. The reaction mixture was concentrated and the crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate). Further purification by flash column chromatography (silica gel hexanes/ethyl acetate) yielded the title compound (180 mg, 95% purity).

[1402] LC-MS (Method a): R.sub.t=1.26 min; MS (ESIpos): m/z=610 [M+H].sup.+

[1403] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.38 (s, 9H), 1.50-1.66 (m, 4H), 2.89-2.96 (m, 3H), 3.11-3.18 (m, 3H), 3.41-3.49 (m, 2H), 3.99-4.06 (m, 2H), 4.71-4.84 (m, 2H), 5.79-5.88 (m, 2H), 6.32-6.38 (m, 1H), 6.56-6.59 (m, 1H), 6.59-6.61 (m, 1H), 6.83-6.92 (m, 1H), 6.96-7.06 (m, 1H), 7.23-7.29 (m, 1H), 7.80-7.86 (m, 1H).

Example 11

Preparation of the End Product

[1404] A degassed suspension of (rac)-tert-butyl [({2-[{4-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]butyl}(methyl)amino]-6-chloropyridin-4-yl}methyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (120 mg), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (32.5 mg), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (18.8 mg) and potassium phosphate (209 mg) in toluene (19 mL) and N-methylpyrrolidone (2.4 mL) was heated at 130 C. for 18 h. Additional portions of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (16.3 mg) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (9.4 mg) were added, and the mixture was stirred for an additional 4 h at 130 C. The mixture was allowed to cool to room temperature, diluted with water (50 mL) and extracted three times with ethyl acetate (30 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to afford crude (rac)-tert-butyl [{[16,20-difluoro-6-methyl-3,4,5,6-tetrahydro-2H-7,11-(azeno)-17,13-(metheno)-1,6,12,14-benzoxatriazacyclononadecin-9(12H)-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (71 mg, 92% purity,) that was contaminated by some impurities and used without further purification.

[1405] To a solution of crude (rac)-tert-butyl[{[16,20-difluoro-6-methyl-3,4,5,6-tetrahydro-2H-7,11-(azeno)-17,13-(metheno)-1,6,12,14-benzoxatriazacyclononadecin-9(12H)-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (70.0 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (240 l) and the mixture was stirred for 4.5 h. The pH value of the reaction mixture was adjusted to pH>7 by the addition of saturated aqueous sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane (15 mL each). The combined organic layers were washed with saturated aqueous sodium chloride, dried and concentrated. The crude product was purified by preparative HPLC. Further purification by preparative HPLC yielded the title compound (8 mg, 99% purity).

[1406] HPLC Purification:

[1407] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBridge C18 5 10030 mm; eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml/min; temperature: 25 C.; DAD scan: 210-400 nm.

[1408] LC-MS (Method a): R.sub.t=1.17 min; MS (ESIpos): m/z=474 [M+H].sup.+

[1409] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.68-1.90 (m, 4H), 2.85-2.89 (m, 3H), 2.93 (s, 3H), 3.48-3.60 (m, 2H), 3.62-3.73 (m, 1H), 4.10-4.26 (m, 4H), 5.96-6.08 (m, 1H), 6.17-6.28 (m, 1H), 6.80-6.97 (m, 1H), 7.02-7.17 (m, 1H), 7.29-7.37 (m, 1H), 8.23-8.34 (m, 2H), 9.31-9.46 (m, 1H).

Example 12

8,16,20-trifluoro-6-methyl-9-[(methylsulfanyl)methyl]-3,4,5,6-tetrahydro-2H,12H-11,7-(azeno)-13,17-(metheno)-1,6,12,14-benzoxatriazacyclononadecine

[1410] ##STR00150##

[1411] Preparation of Intermediate 12.1:

(2,6-dichloro-3-fluoropyridin-4-yl)methanol

[1412] ##STR00151##

[1413] To a solution of 2,6-dichloro-3-fluoropyridine-4-carboxylic acid (4.90 g, purchased from FCH group) in THF (86 mL) at 0 C. was slowly added borane THF complex solution (93 mL, 1.0 M). The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was carefully stopped by the addition of MeOH (20 mL). The mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (100 mL), and the aqueous layer was extracted three times with ethyl acetate (150 mL each). The combined organic layers were washed with saturated aqueous sodium chloride, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield (2,6-dichloro-3-fluoropyridin-4-yl)methanol (4.41 g, 99% purity).

[1414] LC-MS (Method a): R.sub.t=0.90 min; MS (ESIpos): m/z=196 [M+H].sup.+

[1415] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=4.60-4.69 (m, 2H), 5.75-5.83 (m, 1H), 7.51-7.60 (m, 1H).

[1416] Preparation of Intermediate 12.2:

2,6-dichloro-4-(chloromethyl)-3-fluoropyridine

[1417] ##STR00152##

[1418] To a solution of (2,6-dichloro-3-fluoropyridin-4-yl)methanol (4.30 g) and pyridine (2.0 mL) in toluene (17 mL) at 0 C. was added thionyl chloride (2.1 mL). The mixture was stirred for an additional 30 min at 0 C. and for 24 h at room temperature. The reaction was stopped by the addition of water (200 mL) and the mixture was extracted three times with ethyl acetate (150 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated to yield the title compound (4.67 g, 80% purity) that was used without further purification.

[1419] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=4.81-4.88 (m, 2H), 7.80-7.86 (m, 1H).

[1420] Preparation of Intermediate 12.3:

2,6-dichloro-3-fluoro-4-[(methylsulfanyl)methyl]pyridine

[1421] ##STR00153##

[1422] To a solution of crude 2,6-dichloro-4-(chloromethyl)-3-fluoropyridine (4.67 g) in ethanol (41 mL) at 0 C. was added sodium thiomethoxide (1.10 g) portionwise. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was stopped by the addition of half-saturated aqueous sodium chloride solution (200 mL) and the mixture was extracted three times with ethyl acetate (150 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was combined with a second reaction batch carried out as described above but with 100 mg of 2,6-dichloro-4-(chloromethyl)-3-fluoropyridine. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate) yielded the title compound (2.22 g, 95% purity).

[1423] LC-MS (Method a): R.sub.t=1.26 min; MS (ESIpos): m/z=226 [M+H].sup.+

[1424] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=2.03 (s, 3H), 3.75-3.82 (m, 2H), 7.63-7.69 (m, 1H).

[1425] Preparation of Intermediate 12.4:

4-[{6-chloro-3-fluoro-4-[(methylsulfanyl)methyl]pyridin-2-yl}(methyl)amino]butan-1-ol

[1426] ##STR00154##

[1427] A solution of 2,6-dichloro-3-fluoro-4-[(methylsulfanyl)methyl]pyridine (2.00 g), 4-(methylamino)butan-1-ol (1.10 g) and 2,6-lutidine (3.1 mL) in DMSO (110 mL) was heated at 130 C. for 3.5 h. The mixture was allowed to cool to room temperature, diluted with water (300 mL) and extracted three times with ethyl acetate (150 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate). Further purification by flash column chromatography (silica gel, hexanes/ethyl acetate) yielded the title compound (935 mg, 95% purity).

[1428] LC-MS (Method a): R.sub.t=1.24 min; MS (ESIpos): m/z=293 [M+H].sup.+

[1429] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.34-1.45 (m, 2H), 1.48-1.63 (m, 2H), 2.02 (s, 3H), 3.01 (s, 3H), 3.36-3.46 (m, 4H), 3.60-3.66 (m, 2H), 4.38-4.44 (m, 1H), 6.67-6.70 (m, 1H).

[1430] Preparation of Intermediate 12.5:

N-{4-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]butyl}-6-chloro-3-fluoro-N-methyl-4-[(methylsulfanyl)methyl]pyridin-2-amine

[1431] ##STR00155##

[1432] To a suspension of 4-[{6-chloro-3-fluoro-4-[(methylsulfanyl)methyl]pyridin-2-yl}(methyl)amino]butan-1-ol (930 mg), 2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenol (see Intermediate 1.3; 847 mg) and triphenylphosphine (916 mg) in dichloromethane (12 mL) was added diisopropyl azodicarboxylate (690 l) in dichloromethane (3 mL), and the mixture was stirred at room temperature for 7.5 h. The mixture was concentrated and the crude product was purified by flash column chromatography to yield the title compound (2.05 g, 80% purity) that was used without further purification.

[1433] LC-MS (Method a): R.sub.t=1.44 min; MS (ESIpos): m/z=497 [M+H].sup.+

[1434] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.54-1.66 (m, 4H), 1.97-2.00 (m, 2H), 2.92-2.97 (m, 3H), 3.37-3.44 (m, 2H), 3.60-3.64 (m, 2H), 4.00-4.04 (m, 2H), 5.80-5.86 (m, 2H), 6.32-6.38 (m, 1H), 6.67-6.72 (m, 1H), 6.80-6.90 (m, 1H), 6.98-7.05 (m, 1H), 7.23-7.33 (m, 1H), 7.76-7.83 (m, 1H).

Example 12

Preparation of the End Product:

[1435] A degassed suspension of crude N-{4-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenoxy]butyl}-6-chloro-3-fluoro-N-methyl-4-[(methylsulfanyl)methyl]pyridin-2-amine (1.90 g), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (506 mg), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (292 mg) and potassium phosphate (1.95 g) in toluene (150 mL) and N-methylpyrrolidone (15 mL) was heated at 130 C. for 18 h. Additional portions of chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (506 mg) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (292 mg) were added, and the mixture was stirred for an additional 7 h at 130 C. The mixture was allowed to cool to room temperature, diluted with water (150 mL) and extracted three times with ethyl acetate (100 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate). Further purification by flash column chromatography (silica gel, hexanes/ethyl acetate) and preparative HPLC yielded the title compound (221 mg, 95% purity).

[1436] HPLC Purification:

[1437] Instrument: pump: Labomatic HD-5000, head HDK 280, low pressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 m, 12530 mm; solvent A: water+0.2 vol-% ammonia (32%), solvent B: acetonitrile; gradient: 0.00-0.50 min 65% B (150 ml/min), 0.50-6.00 min 65-100% B (150 ml/min), 6.00-8.00 min 100% B (150 ml/min); detection: UV 277 nm.

[1438] LC-MS (Method b): R.sub.t=1.59 min; MS (ESIpos): m/z=461 [M+H].sup.+

[1439] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.75-1.91 (m, 4H), 2.01-2.08 (m, 3H), 3.01-3.10 (m, 3H), 3.33-3.41 (m, 2H), 3.51-3.59 (m, 2H), 4.03-4.15 (m, 2H), 6.19-6.27 (m, 1H), 6.81-6.93 (m, 1H), 7.06-7.13 (m, 1H), 7.25-7.34 (m, 1H), 8.08-8.15 (m, 1H), 8.22-8.29 (m, 1H), 8.22-8.29 (m, 1H), 9.35-9.45 (m, 1H).

Example 13

(rac)-tert-butyl[{[15,19-difluoro-1,2,3,4-tetrahydro-16,12-(azeno)-6,10-(metheno)-5,1,11,13-benzoxatriazacyclooctadecin-8(11H)-yl]methyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1440] ##STR00156##

[1441] Preparation of Intermediate 13.1

2-(3-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}propyl)-1H-isoindole-1,3(2H)-dione

[1442] ##STR00157##

[1443] To a solution of 3-[(methylsulfanyl)methyl]-5-nitrophenol (2.21 g, prepared according to WO2015/155197 A1, 2015, Intermediate 1.2) in DMF (22 mL) was sequentially added potassium carbonate (2.30 g) and 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione (3.27 g) and the mixture was stirred at room temperature for 22 h. The reaction mixture was diluted with EtOAc (50 mL), and the reaction was stopped by the addition of saturated aqueous sodium bicarbonate solution (50 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc (50 mL each). The combined organic layers were sequentially washed with water and saturated aqueous sodium chloride, dried and concentrated to yield the title compound (4.25 g, 95% purity) that was used without further purification.

[1444] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.93 (s, 3H), 2.06-2.13 (m, 2H), 3.73-3.81 (m, 4H), 4.11-4.17 (m, 2H), 7.15-7.20 (m, 1H), 7.37-7.44 (m, 1H), 7.72-7.78 (m, 1H), 7.81-7.89 (m, 4H).

