PTEFb inhibiting macrocyclic compounds

Abstract

The present invention relates to novel modified macrocyclic compounds with improved tolerability 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). ##STR00001##

Claims

1. A compound of general formula (I) ##STR00189## wherein A represents a bivalent moiety selected from the group consisting of —S—, —S(═O)—, —S(═O).sub.2—, —S(═O)(═NR.sup.5)—, and —S(═NR.sup.6)(═NR.sup.7)—; Z represents a hydrogen atom or a fluorine atom; L represents a C.sub.3-C.sub.8-alkylene moiety, wherein said moiety is optionally substituted with (i) one substituent selected from hydroxy, —NR.sup.8R.sup.9, 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, and —(CH.sub.2)NR.sup.8R.sup.9, 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.3-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—, and —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.1 represents a group selected from C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.7-cycloalkyl-, and heterocyclyl-, 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 amine, —OP(═O)(OH).sub.2, —C(═O)OH, and —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-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.3 and 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-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.5 represents a group selected from a hydrogen atom, cyano, —C(═O)R.sup.10, —C(═O)OR.sup.10, —S(═O.sub.2) R.sup.10, —C(═O)NR.sup.8R.sup.9, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, and heterocyclyl-, wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl- and heterocyclyl-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 amine, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.6 and R.sup.7 represent, independently from each other, a group selected from a hydrogen atom, cyano, —C(═O)R.sup.10, —C(═O)OR.sup.10, —S(═O).sub.2R.sup.10, —C(═O)NR.sup.8R.sup.9, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, and heterocyclyl-, wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl- or heterocyclyl-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 amine, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.8 and R.sup.9 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- and 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 amine, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-, or R.sup.8 and R.sup.9, together with the nitrogen atom they are attached to, form a cyclic amine; R.sup.10 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 amine, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

2. The compound of general 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)—, and —S(═NR.sup.6)(═NR.sup.7)—; Z represents a hydrogen atom or a fluorine atom; L represents a C.sub.3-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-, and —(CH.sub.2)NR.sup.8R.sup.9, and/or ii) one or two or three substituents, identically or differently, selected from halogen and C.sub.1-C.sub.3-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.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 amine, —OP(═O)(OH).sub.2, —C(═O)OH, and —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-, and C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.3 and 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-, and C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.5 represents a group selected from a hydrogen atom, cyano, —C(═O)R.sup.10, —C(═O)OR.sup.10, —S(═O).sub.2R.sup.10, —C(═O)NR.sup.8R.sup.9, C.sub.1-C.sub.6-alkyl-, and C.sub.3-C.sub.5-cycloalkyl-, wherein said C.sub.1-C.sub.6-alkyl- and C.sub.3-C.sub.5-cycloalkyl-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 amine, fluoro-C.sub.1-C.sub.2-alkyl-, and C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.6 and R.sup.7 represent, independently from each other, a group selected from a hydrogen atom, cyano, —C(═O)R.sup.10, —C(═O)OR.sup.10, —S(═O).sub.2R.sup.10, —C(═O)NR.sup.8R.sup.9, C.sub.1-C.sub.6-alkyl-, and C.sub.3-C.sub.5-cycloalkyl-, wherein said C.sub.1-C.sub.6-alkyl- and C.sub.3-C.sub.5-cycloalkyl-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 amine, fluoro-C.sub.1-C.sub.2-alkyl-, and C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.8 and R.sup.9 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- and 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 amine, fluoro-C.sub.1-C.sub.2-alkyl-, and C.sub.1-C.sub.2-fluoroalkoxy-, or R.sup.8 and R.sup.9, together with the nitrogen atom they are attached to, form a cyclic amine; R.sup.10 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 amine, fluoro-C.sub.1-C.sub.2-alkyl-, and C.sub.1-C.sub.2-fluoroalkoxy-, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

3. The compound of general 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)—, and —S(═NR.sup.6)(═NR.sup.7)—; Z represents a hydrogen atom or a fluorine atom; L represents a C.sub.3-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 or three C.sub.1-C.sub.2-alkyl-group substituents, identically or differently; 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, halogen, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-, —NH.sub.2, and —C(═O)OH; R.sup.2 represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-, and trifluoromethoxy-; R.sup.3 represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-, and 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.10, —C(═O)OR.sup.10, —S(═O).sub.2R.sup.10, —C(═O)NR.sup.8R.sup.9, and 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-, and cyclic amine; R.sup.6 and R.sup.7 represent, independently from each other, a group selected from a hydrogen atom, cyano, —C(═O)R.sup.10, —C(═O)OR.sup.10, —S(═O).sub.2R.sup.10, —C(═O)NR.sup.8R.sup.9, and 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-, and cyclic amine; R.sup.8 and R.sup.9 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- and 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-, and cyclic amine, or R.sup.8 and R.sup.9, together with the nitrogen atom they are attached to, form a cyclic amine; R.sup.10 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-, and —NH.sub.2, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

4. The compound of general 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)—, and —S(═NR.sup.6)(═NR.sup.7)—; Z represents a hydrogen atom or a fluorine atom; 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.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, and —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.10, —C(═O)OR.sup.10, —C(═O)NR.sup.8R.sup.9, and 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-, and dialkylamino-; R.sup.6 and R.sup.7 represent, independently from each other, a group selected from a hydrogen atom, cyano, and C.sub.1-C.sub.4-alkyl-, wherein said C.sub.1-C.sub.4-alkyl-group is optionally substituted with one hydroxy group; R.sup.8 and R.sup.9 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-, or R.sup.8 and R.sup.9, together with the nitrogen atom they are attached to, form a cyclic amine; R.sup.10 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-, and —NH.sub.2, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

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

6. The compound of general formula (I) according to claim 1, wherein A represents a bivalent moiety selected from the group consisting of —S(═O).sub.2—, —S(═O)(═NR.sup.5)—, and —S(═NR.sup.6)(═NR.sup.7)—; Z represents a hydrogen atom or a fluorine atom; 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 methyl-group; R.sup.2 represents a hydrogen atom; R.sup.3 represents a group selected from 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, cyano, —C(═O)R.sup.10, —C(═O)OR.sup.10, and 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-, and dialkylamino-; R.sup.6 and R.sup.7 represent, independently from each other, a group selected from a hydrogen atom, cyano, and C.sub.1-C.sub.4-alkyl-, wherein said C.sub.1-C.sub.4-alkyl-group is optionally substituted with one hydroxy group; R.sup.8 and R.sup.9 represent, independently from each other, a group selected from a hydrogen atom, C.sub.1-C.sub.2-alkyl; R.sup.10 represents a C.sub.1-C.sub.4-alkyl group, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

7. The compound of general 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—, and —S(═O)(═NR.sup.5)—; Z represents a hydrogen atom or a fluorine atom; 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.10, —C(═O)OR.sup.10, and C.sub.1-C.sub.3-alkyl-; R.sup.6 and R.sup.7 represent, independently from each other, a group selected from a hydrogen atom, cyano, —C(═O)R.sup.10, —C(═O)OR.sup.10, and C.sub.1-C.sub.3-alkyl-; R.sup.10 represents a group selected from C.sub.1-C.sub.4-alkyl-, trifluoromethyl-, and benzyl-, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

8. The compound of general 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)—, and —S(═NR.sup.6)(═NR.sup.7)—; Z represents a group selected from a hydrogen atom and a fluorine atom; L represents a C.sub.4-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 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 and —C(═O)OR.sup.10; R.sup.6 and R.sup.7 represent, independently from each other, a group selected from a hydrogen atom and —C(═O)OR.sup.10; R.sup.10 represents a group selected from tert-butyl- and benzyl-, or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

9. The compound of general formula (I) according to claim 1, wherein represents a group selected from a hydrogen atom and a fluorine atom, 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 general formula (I) according to claim 1, wherein A represents a bivalent moiety —S(═O)(═NR.sup.5)—; Z represents a group selected from a hydrogen atom and a fluorine atom, 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 methyl-group; R.sup.2 represents a hydrogen atom; R.sup.3 represents a fluorine atom; R.sup.4 represents a hydrogen atom; R.sup.5 represents a hydrogen atom or a —C(═O)OR.sup.10 group; R.sup.10 represents a tert butyl-group; or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

11. The compound according to claim 1, which is selected from the group consisting of: ##STR00190## ##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195## or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

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

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

14. A process for the preparation of a compound of formula (Ia), comprising reacting a compound of the formula (7) ##STR00196## wherein: Z represents a hydrogen atom or a fluorine atom; L represents a C.sub.3-C.sub.8-alkylene moiety, wherein said moiety is optionally substituted with (i) one substituent selected from hydroxy, —NR.sup.8R.sup.9, 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, and —(CH.sub.2)NR.sup.8R.sup.9, 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.3-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—, and —CH.sub.2OCH.sub.2—; R.sup.1 represents a group selected from C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.7-cycloalkyl-, and heterocyclyl-, 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 amine, —OP(═O)(OH).sub.2, —C(═O)OH, and —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-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.3 and 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-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.8 and R.sup.9 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- and 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-, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amine, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-, or R.sup.8 and R.sup.9, together with the nitrogen atom they are attached to, form a cyclic amine; in a C—N cross-coupling reaction to give compounds of the formula ##STR00197## 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.

15. A process for the preparation of a compound of formula (Id), comprising reacting a compound of the formula (19) ##STR00198## wherein: Z represents a hydrogen atom or a fluorine atom; L represents a C.sub.3-C.sub.8-alkylene moiety, wherein said moiety is optionally substituted with (i) one substituent selected from hydroxy, —NR.sup.8R.sup.9, 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, and —(CH.sub.2)NR.sup.8R.sup.9, 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.3-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—, and —CH.sub.2OCH.sub.2—; R.sup.1 represents a group selected from C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.7-cycloalkyl-, and heterocyclyl-, 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 amine, —OP(═O)(OH).sub.2, —C(═O)OH, and —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-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.3 and 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-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.8 and R.sup.9 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- and 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-, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amine, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-, or R.sup.8 and R.sup.9, together with the nitrogen atom they are attached to, form a cyclic amine; in a C—N cross-coupling reaction to give compounds of the formula (Id), ##STR00199## 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.

16. A method for the treatment of a hyper-proliferative disorder selected from the group consisting of cervical cancer, non-small cell lung cancer, prostate cancer, colorectal cancer, melanoma, ovarian cancer, acute myeloid leukemia, breast cancer, osteosarcoma, and lymphoma, comprising administering a therapeutically effective amount of the compound of general formula (I) according to claim 1 to a patient in need thereof.

17. The method of claim 16, wherein the prostate cancer is hormone-independent human prostate cancer.

18. The method of claim 16, wherein the cervical cancer is multidrug-resistant human cervical cancer.

19. A method for the treatment of a hyper-proliferative disorder selected from the group consisting of cervical cancer, non-small cell lung cancer, prostate cancer, colorectal cancer, melanoma, ovarian cancer, acute myeloid leukemia, breast cancer, osteosarcoma, and lymphoma, comprising administering a therapeutically effective amount of the pharmaceutical combination according to claim 12 to a patient in need thereof.

