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).

Claims

1. A compound of general formula (10): ##STR00113## wherein: Z is hydrogen or fluorine; L is 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-, —(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—, —CH.sub.2OCH.sub.2—; R.sup.1 is C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.7-cycloalkyl-, or heterocyclyl-; wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.7-cycloalkyl-, or heterocyclyl- is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.3-fluoroalkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, —OP(═OH).sub.2, —C(1)OH, and —C(═O)NH.sub.2; R.sup.2 is hydrogen, fluorine, chlorine, bromine, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-, or C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.3 and R.sup.4 are independently from each other, hydrogen, fluorine, chlorine, bromine, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-, or C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.8 and R.sup.9 are independently from each other, hydrogen, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, or heteroaryl-: wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, or heteroaryl- group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C.sub.1-C.sub.3-alkyl-, 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; or a salt thereof.

2. The compound of claim 1, wherein: Z is hydrogen or fluorine; L is 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-, —(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-; R.sup.1 is C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.5-cycloalkyl-; wherein said C.sub.1-C.sub.6-alkyl- or C.sub.3-C.sub.5-cycloalkyl- is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C.sub.1-C.sub.3-alkyl-, fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.3-alkoxy-, C.sub.1-C.sub.2-fluoroalkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, cyclic amines, —OP(XOH).sub.2, —C(1)OH, and —C(CI)NH.sub.2; R.sup.2 is hydrogen, fluorine, chlorine, cyano, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-, fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.3 and R.sup.4 are independently from each other, a group selected from hydrogen, fluorine, chlorine, 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.8 and R.sup.9 are independently from each other, a group selected from hydrogen, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, phenyl-, and benzyl-; wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, phenyl- or benzyl- is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C.sub.1C3-alkyl-, C.sub.1-C.sub.3-alkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, cyclic amines, 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; or a salt thereof.

3. The compound of claim 1, wherein: Z is hydrogen or fluorine; L is 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-, hydroxymethyl, and/or (ii) one or two or three C.sub.1-C.sub.2-alkyl- group substituents, identically or differently; R.sup.1 is C.sub.1-C.sub.4-alkyl- or C.sub.3-C.sub.5-cycloalkyl-; wherein said C.sub.1-C.sub.4-alkyl- or C.sub.3-C.sub.5-cycloalkyl- 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 is hydrogen, fluorine, chlorine, cyano, methyl-, methoxy-, trifluoromethyl-, or trifluoromethoxy-; R.sup.3 is hydrogen, fluorine, chlorine, cyano, methyl-, methoxy-, trifluoromethyl-, or trifluoromethoxy-; and R.sup.4 is hydrogen or fluorine; or a salt thereof.

4. The compound of claim 1, wherein: Z is hydrogen or fluorine; L is C.sub.3-C.sub.5-alkylene; R.sup.1 is C.sub.1-C.sub.4-alkyl optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, C.sub.1-C.sub.2-alkoxy-, and —NH.sub.2, —C(═O)OH; R.sup.2 is hydrogen or fluorine; R.sup.3 is hydrogen, fluorine, or methoxy; and R.sup.4 is hydrogen; or a salt thereof.

5. The compound of claim 1, wherein: L is C.sub.3-C.sub.5-alkylene, or a salt thereof.

6. The compound of claim 1, wherein: Z is hydrogen or fluorine; L is C.sub.3-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is hydrogen; R.sup.3 is hydrogen or fluorine; and R.sup.4 is hydrogen; or a salt thereof.

7. The compound of claim 1, wherein: Z is hydrogen or fluorine; L is C.sub.3-C.sub.5-alkylene; R.sup.1 is C.sub.1-C.sub.3-alkyl; R.sup.2 is hydrogen or fluorine; R.sup.3 is hydrogen, fluorine, or methoxy; and R.sup.4 is hydrogen; or a salt thereof.

8. The compound of claim 1, wherein: Z is hydrogen or fluorine; L is C.sub.4-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is hydrogen; R.sup.3 is hydrogen or fluorine; and R.sup.4 is hydrogen; or a salt thereof.

9. The compound of claim 1, wherein: Z is hydrogen or fluorine; R.sup.3 is fluorine; and R.sup.4 is hydrogen; or a salt thereof.

10. The compound of claim 1, wherein: Z is hydrogen; L is C.sub.3-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is hydrogen; R.sup.3 is fluorine; and R.sup.4 is hydrogen; or a salt thereof.

11. A compound of general formula (21): ##STR00114## Z is hydrogen or fluorine; IDC-138,C.sub.1 L is 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-, —(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—, —CH.sub.2OCH.sub.2—; R.sup.1 is C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.7-cycloalkyl-, or heterocyclyl-; wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl-, C.sub.3-C.sub.7-cycloalkyl-, or heterocyclyl- is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.3-fluoroalkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, —OP(═O)(OH).sub.2, —C(═O)OH, and —C(═O)NH.sub.2; R.sup.2 is hydrogen, fluorine, chlorine, bromine, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-, or C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.3 and R.sup.4 are independently from each other, hydrogen, fluorine, chlorine, bromine, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-, or C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.8 and R.sup.9 are independently from each other, hydrogen, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, or heteroaryl-: wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, or heteroaryl- is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C.sub.1-C.sub.3-alkyl-, 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; or a salt thereof.

12. The compound of claim 11, wherein: Z is hydrogen or fluorine; L is 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-, —(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-; R.sup.1 is C.sub.1-C.sub.6-alkyl- or C.sub.3-05-cycloalkyl-; wherein said C.sub.1-C.sub.6-alkyl- or C.sub.3-05-cycloalkyl- is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C.sub.1-C.sub.3-alkyl-, fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.3-alkoxy-, C.sub.1-C.sub.2-fluoroalkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, cyclic amines, —OP(═O)(OH).sub.2, —C(═O)OH, and —C(═O)NH.sub.2; R.sup.2 is hydrogen, fluorine, chlorine, cyano, C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-, fluoro-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.3 and R.sup.4 are independently from each other, a group selected from hydrogen, fluorine, chlorine, 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.8 and R.sup.9 are independently from each other, a group selected from hydrogen, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, phenyl-, and benzyl-; wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.5-cycloalkyl-, phenyl- or benzyl- is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, cyclic amines, fluoro-C.sub.1-C.sub.2-alkyl-, 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; or a salt thereof.

13. The compound of claim 11, wherein: Z is hydrogen or fluorine; L is 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-, hydroxymethyl, and/or (ii) one or two or three C.sub.1-C.sub.2-alkyl- group substituents, identically or differently; R.sup.1 is C.sub.1-C.sub.4-alkyl- or C.sub.3-C.sub.5-cycloalkyl-; wherein said C.sub.1-C.sub.4-alkyl- or C.sub.3-C.sub.5-cycloalkyl- 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 is hydrogen, fluorine, chlorine, cyano, methyl-, methoxy-, trifluoromethyl-, or trifluoromethoxy-; R.sup.3 is hydrogen, fluorine, chlorine, cyano, methyl-, methoxy-, trifluoromethyl-, or trifluoromethoxy-; and R.sup.4 is hydrogen or fluorine; or a salt thereof.

14. The compound of claim 11, wherein: Z is hydrogen or fluorine; L is C.sub.3-C.sub.5-alkylene; R.sup.1 is C.sub.1-C.sub.4-alkyl optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, C.sub.1-C.sub.2-alkoxy-, and —NH.sub.2, —C(═O)OH; R.sup.2 is hydrogen or fluorine; R.sup.3 is hydrogen, fluorine, or methoxy; and R.sup.4 is hydrogen; or a salt thereof.

15. The compound of claim 11, wherein: L is C.sub.3-C.sub.5-alkylene, or a salt thereof.

16. The compound of claim 11, wherein: Z is hydrogen or fluorine; L is C.sub.3-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is hydrogen; R.sup.3 is hydrogen or fluorine; and R.sup.4 is hydrogen; or a salt thereof.

17. The compound of claim 11, wherein: Z is hydrogen or fluorine; L is C.sub.3-C.sub.5-alkylene; R.sup.1 is C.sub.1-C.sub.3-alkyl; R.sup.2 is hydrogen or fluorine; R.sup.3 is hydrogen, fluorine, or methoxy; and R.sup.4 is hydrogen; or a salt thereof.

18. The compound of claim 11, wherein: Z is hydrogen or fluorine; L is C.sub.4-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is hydrogen; R.sup.3 is hydrogen or fluorine; and R.sup.4 is hydrogen; or a salt thereof.

19. The compound of claim 11, wherein: Z is hydrogen or fluorine; R.sup.3 is fluorine; and R.sup.4 is hydrogen; or a salt thereof.

20. The compound of claim 11, wherein: Z is hydrogen; L is C.sub.3-C.sub.5-alkylene; R.sup.1 is methyl; R.sup.2 is hydrogen; R.sup.3 is fluorine; and R.sup.4 is hydrogen; or a salt thereof.

Description

PREPARATIVE EXAMPLES

(1) Syntheses of Compounds

(2) The syntheses of the macrocyclic compounds of formula (I) according to the present invention are preferably carried out according to the general synthetic sequences as shown in Schemes 1a, 1b, 1c, 1d, 1e, 1f, 2a, 2b, 2c, 2d and 2e.

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

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

(5) The syntheses of the pyrimidine derivatives of formula (Ia), (Ib) and (Ic), constituting sub-sets of the general formula (I) according to the present invention, are preferably carried out according to the general synthetic sequences as shown in Schemes 1a, 1b and 1c, 1d, 1e and 1f.

(6) Schemes 1a, 1b, 1c, 1d, 1e and 1f, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z and L are as defined for the compound of general formula (I) according to the present invention, outline the preparation of pyrimidine compounds of the general formula (I) from 2,4-dichloro-5-fluoropyrimidine (CAS #2927-71-1, 1).