[1445] Preparation of Intermediate 13.2:

rac-2-[3-(3-{[(S)-methylsulfinyl]methyl}-5-nitrophenoxy)propyl]-1H-isoindole-1,3(2H)-dione

[1446] ##STR00158##

[1447] To a solution of 2-(3-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}propyl)-1H-isoindole-1,3(2H)-dione (4.23 g, 95% purity) in acetonitrile (320 ml) at 0 C. was added iron trichloride (169 mg) and the mixture was stirred for 10 min Then, periodic acid (7.11 g) was added and the mixture was stirred for an additional 2 h at 0 C. The reaction was stopped by the addition of saturated aqueous sodium thiosulfate solution (100 mL). The mixture was stirred for 10 min and extracted twice with ethyl acetate (250 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated to yield crude the title compound (4.55 g, 90% purity) that was used without further purification.

[1448] LC-MS (Method a): R.sub.t=0.99 min; MS (ESIpos): m/z=403 [M+H].sup.+

[1449] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=2.06-2.15 (m, 2H), 2.48 (s, 3H), 3.75-3.83 (m, 2H), 3.99-4.08 (m, 1H), 4.13-4.20 (m, 2H), 4.22-4.29 (m, 1H), 7.20-7.26 (m, 1H), 7.50-7.55 (m, 1H), 7.75-7.80 (m, 1H), 7.82-7.89 (m, 4H).

[1450] Preparation of Intermediate 13.3:

(rac)-tert-butyl[{3-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]-5-nitrobenzyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1451] ##STR00159##

[1452] To a suspension of crude rac-2-[3-(3-{[(S)-methylsulfinyl]methyl}-5-nitrophenoxy)propyl]-1H-isoindole-1,3(2H)-dione (4.55 g), tert-butyl carbamate (1.98 g), magnesium oxide (1.82 g) and rhodium(II)acetate dimer (125 mg) in dichloromethane (120 mL) was added portionwise iodobenzene diacetate (5.46 g), and the mixture was heated to 40 C. for 4 h. The mixture was kept at 20 C. for 72 h and subsequently stirred at 40 C. for an additional 3 h. The mixture was allowed to cool to room temperature, filtered over a pad of Celite and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to yield the title compound (5.83 g, 80% purity) that was used without further purification.

[1453] LC-MS (Method a): R.sub.t=1.20 min; MS (ESIpos): m/z=518 [M+H].sup.+

[1454] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.36 (s, 9H), 1.93-1.93 (m, 1H), 2.06-2.15 (m, 2H), 3.13 (s, 3H), 3.74-3.80 (m, 2H), 4.13-4.20 (m, 2H), 4.93-5.04 (m, 2H), 7.35-7.41 (m, 1H), 7.59-7.64 (m, 1H), 7.81-7.91 (m, 5H).

[1455] Preparation of Intermediate 13.4

(rac)-tert-butyl[{3-amino-5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]benzyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1456] ##STR00160##

[1457] To a solution of crude (rac)-tert-butyl [{3-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]-5-nitrobenzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (2.90 g) in methanol (120 mL) was added platinum 1% and vanadium 2% on activated carbon (344 mg). The mixture was purged with hydrogen gas (1 atm) and stirred for 0.5 h. Additional platinum 1% and vanadium 2% on activated carbon (200 mg) was added and the mixture was stirred under an atmosphere of hydrogen for 2 h. Additional platinum 1% and vanadium 2% on activated carbon (150 mg) was added and the mixture was stirred under an atmosphere of hydrogen for 1.5 h. The mixture was stirred under nitrogen for 15 h. Additional platinum 1% and vanadium 2% on activated carbon (200 mg) was added and the mixture was stirred under an atmosphere of hydrogen for 1 h. The mixture was diluted with THF (75 mL) and additional platinum 1% and vanadium 2% on activated carbon (200 mg) was added and the mixture was stirred under an atmosphere of hydrogen for 1 h. The mixture was filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to yield the title compound (740 mg, 95% purity).

[1458] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.38 (s, 9H), 1.98-2.06 (m, 2H), 3.04 (s, 3H), 3.71-3.76 (m, 2H), 3.85-3.93 (m, 2H), 4.48-4.62 (m, 2H), 5.16-5.23 (m, 2H), 6.03-6.12 (m, 2H), 6.13-6.19 (m, 1H), 7.81-7.89 (m, 4H).

[1459] Preparation of Intermediate 13.5:

(rac)-tert-butyl[(3-{[4-(2,4-difluorophenyl)-5-fluoropyrimidin-2-yl]amino}-5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]benzyl)(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1460] ##STR00161##

[1461] A suspension of (rac)-tert-butyl [{3-amino-5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (250 mg), 2-chloro-4-(2,4-difluorophenyl)-5-fluoropyrimidine (251 mg, purchased from Apollo Scientific), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (42.4 mg), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (24.4 mg) and potassium phosphate (544 mg) in toluene (51 mL) and N-methylpyrrolidone (6.2 mL) was stirred for 18 h at 130 C. Additional portions of 2-chloro-4-(2,4-difluorophenyl)-5-fluoropyrimidine (125 mg), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (21.2 mg) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (12.2 mg) were added, and the mixture was stirred for 4 h at 130 C. Additional portions of 2-chloro-4-(2,4-difluorophenyl)-5-fluoropyrimidine (63 mg), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (10.6 mg) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (6.1 mg) were added, and the mixture was stirred for 16 h at 110 C. The mixture was allowed to cool to room temperature, filtered, diluted with water (100 mL) and extracted three times with ethyl acetate (150 mL each). The combined organic layers were washes with saturated aqueous sodium chloride solution, dried and concentrated. The residue was treated with saturated aqueous sodium chloride solution (100 mL) and extracted three times with diethyl ether (120 mL each). The combined organic layers were purified and concentrated. The crude product was combined with a second reaction batch carried out similarly as described above but with 200 mg of (rac)-tert-butyl[{3-amino-5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to yield the title compound (337 mg, 80% purity) that was contaminated by impurities and used without further purification.

[1462] LC-MS (Method a): R.sub.t=1.45 min; MS (ESIpos): m/z=696 [M+H].sup.+

[1463] Preparation of Intermediate 13.6:

(rac)-tert-butyl{[3-(3-aminopropoxy)-5-{[4-(2,4-difluorophenyl)-5-fluoropyrimidin-2-yl]amino}benzyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1464] ##STR00162##

[1465] To a suspension of crude (rac)-tert-butyl [(3-{[4-(2,4-difluorophenyl)-5-fluoropyrimidin-2-yl]amino}-5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (337 mg, 80% purity) in ethanol (14 mL) and THF (3.0 mL) was added aqueous hydrazine (210 L, 35% purity) and the mixture was heated to reflux for 4 h. The mixture was cooled to 5 C., filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to yield the title compound (165 mg, 95% purity).

[1466] LC-MS (Method a): R.sub.t=1.03 min; MS (ESIpos): m/z=566 [M+H].sup.+

[1467] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.36 (s, 9H), 1.75-1.78 (m, 2H), 2.65-2.70 (m, 2H), 3.07-3.12 (m, 2H), 3.13-3.19 (m, 2H), 3.96-4.00 (m, 2H), 4.69-4.83 (m, 2H), 6.54-6.64 (m, 1H), 7.30-7.41 (m, 2H), 7.42-7.54 (m, 2H), 7.79-7.91 (m, 1H), 8.65-8.74 (m, 1H), 9.95-10.02 (m, 1H).

Example 13

Preparation of the End Product

[1468] To a solution of (rac)-tert-butyl {[3-(3-aminopropoxy)-5-{[4-(2,4-difluorophenyl)-5-fluoropyrimidin-2-yl]amino}benzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (165 mg) in DMSO (11 mL) was added triethylamine (49 L) and the mixture was heated to 150 C. for 5 h. The mixture was allowed to cool to room temperature, diluted with water (25 mL) and extracted twice with with ethyl acetate (100 mL each). The combined organic layers were sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (255 mg, 88% purity) that was used without further purification. A pure sample was obtained by preparative HPLC.

[1469] HPLC Purification:

[1470] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBridge C18 5 10030 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml/min; temperature: 25 C.; DAD scan: 210-400 nm.

[1471] LC-MS (Method a): R.sub.t=1.37 min; MS (ESIpos): m/z=546 [M+H].sup.+

[1472] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.38 (s, 9H), 1.94 (br s, 2H), 3.11-3.21 (m, 5H), 4.26 (br t, 2H), 4.72 (s, 2H), 6.38-6.50 (m, 1H), 6.55 (s, 1H), 6.59-6.64 (m, 1H), 6.79 (s, 1H), 7.58-7.66 (m, 1H), 7.67-7.75 (m, 1H), 8.29 (s, 1H), 8.52-8.57 (m, 1H), 8.65 (d, 1H), 9.94 (s, 1H).

Example 14

rac-15,19-difluoro-8-[(S-methylsulfonimidoyl)methyl]-1,2,3,4-tetrahydro-16,12-(azeno)-6,10-(metheno)-5,1,11,13-benzoxatriazacyclooctadecine

[1473] ##STR00163##

[1474] To a solution of (rac)-tert-butyl [{[15,19-difluoro-1,2,3,4-tetrahydro-16,12-(azeno)-6,10-(metheno)-5,1,11,13-benzoxatriazacyclooctadecin-8(11H)-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (215 mg, 88% purity) in dichloromethane (2.7 mL) was added trifluoroacetic acid (870 l) and the mixture was stirred for 2 h. The pH value of the reaction mixture was adjusted to pH>7 by the addition of saturated aqueous sodium bicarbonate (30 mL), and the mixture was extracted three times with dichloromethane (60 mL each). The combined organic layers were washed with saturated aqueous sodium chloride, dried and concentrated. The crude product was purified by preparative HPLC to yield the title compound (14.6 mg, 94% purity, 9%).

[1475] HPLC Purification:

[1476] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBridge C18 5 10030 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml/min; temperature: 25 C.; DAD scan: 210-400 nm.

[1477] LC-MS (Method a): R.sub.t=1.14 min; MS (ESIpos): m/z=446 [M+H].sup.+

[1478] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.86-2.02 (m, 2H), 2.81 (s, 3H), 3.08-3.22 (m, 2H), 3.57 (s, 1H), 4.16-4.30 (m, 4H), 6.39-6.51 (m, 1H), 6.51-6.66 (m, 2H), 6.67-6.85 (m, 1H), 7.60-7.71 (m, 1H), 7.75-7.85 (m, 1H), 8.11-8.28 (m, 1H), 8.59-8.69 (m, 1H), 9.81-9.95 (m, 1H).

Example 15

(rac)-tert-butyl[{[16,20-difluoro-2,3,4,5-tetrahydro-1H,12H-13,17-(azeno)-11,7-(metheno)-6,1,12,14-benzoxatriazacyclononadecin-9-yl]methyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1479] ##STR00164##

[1480] Preparation of Intermediate 15.1:

ethyl 4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butanoate

[1481] ##STR00165##

[1482] To a suspension of 3-[(methylsulfanyl)methyl]-5-nitrophenol (6.00 g) and potassium carbonate (4.99 g) in DMF (58 ml) at 0 C. was added dropwise ethyl 4-bromobutanoate (4.7 mL). The mixture was allowed to warm to room temperature and stirred for 24 h. The reaction was diluted with water (300 mL) and the mixture was extracted three times with ethyl acetate (200 mL each). The combined organic layers were washed with saturated aqueous sodium chloride, dried and concentrated to yield the title compound (11.69 g, 90% purity) that was contaminated by DMF and excess ethyl 4-bromobutanoate and which was used without further purification.

[1483] LC-MS (Method a): R.sub.t=1.35 min; MS (ESIpos): m/z=314 [M+H].sup.+

[1484] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.15-1.21 (m, 3H), 1.94-2.03 (m, 5H), 3.74-3.81 (m, 2H), 4.02-4.14 (m, 4H), 7.33-7.36 (m, 1H), 7.57-7.61 (m, 1H), 7.75-7.80 (m, 1H) (one methylene group is overlayed by residual DMSO).