20. The method of claim 19, wherein the prostate cancer is hormone-independent human prostate cancer and the cervical cancer is multidrug-resistant human cervical cancer.

21. A method for the treatment of a hyper-proliferative disorder selected from the group consisting of cervical cancer, non-small cell lung cancer, prostate cancer, colorectal cancer, melanoma, ovarian cancer, acute myeloid leukemia, breast cancer, osteosarcoma, and lymphoma, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 13 to patient in need thereof.

22. The method of claim 21, wherein the prostate cancer is hormone-independent human prostate cancer and the cervical cancer is multidrug-resistant human cervical cancer.

Description

EXAMPLE 1

(rac)-tert-butyl [{[3,20-difluoro-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.SUP.2,6..1.SUP.8,12.]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(methyl)oxido-λ.SUP.6.-sulfanylidene]carbamate

(1) ##STR00030##

Preparation of Intermediate 1.1

2-chloro-5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridine

(2) ##STR00031##

(3) A batch with 2-chloro-5-fluoro-4-iodopyridine [CAS-RN: 884494-49-9] (3000 mg; 11.65 mmol), (4-fluoro-3-methoxyphenyl)boronic acid [CAS-RN: 854778-31-7] (1981 mg; 11.65 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [CAS-RN: 72287-26-4] (952 mg; 1.17 mmol) in 1,2-dimethoxyethane (30.0 mL) and 2 M aqueous solution of potassium carbonate (23 mL) was degassed using argon. The batch was stirred under an atmosphere of argon for 4 hours 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 title compound (2600 mg; 10.2 mmol).

(4) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=3.92 (s, 3H), 7.28 (ddt, 1H), 7.39 (dd, 1H), 7.48 (dd, 1H), 7.86 (d, 1H), 8.55 (d, 1H).

Preparation of Intermediate 1.2

5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridin-2-amine

(5) ##STR00032##

(6) A solution of lithium bis(trimethylsilyl)amide in THF (1M; 10.2 mL; 10.17 mmol; Aldrich Chemical Company Inc.) [CAS-RN: 4039-32-1] was added to a mixture of 2-chloro-5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridine (1.30 μg; 5.09 mmol; see Intermediate 1.1), tris(dibenzylideneacetone)dipalladium (0) (0.09 g; 0.10 mmol; Aldrich Chemical Company Inc.) [CAS-RN: 51364-51-3] and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.10 g; 0.20 mmol; Aldrich Chemical Company Inc.) [CAS-RN: 564483-18-7] in THF (10.4 mL) under an atmosphere of argon at room temperature. The mixture was stirred at 60° C. for 5 hours. The mixture was cooled to −20° C. and the pH was adjusted under cooling to 4-6 by the addition of aqueous hydrogen chloride solution (1N). The mixture was stirred at room temperature for 15 minutes before the pH was adjusted to 11 by the addition of aqueous sodium hydroxide solution (2N). The mixture was three times extracted 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 80%) to give the title compound (0.99 g; 4.2 mmol).

(7) 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.32-2.45 (m, 1H), 2.67 (s, 1H), 3.50 (s, 1H), 3.88 (s, 3H), 5.92 (s, 2H), 6.55 (d, 1H), 7.10 (ddd, 1H), 7.28-7.37 (m, 2H), 7.94 (d, 1H).

Preparation of Intermediate 1.3

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

(8) ##STR00033##

(9) A solution of boron tribromide in DCM (1M; 11.7 mL; 11.7 mmol; Aldrich Chemical Company Inc.) [CAS-RN: 10294-33-4] was added dropwise to a stirred solution of 5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridin-2-amine (988 mg; 4.18 mmol) in DCM (19 mL) at 0° C. The mixture was slowly warmed to room temperature while stirring overnight. The mixture was cautiously diluted with a saturated, aqueous solution of sodium bicarbonate under stirring at 0° C. and was stirred at room temperature for 1 hour. A saturated 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 title compound (1240 mg) that was used without further purification.

(10) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=5.92 (s, 2H), 6.48 (d, 1H), 6.96 (ddd, 1H), 7.13 (dt, 1H), 7.25 (dd, 1H), 7.92 (d, 1H), 10.19 (br s, 1H).

Preparation of Intermediate 1.4

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

(11) ##STR00034##

(12) To a stirred solution 2,6-dichloroisonicotinic acid (10.0 g, 52.1 mmol) [CAS-RN: 5398-44-7] in THF (300 mL) at 0° C. was added a solution of sulfanediyldimethane-borane (1:1) [CAS-RN: 13292-87-0](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 title compound (8.3 g; 46.6 mmol).

(13) .sup.1H-NMR (400 MHz, CDCl3, 300K): δ [ppm]=2.24 (br s, 1H), 4.77 (s, 2H), 7.25 (s, 2H),

Preparation of Intermediate 1.5

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

(14) ##STR00035##

(15) (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 [CAS-RN: 124-63-0] (0.9 g, 7.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. 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.

Preparation of Intermediate 1.6

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

(16) ##STR00036##

(17) (2,6-Dichloropyridin-4-yl)methyl methanesulfonate (1.40 g) 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 title compound (0.54 g; 2.60 mmol).

(18) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.97 (s, 3H), 3.53-3.92 (s, 2H), 7.54 (s, 2H).

Preparation of Intermediate 1.7

4-({6-Chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)butan-1-ol)

(19) ##STR00037##

(20) Sodium hydride (55-60%; 1.15 g) was added to a stirred solution of butane-1,4-diol (5.41 g; 60.1 mmol) in THF (165 mL) at 0° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 30 min. 2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine (5.0 g; 24.0 mmol) was added and the reaction mixture was stirred under reflux overnight. After cooling the batch was concentrated and ethyl acetate and water was added. The mixture was three times extracted with ethyl acetate. The combined organic layers were 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 60%) to give the title compound (4.3 g; 16.4 mmol).

(21) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.49-1.61 (m, 2H), 1.64-1.90 (m, 2H), 1.95-2.00 (m, 3H), 3.37-3.47 (m, 2H), 3.58-3.70 (m, 2H), 4.21 (t, 2H), 4.46 (t, 1H), 6.74 (s, 1H), 7.02 (d, 1H).

Preparation of Intermediate 1.8

(rac)-4-({6-chloro-4-[(methylsulfinyl)methyl]pyridin-2-yl}oxy)butan-1-ol

(22) ##STR00038##

(23) Iron(III)chloride (37 mg; 0.22 mmol) was added to a mixture of 4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)butan-1-ol (2000 mg; 7.64 mmol) in acetonitrile (18.5 mL) and the batch was stirred at room temperature for 10 minutes. The batch was cooled to 0° C. and periodic acid (1.86 g; 8.18 mmol) was added under stirring in one portion. After 5 hours the ice bath was removed and the mixture was stirred at room temperature. Additional periodic acid (0.52 g; 2.29 mmol) was added and the mixture was stirred for 2 hours at room temperature before it was added to a stirred solution of sodium thiosulfate pentahydrate [CAS-RN: 10102-17-7] (10.62 g; 42.79 mmol) in ice water (220 mL). The batch was stirred at room temperature for 1 hour and then extracted twice with ethyl acetate. The combined organic layers were 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 (ethyl acetate to ethyl acetate/ethanol 30%) to give the title compound (1.30 g; 4.68 mmol).

(24) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.48-1.58 (m, 2H), 1.65-1.81 (m, 2H), 3.35-3.51 (m, 2H), 3.90-4.05 (m, 1H), 4.13-4.26 (m, 3H), 4.45 (t, 1H), 6.75 (d, 1H), 7.02 (d, 1H).

Preparation of Intermediate 1.9

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

(25) ##STR00039##

(26) To a suspension of (rac)-4-({6-chloro-4-[(methylsulfinyl)methyl]pyridin-2-yl}oxy)butan-1-ol (1.30 g, 4.68 mmol), tert-butyl carbamate (822 mg, 7.02 mmol), magnesium oxide (754 mg, 18.72 mmol) and rhodium(II) acetate dimer [CAS-RN: 15956-28-2] (103 mg, 0.23 mmol) in DCM (45 mL) was added iodobenzene diacetate [CAS-RN: 3240-34-4] (2.26 g, 7.02 mmol) at room temperature. The batch was stirred for 18 h at room temperature, filtered over celite and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate) to give the title compound (960 mg, 2.44 mmol).

(27) 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.29-1.41 (m, 9H), 1.48-1.58 (m, 2H), 1.66-1.81 (m, 2H), 3.15-3.29 (m, 3H), 3.36-3.47 (m, 2H), 4.20-4.29 (m, 2H), 4.46 (t, 1H), 4.91 (d, 2H), 6.86 (s, 1H), 7.08 (d, 1H).

Preparation of Intermediate 1.10

(rac)-4-[(4-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-6-chloropyridin-2-yl)oxy]butyl Methanesulfonate

(28) ##STR00040##

(29) Methanesulfonyl chloride [CAS-RN: 124-63-0] (133 mg; 1.16 mmol) was added dropwise to a stirred solution of (rac)-tert-butyl [{[2-chloro-6-(4-hydroxybutoxy)pyridin-4-yl]methyl}(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (380 mg; 0.97 mmol) and trimethylamine (196 mg; 1.93 mmol) in DCM (4.2 mL) at 0° C. The ice bath was removed after 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with water and 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 70%) to give the title compound (450 mg, 0.96 mmol).

(30) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.39 (s, 9H), 1.75-1.86 (m, 4H), 3.18 (s, 6H), 4.22-4.31 (m, 4H), 4.91 (d, 2H), 6.88 (d, 1H), 7.10 (d, 1H).

Preparation of Intermediate 1.11

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

(31) ##STR00041##

(32) A mixture of 5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol (see Intermediate 1.3; 94 mg, 0.43 mmol), (rac)-4-[(4-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-6-chloropyridin-2-yl)oxy]butyl methanesulfonate (200 mg; 0.43 mmol) potassium carbonate (70 mg; 0.51 mmol) and potassium iodide (7 mg; 0.04 mmol) in DMF (3.3 mL) was stirred at 40° C. overnight. After cooling the mixture was diluted with ethyl acetate and washed with water. The organic phase was concentrated and the residue was purified by preparative HPLC (see method Autopurifier: acidic conditions) to give the title compound (70 mg; 0.12 mmol).

EXAMPLE 1 PREPARATION OF END PRODUCT

(33) To a solution of (rac)-tert-butyl {[(2-{4-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]butoxy}-6-chloropyridin-4-yl)methyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (70 mg, 0.12 mmol) in toluene (8.4 mL) and NMP (0.6 mL) was sequentially added potassium phosphate (124 mg, 0.59 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [CAS-RN: 564483-18-7] (5.6 mg, 0.01 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl) [2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct [CAS-RN: 1028206-56-5] (9.7 mg, 0.01 mmol). The suspension was degassed and heated under an atmosphere of argon to 110° C. for 4 hours. After cooling, the reaction mixture was diluted with aqueous sodium chloride solution and extracted three times with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified with preparative HPLC (see method Autopurifier: acidic conditions) to give the title compound (3 mg) still showing minor impurities.