(7) ##STR00011##

(8) As shown in Scheme 1a, said starting material (1) can be reacted with a boronic acid derivative of formula (2), wherein R.sup.3, R.sup.4 and Z are as defined for the compound of general formula (I) according to the present invention, to give a compound of formula (3). The boronic acid derivative (2) may be a boronic acid (R═—H) or an ester of the boronic acid, e.g. its isopropyl ester (R═—CH(CH.sub.3).sub.2), or an ester derived from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (R—R═—C(CH.sub.3).sub.2—C(CH.sub.3).sub.2—). Boronic acids and their esters are commercially available and well-known to the person skilled in the art; see e.g. D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein.

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

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

(11) In the second step, a compound of formula (3) can be reduced to a compound of formula (4), by means of hydrogenating the nitro- group present in compounds of the formula (3). The reduction can be carried out analogously to known processes (see for example: (a) Sammond et al; Bioorg. Med. Chem. Lett. 2005, 15, 3519; (b) R. C. Larock, Comprehensive Organic Transformations, VCH, New York, 1989, 411-415). Preferred is the herein described use of hydrogen gas in the presence of commercial catalysts containing platinum and vanadium on carbon, preferably on activated carbon, in a suitable solvent such as an aliphatic alcohol of the formula C.sub.1-C.sub.3-alkyl-OH, optionally containing a cyclic ether such as tetrahydrofuran or 1,4-dioxane as co-solvent, preferably in methanol or a mixture of methanol and tetrahydrofuran. Alternatively, titanium(III)chloride in a mixture of aqueous hydrochloric acid and tetrahydrofuran can be used.

(12) In a third step, a compound of formula (4) can be reacted with 2-nitrobenzenesulfonyl chloride (NsCl) to give a compound of the formula (5), in which Ns represents a 2-nitrobenzenesulfonyl group. This reaction can be carried out in the presence of an organic base, preferably pyridine, and catalytic amounts of 4-dimethylaminopyridine in solvents such as dichloromethane. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20° C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

(13) ##STR00012##

(14) In a fourth step, a compound of the formula (5), can be reacted with with an alcohol of formula (6), in which R.sup.1, R.sup.2 and L are as defined for the compound of the general formula (I) and which can be prepared according to Scheme 1f, in the presence of a tertiary phosphine, such as triphenylphosphine, and a dialkyl diazodicarboxylate (known as Mitsunobu reaction, see for example: K. C. K. Swamy et al, Chem. Rev. 2009, 109, 2551), to yield a compound of formula (7). Preferred is the use of diisopropyl azodicarboxylate and triphenylphosphine as coupling reagent in a solvent such as dichloromethane or THF. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20° C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

(15) ##STR00013## ##STR00014## ##STR00015##

(16) As outlined in Scheme 1c, a compound of the formula (7), in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z and L are as defined for the compound of the general formula (I), and in which Ns represents a 2-nitrobenzenesulfonyl group, can be reacted with thiophenol to yield a compound of the formula (8). This reaction can be carried out in the presence of an organic or an inorganic base, such as cesium carbonate and preferably in a carboxamide based solvent, such as DMF or NMP. The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20° C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

(17) Alternatively, compounds of the formula (8) can be prepared by reaction of an aniline derivative of the formula (4), in which Wand R.sup.4 are as defined for the compound of the general formula (I), with an aldeyhyde of the formula (9), in which R.sup.1 and R.sup.2 are as defined for the compound of the general formula (I) and in which L′ represents a C.sub.2-C.sub.7-alkylene group featuring one carbon atom less as compared to the corresponding group L in formula (8), L in turn being as defined for the compound of general formula (I) and which can be prepared according to Scheme 1f. This reaction, so called reductive amination, can be performed in the presence of a suitable reducing agent, preferentially sodium triacetoxyborohydride or sodium cyanoborohydride, in a chlorinated hydrocarbon such as dichloromethane or 1,2-dichloroethane, or in a protic solvent, such as methanol, in the presence of an organic acid such as acetic acid (for an overview, see: E. W. Baxter, A. B. Reitz ‘Reductive Amination of Carbonyl Compounds with Borodydride and Borane Reducing Agents’, Org. Reactions 2004, 59, 1-714). The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20° C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

(18) Subsequently, the resulting compound of formula (8) can be reduced to give an aniline derivative of formula (10). The reduction can be performed analogously to known processes (see for example: (a) Sammond et al; Bioorg. Med. Chem. Lett. 2005, 15, 3519; (b) R. C. Larock, Comprehensive Organic Transformations, VCH, New York, 1989, 411-415). Preferred is the herein described use of platinum and vanadium on activated carbon under an atmosphere of hydrogen gas in a solvent mixture of methanol and THF. (For an overview on heterogeneous catalytic hydrogenation, see: S. Nishimura, ‘Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis’, Wiley-VCH, Weinheim, 2001).

(19) The resulting compound of formula (10) can be converted to a macrocyclic compound of formula (Ia). This cyclization reaction can be carried out by an intramolecular Palladium-catalyzed C—N cross-coupling reaction (for a review on C—N cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’, 2.sup.nd a ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably potassium phosphate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent, preferably a mixture of toluene and NMP, as a solvent. The reactions are preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 130° C. in a microwave oven or in an oil bath.

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

(21) ##STR00016## ##STR00017##

(22) Scheme 1e, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z and L are as defined for the compound of general formula (I) according to the present invention, outlines the preparation of a N-substituted sulfoximine compound of the formula (Ic) from an N-unsubstituted sulfoximine compound of the formula (Ib).

(23) As outlined in Scheme 1e, a N-unprotected sulfoximine of formula (Tb) (R.sup.5═H) may be further converted into a N-functionalized derivative of formula (Ic). There are multiple methods for the preparation of N-functionalized sulfoximines by functionalization of the nitrogen of the sulfoximine group: Alkylation: see for example: a) U. Lücking et al, US 2007/0232632; b) C. R. Johnson, J. Org. Chem. 1993, 58, 1922; c) C. Bolm et al, Synthesis 2009, 10, 1601. Acylation: see for example: a) C. Bolm et al, Chem. Europ. J. 2004, 10, 2942; b) C. Boln et al, Synthesis 2002, 7, 879; c) C. Bolm et al, Chem. Eur. J. 2001, 7, 1118. Arylation: see for example: a) C. Bolm et al, Tet. Lett. 1998, 39, 5731; b) C. Boln et al., J. Org. Chem. 2000, 65, 169; c) C. Bolm et al, Synthesis 2000, 7, 911; d) C. Bolm et al, J. Org. Chem. 2005, 70, 2346; e) U. Lücking et al, WO2007/71455. Reaction with isocyanates: see for example: a) V. J. Bauer et al, J. Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al, J. Am. Chem. Soc. 1970, 92, 6594; c) S. Allenmark et al, Acta Chem. Scand. Ser. B 1983, 325; d) U. Lücking et al, US2007/0191393. Reaction with sulfonylchlorides: see for example: a) D. J. Cram et al, J. Am. Chem. Soc. 1970, 92, 7369; b) C. R. Johnson et al, J. Org. Chem. 1978, 43, 4136; c) A. C. Barnes, J. Med. Chem. 1979, 22, 418; d) D. Craig et al, Tet. 1995, 51, 6071; e) U. Lücking et al, US2007/191393. Reaction with chloroformiates: see for example: a) P. B. Kirby et al, DE2129678; b) D. J. Cram et al, J. Am. Chem. Soc. 1974, 96, 2183; c) P. Stoss et al, Chem. Ber. 1978, 111, 1453; d) U. Lücking et al, WO2005/37800. Reaction with bromocyane: see for example: a) D. T. Sauer et al, Inorganic Chemistry 1972, 11, 238; b) C. Bolm et al, Org. Lett. 2007, 9, 2951; c) U. Lücking et al, WO 2011/29537.

(24) ##STR00018##

(25) Compounds of the formula (6) and compounds of the formula (9) can be obtained as outlined in Scheme 1f. In a first step, a thioether derivative of formula (11), in which R.sup.1 and R.sup.2 are as defined for the compound of general formula (I), can be reacted with a carboxylic ester of formula (12), in which R.sup.E represents a C.sub.1-C.sub.4-alkyl group, and LG.sup.3 represents a leaving group such as a chlorine atom, a bromine atom, a iodine atom, C.sub.1-C.sub.4-alkyl-S(═O).sub.2O—, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, or para-toluenesulfonyloxy-, and in which L′ represents a C.sub.2-C.sub.7-alkylene group featuring one carbon atom less as compared to the corresponding group L in formula (6), L in turn being as defined for the the compound of general formula (I), in the presence of a base, such as an alkali carbonate, preferably potassium carbonate, in N,N-dimethylformamide (DMF) as a solvent, to give a compound of formula (13). Compounds of the formula (11) are known to the person skilled in the art and are described in literature (see e.g. WO 2015/155197). Compounds of the formula (12) are widely commercially available.

(26) ##STR00019## ##STR00020##

(27) In a second step, oxidation of a thioether of formula (13) can be used to obtain the corresponding sulfoxide of formula (14). The oxidation can be performed analogously to known processes (see for example: (a) M. H. Ali et al, Synthesis 1997, 764; (b) M. C. Carreno, Chem. Rev. 1995, 95, 1717; (c) I. Patel et al, Org. Proc. Res. Dev. 2002, 6, 225; (d) N. Khiar et al, Chem. Rev. 2003, 103, 3651). Preferred is the herein described use of periodic acid und iron(III) chloride.