[1485] Preparation of Intermediate 15.2:

(rac)-ethyl 4-(3-{[S-methylsulfinyl]methyl}-5-nitrophenoxy)butanoate

[1486] ##STR00166##

[1487] To a solution of crude ethyl 4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butanoate (11.7 g) in acetonitrile (410 mL) at 0 C. was added iron trichloride (605 mg) and the mixture was stirred for 15 min. Then, periodic acid (25.5 g) was added and the reaction was stirred for 1.5 h at 0 C. The reaction was stopped by the addition of saturated aqueous sodium thiosulfate solution, and the mixture was extracted three times with ethyl acetate (300 mL each). The combined organic layers were washed with saturated aqueous sodium chloride, dried and concentrated to yield the title compound (10.5 g, 99% purity) that was used without further purification.

[1488] LC-MS (Method a): R.sub.t=0.96 min; MS (ESIpos): m/z=330 [M+H].sup.+

[1489] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.15-1.21 (m, 3H), 1.97-2.06 (m, 2H), 4.04-4.15 (m, 5H), 4.24-4.31 (m, 1H), 7.28-7.36 (m, 1H), 7.65-7.69 (m, 1H), 7.76-7.82 (m, 1H) (the methyl group and one methylene group is overlayed by residual DMSO).

[1490] Preparation of Intermediate 15.3:

(rac)-ethyl 4-(3-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-5-nitrophenoxy)butanoate

[1491] ##STR00167##

[1492] To a suspension of (rac)-ethyl 4-(3-{[S-methylsulfinyl]methyl}-5-nitrophenoxy)butanoate (10.5 g), tert-butyl carbamate (5.60 g), magnesium oxide (5.14 g), and rhodium(II)acetate dimer (352 mg) in dichloromethane (530 mL) was added iodobenzene diacetate (15.4 g), and the mixture was stirred for 4.5 h at 45 C. Additional portions of tert-butyl carbamate (1.87 g), rhodium(II)acetate dimer (117 mg) and iodobenzene diacetate (5.1 g) were added, and the mixture was stirred for further 12 h at 45 C. The mixture was allowed to cool to room temperature, filtered over a pad of Celite and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (12.8 g, 97% purity).

[1493] LC-MS (Method a): R.sub.t=1.22 min; MS (ESIpos): m/z=445 [M+H].sup.+

[1494] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.15-1.24 (m, 3H), 1.39 (s, 9H), 1.98-2.06 (m, 2H), 2.44-2.44 (m, 1H), 3.09-3.19 (m, 3H), 4.04-4.16 (m, 4H), 4.95-5.10 (m, 2H), 7.41-7.47 (m, 1H), 7.73-7.80 (m, 1H), 7.88-7.94 (m, 1H) (two protons overlayed by residual DMSO).

[1495] Preparation of Intermediate 15.4:

(rac)-tert-butyl{[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1496] ##STR00168##

[1497] To a solution of (rac)-ethyl 4-(3-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-5-nitrophenoxy)butanoate (12.8 g) in THF (210 mL) at 20 C. was added dropwise diisobutylaluminum hydride (120 mL, 1.0 M in THF). The mixture was allowed to warm to room temperature and stirred for 2.5 h. The reaction was stopped by the addition of saturated aqueous sodium potassium tartrate solution. The mixture was vigorously stirred for 2 h and subsequently extracted three times with ethyl acetate (100 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to yield the title compound (8.01 g, 97% purity).

[1498] LC-MS (Method a): R.sub.t=1.02 min; MS (ESIpos): m/z=403 [M+H].sup.+

[1499] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.39 (s, 9H), 1.51-1.65 (m, 2H), 1.73-1.83 (m, 2H), 3.14 (s, 3H), 3.43-3.51 (m, 2H), 4.09-4.16 (m, 2H), 4.46-4.51 (m, 1H), 4.93-5.07 (m, 2H), 7.37-7.50 (m, 1H), 7.73-7.79 (m, 1H), 7.86-7.92 (m, 1H).

[1500] Preparation of Intermediate 15.5:

2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoroaniline

[1501] ##STR00169##

[1502] To a solution of 2,4-dichloro-5-fluoropyrimidine (2.46 g), 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.50 g, purchased from Milestone Pharmtech USA Inc.) and tetrakis(triphenylphosphino)palladium(0) (1.71 g) in 1,2-dimethoxyethane (120 mL) was added aqueous potassium carbonate (30 mL, 1.5 M) and the mixture was heated to 90 C. for 16 h. The mixture was allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium chloride, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (2.33 g, 95% purity).

[1503] LC-MS (Method a): R.sub.t=1.11 min; MS (ESIpos): m/z=242 [M+H].sup.+

[1504] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=6.29-6.40 (m, 2H), 6.42-6.51 (m, 1H), 6.54-6.61 (m, 1H), 7.41-7.48 (m, 1H), 8.84-8.89 (m, 1H).

[1505] Preparation of Intermediate 15.6:

[1506] N-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl]-2-nitrobenzenesulfonamide

##STR00170##

[1507] To a suspension of 2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoroaniline (2.33 g), 2-nitrobenzenesulfonyl chloride (2.56 g) and 4-dimethylaminopyridine (58.9 mg) in dichloromethane (12 mL) was added pyridine (940 L) and the mixture was stirred for 16 h. Additional portions of 2-nitrobenzenesulfonyl chloride (2.56 g) (0.4 eq.), 4-dimethylaminopyridine (58.9 mg) and pyridine (940 L) were added, and the mixture was stirred for an additional 4 h. The reaction was stopped by the addition of aqueous hydrochloric acid (1N, 100 mL) and the mixture was extracted three times with dichloromethane (100 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (3.46 g, 95% purity).

[1508] LC-MS (Method a): R.sub.t=1.22 min; MS (ESIpos): m/z=427 [M+H].sup.+

[1509] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=7.11-7.22 (m, 1H), 7.27-7.38 (m, 1H), 7.54-7.65 (m, 1H), 7.78-7.93 (m, 3H), 7.94-8.02 (m, 1H), 8.84-8.94 (m, 1H), 10.50-10.69 (m, 1H).

[1510] Preparation of Intermediate 15.7

(rac)-tert-butyl{[3-(4-{[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl][(2-nitrophenyl)sulfonyl]amino}butoxy)-5-nitrobenzyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1511] ##STR00171##

[1512] To a solution of N-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl]-2-nitrobenzenesulfonamide (3.00 g), (rac)-tert-butyl {[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (2.83 g) and triphenylphopshine (3.69 g) in dichloromethane (140 mL) at 0 C. was added diisopropyl azodicarboxylate (2.8 mL). The mixture was allowed to warm to room temperature, stirred for 4 h and concentrated. The residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (4.58 g, 70% purity) that was used without further purification.

[1513] LC-MS (Method a): R.sub.t=1.39 min; MS (ESIpos): m/z=812 [M+H].sup.+

[1514] Preparation of Intermediate 15.8:

(rac)-tert-butyl{[3-(4-{[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl]amino}butoxy)-5-nitrobenzyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1515] ##STR00172##

[1516] To a solution of crude (rac)-tert-butyl {[3-(4-{[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl][(2-nitrophenyl)sulfonyl]amino}butoxy)-5-nitrobenzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (4.58 g) in DMF (75 ml) was added cesium carbonate (2.58 g) and the mixture was stirred for 2 min. Then, thiophenol (490 l) was added and the mixture was stirred for 18 h. The mixture was diluted with water (150 mL) and extracted three times with ethyl acetate (100 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by preparative HPLC to yield the title compound (1.09 g, 99% purity).

[1517] HPLC Purification:

[1518] Instrument: Labomatic HD3000, AS-3000, Labcol Vario 4000 Plus, Knauer DAD 2600; column: YMC 10; eluent A: water+0.1 Vol-% formic acid (99%), eluent B: acetonitrile; gradient: 0.00-1.00 min 60% B (50.fwdarw.200 mL/min), 1.00-10.00 min 60-80% B (200 mL/min), DAD scan: 254 nm

[1519] LC-MS (Method a): R.sub.t=1.50 min; MS (ESIpos): m/z=626 [M+H].sup.+

[1520] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.37 (s, 9H), 1.68-1.81 (m, 2H), 1.81-1.92 (m, 2H), 3.12-3.17 (m, 3H), 3.18-3.24 (m, 2H), 4.15-4.21 (m, 2H), 4.93-5.06 (m, 2H), 6.44-6.55 (m, 1H), 6.56-6.65 (m, 1H), 6.91-6.99 (m, 1H), 7.40-7.46 (m, 1H), 7.46-7.52 (m, 1H), 7.73-7.81 (m, 1H), 7.87-7.93 (m, 1H), 8.84-8.89 (m, 1H)

[1521] Preparation of Intermediate 15.9:

(rac)-tert-butyl{[3-amino-5-(4-{[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl]amino}butoxy)benzyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1522] ##STR00173##

[1523] To a solution of (rac)-tert-butyl {[3-(4-{[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl]amino}butoxy)-5-nitrobenzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (1.09 g) in methanol (28 mL) and THF (8.5 mL) was added platinum 1% and vanadium 2% on activated carbon (170 mg). The mixture was purged with hydrogen gas (1 atm) and stirred for 2.5 h. The mixture was filtered and concentrated to yield the title compound (1.02 g, 99% purity) that was used without further purification.

[1524] LC-MS (Method a): R.sub.t=1.39 min; MS (ESIpos): m/z=597 [M+H].sup.+

[1525] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) 6 ppm 1.35-1.39 (m, 9H), 1.63-1.74 (m, 2H), 1.74-1.85 (m, 2H), 3.00-3.09 (m, 3H), 3.12-3.22 (m, 2H), 3.85-3.92 (m, 2H), 4.52-4.66 (m, 2H), 5.15-5.24 (m, 2H), 6.11-6.22 (m, 3H), 6.46-6.54 (m, 1H), 6.56-6.64 (m, 1H), 6.91-6.99 (m, 1H), 7.42-7.53 (m, 1H), 8.85-8.90 (m, 1H).

Example 15

Preparation of the End Product

[1526] A degassed suspension of (rac)-tert-butyl {[3-amino-5-(4-{[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl]amino}butoxy)benzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (210 mg), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (58.3 mg), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (84.0 mg) and potassium phosphate (374 mg) in toluene (21 mL) and N-methylpyrrolidone (2.1 mL) was heated at 130 C. for 7 h. The mixture was allowed to cool to room temperature, diluted with water (60 mL) and extracted three times with ethyl acetate (30 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate) yielded the title compound (85 mg, 98% purity).

[1527] LC-MS (Method a): R.sub.t=1.37 min; MS (ESIpos): m/z=560 [M+H].sup.+

[1528] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.38 (s, 9H), 1.57-1.68 (m, 4H), 3.11 (s, 3H), 3.24-3.50 (m, 4H), 4.56-4.73 (m, 2H), 5.93-6.08 (m, 1H), 6.44-6.49 (m, 1H), 6.62-6.67 (m, 1H), 6.70-6.75 (m, 1H), 6.76-6.84 (m, 1H), 7.37-7.49 (m, 1H), 8.00-8.08 (m, 1H), 8.57-8.63 (m, 1H), 9.86-9.95 (m, 1H).

Example 16

(rac)-16,20-difluoro-9-[(S-methylsulfonimidoyl)methyl]-2,3,4,5-tetrahydro-1H-17,13-(azeno)-7,11-(metheno)-6,1,12,14-benzoxatriazacyclononadecine

[1529] ##STR00174##

[1530] To a solution of (rac)-tert-butyl [{[16,20-difluoro-2,3,4,5-tetrahydro-1H-17,13-(azeno)-7,11-(metheno)-6,1,12,14-benzoxatriazacyclononadecin-9(12H)-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (80.0 mg) in dichloromethane (1.2 mL) was added trifluoroacetic acid (280 L) and the mixture was stirred for 1.5 h. The pH value of the reaction mixture was adjusted to pH>7 by the addition of saturated aqueous sodium bicarbonate solution (5 mL), and the mixture was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride, dried and concentrated to yield the title compound (66 mg, 98% purity).

[1531] LC-MS (Method a): R.sub.t=1.15 min; MS (ESIpos): m/z=460 [M+H].sup.+

[1532] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.61-1.84 (m, 4H), 2.79 (s, 3H), 3.15-3.28 (m, 2H), 3.54 (s, 1H), 4.08-4.15 (m, 2H), 4.21 (d, 2H), 6.34-6.46 (m, 1H), 6.45-6.55 (m, 2H), 6.60-6.76 (m, 2H), 7.13-7.24 (m, 1H), 7.90-8.00 (m, 1H), 8.65 (d, 1H), 9.75 (s, 1H).