(34) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.28-1.43 (m, 9H), 1.65-1.82 (m, 4H), 3.20 (s, 3H), 4.41-4.56 (m, 4H), 4.71-4.82 (m, 2H), 6.32 (d, 1H), 6.66 (s, 1H), 7.30-7.42 (m, 2H), 7.60 (d, 1H), 8.32 (d, 1H), 8.80 (d, 1H), 10.02 (s, 1H).

EXAMPLE 2

(rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.SUP.2,6..1.SUP.8,12.]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

(35) ##STR00042##

(36) To a solution of (rac)-tert-butyl [{[3,20-difluoro-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (5 mg) in dichloromethane (0.2 mL) was added trifluoroacetic acid (22 μL) 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. The mixture was extracted three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated to give the title compound (3 mg, 6.5 μmol).

(37) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.62-1.85 (m, 4H), 2.92 (s, 3H), 4.03 (q, 1H), 4.30-4.56 (m, 7H), 6.36 (s, 1H), 6.66 (s, 1H), 7.32-7.41 (m, 2H), 7.62 (d, 1H), 8.33 (d, 1H), 8.83 (d, 1H), 9.97 (s, 1H).

EXAMPLE 3

(rac)-tert-butyl [{[3,20-difluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1.SUP.2,6..1.SUP.8,12.]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(methyl)oxido-λ.SUP.6.-sulfanylidene]carbamate

(38) ##STR00043##

Preparation of Intermediate 3.1

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

(39) ##STR00044##

(40) A batch with 2,4-dichloro-5-fluoropyrimidine [CAS-RN: 1293994-86-1] (1000 mg; 5.99 mmol), (4-fluoro-3-hydroxyphenyl)boronic acid [CAS-RN: 913835-74-2] (1027 mg; 6.59 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [CAS-RN: 72287-26-4] (489 mg; 0.60 mmol) in 1,2-dimethoxyethane (18 mL) and 2 M aqueous solution of potassium carbonate (9 mL) was degassed using argon. The batch was stirred under an atmosphere of argon for 3 hours at 90° C. After cooling, the batch was diluted with ethyl acetate and washed with an 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 30%) to give the title compound (307 mg; 1.3 mmol).

(41) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=7.33-7.41 (m, 1H), 7.53 (dddt, 1H), 7.73 (dd, 1H), 8.93 (d, 1H), 10.42 (br s, 1H).

Preparation of Intermediate 3.2

3-(Chloromethyl)-5-nitrophenol

(42) ##STR00045##

(43) Thionyl chloride (84.0 g; 712 mmol) was added dropwise to a stirred solution of 3-(hydroxymethyl)-5-nitrophenol (60.0 g; 355 mmol) [CAS-RN: 180628-74-4] purchased from Struchem in DMF (1200 mL) at 0° C. The mixture was stirred at 10° C. for 3 hours. The mixture was concentrated, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and concentrated to afford the crude title compound (60.0 g) that was used without further purification.

Preparation of Intermediate 3.3

3-[(Methylsulfanyl)methyl]-5-nitrophenol

(44) ##STR00046##

(45) To a solution of crude 3-(chloromethyl)-5-nitrophenol (60.0 g) in acetone (600 mL) at room temperature was added an aqueous solution of sodium thiomethoxide (21%, 180 mL). The mixture was stirred at room temperature for 3 hours before additional aqueous solution of sodium thiomethoxide (21%, 180 mL) was added and the mixture was stirred at room temperature overnight. Finally, additional aqueous solution of sodium thiomethoxide (21%, 90 mL) was added and the mixture was stirred at room temperature for 6 hours. The batch was diluted with ethyl acetate and an aqueous solution of sodium chloride and extracted three times with ethyl acetate. The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (pentane/ethyl acetate 4:1) to afford the desired product (60.0 g, 302 mmol).

(46) .sup.1H NMR (300 MHz, CDCl.sub.3, 300K) δ=7.71 (1H), 7.57 (1H), 7.15 (1H), 3.66 (2H), 1.99 (3H).

Preparation of Intermediate 3.4

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

(47) ##STR00047##

(48) 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 [CAS-RN: 2969-81-5] (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.

(49) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/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).

Preparation of Intermediate 3.5

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

(50) ##STR00048##

(51) 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.

(52) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/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).

Preparation of Intermediate 3.6

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

(53) ##STR00049##

(54) 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 [CAS-RN: 15956-28-2] (352 mg) in dichloromethane (530 mL) was added iodobenzene diacetate [CAS-RN: 3240-34-4] (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).

(55) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/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)

Preparation of Intermediate 3.7

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

(56) ##STR00050##

(57) 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, hexane/ethyl acetate 40%.fwdarw.ethyl acetate.fwdarw.ethyl acetate/methanol 20%) to yield the title compound (8.01 g, 97% purity).

(58) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/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).

Preparation of Intermediate 3.8

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

(59) ##STR00051##

(60) Under argon, diisopropyl azodicarboxylate [CAS-RN: 2446-83-5] (0.45 mL; 2.27 mmol) was added dropwise to a stirred mixture of 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenol (see Intermediate 3.1; 300 mg; 1.24 mmol), (rac)-tert-butyl {[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (452 mg; 1.12 mmol) and triphenylphosphine (613 mg; 2.34 mmol) in THF (29 mL) at 0° C. The ice bath was removed and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 50%) to give the desired title compound (285 mg), still containing some impurities.

Preparation of Intermediate 3.9

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

(61) ##STR00052##

(62) Platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder, 44 mg) was added to a solution of (rac)-tert-butyl [(3-{4-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]butoxy}-5-nitrobenzyl)(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (282 mg) in methanol (7 mL) and THF (2 mL) and the mixture was stirred for 3 h at room temperature at room temperature under a hydrogen atmosphere. Additional platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder, 44 mg) was added and the mixture was stirred for additional 3 h at room temperature under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated to give the title compound that was used without further purification (231 mg).

EXAMPLE 3—PREPARATION OF THE END PRODUCT

(63) To a solution of (rac)-tert-butyl [(3-amino-5-{4-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]butoxy}benzyl)(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (229 mg) in toluene (29 mL) and NMP (1 mL) was sequentially added potassium phosphate (407 mg, 1.91 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [CAS-RN: 564483-18-7] (18 mg, 0.038 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl) [2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct [CAS-RN: 1028206-56-5] (32 mg, 0.038 mmol). The suspension was degassed and heated under argon to 110° C. for 3 hours. After cooling, the reaction mixture was diluted with aqueous sodium chloride solution and extracted three times 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/ethyl acetate 30% to ethyl acetate) to give the title compound (53 mg; 0.09 mmol).

(64) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.38 (s, 9H), 1.66-1.88 (m, 2H), 1.92-2.03 (m, 2H), 3.16 (s, 3H), 4.16 (t, 2H), 4.30 (t, 2H), 4.70-4.85 (m, 2H), 6.78 (s, 1H), 6.87 (s, 1H), 7.39 (dd, 1H), 7.62-7.71 (m, 1H), 8.01 (t, 1H), 8.18 (dd, 1H), 8.66 (d, 1H), 9.93 (s, 1H).

EXAMPLE 4

(rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1.SUP.2,6..1.SUP.8,12.]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

(65) ##STR00053##

(66) To a solution of (rac)-tert-butyl [{[3,20-difluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (see Example 3; 53 mg; 0.09 mmol) in dichloromethane (0.7 mL) was added trifluoroacetic acid (0.2 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. The mixture was extracted three times with ethyl acetate/THF. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (DCM to DCM/ethanol 20%) to give the title compound (20 mg, 0.04 mmol).

(67) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.70-1.87 (m, 2H), 1.87-2.04 (m, 2H), 2.84 (s, 3H), 3.63 (s, 1H), 4.12-4.21 (m, 2H), 4.25-4.34 (m, 4H), 6.79 (s, 1H), 6.84 (s, 1H), 7.39 (dd, 1H), 7.60-7.72 (m, 1H), 7.95 (t, 1H), 8.19 (dd, 1H), 8.65 (d, 1H), 9.87 (s, 1H).

EXAMPLE 5

(rac)-tert-butyl [{[3,21-difluoro-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1.SUP.2,6..1.SUP.8,12.]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaen-10-yl]methyl}(methyl)oxido-λ.SUP.6.-sulfanylidene]carbamate

(68) ##STR00054##

Preparation of Intermediate 5.1

methyl 5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentanoate

(69) ##STR00055##

(70) To a suspension of 3-[(methylsulfanyl)methyl]-5-nitrophenol (see Intermediate 3.3; 2.00 g; 10.0 mmol) and potassium carbonate (2.08 g; 15.1 mmol) in DMF (20 ml) at 0° C. was added methyl 5-bromopentanoate [CAS-RN: 5454-83-1] (1.7 mL; 12.0 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with aqueous sodium chloride solution and was three times extracted with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated to give the title compound (2.90 g) which was used without further purification.

(71) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.56-1.84 (m, 4H), 1.96 (s, 3H), 2.40 (tr, 3H), 3.33 (s, 3H), 3.79 (s, 2H), 4.10 (t, 2H), 7.35 (s, 1H), 7.59 (t, 1H), 7.78 (s, 1H).

Preparation of Intermediate 5.2

5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentan-1-ol

(72) ##STR00056##

(73) To a solution of methyl 5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentanoate (2.90 g) in THF (45 mL) at −78° C. was added dropwise a solution of diisobutylaluminum hydride in THF (1.0 M; 32.9 mL, 32.9 mmol). The mixture was allowed to warm to 0° C. and stirred for 2 h at this temperature. Water was cautiously added and the pH was adjusted to pH 4 by the addition of an aqueous solution of hydrogen chloride (1N). The mixture was three times extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by flash column chromatography on silica gel (hexane to hexane/ethyl acetate 70%) to give the title compound (2.40 g, 8.4 mmol).

(74) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.35-1.52 (m, 4H), 1.69-1.80 (m, 2H), 1.96 (s, 3H), 3.32-3.43 (m, 2H), 3.76 (s, 3H), 3.97-4.11 (m, 2H), 4.39 (t, 1H), 7.35 (s, 1H), 7.58 (t, 1H), 7.77 (t, 1H).

Preparation of Intermediate 5.3

(rac)-5-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}pentan-1-ol

(75) ##STR00057##

(76) To a solution of 5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentan-1-ol (2.30 g; 8.06 mmol) in acetonitrile (215 mL) at 0° C. was added iron trichloride (38 mg; 0.23 mmol) and the mixture was stirred for 15 min at room temperature. Periodic acid (1.97 g; 8.62 mmol) was added and the reaction was stirred for 4 h at 0° C. The ice bath was removed and the reaction was warmed to room temperature under stirring before it was added to a stirred solution of sodium thiosulfate pentahydrate (11.20 g; 45.14 mmol) in ice water (250 mL). The batch was saturated with solid sodium chloride and extracted twice with THF and extracted twice with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified by flash column chromatography on silica gel (hexane to hexane/ethyl acetate 70%) to give the title compound (1.43 g, 4.75 mmol).