(28) In a third step, Rhodium-catalyzed imination of a sulfoxide of formula (14) can be used to prepare the corresponding sulfoximines of formula (15) (see for example: a) Bolm et al, Org. Lett. 2004, 6, 1305; b) Bull et al, J. Org. Chem. 2015, 80, 6391). This type of reaction can be also performed with R.sup.5 groups different from tert-butoxycarbonyl- (—C(═O)OC(CH.sub.3).sub.3) as shown here, R.sup.5 optionally representing a —C(═O)R.sup.10 or C(═O)OR.sup.10 group, in which R.sup.10 is as defined for the compound of general formula (I); more specifically, R.sup.5 may represent a group such as trifluoroacetyl- (—C(═O)CF.sub.3), or benzyloxycarbonyl-(—C(═O)OCH.sub.2Ph).

(29) In a fourth step, an ester of the formula (15) can be reduced using a reducing agent such as lithium aluminium hydride or di-iso-butylaluminiumhydride (DIBAL), in an ether, preferably tetrahydrofuran, as a solvent, to give compound of the formula (6) which can be further elaborated e.g. as shown in Scheme 1b.

(30) Alcohols of the formula (6) can be oxidized to aldehydes of the formula (9), in which R.sup.1 and R.sup.2 are as defined for the compound of the general formula (I) and in which L′ represents a C.sub.2-C.sub.7-alkylene group featuring one carbon atom less as compared to the corresponding group L in formula (6), L in turn being as defined for the the compound of general formula (I). This oxidation can be carried out using oxidation agents such as Dess-Martin-periodinane in chlorinated solvents such as dichloromethane (for an overview, see G. Tojo, M. Fernández, ‘Oxidation of Alcohols to Aldehydes and Ketones’, Springer US, New Yor, USA. 2006), The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20° C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

(31) The syntheses of the bispyridine derivatives of formula (Id), and (Ie), constituting further sub-sets of the general formula (I) according to the present invention, are preferably carried out according to the general synthetic sequences as shown in Schemes 2a, 2b, 2c, 2d and 2e.

(32) Schemes 2a, 2b, 2c, 2d, and 2e, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z and L are as defined for the compound of general formula (I) according to the present invention, outline the preparation of pyrimidine compounds of the general formula (I) from 2-chloro-5-fluoro-4-iodopyridine (CAS #884494-49-9, 16).

(33) ##STR00021##

(34) As shown in Scheme 1a, said starting material (16) can be reacted with a boronic acid derivative of formula (2), wherein R.sup.3, R.sup.4 and Z are as defined for the compound of general formula (I) according to the present invention, to give a compound of formula (17). The boronic acid derivative (2) may be a boronic acid (R═—H) or an ester of the boronic acid, e.g. its isopropyl ester (R═—CH(CH.sub.3).sub.2), or an ester derived from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (R—R═—C(CH.sub.3).sub.2—C(CH.sub.3).sub.2—). Boronic acids and their esters are commercially available and well-known to the person skilled in the art; see e.g. D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein.

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

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

(37) In the second step, a compound of formula (17) can be reduced to a compound of formula (18), by means of hydrogenating the nitro- group present in compounds of the formula (17). The reduction can be carried out analogously to known processes (see for example: (a) Sammond et al; Bioorg. Med. Chem. Lett. 2005, 15, 3519; (b) R. C. Larock, Comprehensive Organic Transformations, VCH, New York, 1989, 411-415). Preferred is the herein described use of hydrogen gas in the presence of commercial catalysts containing platinum and vanadium on carbon, preferably on activated carbon, in a suitable solvent such as an aliphatic alcohol of the formula C.sub.1-C.sub.3-alkyl-OH, optionally containing a cyclic ether such as tetrahydrofuran or 1,4-dioxane as co-solvent, preferably in methanol or a mixture of methanol and tetrahydrofuran. Alternatively, titanium(III)chloride in a mixture of aqueous hydrochloric acid and tetrahydrofuran can be used.

(38) ##STR00022##

(39) As shown in Scheme 2b, a compound of the formula (21) can be prepared by reaction of an anilin derivative of the formula (18), in which Z, R.sup.3 and R.sup.4 are as defined for the compound of the general formula (I), with an aldehyde of the formula (19), in which R.sup.1 and R.sup.2 are as defined for the compound of the general formula (I) and in which L′ represents a C.sub.2-C.sub.7-alkylene group featuring one carbon atom less as compared to the corresponding group L in formula (20), L in turn being as defined for the the compound of general formula (I) and which can be prepared according to Scheme 2b. This reaction, so called reductive amination, can be performed in the presence of a suitable reducing agent, preferentially sodium triacetoxyborohydride or sodium cyanoborohydride, in a chlorinated hydrocarbon such as dichloromethane or 1,2-dichloroethane or in a protic solvent such as methanol, in the presence of an organic acid such as acetic acid (for an overview, see: E. W. Baxter, A. B. Reitz ‘Reductive Amination of Carbonyl Compounds with Borodydride and Borane Reducing Agents’, Org. Reactions 2004, 59, 1-714). The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20° C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

(40) In a fourth step, both the tert-butoxycarbonyl-group attached to the sulfoximine nitrogen as well as the tert-butoxycarbonyl-group attached to the aniline nitrogen can be cleaved under acidic conditions to give an unprotected sulfoximine of formula (21) (see for example: J. A. Bull, J. Org. Chem. 2015, 80, 6391). Preferred is the herein described use of an acid, preferably trifluoroacetic acid in dichloromethane as a solvent.

(41) ##STR00023##

(42) The resulting compounds of formula (20) can be converted to a macrocyclic compound of formula (Id). This cyclization reaction can be carried out by an intramolecular Palladium-catalyzed C—N cross-coupling reaction (for a review on C—N cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably potassium phosphate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene and a carboxamide based solvent, preferably a mixture of toluene and NMP, as a solvent. The reactions are preferably run under an atmosphere of argon for 2 to 24 hours at 100 to 130° C. in a microwave oven or in an oil bath.

(43) As outlined in Scheme 2d, a N-unprotected sulfoximine of formula (Id) (R.sup.5═H) may be further converted into a N-functionalized derivative of formula (Ie). There are multiple methods for the preparation of N-functionalized sulfoximines by functionalization of the nitrogen of the sulfoximine group: Alkylation: see for example: a) U. Lücking et al, US 2007/0232632; b) C. R. Johnson, J. Org. Chem. 1993, 58, 1922; c) C. Bolm et al, Synthesis 2009, 10, 1601. Acylation: see for example: a) C. Bolm et al, Chem. Europ. J. 2004, 10, 2942; b) C. Boln et al, Synthesis 2002, 7, 879; c) C. Bolm et al, Chem. Eur. J. 2001, 7, 1118. Arylation: see for example: a) C. Bolm et al, Tet. Lett. 1998, 39, 5731; b) C. Boln et al., J. Org. Chem. 2000, 65, 169; c) C. Bolm et al, Synthesis 2000, 7, 911; d) C. Bolm et al, J. Org. Chem. 2005, 70, 2346; e) U. Lücking et al, WO2007/71455. Reaction with isocyanates: see for example: a) V. J. Bauer et al, J. Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al, J. Am. Chem. Soc. 1970, 92, 6594; c) S. Allenmark et al, Acta Chem. Scand. Ser. B 1983, 325; d) U. Lücking et al, US2007/0191393. Reaction with sulfonylchlorides: see for example: a) D. J. Cram et al, J. Am. Chem. Soc. 1970, 92, 7369; b) C. R. Johnson et al, J. Org. Chem. 1978, 43, 4136; c) A. C. Barnes, J. Med. Chem. 1979, 22, 418; d) D. Craig et al, Tet. 1995, 51, 6071; e) U. Lücking et al, US2007/191393. Reaction with chloroformiates: see for example: a) P. B. Kirby et al, DE2129678; b) D. J. Cram et al, J. Am. Chem. Soc. 1974, 96, 2183; c) P. Stoss et al, Chem. Ber. 1978, 111, 1453; d) U. Lücking et al, WO2005/37800. Reaction with bromocyane: see for example: a) D. T. Sauer et al, Inorganic Chemistry 1972, 11, 238; b) C. Bolm et al, Org. Lett. 2007, 9, 2951; c) U. Lücking et al, WO 2011/29537.

(44) ##STR00024##

(45) Compounds of the formula (19) can be obtained as outlined in Scheme 2e. In a first step, a thioether derivative of formula (22) is reacted with a anion formed in situ from a diol of the formula HO-L-OH (23), in which L is as defined for the compound of general formula (I), and an alkali metal, preferably sodium, or an alkali hydride, preferably sodium hydride, in tetrahydrofuran as a solvent, to give intermediate compounds of formula (24).

(46) In a second step, oxidation of a thioether of formula (24) can be used to obtain the corresponding sulfoxide of formula (25). The oxidation can be performed analogously to known processes as outlined above (e.g. as discussed in context of Scheme 1f, conversion of a compound of formula (13) into a compound of formula (14)). Preferred is the herein described use of periodic acid und iron(III)chloride.

(47) In a third step, Rhodium-catalyzed imination of a sulfoxide of formula (25) can be used to prepare the corresponding sulfoximines of formula (26) (see for example: a) Bolm et al, Org. Lett. 2004, 6, 1305; b) Bull et al, J. Org. Chem. 2015, 80, 6391). This type of reaction can be also performed with R.sup.5 groups different from tert-butoxycarbonyl- (—C(═O)OC(CH.sub.3).sub.3) as shown here, R.sup.5 optionally representing a —C(═O)R.sup.8 or C(═O)OR.sup.8 group, in which R.sup.8 is as defined for the compound of general formula (I); more specifically, R.sup.5 may represent a group such as trifluoroacetyl- (—C(═O)CF.sub.3), or benzyloxycarbonyl-(—C(═O)OCH.sub.2Ph).