Example 17

(rac)-16,20-difluoro-6-methyl-9-[(S-methylsulfonimidoyl)methyl]-1,2,3,4,5,6-hexahydro-12H-17,13-(azeno)-11,7-(metheno)-1,6,12,14-benzotetraazacyclononadecine; salt with formic acid

[1533] ##STR00175##

[1534] Preparation of Intermediate 17.1:

tert-butyl [4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]methylcarbamate

[1535] ##STR00176##

[1536] To a solution of tert-butyl (4-hydroxybutyl)methylcarbamate (1.25 g), 1H-isoindole-1,3(2H)-dione (1.36 g) and triphenylphosphine (1.77 g) in dichloromethane (15 ml) at 0 C. was added diisopropyl azodicarboxylate (1.3 mL). The mixture was allowed to warm to room temperature and stirred for an additional 18 h. The reaction was stopped by the addition of water (60 mL) and the mixture was extracted twice with dichloromethane (100 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (3.33 g, 57% purity) that was used without further purification.

[1537] LC-MS (Method a): R.sub.t=1.26 min; MS (ESIpos): m/z=333 [M+H].sup.+

[1538] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.27-1.39 (br s, 9H), 1.41-1.59 (m, 4H), 2.68-2.79 (m, 3H), 3.06-3.23 (m, 2H), 3.51-3.70 (m, 2H), 7.76-7.91 (m, 4H).

[1539] Preparation of Intermediate 17.2:

2-[4-(methylamino)butyl]-1H-isoindole-1,3(2H)-dione

[1540] ##STR00177##

[1541] To a solution of tert-butyl [4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]methylcarbamate (2.83 g) in dichloromethane (66 mL) was added trifluoroacetic acid (21 mL) and the mixture was stirred for 2 h. The pH value of the reaction mixture was adjusted to pH>7 by the addition of saturated aqueous sodium bicarbonate solution (40 mL) and the mixture was extracted three times with dichloromethane (40 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to yield the title compound (870 mg, 99% purity).

[1542] LC-MS (Method a): R.sub.t=0.58 min; MS (ESIpos): m/z=233 [M+H].sup.+

[1543] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.32-1.46 (m, 2H), 1.55-1.65 (m, 2H), 2.18-2.24 (m, 3H), 2.39-2.46 (m, 2H), 3.52-3.61 (m, 2H), 7.81-7.89 (m, 4H) (NH obscured).

[1544] Preparation of Intermediate 17.3:

(rac)-tert-butyl[(3-{[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl](methyl)amino}-5-nitrobenzyl)(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1545] ##STR00178##

[1546] To a solution of 2-[4-(methylamino)butyl]-1H-isoindole-1,3(2H)-dione (795 mg) and (rac)-tert-butyl [(3-fluoro-5-nitrobenzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (see Intermediate 6.5; 1.14 g) in DMSO (34 mL) was added triethylamine (570 L) and the mixture was heated at 100 C. for 5 h, at 115 C. for 16 h and at 150 C. for 4 h. The mixture was allowed to cool to room temperature, diluted with water (50 mL) and extracted three times with ethyl acetate (100 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to yield the title compound (430 mg, 95% purity).

[1547] LC-MS (Method a): R.sub.t=1.31 min; MS (ESIpos): m/z=545 [M+H].sup.+

[1548] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm 1.38 (s, 9H), 1.50-1.65 (m, 4H), 2.95-3.00 (m, 3H), 3.05-3.12 (m, 3H), 3.39-3.48 (m, 2H), 3.57-3.62 (m, 2H), 4.83-4.98 (m, 2H), 7.15-7.19 (m, 1H), 7.34-7.38 (m, 1H), 7.43-7.49 (m, 1H), 7.80-7.89 (m, 4H).

[1549] Preparation of Intermediate 17.4:

(rac)-tert-butyl [(3-amino-5-{[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl](methyl)amino}benzyl)(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1550] ##STR00179##

[1551] To a solution of (rac)-tert-butyl[(3-{[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl](methyl)amino}-5-nitrobenzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (430 mg) in methanol (19 mL) and THF (1.9 mL) was added platinum 1% and vanadium 2% on activated carbon (77 mg). The mixture was purged with hydrogen gas (1 atm) and stirred for 0.75 h. Additional platinum 1% and vanadium 2% on activated carbon (100 mg) was added . The mixture was purged with hydrogen gas (1 atm) and stirred for 2.5 h. The mixture was filtered and concentrated to yield the title compound (403 mg, 95% purity) that was used without further purification.

[1552] LC-MS (Method a): R.sub.t=1.04 min; MS (ESIpos): m/z=516 [M+H].sup.+

[1553] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.36-1.40 (m, 9H), 1.44-1.55 (m, 2H), 1.55-1.63 (m, 2H), 2.76-2.81 (m, 3H), 2.97-3.02 (m, 3H), 3.20-3.27 (m, 2H), 3.55-3.61 (m, 2H), 4.45-4.58 (m, 2H), 4.86-4.97 (m, 2H), 5.87-5.94 (m, 2H), 5.96-6.01 (m, 1H), 7.80-7.89 (m, 4H)

[1554] Preparation of Intermediate 17.5:

(rac)-tert-butyl [(3-{[4-(2,4-difluorophenyl)-5-fluoropyrimidin-2-yl]amino}-5-{[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl](methyl)amino}benzyl)(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1555] ##STR00180##

[1556] A suspension of (rac)-tert-butyl [(3-amino-5-{[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl](methyl)amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (378 mg), 2-chloro-4-(2,4-difluorophenyl)-5-fluoropyrimidine (359 mg, purchased from Apollo Scientific), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (121 mg), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (70.0 mg) and potassium phosphate (1.20 g) in 1,4-dioxane (23 mL) was heated to 115 C. for 3 h. The mixture was allowed to cool to room temperature, filtered, diluted with saturated aqueous sodium chloride solution (50 mL) and extracted three times with ethyl acetate (100 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to yield the title compound (541 mg, 90% purity) that was used without further purification.

[1557] LC-MS (Method a): R.sub.t=1.47 min; MS (ESIpos): m/z=723 [M+H].sup.+

[1558] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.31-1.38 (m, 9H), 1.48-1.59 (m, 4H), 2.81-2.89 (m, 3H), 3.02-3.07 (m, 3H), 3.25-3.31 (m, 2H), 3.53-3.62 (m, 2H), 4.62-4.72 (m, 2H), 6.33-6.43 (m, 1H), 7.05-7.08 (m, 1H), 7.15-7.22 (m, 1H), 7.22-7.34 (m, 2H), 7.41-7.51 (m, 1H), 7.77-7.88 (m, 5H), 8.59-8.65 (m, 1H), 9.68-9.77 (m, 1H)

[1559] Preparation of Intermediate 17.6:

(rac)-tert-butyl[(3-[(4-aminobutyl)(methyl)amino]-5-{[4-(2,4-difluorophenyl)-5-fluoropyrimidin-2-yl]amino}benzyl)(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1560] ##STR00181##

[1561] To a suspension of (rac)-tert-butyl [(3-{[4-(2,4-difluorophenyl)-5-fluoropyrimidin-2-yl]amino}-5-{[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl](methyl)amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (441 mg) in ethanol (23 mL) and THF (4.7 mL) was added aqueous hydrazine (330 L, 35% purity) and the mixture was heated to reflux for 4 h. The mixture was cooled to 5 C., filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to yield the title compound (221 mg, 85% purity).

[1562] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.35 (s, 9H), 1.43-1.59 (m, 4H), 2.83-2.89 (m, 4H), 3.05-3.11 (m, 4H), 3.21-3.31 (m, 2H), 4.63-4.76 (m, 2H), 6.28-6.41 (m, 1H), 7.03-7.11 (m, 1H), 7.18-7.26 (m, 1H), 7.27-7.36 (m, 1H), 7.46-7.55 (m, 1H), 7.79-7.88 (m, 1H), 8.62-8.69 (m, 1H), 9.72-9.80 (m, 1H).

Example 17

Preparation of the End Product

[1563] To a solution (rac)-tert-butyl [(3-[(4-aminobutyl)(methyl)amino]-5-{[4-(2,4-difluorophenyl)-5-fluoropyrimidin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (211 mg) in DMSO (14 mL) was added triethylamine (60 L) and the mixture was stirred at 120 C. for 4 h. The mixture was allowed to cool to room temperature, diluted with water (30 mL) and extracted twice with ethyl acetate (80 mL each). The combined organic layers were sequentially washed with saturated aqueous bicarbonate solution and saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to crude (rac)-tert-butyl[{[16,20-difluoro-6-methyl-1,2,3,4,5,6-hexahydro-12H-17,13-(azeno)-11,7-(metheno)-1,6,12,14-benzotetraazacyclononadecin-9-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (92 mg) that was contaminated by impurities and which was used without further purification.

[1564] To a solution of crude (rac)-tert-butyl [{[16,20-difluoro-6-methyl-1,2,3,4,5,6-hexahydro-12H-17,13-(azeno)-11,7-(metheno)-1,6,12,14-benzotetraazacyclononadecin-9-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (130 mg) in dichloromethane (1.9 mL) was added trifluoroacetic acid (570 l) and the mixture was stirred for 1.5 h. The pH value of the reaction mixture was adjusted to pH>7 by the addition of saturated aqueous sodium bicarbonate (5 mL) and the mixture was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by preparative HPLC to yield the title compound (16 mg, 96% purity).

[1565] HPLC Purification:

[1566] Instrument: pump: Labomatic HD-5000, head HDK 280, low pressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 m, 12530 mm; solvent A: water+0.1 vol-% formic acid, solvent B: acetonitrile; gradient: 0.00-0.50 min 30% B (150 ml/min), 0.50-6.00 min 30-70% B (150 ml/min), 6.00-6.10 min 70-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); detection: UV 254 nm.

[1567] LC-MS (Method a): R.sub.t=1.17 min; MS (ESlneg): m/z=471 [MH].sup.

[1568] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.53-1.69 (m, 4H), 2.78-2.84 (m, 3H), 2.85-2.88 (m, 3H), 3.19-3.27 (m, 2H), 3.43-3.54 (m, 1H), 4.10-4.27 (m, 2H), 6.21-6.31 (m, 1H), 6.33-6.51 (m, 3H), 6.60-6.71 (m, 1H), 7.12-7.24 (m, 1H), 7.67-7.77 (m, 1H), 8.11-8.21 (m, 1H), 8.52-8.65 (m, 1H), 9.46-9.54 (m, 1H).

Example 18

2,19-difluoro-9-[(methylsulfanyl)methyl]-14,15,16,17-tetrahydro-6H,13H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclononadecine

[1569] ##STR00182##

[1570] Preparation of Intermediate 18.1:

5-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenyl]pent-4-yn-1-ol

[1571] ##STR00183##

[1572] To a solution of 2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenyl trifluoromethanesulfonate (see Intermediate 4.1; 3.00 g) in DMF (56 mL) was sequentially added pent-4-yn-1-ol (855 mg), copper(I)iodide (323 mg), triethylamine (2.4 mL) and bis(triphenylphosphino)palladium(II) chloride (594 mg), and the mixture was stirred at 80 C. for 16 h. The reaction was allowed to cool to room temperature, filtered over a pad of Celite and concentrated. The residue was portioned between ethyl acetate (150 mL) and water (50 mL). The organic layer was consecutively washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate to ethyl acetate/methanol) to yield the title compound (841 mg, 96% purity).

[1573] LC-MS (Method a): R.sub.t=0.84 min; MS (ESIpos): m/z=289 [M+H].sup.+

[1574] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.46-1.57 (m, 2H), 2.28-2.38 (m, 2H), 3.33-3.37 (m, 2H), 4.39-4.49 (m, 1H), 5.86-5.93 (m, 2H), 6.36-6.45 (m, 1H), 7.24-7.33 (m, 1H), 7.35-7.44 (m, 2H), 7.88-7.93 (m, 1H) (propargylic protons are overlayed by residual DMSO).