(77) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.40-1.52 (m, 4H), 1.75 (quin, 2H), 3.38-3.44 (m, 2H), 4.03-4.12 (m, 3H), 4.28 (d, 1H), 4.39 (t, 1H), 7.35 (s, 1H), 7.68 (t, 1H), 7.79 (s, 1H).

Preparation of Intermediate 5.4

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

(78) ##STR00058##

(79) To a suspension of (rac)-5-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}pentan-1-ol (1430 mg; 4.75 mmol), tert-butyl carbamate (833 mg; 7.11 mmol), magnesium oxide (765 mg; 18.98 mmol), and rhodium(II)acetate dimer [CAS-RN: 15956-28-2] (105 mg; 0.24 mmol) in dichloromethane (46 mL) was added iodobenzene diacetate [CAS-RN: 3240-34-4] (2293 mg; 7.12 mmol), and the mixture was stirred at room temperature overnight. Additional portions of tert-butyl carbamate (416 mg; 3.56 mmol), magnesium oxide (382 mg; 9.49 mmol), rhodium(II)acetate dimer (52 mg; 0.12 mmol) and iodobenzene diacetate (1146 mg; 3.56 mmol) were added, and the mixture was stirred for further 12 h at room temperature. The mixture was filtered over a pad of Celite and concentrated. The residue was purified by flash column chromatography on silica gel, (hexane to hexane/ethyl acetate 30%) to give the title compound (920 mg; 2.20 mmol).

(80) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.32-1.55 (m, 13H), 1.70-1.83 (m, 2H), 3.14 (s, 3H), 3.35-3.44 (m, 2H), 4.06-4.13 (m, 2H), 4.39 (t, 1H), 4.95-5.05 (m, 2H), 7.44 (s, 1H), 7.72-7.77 (m, 1H), 7.90 (s, 1H).

Preparation of Intermediate 5.5

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

(81) ##STR00059##

(82) Under an atmosphere of argon, diisopropyl azodicarboxylate [CAS-RN: 2446-83-5] (0.88 mL; 4.46 mmol) was added dropwise to a stirred mixture of 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenol (see Intermediate 3.1; 589 mg; 2.43 mmol), (rac)-tert-butyl [{3-[(5-hydroxypentyl)oxy]-5-nitrobenzyl}(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (920 mg; 2.21 mmol) and triphenylphosphine (1205 mg; 4.60 mmol) in THF (10 mL) at 0° C. The ice bath was removed and the mixture was stirred at room temperature overnight. Additional portions of triphenylphosphine (1205 mg; 4.60 mmol) and diisopropyl azodicarboxylate (0.88 mL; 4.46 mmol) were added and the mixture was stirred for 5 h at room temperature. The mixture was concentrated and the residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 50%) to give the desired title compound (456 mg), still containing some impurities.

Preparation of Intermediate 5.6

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

(83) ##STR00060##

(84) Platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder, 117 mg) was added to a solution of (rac)-tert-butyl {[3-({5-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]pentyl}oxy)-5-nitrobenzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (456 mg; 0.71 mmol) in methanol (115 mL) and the mixture was stirred for 2 h at room temperature under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated to give the title compound that was used without further purification (385 mg).

EXAMPLE 5—PREPARATION OF THE END PRODUCT

(85) To a solution of (rac)-tert-butyl {[3-amino-5-({5-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]pentyl}oxy)benzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (385 mg) in toluene (47 mL) and NMP (6 mL) was sequentially added potassium phosphate (668 mg, 3.15 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [CAS-RN: 564483-18-7] (30 mg, 0.063 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl) [2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct [CAS-RN: 1028206-56-5] (52 mg, 0.063 mmol). The suspension was degassed and heated under argon to 110° C. for 5 hours. After cooling, the reaction mixture was diluted with aqueous sodium chloride solution and extracted twice with DCM and extracted twice with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified with preparative HPLC see method: Autopurifier: acidic conditions) to give the title compound (60 mg; 0.10 mmol).

(86) .sup.1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.39 (s, 9H), 1.61-1.70 (m, 2H), 1.81-1.87 (m, 2H), 1.88-1.97 (m, 2H), 3.16 (s, 3H), 3.97 (t, 2H), 4.26-4.32 (m, 2H), 4.72-4.80 (m, 2H), 6.62 (s, 1H), 6.88 (s, 1H), 7.41 (dd, 1H), 7.59-7.75 (m, 1H), 8.16 (dd, 1H), 8.47 (t, 1H), 8.68 (d, 1H), 10.01 (s, 1H).

EXAMPLE 6

(rac)-3,21-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1.SUP.2,6..1.SUP.8,12.]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

(87) ##STR00061##

(88) To a solution of (rac)-tert-butyl [{[3,21-difluoro-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaen-10-yl]methyl}(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (58 mg; 0.10 mmol) in dichloromethane (0.90 mL) was added trifluoroacetic acid (0.25 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. The mixture was extracted three times with ethyl acetate. The combined organic layers filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC (see method: Autopurifier: basic conditions) to give the title compound (5 mg, 0.01 mmol).

(89) .sup.1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.60-1.70 (m, 2H), 1.80-1.99 (m, 4H), 2.85 (s, 3H), 3.62 (s, 1H), 3.97 (t, 2H), 4.23-4.34 (m, 4H), 6.63 (s, 1H), 6.84 (s, 1H), 7.41 (dd, 1H), 7.56-7.75 (m, 1H), 8.16 (dd, 1H), 8.42 (t, 1H), 8.67 (d, 1H), 9.95 (s, 1H).

EXAMPLE 7

(rac)-tert-butyl [methyl(oxido){[3,20,23-trifluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1.SUP.2,6..1.SUP.8,12.]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}-1λ.SUP.6.-sulfanylidene]carbamate

(90) ##STR00062##

Preparation of Intermediate 7.1

2-chloro-4-(2,4-difluoro-3-methoxyphenyl)-5-fluoropyrimidine

(91) ##STR00063##

(92) A batch with 2,4-dichloro-5-fluoropyrimidine [CAS-RN: 2927-71-1] (3978 mg; 23.82 mmol), (2,4-difluoro-3-methoxyphenyl)boronic acid [CAS-RN: 406482-18-6) (4925 mg; 26.21 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [CAS-RN: 72287-26-4] (1945 mg; 2.38 mmol) in 1,2-dimethoxyethane (70 mL) and 2 M aqueous solution of potassium carbonate (36 mL) was degassed using argon. The batch was stirred under an atmosphere of argon for 3 hours at 100° C. After cooling, the batch was diluted with ethyl acetate 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 33%) to give the title compound (4030 mg; 14.7 mmol).

(93) 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.99 (s, 3H), 7.39-7.43 (m, 1H), 7.45 (d, 1H), 9.06 (d, 1H).

Preparation of Intermediate 7.2

3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenol

(94) ##STR00064##

(95) A solution of boron tribromide [CAS-RN: 10294-33-4] in DCM (1M; 74.9 mL; 74.9 mmol) was added dropwise to a stirred solution of 2-chloro-4-(2,4-difluoro-3-methoxyphenyl)-5-fluoropyrimidine (3700 mg; 13.5 mmol) in DCM (325 mL) at 0° C. The mixture was slowly warmed to room temperature while stirring overnight. The mixture was cautiously diluted with a saturated, aqueous solution of sodium bicarbonate under stirring at 0° C. and then solid sodium bicarbonate was added. The mixture was stirred at room temperature for 1 hour before being filtered using a Whatman filter. The filtrate was concentrated to give the crude product (2160 mg) that was used without further purification.

(96) .sup.1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.15 (ddd, 1H), 7.25-7.31 (m, 1H), 9.03 (d, 1H), 10.73 (br s, 1H).

Preparation of Intermediate 7.3

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

(97) ##STR00065##

(98) Under an atmosphere of argon, diisopropyl azodicarboxylate [CAS-RN: 2446-83-5] (0.21 mL; 1.06 mmol) was added dropwise to a stirred mixture of crude 3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenol (150 mg), (rac)-tert-butyl {[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (see Intermediate 3.7; 211 mg; 0.52 mmol) and triphenylphosphine (285 mg; 1.09 mmol) in THF (2.5 mL) at 0° C. The ice bath was removed and the mixture was stirred at room temperature for 3 days. The mixture was concentrated and the residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 50%) to give the desired title compound (309 mg), still containing some impurities.

Preparation of Intermediate 7.4

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

(99) ##STR00066##

(100) Platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder, 46 mg) was added to a solution of (rac)-tert-butyl [(3-{4-[3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenoxy]butoxy}-5-nitrobenzyl)(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (307 mg) in methanol (7 mL) and THF (2 mL) and the mixture was stirred for 3 h at room temperature under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated to give the title compound that was used without further purification (310 mg).

EXAMPLE 7—PREPARATION OF THE END PRODUCT

(101) To a solution of (rac)-tert-butyl [(3-amino-5-{4-[3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenoxy]butoxy}benzyl)(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (100 mg) in toluene (12 mL) and NMP (1.5 mL) was sequentially added potassium phosphate (172 mg, 0.81 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [CAS-RN: 564483-18-7] (8 mg, 0.016 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl) [2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct [CAS-RN: 1028206-56-5] (13 mg, 0.016 mmol). The suspension was degassed and heated under an atmosphere of argon to 110° C. for 3 hours. After cooling, the reaction mixture was diluted with aqueous sodium chloride solution and extracted three times with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified with preparative HPLC (see method: Autopurifier: acidic conditions) to give the title compound (3 mg; 0.01 mmol).

(102) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.38 (s, 9H), 1.63-1.79 (m, 2H), 1.80-1.95 (m, 2H), 3.13 (s, 3H), 3.90-4.01 (m, 2H), 4.37 (br t, 2H), 4.64-4.78 (m, 2H), 6.57 (s, 1H), 6.84 (s, 1H), 7.32 (t, 1H), 7.47 (q, 1H), 8.36 (s, 1H), 8.77 (d, 1H), 10.06 (s, 1H).

EXAMPLE 8

(rac)-3,20,23-trifluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1.SUP.2,6..1.SUP.8,12.]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

(103) ##STR00067##

(104) To a solution of (rac)-tert-butyl [methyl(oxido){[3,20,23-trifluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}-λ.sup.6-sulfanylidene]carbamate (3.0 mg; 0.005 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.012 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. The mixture was extracted with three times with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated to give the title compound (2.6 mg, 0.005 mmol).

(105) .sup.1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.62-1.78 (m, 2H), 1.80-1.99 (m, 2H), 2.99 (s, 3H), 3.87-4.05 (m, 2H), 4.33-4.49 (m, 4H), 6.59 (s, 1H), 6.83 (s, 1H), 7.32 (t, 1H), 7.41-7.65 (m, 1H), 8.35 (t, 1H), 8.77 (d, 1H), 10.05 (s, 1H).