(48) ##STR00025## ##STR00026##

(49) In a fourth step, said compound of formula (26) can be converted to a compound of formula (27). This reaction is an intermolecular Palladium-catalyzed C—N cross-coupling reaction (for a review on C—N cross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’, 2.sup.nd a ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred is the herein described use of chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct, 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl as catalyst and ligand, an alkali carbonate or an alkali phosphate, preferably cesium carbonate, as a base, in a mixture of a C.sub.1-C.sub.3-alkylbenzene or a carboxamide based solvent or an ethereal solvent, preferably 1,4-dioxane, as a solvent. The reactions are preferably run under an atmosphere of argon for 1 to 24 hours at 80 to 130° C. in a microwave oven or in an oil bath.

(50) An alcohols of the formula (27) can finally be oxidized to an aldehyde of the formula (19), in which R.sup.1 and R.sup.2 are as defined for the compound of the general formula (I) and in which L′ represents a C.sub.2-C.sub.7-alkylene group featuring one carbon atom less as compared to the corresponding group L in formula (20), L in turn being as defined for the the compound of general formula (I). This oxidation can be carried out using oxidation agents such as Dess-Martin-periodinane in chlorinated solvents such as dichloromethane (for an overview, see G. Tojo, M. Fernández, ‘Oxidation of Alcohols to Aldehydes and Ketones’, Springer US, New Yor, USA. 2006), The reaction can be performed at temperatures ranging from room temperature (i.e. approx. 20° C.) to the boiling point of the respective solvent. The reaction is preferably completed after 1 to 36 hours of reaction time.

Abbreviations Used in the Description of the Chemistry and in the Examples that Follow are

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

(52) .sup.1H-NMR Spectra

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

(54) Chemical Naming:

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

(56) Salt Stoichiometry:

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

(58) Unless specified otherwise, suffixes to chemical names or structural formulae such as “hydrochloride”, “trifluoroacetate”, “sodium salt”, or “x HCl”, “x CF.sub.3COOH”, “x Na*”, for example, are to be understood as not a stoichiometric specification, but solely as a salt form.

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

(60) Preparative HPLC Methods:

(61) Autopurifier: Acidic Conditions

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

(63) Autopurifier: Basic Conditions

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

(65) General Methods for LC-MS Analysis

(66) Method a:

(67) Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50×2.1 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

(68) Method b:

(69) Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50×2.1 mm; eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

Example 1

(rac)-tert-butyl [{[3,20-difluoro-13-oxa-5,7,18,25-tetraazatetracyclo[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

(70) ##STR00027##

Preparation of Intermediate 1.1

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

(71) ##STR00028##

(72) To a suspension of 3-[(methylsulfanyl)methyl]-5-nitrophenol (6.00 g, prepared according to WO2015/155197 A1) and potassium carbonate (4.99 g) in DMF (58 mL) at 0° C. was added dropwise ethyl 4-bromobutanoate (4.7 mL). The mixture was allowed to warm to room temperature and stirred for 24 h. The reaction was diluted with water (300 mL) and the mixture was extracted three times with ethyl acetate (200 mL each). The combined organic layers were washed with saturated aqueous sodium chloride, dried and concentrated to yield the title compound (11.69 g, 90% purity) that was contaminated by DMF and excess ethyl 4-bromobutanoate and which was used without further purification.

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

(74) .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 1.2

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

(75) ##STR00029##

(76) 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.

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

(78) .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 1.3

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

(79) ##STR00030##

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

(81) LC-MS (method a): R.sub.t=1.22 min; MS (ESIpos): m/z=446 [M+H].sup.+

(82) .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 1.4

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

(83) ##STR00031##

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

(85) LC-MS (method a): R.sub.t=1.02 min; MS (ESIpos): m/z=404 [M+H].sup.+

(86) .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 1.5

2-chloro-5-fluoro-4-(4-fluoro-3-nitrophenyl)pyrimidine

(87) ##STR00032##

(88) To a suspension of 2,4-dichloro-5-fluoropyrimidine (4.10 g), (4-fluoro-3-nitrophenyl)boronic acid (5.00 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichlorpalladium(II) (complex with dichloromethane, 2.01 g) in 1,2-dimethoxyethane (64 mL) was added aqueous potassium carbonate solution (2M, 37 mL) and the mixture was heated to 90° C. for 2.5 h. The mixture was allowed to cool to room temperature, diluted with water (250 mL) and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (6.14 g, 95% purity).

(89) LC-MS (method a): R.sub.t=1.18 min; MS (ESIpos): m/z=272 [M+H].sup.+

(90) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=7.80-7.87 (m, 1H), 8.41-8.47 (m, 1H), 8.70-8.78 (m, 1H), 9.06-9.12 (m, 1H).

Preparation of Intermediate 1.6

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

(91) ##STR00033##

(92) To a solution of 2-chloro-5-fluoro-4-(4-fluoro-3-nitrophenyl)pyrimidine (6.14 g) in methanol (370 mL) and THF (110 mL) was added platinum (1%) and vanadium (2%) on charcoal (2.20 g) and the mixture was purged with hydrogen gas for 3 h. The mixture was filtered over a pad of celite and the filter cake was washed with methanol and THF. The filtrate was concentrated to yield the title compound (5.51 g).

(93) LC-MS (method a): Rt=1.04 min; MS (ESIpos): m/z=242 [M+H].sup.+

(94) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=5.50-5.61 (m, 2H), 7.15-7.29 (m, 2H), 7.53-7.60 (m, 1H), 8.87-8.93 (m, 1H).

Preparation of Intermediate 1.7

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

(95) ##STR00034##

(96) To a suspension of 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoroaniline (5.51 g), 2-nitrobenzenesulfonyl chloride (6.06 g) and 4-dimethylaminopyridine (139 mg) in dichloromethane (28 mL) was added pyridine (2.2 mL) and the mixture was stirred for 6.5 h at room temperature. Additional 2-nitrobenzenesulfonyl chloride (2.02 g), 4-dimethylaminopyridine (46 mg) and pyridine (0.73 mL) was added and the mixture was stirred for an additional 16 h. The mixture was diluted with aqueous hydrochloric acid solution (1N, 50 mL) and the mixture was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (1.42 g, 98% purity). Further purification of impure fractions by preparative HPLC yielded additional material (6.61 g, 98% purity).

(97) Preparative HPLC

(98) Instrument: pump: Labomatic HD-3000, autosampler Labomatic Labocol AS-3000; detector: Knauer DAD 2600; collector: Labomatic Labocol Vario-4000 plus; column: YMC-Triart C18 5 μm, 100×50 mm; solvent A: water+0.1 vol-% formic acid, solvent B: acetonitrile; gradient: 0.00-1.00 min 50% B (50->150 mL/min), 1.00-7.50 min 50-64% B (180 mL/min); DAD (254 nM).

(99) LC-MS (method a): R.sub.t=1.20 min; MS (ESIpos): m/z=427 [M+H].sup.+

(100) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=7.41-7.55 (m, 1H), 7.80-8.05 (m, 6H), 8.92-9.02 (m, 1H), 10.78-10.93 (m, 1H).

Preparation of Intermediate 1.8

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

(101) ##STR00035##

(102) To a solution of N-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenyl]-2-nitrobenzenesulfonamide (2.00 g, 4.69 mmol), (rac)-tert-butyl {[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (see intermediate 1.4; 2.26 g) and triphenylphosphine (1.47 g) in dichloromethane (20 mL) at 0° C. was added diisopropyl azodicarboxylate (1.1 mL) and the mixture was stirred for 16 h at room temperature. Additional triphenylphosphine (1.47 g) and diisopropyl azodicarboxylate (1.1 mL) was added and the mixture was stirred for an additional 2 h. The mixture was concentrated and purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (3.36 g) which was contaminated by some impurities and used without further purification.

(103) LC-MS (method a): R.sub.t=1.43 min; MS (ESIpos): m/z=811 [M].sup.+

Preparation of Intermediate 1.9

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

(104) ##STR00036##

(105) To a solution of (rac)-tert-butyl {[3-(4-{[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenyl][(2-nitrophenyl)sulfonyl]amino}butoxy)-5-nitrobenzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (3.36 g) in DMF (78 mL) was added cesium carbonate (2.70 g) and the mixture was stirred for 2 min. Then, thiophenol (510 μL) was added and the mixture was stirred for an additional 20 h at room temperature. The mixture was diluted with water (150 mL) and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The crude product was sequentially purified by flash column chromatography (silica gel, hexanes/ethyl acetate) and preparative HPLC to yield the title compound (160 mg, 99% purity).

(106) Preparative HPLC

(107) Instrument: pump: Labomatic HD-3000, autosampler Labomatic Labocol AS-3000; detector: Knauer DAD 2600; collector: Labomatic Labocol Vario-4000 plus; column: YMC-Triart C18 5 μm, 150×50 mm; solvent A: water+0.1 vol-% formic acid, solvent B: acetonitrile; gradient: 0.00-1.00 min 70% B (50->125 mL/min), 1.00-8.00 min 70-86% B (125 mL/min); DAD (254 nM).

(108) LC-MS (method a): R.sub.t=1.46 min; MS (ESIpos): m/z=626 [M+H].sup.+

(109) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.37 (s, 9H), 1.71-1.82 (m, 2H), 1.82-1.91 (m, 2H), 3.19-3.27 (m, 2H), 4.12-4.20 (m, 2H), 4.92-5.06 (m, 2H), 5.85-5.96 (m, 1H), 7.19-7.29 (m, 2H), 7.31-7.36 (m, 1H), 7.41-7.46 (m, 1H), 7.72-7.79 (m, 1H), 7.87-7.93 (m, 1H), 8.88-8.94 (m, 1H).