[1575] Preparation of Intermediate 18.2:

5-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenyl]pentan-1-ol

[1576] ##STR00184##

[1577] To a solution of 5-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenyl]pent-4-yn-1-ol (575 mg) in THF (19 mL) were sequentially added acetic acid (few drops) and palladium 10% on activated carbon (106 mg). The reactor was purged with hydrogen gas (48.9 bar) and the mixture was stirred at 50 C. for 18 h.

[1578] The mixture was cooled to room temperature, filtered (washing with THF) and concentrated to give the title compound (652 mg, 96% purity) that was used without further purification.

[1579] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm 1.12-1.22 (m, 2H), 1.25-1.33 (m, 2H), 1.37-1.48 (m, 2H), 1.88-1.93 (m, 3H), 2.14-2.22 (m, 1H), 2.42-2.47 (m, 2H), 3.26-3.31 (m, 2H), 4.26-4.33 (m, 1H), 5.89-6.00 (m, 2H), 6.23-6.34 (m, 1H), 7.07-7.14 (m, 1H), 7.17-7.25 (m, 2H), 7.89-7.93 (m, 1H).

[1580] Preparation of Intermediate 18.3:

4-{2-[5-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)pentyl]-4-fluorophenyl}-5-fluoropyridin-2-amine

[1581] ##STR00185##

[1582] To a solution of 5-[2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenyl]pentan-1-ol (424 mg) in THF (11 mL) at 0 C. was added sodium hydride (87.0 mg, 60% purity). The mixture was allowed to warm to room temperature and stirred for 30 min Then, 2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine (see Intermediate 1.7; 453 mg) was added and the mixture was heated to 90 C. for 2 h. An additional portion of 2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine (227 mg) was added and the mixture was stirred at 90 C. for an additional 2.5 h. The mixture was allowed to cool to room temperature and concentrated. The residue was diluted with water (20 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted three times with ethyl acetate (50 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (560 mg, 95% purity).

[1583] LC-MS (Method a): R.sub.t=1.48 min; MS (ESIpos): m/z=464 [M+H].sup.+

[1584] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.23-1.34 (m, 2H), 1.44-1.53 (m, 2H), 1.56-1.65 (m, 2H), 1.94 (s, 3H), 3.63 (s, 2H), 4.10-4.18 (m, 2H), 5.88-5.97 (m, 2H), 6.27-6.35 (m, 1H), 6.70-6.74 (m, 1H), 6.97-7.02 (m, 1H), 7.06-7.14 (m, 1H), 7.18-7.27 (m, 2H), 7.85-7.96 (m, 1H) (one methylene group overlayed by residual DMSO).

Example 18

Preparation of the End Product

[1585] A degassed suspension of 4-{2-[5-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)pentyl]-4-fluorophenyl}-5-fluoropyridin-2-amine (510 mg), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (182 mg), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (105 mg) and potassium phosphate (1.17 g) in toluene (100 mL) and N-methylpyrrolidone (10 mL) was heated at 130 C. for 18 h. The mixture was allowed to cool to room temperature, diluted with water (100 mL) and extracted three times with ethyl acetate (150 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The residue was treated with saturated aqueous sodium chloride solution (100 mL) and extracted three times with diethyl ether (150 mL each). The combined organic layers were concentrated and the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to give the crude title compound (310 mg, 80% purity) that was used without further purification. A pure sample was obtained by purification by preparative HPLC.

[1586] HPLC Purification:

[1587] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBridge C18 5 10030 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml/min; temperature: 25 C.; DAD scan: 210-400 nm.

[1588] LC-MS (Method a): R.sub.t=1.59 min; MS (ESIpos): m/z=428 [M+H].sup.+

[1589] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm 1.08-1.27 (m, 2H), 1.72-1.83 (m, 4H), 1.98 (s, 3H), 2.57-2.68 (m, 2H), 3.54 (s, 2H), 3.86-4.11 (m, 2H), 6.05-6.19 (m, 1H), 6.47-6.58 (m, 1H), 7.08-7.19 (m, 1H), 7.21-7.33 (m, 2H), 7.85-8.10 (m, 1H), 8.25-8.43 (m, 1H), 9.65-9.81 (m, 1H).

Example 19

(rac)-2,19-difluoro-9-[(methylsulfinyl)methyl]-14,15,16,17-tetrahydro-6H,13H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclononadecine

[1590] ##STR00186##

[1591] To a solution of 2,19-difluoro-9-[(methylsulfanyl)methyl]-14,15,16,17-tetrahydro-6H,13H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclononadecine (260 mg) in acetonitrile (19 ml) at 0 C. was added iron trichloride (9.9 mg) and the mixture was stirred for 10 min. Then, periodic acid (415 mg) was added and the mixture was stirred for 3 h at 0 C. The reaction was stopped by the addition of saturated aqueous sodium thiosulfate solution (50 mL) and the mixture was stirred for 10 min before being extracted twice with ethyl acetate (75 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated to give the crude title compound (239 mg, 80% purity) that was used without further purification. A pure sample was obtained by further purification by preparative HPLC.

[1592] HPLC Purification:

[1593] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBridge C18 5 10030 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 mL/min; temperature: 25 C.; DAD scan: 210-400 nm.

[1594] LC-MS (Method a): R.sub.t=1.28 min; MS (ESIpos): m/z=444 [M+H].sup.+

[1595] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.15-1.26 (m, 2H), 1.68-1.89 (m, 4H), 2.54 (s,3H), 2.58-2.67 (m, 2H), 3.77-3.88 (m, 1H), 3.94-4.08 (m, 3H), 6.07-6.17 (m, 1H), 6.44-6.53 (m, 1H), 7.10-7.19 (m, 1H), 7.21-7.34 (m, 2H), 7.84-7.96 (m, 1H), 8.29-8.35 (m, 1H), 9.66-9.86 (m, 1H).

Example 20

(rac)-2,19-difluoro-9-[(S-methylsulfonimidoyl)methyl]-14,15,16,17-tetrahydro-6H,13H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclononadecine

[1596] ##STR00187##

[1597] To a vigorously stirred solution of crude (rac)-2,19-difluoro-9-[(methylsulfinyl)methyl]-14,15,16,17-tetrahydro-6H,13H-7,11-(azeno)-5,1-(metheno)-12,4,6-benzoxadiazacyclononadecine (50.0 mg) in chloroform (770 L) at 0 C. was sequentially added sodium azide (58.6 mg) and concentrated aqueous sulfuric acid (120 l) (Caution: the reaction was carefully set up using a blast shield). The mixture was stirred at room temperature for 18 h. The mixture was carefully diluted with a mixture of saturated aqueous sodium chloride solution and saturated aqueous sodium bicarbonate solution (1:1, 35 mL), and then extracted three times with dichloromethane/methanol (9:1, 20 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude material was combined with two additional reaction batches carried out as described above. Purification by preparative HPLC yielded the title compound (11.1 mg, 97% purity).

[1598] HPLC Purification:

[1599] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBridge C18 5 10030 mm; eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml/min; temperature: 25 C.; DAD scan: 210-400 nm.

[1600] LC-MS (Method b): R.sub.t=1.24 min; MS (ESIpos): m/z=459 [M+H].sup.+

[1601] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.05-1.31 (m, 2H), 1.55-2.00 (m, 4H), 2.57-2.68 (m, 2H), 2.86 (s, 3H), 3.66-3.79 (m, 1H), 3.87-4.10 (m, 2H), 4.18-4.33 (m, 2H), 6.16-6.30 (m, 1H), 6.52-6.64 (m, 1H), 7.07-7.19 (m, 1H), 7.22-7.34 (m, 2H), 7.86-7.97 (m, 1H), 8.33 (s, 1H), 9.82 (s, 1H).

Example 21

(rac)-tert-butyl[{[16,20-difluoro-2,3,4,5-tetrahydro-12H-17,13-(azeno)-11,7-(metheno)-6,1,12,14-benzoxathiadiazacyclononadecin-9-yl]methyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1602] ##STR00188##

[1603] Preparation of Intermediate 21.1:

(rac)-tert-butyl[(3-{4-[(2-bromo-5-fluorophenyl)sulfanyl]butoxy}-5-nitrobenzyl)(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1604] ##STR00189##

[1605] To a solution of (rac)-tert-butyl {[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (see Intermediate 15.4; 1.00 g), 2-bromo-5-fluorobenzenethiol (514 mg, purchased from Oakwood Chemicals) and triphenylphosphine (717 mg) in dichloromethane (10 mL) was added diisopropyl azodicarboxylate (540 L) and the reaction was stirred for 3 h at room temperature. The mixture was concentrated and purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (1.03 g, 90% purity).

[1606] LC-MS (Method a): R.sub.t=1.51 min; MS (ESIpos): m/z=591 [M+H].sup.+

[1607] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 22 C.) /ppm=1.38 (s, 9H), 1.75-1.85 (m, 2H), 1.88-1.96 (m, 2H), 3.07-3.19 (m, 5H), 4.14-4.22 (m, 2H), 4.94-5.08 (m, 2H), 6.90-7.02 (m, 1H), 7.19-7.27 (m, 1H), 7.40-7.49 (m, 1H), 7.59-7.66 (m, 1H), 7.74-7.80 (m, 1H), 7.88-7.93 (m, 1H).

[1608] Preparation of Intermediate 21.2:

(rac)-tert-butyl{[3-(4-{[5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfanyl}butoxy)-5-nitrobenzyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1609] ##STR00190##

[1610] A suspension of (rac)-tert-butyl [(3-{4-[(2-bromo-5-fluorophenyl)sulfanyl]butoxy}-5-nitrobenzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (1.90 g), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi-1,3,2-dioxaborolane (979 mg), potassium acetate (1.58 g) and dichlorobis(tricyclohexylphosphine)palladium(II) (119 mg) in 1,4-dioxane (66 mL) was heated at 110 C. for 7 h. The mixture was cooled to room temperature, filtered (the filter cake was washed with ethyl acetate) and concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate) yielded the title compound (820 mg) as a mixture with the corresponding boronic acid and some further impurities. Such material was used without further purification in the next step.

[1611] LC-MS (Method a): R.sub.t=1.53 min; MS (ESIpos): m/z=639 [M+H].sup.+

[1612] Preparation of Intermediate 21.3:

(rac)-tert-butyl{[3-(4-{[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl]sulfanyl}butoxy)-5-nitrobenzyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1613] ##STR00191##

[1614] To a suspension of crude (rac)-tert-butyl {[3-(4-{[5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfanyl}butoxy)-5-nitrobenzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (820 mg), 2,4-dichloro-5-fluoropyrimidine (295 mg, purchased from Apollo Scientific) and [1,1-bis(diphenylphosphino)ferrocene]dichloro palladium(II) complex with dichloromethane (120 mg) in 1,2-dimethoxyethane (3.8 mL) was added aqueous potassium carbonate solution (2.2 mL, 2.0 M) and the mixture was stirred at 90 C. for 3.5 h. The mixture was cooled to room temperature, diluted with water (100 mL) and extracted three times with ethyl acetate (50 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate) yielded the crude title compound (300 mg) that was used in the next step without further purification.

[1615] LC-MS (Method a): R.sub.t=1.53 min; MS (ESIpos): m/z=643 [M+H].sup.+

[1616] Preparation of Intermediate 21.4:

(rac)-tert-butyl{[3-amino-5-(4-{[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl]sulfanyl}butoxy)benzyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1617] ##STR00192##

[1618] To a solution of crude (rac)-tert-butyl {[3-(4-{[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl]sulfanyl}butoxy)-5-nitrobenzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (300 mg) in methanol (11 mL) and THF (1.1 mL) was added platinum 1% and vanadium 2% on activated carbon (45.5 mg). The mixture was purged with hydrogen gas (1 atm) and stirred for 1.5 h at room temperature. The mixture was filtered and concentrated to yield the crude title compound (347 mg) that was used without further purification.

[1619] LC-MS (Method a): R.sub.t=1.39 min; MS (ESIpos): m/z=614 [M+H].sup.+

Example 21

Preparation of the End Product:

[1620] A degassed suspension of crude (rac)-tert-butyl {[3-amino-5-(4-{[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenyl]sulfanyl}butoxy)benzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (170 mg), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (45.9 mg), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (26.4 mg) and potassium phosphate (294 mg) in toluene (17 mL) and N-methylpyrrolidone (1.7 mL) was heated at 130 C. for 18 h. The mixture was allowed to cool to room temperature, diluted with water (50 mL) and extracted three times with ethyl acetate (20 mL each). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. Purification by preparative HPLC yielded the title compound (9.2 mg, 97% purity).