EXAMPLE 9

(rac)-tert-butyl [{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1.SUP.2,6..1.SUP.8,12.]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-yl]methyl}(methyl)oxido-λ.SUP.6.-sulfanylidene]carbamate

(106) ##STR00068##

Preparation of Intermediate 9.1

3-{3-[(Methylsulfanyl)methyl]-5-nitrophenoxy}propan-1-ol

(107) ##STR00069##

(108) 3-Bromopropan-1-ol (1.13 g; 8.1 mmol) was added dropwise to a stirred mixture of 3-[(methylsulfanyl)methyl]-5-nitrophenol (see Intermediate 3.3; 1.5 g; 7.5 mmol) and potassium carbonate (1.25 g; 9.0 mmol) in DMF (15 mL) at 0° C. The ice bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with an aqueous solution of sodium chloride and extracted three times 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 title compound (1.6 g; 6.2 mmol).

(109) .sup.1H NMR (400 MHz, DMSO, 300K) δ=1.85-1.97 (m, 5H), 3.56 (q, 2H), 3.80 (s, 2H), 4.15 (t, 2H), 4.60 (t, 1H), 7.36 (s, 1H), 7.58 (t, 1H), 7.78 (s, 1H).

Preparation of Intermediate 9.2

(rac)-3-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}propan-1-ol

(110) ##STR00070##

(111) (rac)-3-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}propan-1-ol (1.30 g; 4.8 mmol) was prepared from 3-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}propan-1-ol (1.30 g; 5.1 mmol) under similar conditions as described in the preparation protocol for Intermediate 5.3.

(112) .sup.1H NMR (400 MHz, DMSO, 300K) δ=1.89 (quin, 2H), 3.36-3.59 (m, 2H), 4.00-4.10 (m, 1H), 4.12-4.19 (m, 2H), 4.28 (d, 1H), 4.61 (t, 1H), 7.35 (dd, 1H), 7.69 (t, 1H), 7.79 (s, 1H).

Preparation of Intermediate 9.3

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

(113) ##STR00071##

(114) (rac)-tert-butyl {[3-(3-hydroxypropoxy)-5-nitrobenzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (1.10 g; 2.8 mmol) was prepared from (rac)-3-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}propan-1-ol (1.30 g; 4.8 mmol) under similar conditions as described in the preparation protocol for Intermediate 5.4.

(115) .sup.1H NMR (400 MHz, DMSO, 300K) δ=1.39 (s, 9H), 1.89 (quin, 2H), 3.14 (s, 3H), 3.54-3.59 (m, 2H), 4.17 (t, 2H), 4.61 (t, 1H), 4.96-5.05 (m, 2H), 7.45 (dd, 1H), 7.76 (t, 1H), 7.90 (t, 1H).

Preparation of Intermediate 9.4

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

(116) ##STR00072##

(117) (rac)-tert-butyl [(3-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}-5-nitrobenzyl)(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (293 mg; 0.48 mmol) was prepared from 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenol (206 mg; 0.85 mmol) and (rac)-tert-butyl {[3-(3-hydroxypropoxy)-5-nitrobenzyl](methyl)oxido-26-sulfanylidene}carbamate (300 mg; 0.77 mmol) under similar conditions as described in the preparation protocol for Intermediate 5.5.

(118) .sup.1H NMR (400 MHz, DMSO, 300K) δ=1.36 (s, 9H), 2.26-2.32 (m, 2H), 3.14 (s, 3H), 4.28-4.36 (m, 4H), 4.95-5.05 (m, 2H), 7.44-7.50 (m, 2H), 7.61-7.68 (m, 1H), 7.76-7.81 (m, 2H), 7.91 (t, 1H), 8.98 (d, 1H).

Preparation of Intermediate 9.5

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

(119) ##STR00073##

(120) (rac)-tert-butyl [(3-amino-5-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}benzyl)(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (148 mg) was prepared as a crude product from (rac)-tert-butyl [(3-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}-5-nitrobenzyl)(methyl)oxido-λ6-sulfanylidene]carbamate (293 mg; 0.48 mmol) under similar conditions as described in the preparation protocol for Intermediate 5.6.

EXAMPLE 9—PREPARATION OF THE END PRODUCT

(121) (rac)-tert-butyl [{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.sup.8,12]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-yl]methyl}(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (31 mg; 0.06 mmol) was prepared from crude (rac)-tert-butyl [(3-amino-5-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}benzyl)(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (148 mg; 0.25 mmol) under similar conditions as described in the preparation protocol for Example 5. The product was purified by preparative HPLC (see method: Autopurifier: basic conditions).

(122) .sup.1H-NMR (400 MHz, DMSO-d6)=1.37 (s, 9H), 2.14-2.31 (m, 2H), 3.13 (s, 3H), 4.32 (br t, 2H), 4.47 (br t, 2H), 4.74 (s, 2H), 6.70 (s, 1H), 6.84 (s, 1H), 7.36 (dd, 1H), 7.46-7.58 (m, 1H), 8.09-8.16 (m, 2H), 8.67 (d, 1H), 9.91 (s, 1H).

EXAMPLE 10

(rac)-3,19-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1.SUP.2,6..1.SUP.8,12.]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaene

(123) ##STR00074##

(124) (rac)-3,19-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.sup.8,12]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaene (9 mg; 0.02 mmol) was prepared from (rac)-tert-butyl [{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.sup.8,12]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-yl]methyl}(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (28 mg; 0.05 mmol) under similar conditions as described in the preparation protocol for Example 6.

(125) .sup.1H-NMR (400 MHz, DMSO-d6)=2.16-2.31 (m, 2H), 2.81 (s, 3H), 4.15-4.34 (m, 4H), 4.43-4.62 (m, 2H), 6.71 (s, 1H), 6.82 (s, 1H), 7.32-7.41 (m, 1H), 7.47-7.62 (m, 1H), 8.05-8.15 (m, 2H), 8.66 (d, 1H), 9.85 (s, 1H).

EXAMPLE 11

(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.SUP.2,6..1.SUP.8,12.]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

(126) ##STR00075##

Preparation of Intermediate 11.1

5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-one

(127) ##STR00076##

(128) A mixture of 5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol (Intermediate 1.3; 1.00 g; 4.50 mmol), 5-chloropentan-2-one (1.63 g; 13.5 mmol), potassium carbonate (1.86 g; 13.5 mmol) and potassium iodide (0.07 g; 0.45 mmol) in DMF (20 mL) was stirred for 4 h at 80° C. Additional chloropentan-2-one (0.81 g; 6.75 mmol) and potassium carbonate (0.62 g; 4.50 mmol) was added and the mixture was stirred at 80° C. overnight. After cooling the mixture was diluted with water and the mixture was three times extracted 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 (DCM to DCM/EtOH 20%) to give the title compound (1.20 g; 3.91 mmol).

(129) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.77-1.99 (m, 2H), 2.11 (s, 3H), 2.61 (t, 2H), 4.07 (t, 2H), 5.92 (s, 2H), 6.53 (d, 1H), 7.10 (ddd, 1H), 7.28 (d, 1H), 7.33 (t, 1H), 7.94 (d, 1H).

Preparation of Intermediate 11.2

(rac)-5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-ol

(130) ##STR00077##

(131) Sodium borohydride (0.30 g; 7.84 mmol) was added portionwise to a stirred solution of 5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-one (1.20 g; 3.91 mmol) in methanol (18 mL) at 0° C. After the addition the ice bath was removed and the mixture was stirred at room temperature for 1 h. The mixture was concentrated using a rotovab. The residue was taken up with ethyl acetate and was washed two times with a saturated aqueous solution of sodium bicarbonate. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane/ethylacetate 100%) to give the title compound (0.70 g; 2.27 mmol).

(132) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.07 (d, 3H), 1.40-1.53 (m, 2H), 1.62-1.89 (m, 2H), 3.60-3.69 (m, 1H), 4.09 (t, 2H), 4.45 (d, 1H), 5.92 (s, 2H), 6.54 (d, 1H), 7.09 (ddt, 1H), 7.28 (d, 1H), 7.30-7.36 (m, 1H), 7.94 (d, 1H).

Preparation of Intermediate 11.3

6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol

(133) ##STR00078##

(134) Potassium hydroxide (2.0 g; 36.0 mmol) was added to a solution of 2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine (Intermediate 1.6; 5.0 g; 24.0 mmol) in tert-butanol (150 mL) and the mixture was stirred at 100° C. overnight. After cooling the mixture was diluted with a saturated aqueous solution of sodium chloride and extracted three times with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was taken up in ethyl acetate and washed with aqueous hydrogen chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was stirred in hexane for 1 h before it was filtered and dried in vacuo to give the title compound (2.3 g; 12.1 mmol).

(135) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.96 (s, 3H), 3.62 (s, 2H), 6.54 (s, 1H), 6.88 (s, 1H), 11.48 (br s, 1H).

Preparation of Intermediate 11.4

(rac)-4-(3-{[4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)pentyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine

(136) ##STR00079##

(137) Under argon, diisopropyl azodicarboxylate [CAS-RN: 2446-83-5] (0.98 mL; 5.00 mmol) was added dropwise to a stirred mixture of (rac) 5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-ol (Intermediate 11.2; 1.40 g; 4.54 mmol), 6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol (Intermediate 11.3; 861 mg; 4.54 mmol) and triphenylphosphine (1.31 g; 5.00 mmol) in DCM (28 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by column chromatography on silica gel (hexane to hexane/ethyl acetate 80%) to give the desired title compound (1.50 g; 3.13 mmol).

(138) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.29 (d, 3H), 1.73-1.90 (m, 4H), 1.95 (s, 3H), 3.62 (s, 2H), 4.09-4.16 (m, 2H), 5.09-5.17 (m, 1H), 5.92 (s, 2H), 6.53 (d, 1H), 6.68 (s, 1H), 6.99 (d, 1H), 7.09 (ddd, 1H), 7.25-7.35 (m, 2H), 7.93 (d, 1H).

EXAMPLE 11: PREPARATION OF END PRODUCT

(139) To a solution of (rac)-4-(3-{[4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)pentyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine (1.50 g, 3.13 mmol) in toluene (225 mL) and NMP (15 mL) was sequentially added potassium phosphate (3.32 g, 15.63 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [CAS-RN: 564483-18-7] (149 mg, 0.31 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct [CAS-RN: 1028206-56-5] (258 mg, 0.31 mmol). The suspension was degassed and stirred under an atmosphere of argon at 110° C. overnight. After cooling, the reaction mixture was diluted with an aqueous, saturated sodium chloride solution and extracted three times 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 40%) to give the desired title compound (1.30 g; 2.93 mmol).

(140) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.11 (d, 3H), 1.37-1.60 (m, 2H), 1.81-2.04 (m, 5H), 3.50-3.62 (m, 2H), 4.36-4.48 (m, 2H), 5.19-5.27 (m, 1H), 6.20 (s, 1H), 6.60 (s, 1H), 7.37 (d, 2H), 7.58 (d, 1H), 8.30 (d, 1H), 8.68 (d, 1H), 9.83 (s, 1H).

EXAMPLE 12 AND 13

Enantiomers of 3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.SUP.2,6..1.SUP.8,12.]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

(141) ##STR00080##

(142) (rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene (1.30 g; Example 11) was separated into the single enantiomers by preparative chiral HPLC.