Preparation of Intermediate 1.10

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

(110) ##STR00037##

(111) To a solution of (rac)-tert-butyl {[3-(4-{[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenyl]amino}butoxy)-5-nitrobenzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (160 mg) in methanol (6.2 mL) and THF (620 μL) was added platinum (1%) and vanadium (2%) on activated charcoal (24.9 mg) and the mixture was purged with hydrogen gas for 3 h. The mixture was filtered over a pad of celite and the filter cake was washed with methanol and THF. The filtrate was concentrared to yield the title compound (154 mg, 98% purity).

(112) LC-MS (method a): R.sub.t=1.32 min; MS (ESIpos): m/z=595 [M−H].sup.+

(113) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.34-1.37 (m, 9H), 1.69-1.86 (m, 4H), 3.03-3.12 (m, 3H), 3.15-3.23 (m, 3H), 3.84-3.91 (m, 2H), 4.51-4.64 (m, 2H), 5.16-5.24 (m, 2H), 5.84-5.95 (m, 1H), 6.11-6.20 (m, 3H), 7.20-7.27 (m, 2H), 7.29-7.39 (m, 1H), 8.87-8.92 (m, 1H).

Example 1—Preparation of the End Product

(114) A degassed suspension of (rac)-tert-butyl {[3-amino-5-(4-{[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenyl]amino}butoxy)benzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (150 mg), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (41.6 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (24.0 mg) and potassium phosphate (267 mg) in toluene (15 mL) and N-methylpyrrolidone (1.5 mL) was heated to 130° C. for 16 h. The mixture was allowed to cool to room temperature, diluted with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (75 mg, 90% purity), which was contaminated by some impurities and used without further purification. A pure sample was obtaind by preparative HPLC.

(115) Preparative HPLC

(116) Instrument: Waters autopurification system; column: Waters XBrigde C18 5 μm, 100×30 mm; solvent A: water+0.2 vol-% ammonia (32%), solvent B: methanol; gradient: 0.00-0.50 min 31% B (25->70 mL/min), 0.51-5.50 min 61-81% B (70 mL/min); DAD scan: 210-400 nm.

(117) LC-MS (method A): R.sub.t=1.34 min; MS (ESIneg): m/z=558 [M−H].sup.−

(118) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.39 (s, 9H), 1.60-1.71 (m, 2H), 1.74-1.87 (m, 2H), 3.13-3.17 (m, 3H), 3.18-3.25 (m, 2H), 4.10-4.17 (m, 2H), 4.72-4.83 (m, 2H), 5.95-6.03 (m, 1H), 6.76-6.83 (m, 1H), 6.86-6.92 (m, 1H), 7.14-7.22 (m, 1H), 7.23-7.30 (m, 1H), 7.60-7.67 (m, 1H), 8.01-8.13 (m, 1H), 8.57-8.63 (m, 1H), 9.86-9.91 (m, 1H).

Example 2

(rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13-oxa-5,7,18,25-tetraazatetracyclo[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

(119) ##STR00038##

(120) To a solution of (rac)-tert-butyl [{[3,20-difluoro-13-oxa-5,7,18,25-tetraazatetracyclo[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 (75.0 mg) in dichloromethane (2.0 mL) was added trifluoroacetic acid (260 μL) and the mixture was stirred for 1 h at room temperature. The mixture was basified by the addition of saturated aqueous sodium bicarbonate solution and the mixture was extracted with dichloromethane. The combined organic layers were dried and concentrated. The crude product was purified by preparative HPLC to yield the title compound (26 mg, 99% purity).

(121) Preparative HPLC

(122) Instrument: pump: Labomatic HD-5000, head HDK 280, low pressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 μm, 125×30 mm; solvent A: water+0.2 vol-% ammonia (32%), solvent B: acetonitrile; gradient: 0.00-0.50 min 30% B (150 mL/min), 0.50-6.00 min 30-70% B (150 mL/min), 6.00-6.10 min 70-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); UV-Detection (258 nm).

(123) LC-MS (method B): R.sub.t=1.13 min; MS (ESIneg): m/z=458 [M−H].sup.−

(124) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.57-1.67 (m, 2H), 1.74-1.85 (m, 2H), 2.82-2.91 (m, 3H), 3.17-3.28 (m, 2H), 3.58-3.65 (m, 1H), 4.11-4.18 (m, 2H), 4.22-4.33 (m, 2H), 5.95-6.02 (m, 1H), 6.79-6.88 (m, 2H), 7.12-7.21 (m, 1H), 7.24-7.29 (m, 1H), 7.62-7.68 (m, 1H), 7.99-8.06 (m, 1H), 8.57-8.61 (m, 1H), 9.82 (s, 1H).

Example 3

(rac)-3,19-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13-oxa-5,7,17,24-tetraazatetracyclo[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

(125) ##STR00039##

Preparation of Intermediate 3.1

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

(126) ##STR00040##

(127) To a suspension of 3-[(methylsulfanyl)methyl]-5-nitrophenol (5.00 g) and potassium carbonate (4.16 g) in DMF (50 mL) at 0° C. was added 3-bromopropan-1-ol (2.5 mL) and the mixture was stirred for 20 h at room temperature. The mixture was diluted with water (150 mL) and subsequently extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated to yield the title compound (8.98 g, 1:1 mixture with DMF).

(128) LC-MS (method b): R.sub.t=1.04 min; MS (ESIneg): m/z=256 [M−H].sup.−

(129) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.85-1.94 (m, 2H), 1.94-1.98 (m, 3H), 3.53-3.60 (m, 2H), 3.76-3.82 (m, 2H), 4.11-4.22 (m, 2H), 4.56-4.64 (m, 1H), 7.32-7.41 (m, 1H), 7.56-7.61 (m, 1H), 7.75-7.80 (m, 1H), 7.92-7.97 (m, 1H).

Preparation of Intermediate 3.2

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

(130) ##STR00041##

(131) To a solution of 3-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}propan-1-ol (8.98 g, 1:1 mixture with DMF) in acetonitrile (99 mL) at 0° C. was added iron(III) chloride (170 mg) and the mixture was stirred for 15 min. Then, periodic acid (8.75 g) was added portionwise and the mixture was stirred for an additional 1 h. The reaction was stopped by the addition of saturated aqueous sodium thiosulfate solution and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrate to yield the title compound (7.41 g, 95% purity) that was judged to be pure by NMR and used without further purification.

(132) LC-MS (method a): R.sub.t=0.68 min; MS (ESIpos): m/z=274 [M+H].sup.+

(133) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.84-1.95 (m, 2H), 3.52-3.62 (m, 2H), 4.03-4.10 (m, 1H), 4.13-4.20 (m, 2H), 4.24-4.32 (m, 1H), 4.57-4.67 (m, 1H), 7.26-7.40 (m, 1H), 7.65-7.73 (m, 1H), 7.75-7.85 (m, 1H).

Preparation of Intermediate 3.3

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

(134) ##STR00042##

(135) To a suspension of (rac)-3-(3-{[methylsulfinyl]methyl}-5-nitrophenoxy)propan-1-ol (7.41 g), tert-butyl carbamate (4.76 g), magnesium oxide (4.37 g) and rhodium(II) acetate dimer (599 mg) in dichloromethane (250 mL) was added (diacetoxyiodo)benzene (3.45 g) and the mixture was stirred for 24 h at 40° C. Additional tert-butyl carbamate (2.38 g), rhodium(II) acetate dimer (300 mg) and (diacetoxyiodo)benzene (1.72 g) were added and the mixture was stirred for an additional 4 h at 40° C. The mixture was allowed to cool to room temperature and filtered over a pad of celite. The filter cake was washed with dichloromethane and the filtrate was concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate->methanol) to yield the title compound (5.89 g). In addition, starting material was recovered (2.29 g).

(136) LC-MS (method a): R.sub.t=0.96 min; MS (ESIneg): m/z=387 [M−H].sup.−

(137) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.39 (s, 9H), 1.85-1.93 (m, 2H), 3.10-3.19 (m, 3H), 3.52-3.60 (m, 2H), 4.12-4.22 (m, 2H), 4.56-4.67 (m, 1H), 4.93-5.08 (m, 2H), 7.41-7.50 (m, 1H), 7.72-7.78 (m, 1H), 7.88-7.93 (m, 1H).

Preparation of Intermediate 3.4

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

(138) ##STR00043##

(139) To a solution of N-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenyl]-2-nitrobenzenesulfonamide (see intermediate 1.7; 2.00 g), (rac)-tert-butyl {[3-(3-hydroxypropoxy)-5-nitrobenzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (2.18 g) and triphenylphosphine (1.47 g) in dichloromethane (20 mL) at 0° C. was added diisopropyl azodicarboxylate (1.1 mL) and the mixture was stirred for 16 h at room temperature. Additional (rac)-tert-butyl {[3-(3-hydroxypropoxy)-5-nitrobenzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (0.50 g), triphenylphosphine (0.37 g) and diisopropyl azodicarboxylate (0.27 mL) was added and the mixture was stirred for an additional 2.5 h. The mixture was concentrated and the crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (4.76 g) which was contaminated by some impurities and used without further purification.

(140) LC-MS (method a): R.sub.t=1.40 min; MS (ESIpos): m/z=797 [M].sup.+

Preparation of Intermediate 3.5

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

(141) ##STR00044##

(142) To a solution of (rac)-tert-butyl {[3-(3-{[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenyl][(2-nitrophenyl)sulfonyl]amino}propoxy)-5-nitrobenzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (4.76 g) in DMF (110 mL) was added cesium carbonate (3.89 g) and the mixture was stirred for 2 min. Then, thiophenol (740 μL) was added and the mixture was stirred for an additional 20 h at room temperature. The mixture was diluted with water (150 mL) and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was sequentially purified by flash column chromatography (silica gel, hexanes/ethyl acetate) and preparative HPLC to yield the title compound (181 mg, 99% purity).