[1621] HPLC Purification

[1622] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBridge C18 5 10030 mm; eluent A: water+0.2 Vol-% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0.00-0.50 min 44% B (25.fwdarw.70 mL/min), 0.51-7.50 min 44-64% B (70 mL/min), DAD scan: 210-400 nm

[1623] LC-MS (Method b): R.sub.t=1.35 min; MS (ESIpos): m/z=577 [M+H].sup.+

[1624] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.35-1.42 (m, 9H), 1.74-1.90 (m, 4H), 3.08-3.13 (m, 3H), 3.16-3.26 (m, 2H), 3.98-4.09 (m, 2H), 4.66-4.73 (m, 2H), 6.46-6.57 (m, 1H), 6.71-6.77 (m, 1H), 7.06-7.15 (m, 1H), 7.35-7.47 (m, 2H), 8.14-8.23 (m, 1H), 8.69-8.78 (m, 1H), 9.93-9.97 (m, 1H).

Example 22

(rac)-16,20-difluoro-9-[(S-methylsulfonimidoyl)methyl]-2,3,4,5-tetrahydro-12H-17,13-(azeno)-11,7-(metheno)-6,1,12,14-benzoxathiadiazacyclononadecine

[1625] ##STR00193##

[1626] A solution of (rac)-tert-butyl [{[16,20-difluoro-2,3,4,5-tetrahydro-12H-17,13-(azeno)-11,7-(metheno)-6,1,12,14-benzoxathiadiazacyclononadecin-9-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (8.00 mg) in dichloromethane (2.0 mL) was treated with trifluoroacetic acid (27 L) and the mixture was stirred at room temperature for 3.5 h. The pH value of the reaction mixture was adjusted to pH>7 by the addition of saturated aqueous sodium bicarbonate solution. The mixture was then extracted with dichloromethane. The combined organic layers were dried and concentrated. Purification by HPLC yielded the title compound (3.9 mg, 99% purity).

[1627] HPLC Purification:

[1628] Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBridge C18 5 10030 mm; eluent A: water+0.1 vol-% formic acid (99%), eluent B: acetonitrile; gradient: 0.00-0.50 min 17% B (25.fwdarw.70 mL/min), 0.51-5.50 min 33-53% B (70 mL/min), DAD scan: 210-400 nm.

[1629] LC-MS (Method a): R.sub.t=1.10 min; MS (ESIpos): m/z=477 [M+H].sup.+

[1630] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.74-1.94 (m, 4H), 2.72-2.86 (m, 3H), 3.12-3.26 (m, 2H), 3.50-3.59 (m, 1H), 3.98-4.15 (m, 2H), 4.15-4.28 (m, 2H), 6.41-6.58 (m, 1H), 6.62-6.85 (m, 1H), 7.02-7.20 (m, 1H), 7.34-7.50 (m, 2H), 8.07-8.25 (m, 1H), 8.61-8.77 (m, 1H), 9.78-9.95 (m, 1H).

Example 23

(rac)-16,20-difluoro-6-methyl-9-[(S-methylsulfonimidoyl)methyl]-3,4,5,6-tetrahydro-2H,12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzoxatriazacyclononadecine

[1631] ##STR00194##

[1632] Trifluoroacetic acid (0.056 mL) was added to a stirred solution of (rac)-tert-butyl [{[16,20-difluoro-6-methyl-3,4,5,6-tetrahydro-2H,12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzoxatriazacyclononadecin-9-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (see Example 6; 13 mg) in DCM (0.1 mL) and the mixture was stirred for 2 h at room temperature. The pH value of the reaction mixture was adjusted to pH9 by the addition of an aqueous solution of potassium carbonate (2M) and extracted three times with dichloromethane. The combined organic phase was filtered using a Whatman filter and concentrated to give the title compound (7 mg).

[1633] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.61-1.74 (m, 2H), 1.81 (br d, 2H), 2.65-2.88 (m, 6H), 3.14-3.31 (m, 2H), 4.03 (d, 1H), 4.14-4.35 (m, 4H), 6.27 (s, 1H), 6.40 (s, 1H), 6.86 (td, 1H), 7.13 (dd, 1H), 7.36 (ddd, 1H), 7.68 (s, 1H), 8.61 (d, 1H), 9.52 (s, 1H).

Example 24

(rac)-tert-butyl[{[16,20-difluoro-3,4,5,6-tetrahydro-2H,12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzoxatriazacyclononadecin-9-yl]methyl}(methyl)oxido-.SUP.6.-sulfanylidene]carbamate

[1634] ##STR00195##

[1635] Preparation of Intermediate 24.1:

3-[(methylsulfanyl)methyl]-5-nitroaniline

[1636] ##STR00196##

[1637] Thionyl chloride (12.9 mL) was added dropwise to a stirred suspension of (3-amino-5-nitrophenyl)methanol (4.95 g) in DCM (96 mL) at room temperature and the mixture was stirred under under reflux for 18 h. After cooling the mixture was concentrated and the residue was dissolved in acetone (440 mL). An aqueous solution of sodium thiomethoxide (21%, 39 mL) was added under stirring at 0 C. and the mixture was stirred at room temperature for 72 h. The mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by flash chromatography on silica gel (hexane to hexane/ethyl acetate 40%) to give the title compound (4.85 g).

[1638] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.96 (s, 3H), 3.66 (s, 2H), 5.83 (s, 2H), 6.89 (t, 1H), 7.26 (s, 2H).

[1639] Preparation of Intermediate 24.2:

N-{3-[(methylsulfanyl)methyl]-5-nitrophenyl}-2-nitrobenzenesulfonamide

[1640] ##STR00197##

[1641] Pyridine (0.49 mL) was added to a stirred suspension of 3-[(methylsulfanyl)methyl]-5-nitroaniline (1.00 g) and 2-nitrobenzenesulfonyl chloride (1.34 g) in dichloromethane (6.1 mL) at room temperature. The mixture was stirred overnight. An aqueous solution of hydrogen chloride (1N, 8 mL) was added before the mixture was extracted three times with ethyl acetate. The combined organic phase was washed with an aqueous solution of sodium chloride, filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 50%) to give the title compound (1.80 g,).

[1642] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.82 (s, 3H), 3.77 (s, 2H), 7.50 (t, 1H), 7.79-7.91 (m, 4H), 7.95-8.09 (m, 2H), 11.35 (br s, 1H).

[1643] Preparation of Intermediate 24.3:

4-[2-(4-{[tert-butyl(dimethyl)silyl]oxy}butoxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine

[1644] ##STR00198##

[1645] Diisopropyl azodicarboxylate (9.84 mL) was added dropwise to a stirred mixture of 2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenol (6.00 g), 4-{[tert-butyl(dimethyl)silyl]oxy}butan-1-ol (10.11 g) and triphenylphosphine (13.49 g) in THF at 0 C. and the mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 20%) to give the desired title compound (11.1 g; 25.9 mmol), still containing some impurities.

[1646] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=-0.02 (s, 6H), 0.77-0.92 (m, 9H), 1.39-1.57 (m, 2H), 1.57-1.76 (m, 2H), 3.55 (s, 2H), 4.08 (s, 2H), 6.82-7.06 (m, 1H), 7.06-7.21 (m, 1H), 7.46-7.63 (m, 1H), 8.91 (d, 1H).

[1647] Preparation of Intermediate 24.4:

4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butan-1-ol

[1648] ##STR00199##

[1649] A mixture of 4-[2-(4-{[tert-butyl(dimethyl)silyl]oxy}butoxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine (11.1 g) in THF (666 mL) and an aqueous solution of hydrogen chloride (2M, 327 mL) was stirred at room temperature for 3 h. The pH value of the reaction mixture was adjusted to pH>7 by the addition of solid sodium bicarbonate. Solid sodium chloride was added and the mixture was extracted three times with ethyl acetate. The combined organic phase were dried and concentrated to give the crude product, that was used without further purification (9.86 g).

[1650] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.37-1.52 (m, 2H), 1.59-1.75 (m, 2H), 3.35-3.45 (m, 2H), 3.95-4.16 (m, 2H), 4.32-4.51 (m, 1H), 6.87-7.02 (m, 1H), 7.09-7.21 (m, 1H), 7.54 (dd, 1H), 8.93 (d, 1H).

[1651] Preparation of Intermediate 24.5:

N-{4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}-N-{3-[(methylsulfanyl)methyl]-5-nitrophenyl}-2-nitrobenzenesulfonamide

[1652] ##STR00200##

[1653] Diisopropyl azodicarboxylate (0.74 mL) was added dropwise to a stirred mixture of 4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butan-1-ol (591 mg; see Intermediate 1.3), N-{3-[(methylsulfanyl)methyl]-5-nitrophenyl}-2-nitrobenzenesulfonamide (720 mg) and triphenylphosphine (985 mg) in DCM (29 mL) at 0 C. and the mixture was stirred for 6 h at room temperature. The mixture was concentrated and the residue was purified by preparative HPLC (basic conditions) to give the title compound (418 mg).

[1654] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.39-1.53 (m, 2H), 1.62-1.71 (m, 2H), 1.81 (s, 3H), 3.76-3.85 (m, 4H), 4.05 (t, 2H), 6.96 (td, 1H), 7.10 (dd, 1H), 7.51 (dd, 1H), 7.59 (t, 1H), 7.77-7.81 (m, 2H), 7.86-7.97 (m, 3H), 8.21 (t, 1H), 8.76 (d, 1H).

[1655] Preparation of Intermediate 24.6:

(rac)-N-{4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}-N-{3-[(methylsulfinyl)methyl]-5-nitrophenyl}-2-nitrobenzenesulfonamide

[1656] ##STR00201##

[1657] To a stirred solution of N-{4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}-N-{3-[(methylsulfanyl)methyl]-5-nitrophenyl}-2-nitrobenzenesulfonamide (418 mg) in MeCN (16.4 mL) at 0 C. was added iron(III) chloride (2.9 mg) and the mixture was stirred for 10 minutes at room temperature. Then, periodic acid (150 mg) was added and the mixture was stirred for 2 h while cooling with an ice bath. The reaction was stopped by pouring onto ice and saturated aqueous sodium thiosulfate (30 mL) was added. The mixture was stirred for 10 min and the product was extracted twice with ethyl acetate/THF 1:1; (50 mL each). The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (DCM to DCM/EtOH 50%) to yield the title compound (220 mg).

[1658] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.39-1.51 (m, 2H), 1.62-1.71 (m, 2H), 2.34 (s, 3H), 3.82 (br t, 2H), 4.01-4.11 (m, 3H), 4.30 (d, 1H), 6.96 (td, 1H), 7.10 (dd, 1H), 7.12 (d, 1H), 7.51 (dd, 1H), 7.66 (t, 1H), 7.75-7.82 (m, 2H), 7.89-8.00 (m, 3H), 8.20 (d, 1H), 8.20 (s, 1H), 8.78 (d, 1H).

[1659] Preparation of Intermediate 24.7:

(rac)-tert-butyl{[3-({4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}amino)-5-nitrobenzyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1660] ##STR00202##

[1661] To a suspension of (rac)-N-{4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}-N-{3-[(methylsulfinyl)methyl]-5-nitrophenyl}-2-nitrobenzenesulfonamide (420 mg), tert-butyl carbamate (106 mg), magnesium oxide (97 mg) and rhodium(II) acetate dimer (7 mg) in DCM (21 mL) was added iodobenzene diacetate (292 mg) at room temperature under an atmosphere of argon. The mixture was stirred for 18 h at 45 C. The reaction mixture was concentrated to a volume of about 3 mL and the mixture was then purified by column chromatography on silica gel (hexane/ethyl acetate 20% to 70%) to give the desired title compound (396 mg).

[1662] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.37 (s, 9H), 1.40-1.53 (m, 2H), 1.61-1.71 (m, 2H), 3.03 (s, 3H), 3.76-3.88 (m, 2H), 4.00-4.07 (m, 2H), 4.98-5.09 (m, 2H), 6.96 (td, 1H), 7.10 (dd, 1H), 7.51 (dd, 1H), 7.76-7.84 (m, 3H), 7.89-7.98 (m, 2H), 8.06 (t, 1H), 8.31 (t, 1H), 8.77 (d, 1H).