(143) TABLE-US-00003 System: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000 Column: YMC Amylose SA, 5 μm 250 × 30 mm Solvent: Hexane/EtOH 1:1 Flow: 40 mL/min Temperature: 25° C. Solution: 1.30 g in 6 ml DCM/MeOH 1:1 Injection: 6 × 1 mL Detection: UV 280 nm Retention time in min purity in % yield Example 12 5.9-8.1 98.1% 150 mg Enantiomer 1 Example 13 10.1-12.4 94.2% 126 mg Enantiomer 2

EXAMPLES 14 AND 15

(144) Diastereoisomers 1 and 2 of 3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

(145) ##STR00081##

(146) Ammonium carbamate (38 mg; 0.49 mmol) and (diacetoxyiodo)benzene (221 mg; 0.69 mmol) were added to a solution of 3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene (Enantiomer 1, example 12; 145 mg; 0.33 mmol) in methanol (2.2 mL). The mixture was stirred in an open flask for 2 hours at room temperature before it was concentrated. The residue was purified with preparative HPLC (see method: Autopurifier: acidic conditions) to give the mixture of two diastereoisomers (32 mg; 0.06 mmol). The mixture of two diastereoisomers was then separated into the single diastereoisomers by preparative chiral HPLC.

(147) TABLE-US-00004 System: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000 Column: YMC Amylose SA, 5 μm 250 × 30 mm Solvent: tert-Butyl methyl ether/MeOH 1:1 Flow: 40 mL/min Temperature: 25° C. Solution: 20 mg in 1 mL DCM/MeOH 1:1 Injection: 1 × 1 mL Detection: UV 280 nm Retention time in min purity in % yield Example 14 5.4-6.1 99.2% 4.5 mg Diasteroisomer 1 Example 15 6.9-8.1 99.5% 3.6 mg Diasteroisomer 2

EXAMPLE 14

(148) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.09-1.17 (m, 3H), 1.43 (br dd, 1H), 1.57 (td, 1H), 1.82-2.04 (m, 2H), 2.86 (s, 3H), 3.72-3.79 (m, 1H), 4.24-4.48 (m, 4H), 5.21-5.29 (m, 1H), 6.33 (s, 1H), 6.67 (s, 1H), 7.34-7.40 (m, 2H), 7.59 (d, 1H), 8.31 (d, 1H), 8.67 (d, 1H), 9.92 (s, 1H).

EXAMPLE 15

(149) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.08-1.17 (m, 3H), 1.35-1.48 (m, 1H), 1.48-1.66 (m, 1H), 1.86 (ddt, 1H), 1.94-2.03 (m, 1H), 2.87 (s, 3H), 3.71-3.79 (m, 1H), 4.25-4.34 (m, 2H), 4.36-4.49 (m, 2H), 5.21-5.29 (m, 1H), 6.32 (s, 1H), 6.67 (s, 1H), 7.34-7.40 (m, 2H), 7.59 (br d, 1H), 8.31 (d, 1H), 8.67 (d, 1H), 9.91 (s, 1H).

EXAMPLES 16 AND 17

Diastereoisomers 3 and 4 of 3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.SUP.2,6..1.SUP.8,12.]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

(150) ##STR00082##

(151) Ammonium carbamate (32 mg; 0.41 mmol) and (diacetoxyiodo)benzene (186 mg; 0.58 mmol) were added to a solution of 3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene (Enantiomer 2, example 12; 122 mg; 0.28 mmol) in methanol (1.9 mL). The mixture was stirred in an open flask for 2 hours at room temperature before it was concentrated. The residue was purified with preparative HPLC (see method: Autopurifier: acidic conditions) to give the mixture of two diastereoisomers (32 mg; 0.06 mmol). The mixture of two diastereoisomers was separated into the single diastereoisomers by preparative chiral HPLC.

(152) TABLE-US-00005 System: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000 Column: YMC Amylose SA, 5 μm 250 × 30 mm Solvent: tert-Butyl methyl ether/MeOH 1:1 Flow: 40 mL/min Temperature: 25° C. Solution: 20 mg in 1 mL DCM/MeOH 1:1 Injection: 1 × 1 mL Detection: UV 280 nm Retention time in min purity in % yield Example 16 14.1-16.2 99.7% 9.0 mg Diasteroisomer 3 Example 17 16.9-18.9 97.0% 8.3 mg Diasteroisomer 4

EXAMPLE 16

(153) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.09-1.17 (m, 3H), 1.43 (br s, 1H), 1.57 (br d, 1H), 1.87 (br d, 1H), 1.94-2.03 (m, 1H), 2.87 (s, 3H), 3.75 (s, 1H), 4.29 (d, 2H), 4.38-4.48 (m, 2H), 5.25 (br d, 1H), 6.32 (s, 1H), 6.67 (s, 1H), 7.38 (d, 2H), 7.60 (d, 1H), 8.32 (d, 1H), 8.67 (d, 1H), 9.92 (s, 1H).

EXAMPLE 17

(154) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.06-1.18 (m, 3H), 1.44 (br d, 1H), 1.57 (br d, 1H), 1.82-1.93 (m, 1H), 1.99 (br s, 1H), 2.86 (s, 3H), 3.75 (s, 1H), 4.24-4.35 (m, 2H), 4.38-4.48 (m, 2H), 5.21-5.31 (m, 1H), 6.33 (s, 1H), 6.67 (s, 1H), 7.38 (d, 2H), 7.60 (d, 1H), 8.32 (d, 1H), 8.68 (d, 1H), 9.92 (s, 1H).

EXAMPLE 18

(rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.SUP.2,6..1.SUP.8,12.]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

(155) ##STR00083##

Preparation of Intermediate 18.1

(rac)-5-hydroxyhexyl Methanesulfonate

(156) ##STR00084##

(157) Methanesulfonyl chloride (2.6 mL; 33.8 mmol) was added dropwise to a stirred solution of hexane-1,5-diol (5.1 mL; 42.3 mmol) and triethylamine (5.9 mL; 42.3 mmol) in DCM (182 mL) at 0° C. The mixture was stirred at 0° C. for 30 min before the ice bath was removed and the mixture was stirred for 3 hours at room temperature. The mixture was diluted with an aqueous solution of sodium chloride and extracted two times with DCM. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was taken up in ethyl acetate and the solution was washed with water and two times with aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated to give the crude product (5.6 g), that was used without further purification.

Preparation of Intermediate 18.2: 6365-2

6-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]hexan-2-ol

(158) ##STR00085##

(159) (rac)-5-Hydroxyhexyl methanesulfonate (697 mg; 3.56 mmol) was slowly added to a mixture of 5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol (Intermediate 1.3; 790 mg; 3.56 mmol), potassium carbonate (589 mg; 4.27 mmol) and potassium iodide (59 mg; 0.36 mmol) in DMF (28 mL) at 0° C. The mixture was stirred at 60° C. overnight. After cooling, the mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 50% to ethyl acetate 100%) to give the desired title compound (688 mg, 2.13 mmol).

(160) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.00-1.06 (m, 3H), 1.26-1.54 (m, 4H), 1.68-1.79 (m, 2H), 3.53-3.63 (m, 1H), 4.00-4.11 (m, 2H), 4.36 (d, 1H), 5.92 (s, 2H), 6.54 (d, 1H), 7.09 (ddt, 1H), 7.26-7.35 (m, 2H), 7.92-7.96 (m, 1H).

Preparation of Intermediate 18.3

(rac)-4-(3-{[5-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)hexyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine

(161) ##STR00086##

(162) (rac)-4-(3-{[5-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)hexyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine (530 mg; 1.07 mmol) was prepared from 6-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]hexan-2-ol (685 mg; 2.13 mmol) and 6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol (Intermediate 11.3; 403 mg; 2.13 mmol) under similar conditions as described in the preparation protocol for Intermediate 11.4.

(163) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.15-1.29 (m, 3H), 1.41-1.81 (m, 6H), 1.95 (s, 3H), 3.63 (s, 2H), 4.00-4.14 (m, 2H), 5.08 (sxt, 1H), 5.91 (s, 2H), 6.53 (d, 1H), 6.68 (d, 1H), 6.98 (d, 1H), 7.08 (ddt, 1H), 7.25-7.34 (m, 2H), 7.93 (d, 1H).

EXAMPLE 18: PREPARATION OF END PRODUCT

(164) (rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene (215 mg; 0.47 mmol) was prepared from (rac)-4-(3-{[5-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)hexyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine (528 mg; 1.07 mmol) under similar conditions as described in the preparation protocol for Example 11.

(165) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.11 (d, 3H), 1.39-1.54 (m, 1H), 1.57-1.82 (m, 4H), 1.90-2.00 (m, 4H), 3.52-3.60 (m, 2H), 4.36 (brt, 2H), 5.11-5.19 (m, 1H), 6.19 (s, 1H), 6.55 (s, 1H), 7.24-7.45 (m, 3H), 8.25 (d, 1H), 8.31 (d, 1H), 9.77 (s, 1H).

EXAMPLE 19 AND 20

Enantiomers of 3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.SUP.2,6..1.SUP.8,12.]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

(166) ##STR00087##

(167) (rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene (1.32 g) was separated into the single enantiomers by preparative chiral HPLC.

(168) TABLE-US-00006 System: Sepiatec: Prep SFC100 Column: Chiralpak IG, 5 μm 250 × 30 mm Solvent: CO.sub.2/EtOH; 40% EtOH Flow: 100 mL/min Temperature: 40° C. Solution: 1.32 g in 17.5 ml DCM/MeOH/DMSO 1:1:1.5 Injection: 20 × 0.9 mL Detection: UV 254 nm Retention time in min purity in % yield Example 19 6.5-8.5 97.1% 560 mg Enantiomer 1 Example 20  9.8-12.8 98.8% 385 mg Enantiomer 2

EXAMPLE 21

Mixture of two diastereoisomers 1 and 2 of 3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.SUP.2,6..1.SUP.8,12.]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

(169) ##STR00088##

(170) The mixture of diastereoisomers 1 and 2 of 3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene (12 mg; 0.02 mmol) was prepared from enantiomer 1 of 3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene (Example 19; 505 mg; 1.10 mmol) under similar conditions as described in the preparation protocol for Examples 14 and 15.

(171) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.09-1.16 (m, 3H), 1.36-1.55 (m, 1H), 1.58-1.82 (m, 4H), 1.86-2.06 (m, 1H), 2.86 (d, 3H), 3.71-3.88 (m, 1H), 4.20-4.40 (m, 4H), 4.99-5.31 (m, 1H), 6.12-6.45 (m, 1H), 6.50-6.71 (m, 1H), 7.18-7.49 (m, 3H), 8.14-8.28 (m, 1H), 8.28-8.44 (m, 1H), 9.76-9.99 (m, 1H).

EXAMPLE 22

Mixture of two diastereoisomers 3 and 4 of 3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.SUP.2,6..1.SUP.8,12.]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

(172) ##STR00089##

(173) The mixture of diastereoisomers 3 and 4 of 3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene (27 mg; 0.06 mmol) was prepared from enantiomer 2 of 3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene (Example 20; 330 mg; 0.72 mmol) under similar conditions as described in the preparation protocol for Examples 14 and 15.