(143) Preparative HPLC

(144) Instrument: pump: Labomatic HD-3000, autosampler Labomatic Labocol AS-3000; detector: Knauer DAD 2600; collector: Labomatic Labocol Vario-4000 plus; column: YMC-Triart C18 5 μm 150×50 mm; solvent A: water+0.1 vol-% formic acid, solvent B: acetonitrile; gradient: 0.00-1.00 min 64% B (50->125 mL/min), 1.00-8.00 min 64-90% B (125 mL/min); DAD (280 nM).

(145) LC-MS (method a): R.sub.t=1.42 min; MS (ESIpos): m/z=612 [M+H].sup.+

(146) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.32-1.40 (m, 9H), 2.05-2.16 (m, 2H), 3.11-3.16 (m, 3H), 3.28-3.37 (m, 2H), 4.20-4.25 (m, 2H), 4.93-5.06 (m, 2H), 5.92-6.04 (m, 1H), 7.21-7.30 (m, 2H), 7.32-7.40 (m, 1H), 7.42-7.48 (m, 1H), 7.72-7.82 (m, 1H), 7.86-7.94 (m, 1H), 8.88-8.94 (m, 1H), 8.88-8.94 (m, 1H).

Preparation of Intermediate 3.6

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

(147) ##STR00045##

(148) To a solution of (rac)-tert-butyl {[3-(3-{[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenyl]amino}propoxy)-5-nitrobenzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (180 mg) in methanol (7.1 mL) and THF (720 μL) was added platinum (1%) and vanadium (2%) on charcoal (28.7 mg) and the mixture was purged with hydrogen gas for 2.5 h. The mixture was filtered over a pad of celite and the filter cake was washed with methanol and THF. The filtrate was concentrated to yield the title compound (181 mg, 96% purity).

(149) LC-MS (method A): R.sub.t=1.28 min; MS (ESIpos): m/z=582 [M].sup.+

(150) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm 1.33-1.42 (m, 9H), 2.00-2.08 (m, 2H), 3.02-3.09 (m, 3H), 3.26-3.32 (m, 2H), 3.91-4.01 (m, 2H), 4.53-4.65 (m, 2H), 5.16-5.24 (m, 2H), 5.87-5.99 (m, 1H), 6.13-6.21 (m, 3H), 7.21-7.29 (m, 2H), 7.32-7.39 (m, 1H), 8.88-8.95 (m, 1H).

Example 3—Preparation of the End Product

(151) A degassed suspension of (rac)-tert-butyl {[3-amino-5-(3-{[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenyl]amino}propoxy)benzyl](methyl)oxido-λ.sup.6-sulfanylidene}carbamate (180 mg), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (51.1 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (29.5 mg) and potassium phosphate (328 mg) in toluene (18 mL) and N-methylpyrrolidone (1.8 mL) was heated to 130° C. for 16 h. The mixture was allowed to cool to room temperature, diluted with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield (rac)-tert-butyl [{[3,19-difluoro-13-oxa-5,7,17,24-tetraazatetracyclo[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 (86 mg) which was used immediately in the next step.

(152) To a solution of (rac)-tert-butyl [{[3,19-difluoro-13-oxa-5,7,17,24-tetraazatetracyclo[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 (86 mg) in dichloromethane (2.0 mL) was added trifluoroacetic acid (300 μL) and the mixture was stirred for 1 h at room temperature. The mixture was basified by the addition of a saturated aqueous sodium bicarbonate solution and the mixture was extracted with dichloromethane. The combined organic layers were dried and concentrated. The crude product was purified by preparative HPLC to yield the title compound (27 mg, 99% purity).

(153) Preparative HPLC

(154) Instrument: pump: Labomatic HD-5000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 μm, 125×30 mm; solvent A: water+0.2 vol-% ammonia (32%), solvent B: acetonitrile; gradient: 0.00-0.50 min 15% B (150 mL/min), 0.50-6.00 min 15-55% B (150 mL/min), 6.00-6.10 min 55-100% B (150 mL/min), 6.10-8.00 min 100% B (150 mL/min); UV-detection (256 nm).

(155) LC-MS (method b): R.sub.t=1.03 min; MS (ESIpos): m/z=446 [M+H].sup.+

(156) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.93-2.07 (m, 2H), 2.78-2.85 (m, 3H), 3.27-3.33 (m, 2H), 3.56-3.62 (m, 1H), 4.18-4.30 (m, 4H), 6.13-6.23 (m, 1H), 6.61-6.70 (m, 1H), 6.76-6.83 (m, 1H), 7.10-7.18 (m, 2H), 7.56-7.66 (m, 1H), 7.98-8.06 (m, 1H), 8.55-8.64 (m, 1H), 9.73-9.78 (m, 1H).

Example 4

(rac)-tert-butyl [{[3,21-difluoro-13-oxa-5,7,19,26-tetraazatetracyclo[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

(157) ##STR00046##

Preparation of Intermediate 4.1

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

(158) ##STR00047##

(159) To a suspension of 3-[(methylsulfanyl)methyl]-5-nitrophenol (5.00 g) and potassium carbonate (5.20 g) in DMF (49 mL) at 0° C. was added methyl 5-bromopentanoate (4.3 mL) and the mixture was stirred for 16 h at room temperature. Additional methyl 5-bromopentanoate (0.72 mL) was added and the mixture was stirred for an additional 1 h. The reaction was quenched by the addition of water and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated, to yield the title compound (8.18 g) that was used without further purification.

(160) LC-MS (method a): R.sub.t=1.34 min; MS (ESIpos): m/z=314 [M+H].sup.+

(161) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.66-1.82 (m, 4H), 1.93-2.00 (m, 3H), 2.37-2.42 (m, 2H), 3.59 (s, 3H), 3.76-3.82 (m, 2H), 4.06-4.14 (m, 2H), 7.32-7.40 (m, 1H), 7.51-7.61 (m, 1H), 7.71-7.80 (m, 1H).

Preparation of Intermediate 4.2

(rac)-methyl 5-(3-{[(S)-methylsulfinyl]methyl}-5-nitrophenoxy)pentanoate

(162) ##STR00048##

(163) To a solution of methyl 5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentanoate (8.18 g) in acetonitrile (290 mL) at 0° C. was added iron(III) chloride (423 mg) and the mixture was stirred for 10 min. Then, periodic acid (17.8 g) was added and the mixture was stirred for an additional 2 h at 0° C. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate solution. The mixture was stirred for 10 min and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated to yield the crude product (8.66 g) that was used without further purification.

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

(165) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.65-1.82 (m, 4H), 2.37-2.43 (m, 2H), 3.57-3.61 (m, 3H), 4.03-4.16 (m, 3H), 4.25-4.31 (m, 1H), 7.30-7.37 (m, 1H), 7.65-7.69 (m, 1H), 7.78-7.82 (m, 1H) (methyl group overlayed by residual DMSO).

Preparation of Intermediate 4.3

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

(166) ##STR00049##

(167) To a suspension of (rac)-methyl 5-(3-{[(S)-methylsulfinyl]methyl}-5-nitrophenoxy)pentanoate (8.41 g), tert-butyl carbamate (4.49 g), magnesium oxide (4.12 g) and rhodium(II) acetate dimer (282 mg) in dichloromethane (110 mL) at room temperature was added (diacetoxyiodo)benzene (12.3 g) and the mixture was stirred at 45° C. for 3 h. The mixture was allowed to cool to room temperature, combined with another reaction batch (250 mg of (rac)-methyl 5-(3-{[(S)-methylsulfinyl]methyl}-5-nitrophenoxy)pentanoate (8.41 g) and filtered over a pad of celite. The filter cake was washed with dichloromethane and the filtrate was concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate->ethyl acetate/methanol) to yield the title compound (9.60 g).

(168) LC-MS (method a): R.sub.t=1.19 min; MS (ESIneg): m/z=443 [M−H].sup.−

(169) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.36-1.42 (m, 9H), 1.64-1.81 (m, 4H), 2.36-2.45 (m, 2H), 3.10-3.16 (m, 3H), 3.59 (s, 3H), 4.08-4.15 (m, 2H), 4.94-5.06 (m, 2H), 7.39-7.48 (m, 1H), 7.72-7.79 (m, 1H), 7.89-7.93 (m, 1H).

Preparation of Intermediate 4.4

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

(170) ##STR00050##

(171) To a solution of (rac)-methyl 5-(3-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-5-nitrophenoxy)pentanoate (2.00 g) in THF (31 ml) at −78° C. was added dropwise diisobutylaluminum hydride (18 mL, 1.0 M in THF). The mixture was stirred for 10 min at this temperature, allowed to warm to room temperature and stirred for 2 h. The reaction was quenched by carefully adding saturated aqueous sodium potassium tartrate solution and the mixture was vigorously stirred for 1.5 h and subsequently extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (902 mg, 95% purity).

(172) LC-MS (method a): R.sub.t=1.05 min; MS (ESIpos): m/z=417 [M+H].sup.+

(173) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 22° C.) δ ppm 1.34-1.43 (m, 9H), 1.43-1.53 (m, 4H), 1.69-1.81 (m, 2H), 3.11-3.17 (m, 3H), 3.37-3.46 (m, 2H), 4.07-4.14 (m, 2H), 4.35-4.42 (m, 1H), 4.94-5.09 (m, 2H), 7.40-7.46 (m, 1H), 7.73-7.76 (m, 1H), 7.90 (s, 1H).