[1663] Preparation of Intermediate 24.8:

(rac)-tert-butyl{[3-({4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}amino)-5-nitrobenzyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1664] ##STR00203##

[1665] A suspension of (rac)-tert-butyl {[3-({4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}amino)-5-nitrobenzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (200 mg) and cesium carbonate (161 mg) in DMF (4.7 mL) was stirred at room temperature for 2 minutes before thiophenol (33 mg) was added. The mixture was stirred at room temperature for 4 h. Then it was diluted with water and extracted three times with ethyl acetate. The combined organic phase was washed with aqueous sodium chloride solution, dried and concentrated. The residue was purified by preparative HPLC (Autopurifier; acidic conditions) to give the title compound (90 mg), still containing slight impurities.

[1666] Preparation of Intermediate 24.9:

(rac)-tert-butyl{[3-amino-5-({4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}amino)benzyl](methyl)oxido-.SUP.6.-sulfanylidene}carbamate

[1667] ##STR00204##

[1668] Platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder, 21 mg) was added to a solution of (rac)-tert-butyl {[3-({4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}amino)-5-nitrobenzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate(80 mg) in methanol (21 mL) and the mixture was stirred for 1 h at room temperature under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (Autopurifier, acidic conditions) to give the title compound (14 mg).

[1669] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.39 (m, 9H), 1.50-1.63 (m, 2H), 1.67-1.77 (m, 2H), 2.97 (br t, 2H), 3.11 (s, 3H), 4.10 (t, 2H), 4.58-4.67 (m, 2H), 6.14-6.34 (m, 3H), 6.98 (td, 1H), 7.09-7.23 (m, 1H), 7.54 (dd, 1H), 8.87 (d, 1H).

Example 24

Preparation of End Product

[1670] A mixture of (rac)-tert-butyl {[3-amino-5-({4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butyl}amino)benzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate (14.0 mg), chloro(2-dicyclohexylphosphino-2,4,6-tri-iso-propyl-1,1-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (1.9 mg; purchased from ABCR GmbH & CO. KG) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (1.1 mg; purchased from Aldrich Chemical Company Inc.) and potassium phosphate (24.9 mg) in toluene (1.8 mL) and NMP (0.2 mL) was stirred under an atmosphere of argon at 110 C. for 3 h. After cooling, the batch was diluted with with aqueous sodium chloride solution and extracted twice with ethyl acetate. The combined organic phase was dried and concentrated. The residue was purified by preparative HPLC (Autopurifier; basic conditions) to give the desired title compound (6 mg).

[1671] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.37 (s, 9H), 1.66 (br d, 2H), 1.80 (br s, 2H), 3.02-3.14 (m, 5H), 4.25 (br t, 2H), 4.52-4.59 (m, 2H), 5.96 (t, 1H), 6.19 (s, 1H), 6.29 (s, 1H), 6.86 (td, 1H), 7.12 (dd, 1H), 7.32-7.38 (m, 1H), 7.48 (s, 1H), 8.61 (d, 1H), 9.50 (s, 1H).

Example 25

(rac)-16,20-difluoro-9-[(S-methylsulfonimidoyl)methyl]-3,4,5,6-tetrahydro-2H,12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzoxatriazacyclononadecine

[1672] ##STR00205##

[1673] Trifluoroacetic acid (0.03 mL) was added to a stirred solution of (rac)-tert-butyl [{[16,20-difluoro-3,4,5,6-tetrahydro-2H,12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzoxatriazacyclononadecin-9-yl]methyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (6 mg) in DCM (0.1 mL) and the mixture was stirred for 2 h at room temperature. The mixture was diluted with aqueous sodium bicarbonate solution and extracted three times with ethyl acetate/THF (1:1). The combined organic phase was dried and concentrated. The residue was purified by preparative HPLC (Autopurifier; basic conditions) to give the desired product (4 mg).

[1674] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 295 K) /ppm=1.67 (br s, 2H), 1.77-1.84 (m, 2H), 2.81 (s, 3H), 3.01-3.08 (m, 2H), 3.42 (s, 1H), 4.08 (s, 1H), 4.13 (s, 1H), 4.25 (br t, 2H), 5.91 (t, 1H), 6.18 (s, 1H), 6.27 (s, 1H), 6.86 (td, 1H), 7.12 (dd, 1H), 7.35 (t, 1H), 7.44 (s, 1H), 8.60 (d, 1H), 9.45 (s, 1H).

[1675] The following Table 1 provides an overview on the compounds described in the example section:

TABLE-US-00003 TABLE 1 Example No. Structure Name of compound 1 [00206] 15,19-difluoro-8-[(methylsulfanyl)methyl]- 2,3,4,5-tetrahydro-11H-10,6-(azeno)-12,16- (metheno)-1,5,11,13- benzoxatriazacyclooctadecine 2 [00207] (rac)-benzyl[{[16,20-difluoro-3,4,5,6- tetrahydro-2H,12H-11,7-(azeno)-13,17- (metheno)-1,6,12,14- benzoxatriazacyclononadecin-9- yl]methyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 3 [00208] (rac)-16,20-difluoro-9-[(S- methylsulfonimidoyl)methyl]-3,4,5,6- tetrahydro-2H,12H-11,7-(azeno)-13,17- (metheno)-1,6,12,14- benzoxatriazacyclononadecine 4 [00209] 2,18-difluoro-9-[(methylsulfanyl)methyl]- 13,14,15,16-tetrahydro-6H-7,11-(azeno)-5,1- (metheno)-12,4,6- benzoxadiazacyclooctadecine 5 [00210] (rac)-2,18-difluoro-9- [(methylsulfinyl)methyl]-13,14,15,16- tetrahydro-6H-7,11-(azeno)-5,1-(metheno)- 12,4,6-benzoxadiazacyclooctadecine 6 [00211] (rac)-tert-butyl[{[16,20-difluoro-6-methyl- 3,4,5,6-tetrahydro-2H,12H-13,17-(azeno)- 11,7-(metheno)-1,6,12,14- benzoxatriazacyclononadecin-9- yl]methyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 7 [00212] (rac)-tert-butyl[{[15,19-difluoro-2,3,4,5- tetrahydro-11H-10,6-(azeno)-16,12- (metheno)-1,5,11,13- benzoxatriazacyclooctadecin-8- yl]methyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 8 [00213] (rac)-15,19-difluoro-8-[(S- methylsulfonimidoyl)methyl]-2,3,4,5- tetrahydro-11H-10,6-(azeno)-16,12- (metheno)-1,5,11,13- benzoxatriazacyclooctadecine 9 [00214] (rac)-tert-butyl[{[17,21-difluoro-2,3,4,5,6,7- hexahydro-13H-12,8-(azeno)-14,18- (metheno)-1,7,13,15- benzoxatriazacycloicosin-10- yl]methyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 10 [00215] (rac)-17,21-difluoro-10-[(S- methylsulfonimidoyl)methyl]-2,3,4,5,6,7- hexahydro-13H-12,8-(azeno)-14,18- (metheno)-1,7,13,15- benzoxatriazacycloicosine 11 [00216] (rac)-16,20-difluoro-6-methyl-9-[(S- methylsulfonimidoyl)methyl]-3,4,5,6- tetrahydro-2H-7,11-(azeno)-17,13- (metheno)-1,6,12,14- benzoxatriazacyclononadecine 12 [00217] 8,16,20-trifluoro-6-methyl-9- [(methylsulfanyl)methyl]-3,4,5,6-tetrahydro- 2H,12H-11,7-(azeno)-13,17-(metheno)- 1,6,12,14-benzoxatriazacyclononadecine 13 [00218] (rac)-tert-butyl[{[15,19-difluoro-1,2,3,4- tetrahydro-16,12-(azeno)-6,10-(metheno)- 5,1,11,13-benzoxatriazacyclooctadecin- 8(11H)-yl]methyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 14 [00219] (rac)-15,19-difluoro-8-[(S- methylsulfonimidoyl)methyl]-1,2,3,4- tetrahydro-16,12-(azeno)-6,10-(metheno)- 5,1,11,13-benzoxatriazacyclooctadecine 15 [00220] (rac)-tert-butyl[{[16,20-difluoro-2,3,4,5- tetrahydro-1H,12H-13,17-(azeno)-11,7- (metheno)-6,1,12,14- benzoxatriazacyclononadecin-9- yl]methyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 16 [00221] (rac)-16,20-difluoro-9-[(S- methylsulfonimidoyl)methyl]-2,3,4,5- tetrahydro-1H-17,13-(azeno)-7,11- (metheno)-6,1,12,14- benzoxatriazacyclononadecine 17 [00222] (rac)-16,20-difluoro-6-methyl-9-[(S- methylsulfonimidoyl)methyl]-1,2,3,4,5,6- hexahydro-12H-17,13-(azeno)-11,7- (metheno)-1,6,12,14- benzotetraazacyclononadecine; salt with formic acid 18 [00223] 2,19-difluoro-9-[(methylsulfanyl)methyl]- 14,15,16,17-tetrahydro-6H,13H-7,11- (azeno)-5,1-(metheno)-12,4,6- benzoxadiazacyclononadecine 19 [00224] (rac)-2,19-difluoro-9-[(- methylsulfinyl)methyl]-14,15,16,17- tetrahydro-6H,13H-7,11-(azeno)-5,1- (metheno)-12,4,6- benzoxadiazacyclononadecine 20 [00225] (rac)-2,19-difluoro-9-[(S- methylsulfonimidoyl)methyl]-14,15,16,17- tetrahydro-6H,13H-7,11-(azeno)-5,1- (metheno)-12,4,6- benzoxadiazacyclononadecine 21 [00226] (rac)-tert-butyl[{[16,20-difluoro-2,3,4,5- tetrahydro-12H-17,13-(azeno)-11,7- (metheno)-6,1,12,14- benzoxathiadiazacyclononadecin-9- yl]methyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 22 [00227] (rac)-16,20-difluoro-9-[(S- methylsulfonimidoyl)methyl]-2,3,4,5- tetrahydro-12H-17,13-(azeno)-11,7- (metheno)-6,1,12,14- benzoxathiadiazacyclononadecine 23 [00228] (rac)-16,20-difluoro-6-methyl-9-[(S- methylsulfonimidoyl)methyl]-3,4,5,6- tetrahydro-2H,12H-13,17-(azeno)-11,7- (metheno)-1,6,12,14- benzoxatriazacyclononadecine 24 [00229] (rac)-tert-butyl[{[16,20-difluoro-3,4,5,6- tetrahydro-2H,12H-13,17-(azeno)-11,7- (metheno)-1,6,12,14- benzoxatriazacyclononadecin-9- yl]methyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 25 [00230] (rac)-16,20-difluoro-9-[(S- methylsulfonimidoyl)methyl]-3,4,5,6- tetrahydro-2H,12H-13,17-(azeno)-11,7- (metheno)-1,6,12,14- benzoxatriazacyclononadecine

[1676] Results:

[1677] Table 2: Inhibition for CDK9 and CDK2 of compounds according to the present invention

[1678] The IC.sub.50 (inhibitory concentration at 50% of maximal effect) values are indicated in nM, n.t. means that the compounds have not been tested in the respective assay. [1679] {circle around (1)}: Example Number [1680] {circle around (2)}: CDK9: CDK9/CycT1 kinase assay as described under Method 1a. of Materials and Methods [1681] {circle around (3)}: CDK2: CDK2/CycE kinase assay as described under Method 2. of Materials and Methods [1682] {circle around (4)}: Selectivity CDK9 over CDK2: IC.sub.50 (CDK2)/IC.sub.50 (CDK9) according to Methods 1 a. and 2a. of Materials and Methods [1683] {circle around (5)}: high ATP CDK9: CDK9/CycT1 kinase assay as described under Method 1b. of Materials and Methods [1684] {circle around (6)}: high ATP CDK2: CDK2/CycE kinase assay as described under Method 2b. of Materials and Methods [1685] {circle around (7)}: Selectivity high ATP CDK9 over high ATP CDK2: IC.sub.50 (high ATP CDK2)/IC.sub.50 (high ATP CDK9) according to Methods 1b. and 2b. of Materials and Methods

[1686] Noteworthily, in the CDK9 assays, as described supra in the Methods 1a. and 1b. of Materials and Methods, resolution power is limited by the enzyme concentrations, the lower limit for IC.sub.50S is about 1-2 nM in the CDK9 high ATP assay and 2-4 nM in the CDK low ATP assays. For compounds exhibiting IC.sub.50S in this range the true affinity to CDK9 and thus the selectivity for CDK9 over CDK2 might be even higher, i.e. for these compounds the selectivity factors calculated in columns 4 and 7 of Table 2, infra, are minimal values, they could be also higher.