(174) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.10-1.14 (m, 3H), 1.49 (br d, 1H), 1.59-1.82 (m, 4H), 1.89-2.00 (m, 1H), 2.87 (d, 3H), 3.76 (s, 1H), 4.23-4.39 (m, 4H), 5.12-5.20 (m, 1H), 6.32 (dd, 1H), 6.61 (d, 1H), 7.28 (br s, 1H), 7.33-7.45 (m, 2H), 8.24 (dd, 1H), 8.32 (d, 1H), 9.84 (d, 1H).

EXAMPLE 23

(rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1.SUP.2,6..1.SUP.8,12.]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene

(175) ##STR00090##

Preparation of Intermediate 23.1

(rac)-6-hydroxyheptyl Methanesulfonate

(176) ##STR00091##

(177) Crude (rac)-6-hydroxyheptyl methanesulfonate (4.0 g) was prepared from heptane-1,6-diol (3.5 g; 26.5 mmol) under similar conditions as described in the preparation protocol for Intermediate 18.1.

Preparation of Intermediate 23.2

(rac)-7-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]heptan-2-ol

(178) ##STR00092##

(179) (rac)-7-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]heptan-2-ol (528 mg; 1.57 mmol) was prepared from crude (rac)-6-hydroxyheptyl methanesulfonate (748 mg) and 5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol (Intermediate 1.3; 790 mg; 3.56 mmol) under similar conditions as described in the preparation protocol for Intermediate 18.2.

(180) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.03 (d, 3H), 1.23-1.45 (m, 6H), 1.69-1.79 (m, 2H), 3.57 (dt, 1H), 4.09 (t, 2H), 4.32 (d, 1H), 5.92 (s, 2H), 6.54 (d, 1H), 7.06-7.12 (m, 1H), 7.26-7.36 (m, 2H), 7.92-7.96 (m, 1H).

Preparation of Intermediate 23.3

(rac)-4-(3-{[6-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)heptyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine

(181) ##STR00093##

(182) (rac)-4-(3-{[6-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)heptyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine (573 mg; 1.13 mmol) was prepared from (rac)-7-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]heptan-2-ol (476 mg; 1.42 mmol)) and 6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol (Intermediate 11.3; 268 mg; 1.42 mmol) under similar conditions as described in the preparation protocol for Intermediate 18.3.

EXAMPLE 23: PREPARATION OF END PRODUCT

(183) (rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene (224 mg; 0.48 mmol) was prepared from (rac)-4-(3-{[6-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)heptyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine (571 mg; 1.12 mmol) under similar conditions as described in the preparation protocol for Example 18.

(184) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.05 (d, 3H), 1.29-1.55 (m, 5H), 1.62-1.75 (m, 3H), 1.99-2.02 (m, 3H), 3.53-3.60 (m, 2H), 4.28 (dt, 1H), 4.36-4.45 (m, 1H), 4.82-4.90 (m, 1H), 6.16-6.19 (m, 1H), 6.57 (s, 1H), 7.25-7.39 (m, 2H), 7.50 (dd, 1H), 8.29 (d, 1H), 8.53 (d, 1H), 9.81 (s, 1H).

EXAMPLE 24 AND 25

Enantiomers of 3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1.SUP.2,6..1.SUP.8,12.]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene

(185) ##STR00094##

(186) (rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene (150 mg) was separated into the single enantiomers by preparative chiral HPLC.

(187) TABLE-US-00007 System: Sepiatec: Prep SFC100 Column: Chiralpak IA, 5 μm 250 × 30 mm Solvent: CO.sub.2/EtOH; 35% EtOH Flow: 100 mL/min Temperature: 40° C. Solution: 150 mg in 2 mL DMSO Injection: 5 × 0.4 mL Detection: UV 254 nm Retention time in min purity in % yield Example 24 5.5-7.0 99.7% 65 mg Enantiomer 1 Example 25  7.4-10.0 97.6% 75 mg Enantiomer 2

EXAMPLE 26

Mixture of two diastereoisomers 1 and 2 of 3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1.SUP.2,6..1.SUP.8,12.]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene

(188) ##STR00095##

(189) The mixture of diastereoisomers 1 and 2 of 3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene (14 mg; 0.03 mmol) was prepared from Enantiomer 1 of 3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene (Example 24; 60 mg; 0.13 mmol) under similar conditions as described in the preparation protocol for Examples 14 and 15.

(190) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.02-1.10 (m, 3H), 1.30-1.60 (m, 5H), 1.61-1.78 (m, 3H), 2.88 (s, 3H), 3.76 (s, 1H), 4.25-4.33 (m, 3H), 4.40 (s, 1H), 4.79-4.95 (m, 1H), 6.30 (s, 1H), 6.64 (s, 1H), 7.29 (br s, 1H), 7.34-7.40 (m, 1H), 7.50 (d, 1H), 8.30 (d, 1H), 8.53 (dd, 1H), 9.89 (d, 1H).

EXAMPLE 27

Mixture of two diastereoisomers 3 and 4 of 3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1.SUP.2,6..1.SUP.8,12.]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene

(191) ##STR00096##

(192) The mixture of diastereoisomers 3 and 4 of 3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene (6 mg; 0.01 mmol) was prepared from Enantiomer 2 of 3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo [19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene (Example 25; 70 mg; 0.15 mmol) under similar conditions as described in the preparation protocol for Examples 14 and 15.

(193) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.04-1.14 (m, 3H), 1.30-1.56 (m, 5H), 1.58-1.79 (m, 3H), 2.88 (s, 3H), 3.76 (s, 1H), 4.24-4.44 (m, 4H), 4.86 (br s, 1H), 6.30 (s, 1H), 6.64 (s, 1H), 7.25-7.43 (m, 2H), 7.50 (dd, 1H), 8.24-8.32 (m, 1H), 8.53 (dd, 1H), 9.83-9.91 (m, 1H).

EXAMPLE 28

Mixture of enantiomers of 3,20-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.SUP.2,6..1.SUP.8,12.]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

(194) ##STR00097##

(195) 3-Chloroperbenzoic acid (23 mg; 0.14 mmol) was added to a solution of (rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene (30 mg; 0.07 mmol) in DCM (0.7 mL) at 0° C. The ice bath was removed and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with an aqueous solution of sodium bicarbonate and extracted two times with DCM. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified with preparative HPLC (see method: Autopurifier: acidic conditions) to give the title compound (7 mg; 0.01 mmol).

(196) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.11 (d, 3H), 1.40 (br dd, 1H), 1.53-1.62 (m, 1H), 1.81-1.94 (m, 1H), 1.97-2.01 (m, 1H), 2.94-3.00 (m, 3H), 4.30-4.46 (m, 4H), 5.19-5.27 (m, 1H), 6.28 (s, 1H), 6.65 (s, 1H), 7.33-7.40 (m, 2H), 7.56 (br d, 1H), 8.30 (d, 1H), 8.65 (d, 1H), 9.90 (s, 1H).

EXAMPLES 29 AND 30

Enantiomer 1 and 2 of 3,21-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.SUP.2,6..1.SUP.8,12.]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

(197) ##STR00098##

(198) 3-Chloroperbenzoic acid (75 mg; 0.43 mmol) was added to a solution of (rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene (Example 18; 100 mg; 0.22 mmol) in DCM (2.1 mL) at 0° C. The ice bath was removed and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with an aqueous solution of sodium bicarbonate and extracted two times with DCM. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified with preparative HPLC (see method: Autopurifier: acidic conditions) to give the racemate (32 mg; 0.07 mmol).

(199) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.12 (d, 3H), 1.49 (br d, 1H), 1.58-1.83 (m, 4H), 1.87-2.01 (m, 1H), 2.99 (s, 3H), 4.32-4.47 (m, 4H), 5.12-5.21 (m, 1H), 6.28 (s, 1H), 6.62 (s, 1H), 7.27 (br dd, 1H), 7.36 (t, 1H), 7.43 (d, 1H), 8.24 (d, 1H), 8.33 (d, 1H), 9.90 (s, 1H).

(200) The racemate was separated into the single enantiomers by preparative chiral HPLC.

(201) TABLE-US-00008 System: Sepiatec: Prep SFC100 Column: Chiralpak IA, 5 μm 250 × 30 mm Solvent: CO.sub.2/EtOH + 0.2 vol % aqueous ammonia (32%); 50% EtOH Flow: 100 mL/min Temperature: 40° C. Solution: 150 mg in 2 mL DMSO Injection: 5 × 0.4 mL Detection: UV 220 nm Retention time in min purity in % yield Example 29 7.1-9.1 99.7% 5 mg Enantiomer 1 Example 30 10.1-13.1 97.9% 5 mg Enantiomer 2

EXAMPLE 31 AND 32

Enantiomer 1 and 2 of 3,22-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1.SUP.2,6..1.SUP.8,12.]hexacosa-1 (25),2(27),3,5,8(26),9,11,21,23-nonaene

(202) ##STR00099##

(203) 3-Chloroperbenzoic acid (71 mg; 0.31 mmol) was added to a solution of (rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene (Example 23; 68 mg; 0.14 mmol) in DCM (3.5 mL) at 0° C. The ice bath was removed and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with an aqueous solution of sodium bicarbonate and extracted two times with DCM. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified with preparative HPLC (see method: Autopurifier: acidic conditions) to give the racemate (35 mg; 0.07 mmol).

(204) 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.06 (d, 3H), 1.32-1.56 (m, 5H), 1.64-1.74 (m, 3H), 3.00 (s, 3H), 4.27 (dt, 1H), 4.39-4.46 (m, 3H), 4.83-4.91 (m, 1H), 6.26 (d, 1H), 6.64 (d, 1H), 7.26-7.31 (m, 1H), 7.34-7.39 (m, 1H), 7.51 (dd, 1H), 8.31 (d, 1H), 8.52 (d, 1H), 9.95 (s, 1H).

(205) The racemate was separated into the single enantiomers by preparative chiral HPLC.