Preparation of Intermediate 4.5

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

(174) ##STR00051##

(175) To a solution of (rac)-tert-butyl [{3-[(5-hydroxypentyl)oxy]-5-nitrobenzyl}(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (902 mg) in dichloromethane (4 mL) at room temperature was added Dess-Martin periodinane (2.76 g) and the mixture was stirred for 2.5 h. The mixture was diluted with diethyl ether and water/saturated aqueous sodium thiosulphate solution/saturated aqueous sodium bicarbonate solution (v/v/v=1/1/1) and the mixture was vigorously stirred for 16 h to obtain two clear layers. The organic layer was separated, dried and concentrated to yield the title compound (913 mg) that was used without further purification.

(176) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.39 (s, 9H), 1.62-1.82 (m, 4H), 2.51-2.57 (m, 2H), 3.09-3.18 (m, 3H), 4.07-4.18 (m, 2H), 4.94-5.08 (m, 2H), 7.41-7.47 (m, 1H), 7.73-7.79 (m, 1H), 7.87-7.93 (m, 1H), 9.64-9.71 (m, 1H).

Preparation of Intermediate 4.6

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

(177) ##STR00052##

(178) To a suspension of 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoroaniline (277 mg) and (rac)-tert-butyl (methyl{3-nitro-5-[(5-oxopentyl)oxy]benzyl}oxido-λ.sup.6-sulfanylidene)carbamate (713 mg) in 1,2-dichloroethane (8.3 mL) was added acetic acid (5.3 mL) followed by sodium triacetoxyborohydride (729 mg) and the mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was sequentially purified by flash column chromatography (silica gel, hexanes/ethyl acetate) and preparative HPLC to yield the title compound (164 mg).

(179) Preparative HPLC

(180) Instrument: pump: Labomatic HD-5000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 μm, 125×30 mm; solvent A: water+0.1 vol-% formic acid (99%), solvent B: acetonitrile; gradient: 0.00-0.50 min 40% B (150 mL/min), 0.50-6.00 min 40-80% B (150 mL/min), 6.00-6.10 min 80-100% B (150 mL/min), 6.10-8.00 min 100% B (150 mL/min); UV-Detection (242 nm).

(181) LC-MS (method a): R.sub.t=1.52 min; MS (ESIpos): m/z=641 [M+H].sup.+

(182) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.35-1.41 (m, 9H), 1.50-1.58 (m, 2H), 1.63-1.72 (m, 2H), 1.75-1.85 (m, 2H), 3.08-3.19 (m, 5H), 4.07-4.17 (m, 2H), 4.93-5.06 (m, 2H), 5.82-5.89 (m, 1H), 7.19-7.26 (m, 2H), 7.28-7.38 (m, 1H), 7.38-7.44 (m, 1H), 7.71-7.77 (m, 1H), 7.86-7.91 (m, 1H), 8.87-8.92 (m, 1H).

Preparation of Intermediate 4.7

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

(183) ##STR00053##

(184) To a solution of (rac)-tert-butyl [{3-[(5-{[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenyl]amino}pentyl)oxy]-5-nitrobenzyl}(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (160 mg) in methanol (6.1 mL) and THF (610 μL) was added platinum (1%) and vanadium (2%) on activated carbon (25 mg). The mixture was purged with hydrogen gas (1 atm) and stirred for 6 h. Additional platinum (1%) and vanadium (2%) on activated carbon (25 mg) was added, the mixture was purged with hydrogen gas (1 atm) and stirred for 5 h. The mixture was filtered and the filter cake was washed with methanol and THF. The filtrate was concentrated to yield the title compound (146 mg) that was used without further purification.

(185) LC-MS (method a): R.sub.t=1.40 min; MS (ESIpos): m/z=611 [M+H].sup.+

(186) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.37 (s, 9H), 1.47-1.55 (m, 2H), 1.63-1.80 (m, 5H), 3.03-3.08 (m, 3H), 3.14-3.18 (m, 2H), 3.83-3.89 (m, 2H), 4.52-4.64 (m, 2H), 5.16-5.22 (m, 2H), 5.81-5.88 (m, 1H), 6.12-6.19 (m, 3H), 7.19-7.27 (m, 2H), 7.30-7.35 (m, 1H), 8.87-8.93 (m, 1H).

Example 4—Preparation of the End Product

(187) A degassed suspension of (rac)-tert-butyl [{3-amino-5-[(5-{[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenyl]amino}pentyl)oxy]benzyl}(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (140 mg), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (19 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (11 mg) and potassium phosphate (244 mg) in toluene (14 mL) and N-methylpyrrolidone (1.4 mL) was heated at 130° C. for 18 h. The mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (61 mg, 97% purity).

(188) LC-MS (method a): R.sub.t=1.43 min; MS (ESIpos): m/z=574 [M+H].sup.+

(189) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.36-1.41 (m, 9H), 1.52-1.60 (m, 2H), 1.72-1.85 (m, 4H), 3.13-3.18 (m, 3H), 3.18-3.27 (m, 2H), 3.97-4.02 (m, 2H), 4.70-4.79 (m, 2H), 5.77-5.84 (m, 1H), 6.58-6.65 (m, 1H), 6.84-6.88 (m, 1H), 7.14-7.26 (m, 2H), 7.51-7.57 (m, 1H), 8.32-8.39 (m, 1H), 8.58-8.66 (m, 1H), 9.89-9.96 (m, 1H).

Example 5

(rac)-3,21-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13-oxa-5,7,19,26-tetraazatetracyclo[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

(190) ##STR00054##

(191) To a solution of (rac)-tert-butyl [{[3,20-difluoro-13-oxa-5,7,18,25-tetraazatetracyclo[17.3.1.1.sup.2,61.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 (55 mg) in dichloromethane (980 μL) was added trifluoroacetic acid (180 μL) and the mixture was stirred for 1 h at room temperature. The mixture was basified by the addition of saturated aqueous sodium bicarbonate solution and the mixture was extracted with dichloromethane. The combined organic layers were dried and concentrated. The crude product was suspended in dichloromethane and the precipitate was isolated by filtration and dried to yield the title compound (8 mg, 99% purity).

(192) LC-MS (method a): R.sub.t=1.18 min; MS (ESIpos): m/z=474 [M+H].sup.+

(193) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.48-1.61 (m, 2H), 1.73-1.88 (m, 4H), 2.80-2.92 (m, 3H), 3.17-3.28 (m, 2H), 3.52-3.64 (m, 1H), 3.96-4.07 (m, 2H), 4.21-4.35 (m, 2H), 5.76-5.84 (m, 1H), 6.57-6.68 (m, 1H), 6.78-6.86 (m, 1H), 7.13-7.24 (m, 2H), 7.49-7.61 (m, 1H), 8.27-8.38 (m, 1H), 8.55-8.64 (m, 1H), 9.80-9.92 (m, 1H).

Example 6

(rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13-oxa-5,7,18,24-tetraazatetracyclo[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) ##STR00055##

Preparation of Intermediate 6.1

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

(195) ##STR00056##

(196) To a suspension of 2-chloro-5-fluoro-4-iodopyridine (3.18 g), 2-(4-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.00 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichlorpalladium(II) (complex with dichloromethane, 917 mg) in 1,2-dimethoxyethane (29 mL) at room temperature was added aqueous potassium carbonate solution (2M, 17 mL) and the mixture was stirred at 90° C. for 3 h. The mixture was allowed to cool to room temperature, diluted with water and subsequently extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (2.70 g).

(197) LC-MS (method a): R.sub.t=1.21 min; MS (ESIpos): m/z=271 [M+H].sup.+

(198) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=7.76-7.84 (m, 1H), 7.92-7.97 (m, 1H), 8.12-8.20 (m, 1H), 8.47-8.54 (m, 1H), 8.59-8.64 (m, 1H).

Preparation of Intermediate 6.2

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

(199) ##STR00057##

(200) A suspension of 2-chloro-5-fluoro-4-(4-fluoro-3-nitrophenyl)pyridine (2.70 g) and platinum (1%) and vanadium (2%) on activated carbon (974 mg) in methanol (240 mL) and THF (24 mL) was stirred under an atmosphere of hydrogen gas at room temperature for 3 h. The mixture was filtered over a pad of celite and the filter cake was washed with methanol. The filtrate was concentrated to yield the title compound (2.29 g) that was used without further purification.

(201) LC-MS (method a): R.sub.t=1.12 min; MS (ESIpos): m/z=241 [M+H].sup.+

(202) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=5.37-5.48 (m, 2H), 6.76-6.87 (m, 1H), 7.04-7.11 (m, 1H), 7.11-7.19 (m, 1H), 7.62-7.69 (m, 1H), 8.49-8.53 (m, 1H).

Preparation of Intermediate 6.3

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

(203) ##STR00058##

(204) To a solution of butane-1,4-diol (5.3 mL) in THF (160 mL) at 0° C. was added sodium hydride (60 wt % in mineral oil, 1.15 g). The mixture was allowed to warm to room temperature and stirred for 30 min. Then, 2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine (5.00 g, prepared according to WO2015/155197 A1) was carefully added and the mixture was heated at reflux for 16 h. The mixture was allowed to cool to room temperature and carefully concentrated. The resulting residue was partitioned between ethyl acetate and water and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (2.78 g).

(205) LC-MS (method a): R.sub.t=1.10 min; MS (ESIpos): m/z=262 [M+H].sup.+

(206) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.46-1.58 (m, 2H), 1.65-1.78 (m, 2H), 1.92-1.97 (m, 3H), 3.40-3.47 (m, 2H), 3.63-3.68 (m, 2H), 4.18-4.24 (m, 2H), 4.42-4.49 (m, 1H), 6.72-6.76 (m, 1H), 7.00-7.04 (m, 1H).