TABLE-US-00004 TABLE 2 {circle around (1)} Structure {circle around (2)} {circle around (3)} {circle around (4)} {circle around (5)} {circle around (6)} {circle around (7)} 1 [00231] 2.9 81.5 28.1 3.8 531 140 2 [00232] 14.7 698 47.5 12.7 8050 634 3 [00233] 8.3 44. 5.3 3.9 650 167 4 [00234] 36 >20000 >556 323 >20000 >61.9 5 [00235] 6.2 275 44.4 6.0 8250 1375 7 [00236] 7.5 27 3.6 1.9 61 32.1 8 [00237] 2.7 9.1 3.4 0.7 29 41.4 9 [00238] 13 96 7.4 6.8 253 37.2 10 [00239] 3.4 28 8.2 1.0 102 102 11 [00240] 5.1 34 6.7 2.6 80 31 12 [00241] 25 27 1.1 10 n.t. 13 [00242] 6.5 n.t. 3.0 1280 426 14 [00243] 3.2 n.t. 1.0 94 94 15 [00244] 8.9 262 29.4 4.7 3350 713 16 [00245] 3.9 30 7.7 1.5 227 151 17 [00246] 4.2 74 17.6 2.2 622 283 18 [00247] 99 2560 25.9 246 >20000 >81.3 19 [00248] 15 371 24.7 17 1410 82.9 20 [00249] 5.5 162 29.5 5.2 921 177 21 [00250] 13 11900 915 22 [00251] 4.5 1100 244 23 [00252] 5.2 104 20.0 2.1 1320 629 24 [00253] 91 2570 28.2 44 >20000 >454 25 [00254] 3.3 742 224

[1687] Tables 3a and 3b: Inhibition of proliferation of HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 and MOLM-13 cells by compounds according to the present invention, determined as described under Method 3. of Materials and Methods. All IC.sub.50 (inhibitory concentration at 50% of maximal effect) values are indicated in nM, n.t. means that the compounds have not been tested in the respective assay. [1688] {circle around (1)}: Example Number [1689] {circle around (2)}: Inhibition of HeLa cell proliferation [1690] {circle around (3)}: Inhibition of HeLa-MaTu-ADR cell proliferation [1691] {circle around (4)}: Inhibition of NCI-H460 cell proliferation [1692] {circle around (5)}: Inhibition of DU145 cell proliferation [1693] {circle around (6)}: Inhibition of Caco-2 cell proliferation [1694] {circle around (7)}: Inhibition of B16F10 cell proliferation [1695] {circle around (8)}: Inhibition of A2780 cell proliferation [1696] {circle around (9)}: Inhibition of MOLM-13 cell proliferation

TABLE-US-00005 TABLE 3a Indications represented by cell lines Cell line Source Indication HeLa ATCC Human cervical tumour HeLa-MaTu-ADR EPO-GmbH Berlin Multidrug-resistant human cervical carcinoma NCI-H460 ATCC Human non-small cell lung carcinoma DU 145 ATCC Hormone-independent human prostate carcinoma Caco-2 ATCC Human colorectal carcinoma B16F10 ATCC Mouse melanoma A2780 ECACC Human ovarian carcinoma MOLM-13 DSMZ Human acute myeloid leukemia

TABLE-US-00006 TABLE 3b Inhibition of proliferation {circle around (1)} Structure {circle around (2)} {circle around (3)} {circle around (4)} {circle around (5)} {circle around (6)} {circle around (7)} {circle around (8)} {circle around (9)} 1 [00255] 28 28 31 30 36 51 9 8 2 [00256] 77 >100 >100 119 80 93 98 77 38 3 3 [00257] 5.5 3.4 4 [00258] 9280 5570 4770 >10000 2550 >10000 21100 >3000 970 5 [00259] 955 830 1070 836 761 270 24 7 [00260] 32 53 37 30 33 44 7.0 6.8 8 [00261] 3.3 5.0 39 5.6 7.6 11 1.4 2.2 9 [00262] 33 75 39 36 48 85 27 19 10 [00263] 14 19 18 11 13 26 5.2 4.4 11 [00264] 10 12 12 12 8.9 12 4.6 8.2 12 [00265] 851 872 588 852 441 991 >100 100 13 [00266] 78 94 79 55 68 19 14 14 [00267] 4.7 3.1 15 [00268] 33 63 64 40 48 83 31 18 16 [00269] 10 13 20 12 12 18 8.2 4.1 17 [00270] 31 30 35 30 24 38 6.5 13 18 [00271] >10000 >10000 >10000 >10000 4640 >10000 >100 19 [00272] 1000 888 1150 942 944 1550 >100 231 20 [00273] 408 360 579 347 350 867 >100 161 79 21 [00274] 327 334 476 327 243 543 >100 162 22 [00275] 102 105 115 36 74 110 45 23 23 [00276] 13 9.8

[1697] Table 4a: Equilibrium dissociation constants K.sub.D [1/s], dissociation rate constants k.sub.off [1/s], and target resident times [min] as determined by Method 8. at 25 C. as described in Materials and Methods. Slight variations of experimental parameters are indicated by letters (A-G):

[1698] Parameters A: Described in Materials and Methods section 8.

[1699] Parameters B: Flow rate: 100 l/min, Injection time: 70 s, Dissociation time: 1200 s, Serial dilutions of compound (3.13 nM up to 100 nM)

[1700] Parameters C: Flow rate: 50 l/min, Injection time: 60 s, Dissociation time: 1200 s, Serial dilutions of compound (0.82 nM up to 200 nM)

[1701] Parameters D: Flow rate: 100 l/min, Injection time: 80 s, Dissociation time: 1200 s, Serial dilutions of compound (3.13 nM up to 100 nM)

[1702] Parameters E: Flow rate: 100 l/min, Injection time: 70 s, Dissociation time: 1100 s, Serial dilutions of compound (0.78 nM up to 25 nM) and measured at 37 C.

[1703] Parameters F: Flow rate: 100 l/min, Injection time: 70 s, Dissociation time: 1100 s, Serial dilutions of compound (1.56 nM up to 50 nM)

[1704] Parameters G: Flow rate: 100 l/min, Injection time: 70 s, Dissociation time: 1100 s, Serial dilutions of compound (3.13 nM up to 100 nM)

[1705] Dissociation rate constants below of what is resolvable with the respective assay are reported using the <-symbol (e.g. <2.5 E-5 s.sup.1)

[1706] Values labeled with * represent arithmetic means of more than one value. [1707] {circle around (1)}: Example Number [1708] {circle around (2)}: Equilibrium dissociation constant K.sub.D [1/s] [1709] {circle around (3)}: Dissociation rate constant k.sub.off [1/s] [1710] {circle around (4)}: Target resident time [min] [1711] {circle around (5)}: Experimental parameters as specified above [A-G]

TABLE-US-00007 TABLE 4a {circle around (1)} Structure {circle around (2)} {circle around (3)} {circle around (4)} {circle around (5)} 1 [00277] 3.49E9* 1.81E9 2.95E4* 1.41E4 .sup.56.6* .sup.118.2 A C 2 [00278] 4.01E9* 3.12E9 3.71E4* 5.04E4 .sup.44.9* .sup.33.1 A D 3 [00279] 1.00E9 1.05E9 1.40E9 <2.50E5 8.74E5 5.02E5 2.15E4 >666 .sup.190.7 .sup.332.0 .sup.77.5 B B B D 4 [00280] 1.18E8 1.14E3 .sup.14.6 C 5 [00281] 4.46E9 9.68E4 .sup.17.2 D 7 [00282] <2.50E5* >666* G 8 [00283] 5.29E10 3.70E10 1.28E10 7.61E10 <2.50E5 <2.50E5 7.92E5 6.84E5 3.32E5 9.18E5 <2.50E5 <2.50E5 >666 >666 .sup.210.4 .sup.243.7 .sup.502.0 .sup.181.6 >666 >666 G G G G G G G G 9 [00284] 7.52E9 3.17E9 3.96E4 2.87E4 <2.50E5 <2.50E5 .sup.42.1 .sup.58.1 >666 >666 G G G G 11 [00285] <2.50E5* >666* G 14 [00286] 3.53E10 <2.50E5 7.28E5 <2.50E5 <2.50E5 <2.50E5 <2.50E5 <2.50E5 <2.50E5 >666 .sup.228.9 >666 >666 >666 >666 >666 >666 G G G G G G G G 15 [00287] 9.21E11 <2.50E5 <2.50E5 <2.50E5 4.47E5 >666 >666 >666 .sup.372.9 F F F F 16 [00288] 2.09E10 3.06E10 6.80E5 9.15E5 <2.50E5 <2.50E5 <2.50E5 .sup.245.1 .sup.182.1 >666 >666 >666 G G G G G 18 [00289] >1.00E5* G 19 [00290] 1.13E8* 3.45E3* 4.8* G 20 [00291] 1.26E9* 1.13E3* .sup.14.7* F 23 [00292] 7.29E10* 1.91E4* .sup.87.3* D

[1712] Table 4b: Equilibrium dissociation constants K.sub.D [1/s], dissociation rate constants k.sub.off [1/s], and target resident times [min] as determined by Method 8. at 37 C. as described in Materials and Methods. Slight variations of experimental parameters are indicated by letters (A-G):

[1713] Parameters A: Described in Materials and Methods section 8.

[1714] Parameters B: Flow rate: 100 l/min, Injection time: 70 s, Dissociation time: 1200 s, Serial dilutions of compound (3.13 nM up to 100 nM)

[1715] Parameters C: Flow rate: 50 l/min, Injection time: 60 s, Dissociation time: 1200 s, Serial dilutions of compound (0.82 nM up to 200 nM)

[1716] Parameters D: Flow rate: 100 l/min, Injection time: 80 s, Dissociation time: 1200 s, Serial dilutions of compound (3.13 nM up to 100 nM)

[1717] Parameters E: Flow rate: 100 l/min, Injection time: 70 s, Dissociation time: 1100 s, Serial dilutions of compound (0.78 nM up to 25 nM) and measured at 37 C.

[1718] Parameters F: Flow rate: 100 l/min, Injection time: 70 s, Dissociation time: 1100 s, Serial dilutions of compound (1.56 nM up to 50 nM)

[1719] Parameters G: Flow rate: 100 l/min, Injection time: 70 s, Dissociation time: 1100 s, Serial dilutions of compound (3.13 nM up to 100 nM)

[1720] Dissociation rate constants below of what is resolvable with the respective assay are reported using the <-symbol (e.g. <8.0 E-5 s.sup.1).

[1721] Values labeled with * represent arithmetic means of more than one value. [1722] {circle around (1)}: Example Number [1723] {circle around (2)}: Equilibrium dissociation constant K.sub.D [1/s] [1724] {circle around (3)}: Dissociation rate constant k.sub.off [1/s] [1725] {circle around (4)}: Target resident time [min] [1726] {circle around (5)}: Experimental parameters as specified above [A-G]

[1727] It is expected that that the prolonged residence time of macrocyclic CDK9 inhibitors according to the invention will result in a sustained inhibitory effect on CDK9 signaling, ultimately contributing to sustained target engagement and anti-tumor efficacy.

TABLE-US-00008 TABLE 4b {circle around (1)} Structure {circle around (2)} {circle around (3)} {circle around (4)} {circle around (5)} 11 [00293] 2.92E10 2.83E10 1.87E4 1.46E4 <8.0E5 <8.0E5 <8.0E5 <8.0E5 89.1 114.2 >208 >208 >208 >208 E E E E E E 16 [00294] 2.38E10* 3.60E4* 46.3* E 17 [00295] 3.32E10* 1.44E4* 115.7* E 22 [00296] 1.10E9* 9.54E4* 17.5* E 25 [00297] 5.84E10* 1.13E3* 14.7* E