(206) TABLE-US-00009 System: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000 Column: YMC Amylose SA, 5 μm 250 × 30 mm Solvent: Hexane/EtOH 60:40 Flow: 40 mL/min Temperature: 25° C. Solution: 31 mg in 1 mL DCM/MeOH 1:1 Injection: 1 × 1 mL Detection: UV 254 nm Retention time in min purity in % yield Example 31 14.2-16.0 98.1% 15 mg Enantiomer 1 Example 32 20.0-22.0 96.6% 15 mg Enantiomer 2

(207) The following Table 1 provides an overview on the compounds described in the example section:

(208) TABLE-US-00010 TABLE 1 Example No. Structure Name of compound  1 00 - (rac)-tert-butyl [{[3,20-difluoro-13,18-dioxa- 5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12[pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10- yl]methyl{(methyl)oxido-λ.sup.6- sulfanylidene]carbamate  2 01 - (rac)-3,20-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13,18-dioxa- 5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaene  3 02 - (rac)-tert-butyl [{[3,20-difluoro-13,18-dioxa- 5,7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10- yl]methyl}(methyl)oxido-λ.sup.6- sulfanylidene]carbamate  4 03 - (rac)-3,20-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13,18-dioxa- 5,7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaene  5 04 - (rac)-tert-butyl [{[3,21-difluoro-13,19-dioxa- 5,7,26-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa- 1(24),2(26),3,5,8(25),9,11,20,22-nonaen-10- yl]methyl}(methyl)oxido-λ.sup.6- sulfanylidene]carbamate  6 05 - (rac)-3,21-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13,19-dioxa- 5,7,26-triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa- 1(24),2(26),3,5,8(25),9,11,20,22-nonaene  7 06 - (rac)-tert-butyl [methyl(oxido){[3,20,23- trifluoro-13,18-dioxa-5,7,25- triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10- yl]methyl}-1 λ.sup.6-sulfanylidene]carbamate  8 07 - (rac)-3,20,23-trifluoro-10-[(S- methylsulfonimidoyl)methyl]-13,18-dioxa- 5,7,25-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaene  9 08 - (rac)-tert-butyl [{[3,19-difluoro-13,17-dioxa- 5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.sup.8,12]tetracosa- 1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10- yl]methyl}(methyl)oxido-λ.sup.6- sulfanylidene]carbamate 10 09 - (rac)-3,19-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13,17-dioxa- 5,7,24-triazatetracyclo[16.3.1.1.sup.2,6.1.sup.8,12]tetracosa- 1(22),2(24),3,5,8(23),9,11,18,20-nonaene 11 0 - (rac)-3,20-difluoro-14-methyl-10- [(methylsulfanyl)methyl]-13,18-dioxa-5,7,24- triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaene 12 - Enantiomer 1 of (rac)-3,20-difluoro-14-methyl- 10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24- triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaene 13 - Enantiomer 2 of (rac)-3,20-difluoro-14-methyl- 10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24- triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaene 14 Diastereoisomer 1 of 3,20-difluoro-14-methyl-10- [(S-methylsulfonimidoyl)methyl]-13,18-dioxa- 5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaene - 15 Diastereoisomer 2 of 3,20-difluoro-14-methyl-10- [(S-methylsulfonimidoyl)methyl]-13,18-dioxa- 5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaene - 16 Diastereoisomer 3 of 3,20-difluoro-14-methyl-10- [(S-methylsulfonimidoyl)methyl}-13,18-dioxa- 5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaene - 17 Diastereoisomer 4 of 3,20-difluoro-14-methyl-10- [(S-methylsulfonimidoyl)methyl]-13,18-dioxa- 5,7,24-triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaene - 18 (rac)-3,21-difluoro-14-methyl-10- [(methylsulfanyl)methyl]-13,19-dioxa-5,7,25- triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa- 1(24),2(26),3,5,8(25),9,11,20,22-nonaene 19 Enantiomer 1 of 3,21-difluoro-14-methyl-10- [(methylsulfanyl)methyl]-13,19-dioxa-5,7,25- triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa- 1(24),2(26),3,5,8(25),9,11,20,22-nonaene 20 Enantiomer 2 of 3,21-difluoro-14-methyl-10- [(methylsulfanyl)methyl]-13,19-dioxa-5,7,25- triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa- 1(24),2(26),3,5,8(25),9,11,20,22-nonaene 21 0 Mixture of diastereoisomers 1 and 2 of 3,21-difluoro- 14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,19-dioxa-5,7,25- triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa- 1(24),2(26),3,5,8(25),9,11,20,22-nonaene 22 Mixture of diastereoisomers 3 and 4 of 3,21-difluoro- 14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,19-dioxa-5,7,25- triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa- 1(24),2(26),3,5,8(25),9,11,20,22-nonaene 23 (rac)-3,22-difluoro-14-methyl-10- [(methylsulfanyl)methyl]-13,20-dioxa-5,7,26- triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa- 1(25),2(27),3,5,8(26),9,11,21,23-nonaene 24 Enantiomer 1 of 3,22-difluoro-14-methyl-10- [(methylsulfanyl)methyl]-13,20-dioxa-5,7,26- triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa- 1(25),2(27),3,5,8(26),9,11,21,23-nonaene 25 Enantiomer 2 of 3,22-difluoro-14-methyl-10- [(methylsulfanyl)methyl]-13,20-dioxa-5,7,26- triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa- 1(25),2(27),3,5,8(26),9,11,21,23-nonaene 26 Mixture of diastereoisomers 1 and 2 of 3,22-difluoro- 14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,20-dioxa-5,7,26- triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa- 1(25),2(27),3,5,8(26),9,11,21,23-nonaene 27 Mixture of diastereoisomers 3 and 4 of 3,22-difluoro- 14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,20-dioxa-5,7,26- triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa- 1(25),2(27),3,5,8(26),9,11,21,23-nonaene 28 Mixture of enantiomers of 3,20-difluoro-14-methyl- 10-[(methylsulfonyl)methyl]-13,18-dioxa-5,7,24- triazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,12]pentacosa- 1(23),2(25),3,5,8(24),9,11,19,21-nonaene 29 Enantiomer 1 of 3,21-difluoro-14-methyl-10- [(methylsulfonyl)methyl]-13,19-dioxa-5,7,25- triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa- 1(24),2(26),3,5,8(25),9,11,20,22-nonaene 30 Enantiomer 2 of 3,21-difluoro-14-methyl-10- [(methylsulfonyl)methyl]-13,19-dioxa-5,7,25- triazatetracyclo[18.3.1.1.sup.2,6.1.sup.8,12]hexacosa- 1(24),2(26),3,5,8(25),9,11,20,22-nonaene 31 0 Enantiomer 1 of 3,22-difluoro-14-methyl-10- [(methylsulfonyl)methyl]-13,20-dioxa-5,7,26- triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]hexacosa- 1(25),2(27),3,5,8(26),9,11,21,23-nonaene 32 Enantiomer 2 of 3,22-difluoro-14-methyl-10- [(methylsulfonyl)methyl]-13,20-dioxa-5,7,26- triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]hexacosa- 1(25),2(27),3,5,8(26),9,11,21,23-nonaene
Results:
Table 2: Inhibition for CDK9 and CDK2 of Compounds According to the Present Invention

(209) 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. {circle around (1)}: Example Number {circle around (2)}: high ATP CDK9: CDK9/CycT1 kinase assay as described under Method 1b. of Materials and Methods {circle around (3)}: high ATP CDK2: CDK2/CycE kinase assay as described under Method 2b. of Materials and Methods {circle around (4)}: 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

(210) 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.

(211) TABLE-US-00011 TABLE 2 {circle around (1)} Structure {circle around (2)} {circle around (3)} {circle around (4)}  2 7 737 105  3 5 >20000 >4000  4 3 1540 513  5 24 >20000 >833  6 5 16200 3240  8 17 6520 385 10 25 4750 190 11 7 4670 667 12 0 4 6450 1613 13 4 711 178 14 3 1510 503 15 3 1620 540 16 2 144 72 17 1 132 132 18 32 >20000 >625 19 138 >20000 >145 20 23 12600 548 21 2 2450 1225 22 0 2 501 251 23 67 >20000 >298 24 68 >20000 >294 25 93 >20000 >215 26 4 13000 3250 27 5 2720 544 28 2 360 189 29 4 691 173 30 3 3590 1196 31 16 >20000 1250 32 0 18 4980 277
Tables 3a and 3b:

(212) 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. {circle around (1)}: Example Number {circle around (2)}: Inhibition of HeLa cell proliferation {circle around (3)}: Inhibition of HeLa-MaTu-ADR cell proliferation {circle around (4)}: Inhibition of NCI-H460 cell proliferation {circle around (5)}: Inhibition of DU145 cell proliferation {circle around (6)}: Inhibition of Caco-2 cell proliferation {circle around (7)}: Inhibition of B16F10 cell proliferation {circle around (8)}: Inhibition of A2780 cell proliferation {circle around (9)}: Inhibition of MOLM-13 cell proliferation

(213) TABLE-US-00012 TABLE 3a Indications represented by cell lines Cell line Source Indication HeLa ATCC Human cervical tumour HeLa-MaTu-ADR EPO-GmbH Multidrug-resistant human cervical Berlin 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

(214) TABLE-US-00013 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)}  2 90 78 157 85 96 110 9 27  3 244 218 267 206 163 270 56 108  4 150 140 331 138 177 176 41 20  5 964 1000 479 585 658 993 >100 228  6 199 169 277 121 144 171 39 140  8 177 179 217 196 181 224 68 45 10 128 155 238 180 159 209 48 33 11 n.t. n.t. n.t. n.t. n.t. n.t. 346 n.t. 14 n.t. n.t. n.t. n.t. n.t. n.t. 23 n.t. 15 0 n.t. n.t. n.t. n.t. n.t. n.t. 16 n.t. 16 n.t. n.t. n.t. n.t. n.t. n.t. 6 n.t. 17 n.t. n.t. n.t. n.t. n.t. n.t. 6 n.t. 21 n.t. n.t. n.t. n.t. n.t. n.t. 27 n.t. 22 n.t. n.t. n.t. n.t. n.t. n.t. 0.7 n.t. 26 n.t. n.t. n.t. n.t. n.t. n.t. 53 n.t. 27 n.t. n.t. n.t. n.t. n.t. n.t. 102 n.t. 28 n.t. n.t. n.t. n.t. n.t. n.t. 16. n.t. 29 n.t. n.t. n.t. n.t. n.t. n.t. 25 n.t. 30 n.t n.t. n.t. n.t. n.t. n.t. 55 n.t. 31 0 n.t. n.t. n.t. n.t. n.t. n.t. 121 n.t. 32 n.t. n.t. n.t. n.t. n.t. n.t. 146 n.t.
Table 4:

(215) Equilibrium dissociation constants K.sub.D [M], dissociation rate constants k.sub.off [1/s], and target residence times [min] as determined by Method 8.

(216) 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).

(217) Values labeled with “*” represent arithmetic means of more than one value. {circle around (0)}: Example Number {circle around (2)}: Equilibrium dissociation constant K.sub.D [M] {circle around (3)}: Dissociation rate constant k.sub.off[1/s] {circle around (4)}: Target residence time [min]

(218) TABLE-US-00014 TABLE 4 {circle around (1)} Structure {circle around (2)} {circle around (3)} {circle around (4)}  2 1.2E−9*   2.2E−4*    75*  4 1.2E−9*   6.7E−4*    25* 16 2.8E−10 6.6E−11 2.4E−11 2.9E−11 <8.0E−5 <8.0E−5   1.3E−4 <8.0E−5 >208 >208   131 >208 17 7.7E−11* <8.0E−5* >208* 21 1.0E−9*   1.6E−3*    10* 22 1.9E−10*   3.9E−4*    43* 28 9.2E−11 9.1E−11 1.2E−10 1.5E−13   3.5E−4 <8,0E−5   3.1E−4 <8.0E−5    48 >208    54 >208

(219) 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.