Preparation of Intermediate 6.4

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

(207) ##STR00059##

(208) To a solution of 4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)butan-1-ol (2.78 g) in acetonitrile (30 mL) at 0° C. was added iron(III) chloride (172 mg) and the mixture was stirred for 10 min. Then, periodic acid (7.26 g) was added and the mixture was stirred for an additional 2 h at 0° C.

(209) The mixture was poured on ice and diluted saturated aqueous sodium thiosulphate solution (200 mL) was added. The mixture was stirred for 16 h and was subsequently extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated to yield the crude titlr compound (2.90 g) that was used without further purification.

(210) LC-MS (method a): R.sub.t=0.71 min; MS (ESIpos): m/z=278 [M+H].sup.+

(211) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.42-1.60 (m, 2H), 1.67-1.79 (m, 3H), 3.39-3.47 (m, 2H), 3.89-3.97 (m, 1H), 4.12-4.19 (m, 1H), 4.20-4.25 (m, 2H), 6.72-6.76 (m, 1H), 7.00-7.04 (m, 1H) (three protons overlayed by residual DMSO).

Preparation of Intermediate 6.5

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

(212) ##STR00060##

(213) To a suspension of (rac)-4-[(6-chloro-4-{[methylsulfinyl]methyl}pyridin-2-yl)oxy]butan-1-ol (2.90 g), magnesium oxide (1.68 g) and rhodium(II) acetate dimer (115 mg) in dichloromethane (46 mL) was added bisacetoxyiodobenzene (5.04 g) and the mixture was stirred at 45° C. for 3 h. The mixture was allowed to cool to room temperature and filtered. The filter cake was washed with dichloromethane and the filtrate was concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/methanol) to yield the title compound (2.12 g).

(214) LC-MS (method a): R.sub.t=1.04 min; MS (ESIneg): m/z=391 [M−H].sup.−

(215) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.39 (s, 9H), 1.49-1.58 (m, 2H), 1.70-1.78 (m, 2H), 3.14-3.19 (m, 3H), 3.40-3.48 (m, 2H), 4.20-4.28 (m, 2H), 4.43-4.48 (m, 1H), 4.87-4.95 (m, 2H), 6.83-6.88 (m, 1H), 7.07-7.10 (m, 1H)

Preparation of Intermediate 6.6

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

(216) ##STR00061##

(217) To a suspension of (rac)-tert-butyl [{[2-chloro-6-(4-hydroxybutoxy)pyridin-4-yl]methyl}(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (500 mg), cesium carbonate (829 mg) and tert-butyl carbamate (224 mg) in 1,4-dioxane (160 ml) at room temperature was added 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (61 mg) and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (105 mg). The mixture was degassed and stirred at 90° C. for 2 h. The mixture was allowed to cool to room temperature and filtered. The filtrate was diluted with water and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate.fwdarw.ethyl acetate/ethanol) to yield the title compound (359 mg, 95% purity).

(218) LC-MS (method b): R.sub.t=1.15 min; MS (ESIpos): m/z=473 [M−H].sup.+

(219) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.33-1.40 (m, 9H), 1.43-1.47 (m, 9H), 1.49-1.56 (m, 2H), 1.65-1.76 (m, 2H), 3.11-3.18 (m, 3H), 3.39-3.49 (m, 2H), 4.16-4.24 (m, 2H), 4.41-4.48 (m, 1H), 4.78-4.87 (m, 2H), 6.43-6.51 (m, 1H), 7.38-7.46 (m, 1H), 9.64-9.70 (m, 1H).

Preparation of Intermediate 6.7

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

(220) ##STR00062##

(221) To a solution of (rac)-tert-butyl [({2-[(tert-butoxycarbonyl)amino]-6-(4-hydroxybutoxy)pyridin-4-yl}methyl)(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (309 mg) in dichloromethane (6.2 mL) at room temperature was added Dess-Martin periodinane (830 mg) and the mixture was stirred for 2 h. The mixture was diluted with diethyl ether and the reaction was quenched by the addition of water/saturated aqueous sodium thiosulphate solution/saturated aqueous sodium bicarbonate solution (v/v/v=1/1/1). The mixture was vigorously stirred until two clear layers were obtained. The organic layer was separated, dried and concentrated to yield the title compound (330 mg) that was used without further purification.

(222) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 293 K) δ/ppm=1.38 (s, 9H), 1.47 (s, 9H), 1.93-2.01 (m, 2H), 2.54-2.59 (m, 2H), 3.10-3.16 (m, 3H), 4.15-4.23 (m, 2H), 4.81-4.87 (m, 2H), 6.43-6.48 (m, 1H), 7.39-7.45 (m, 1H), 9.65-9.73 (m, 2H)

Preparation of Intermediate 6.8

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

(223) ##STR00063##

(224) To a solution of 5-(2-chloro-5-fluoropyridin-4-yl)-2-fluoroaniline (89 mg) and (rac)-tert-butyl [({2-[(tert-butoxycarbonyl)amino]-6-(4-oxobutoxy)pyridin-4-yl}methyl)(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (330 mg) in 1,2-dichloroethane (2.7 mL) and acetic acid (1.7 mL) at room temperature was added sodium triacetoxyborohydride (234 mg) and the mixture was stirred for 2 h. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution, the pH was adjusted to 7 and the mixture was extracted with ethyl acetate. The combined organic layers were dried and concentrated. The crude product was combined with the crude product from a smaller reaction batch (8 mg of of 5-(2-chloro-5-fluoropyridin-4-yl)-2-fluoroaniline) and purified by flash column chromatography (silica gel, hexanes/ethyl acetate->ethyl acetate/ethanol) to yield the title compound (168 mg) that was contaminated by some minor impurities and used without further purification.

(225) LC-MS (method a): R.sub.t=1.58 min; MS (ESIpos): m/z=698 [M+H.sup.+]

(226) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.32-1.38 (m, 9H), 1.42-1.51 (m, 9H), 1.65-1.74 (m, 2H), 1.74-1.82 (m, 2H), 3.09-3.16 (m, 3H), 3.16-3.24 (m, 2H), 4.19-4.27 (m, 2H), 4.77-4.85 (m, 2H), 5.69-5.79 (m, 1H), 6.41-6.45 (m, 1H), 6.79-6.86 (m, 1H), 6.93-7.00 (m, 1H), 7.13-7.22 (m, 1H), 7.40-7.45 (m, 1H), 7.68-7.79 (m, 1H), 8.46-8.52 (m, 1H), 9.64-9.68 (m, 1H).

Preparation of Intermediate 6.9

(rac)-6-(4-{[5-(2-chloro-5-fluoropyridin-4-yl)-2-fluorophenyl]amino}butoxy)-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-amine

(227) ##STR00064##

(228) To a solution of (rac)-tert-butyl [({2-[(tert-butoxycarbonyl)amino]-6-(4-{[5-(2-chloro-5-fluoropyridin-4-yl)-2-fluorophenyl]amino}butoxy)pyridin-4-yl}methyl)(methyl)oxido-λ.sup.6-sulfanylidene]carbamate (168 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (460 μL) and the mixture was stirred for 1 h. Additional trifluoroacetic acid (460 μL) was added and the mixture was stirred for an additional 30 min. The reaction was basified by the addition of saturated aqueous sodium bicarbonate (15 mL) and the mixture was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated to yield the title compound (130 mg, 96% purity) that was used without further purification.

(229) LC-MS (method b): R.sub.t=1.13 min; MS (ESIpos): m/z=496 [M+H.sup.+]

(230) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.64-1.79 (m, 4H), 2.75-2.82 (m, 3H), 3.14-3.24 (m, 2H), 3.59-3.67 (m, 1H), 4.10-4.18 (m, 4H), 5.72-5.77 (m, 1H), 5.88-5.95 (m, 3H), 5.99-6.03 (m, 1H), 6.80-6.86 (m, 1H), 6.94-7.01 (m, 1H), 7.11-7.22 (m, 1H), 7.71-7.76 (m, 1H), 8.46-8.51 (m, 1H).

Example 6—Preparation of the End Product

(231) A degassed suspension of (rac)-6-(4-{[5-(2-chloro-5-fluoropyridin-4-yl)-2-fluorophenyl]amino}butoxy)-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-amine (117 mg), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (20 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (11 mg) and potassium phosphate (250 mg) in toluene (12 mL) and N-methylpyrrolidone (1.2 mL) was stirred at 120° C. for 2 h. The mixture was allowed to cool to room temperature, diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried and concentrated. The crude product was combined with the crude product of a smaller reaction batch (12 mg of (rac)-6-(4-{[5-(2-chloro-5-fluoropyridin-4-yl)-2-fluorophenyl]amino}butoxy)-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-amine) and purified by preparative HPLC to yield the title compound (16 mg, 95% purity).

(232) Preparative HPLC:

(233) Instrument: pump: Labomatic HD-5000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 μm, 125×30 mm; solvent A: water+0.1 vol-% formic acid, solvent B: acetonitrile; gradient: 0.00-0.50 min 30% B (150 ml/min), 0.50-6.00 min 30-70% B (150 ml/min), 6.00-6.10 min 70-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); UV-Detection (235 nm).

(234) LC-MS (method a): R.sub.t=1.15 min; MS (ESIpos): m/z=459 [M+H.sup.+]

(235) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.50-1.61 (m, 2H), 1.71-1.82 (m, 2H), 2.80-2.88 (m, 3H), 3.24-3.30 (m, 2H), 3.70-3.76 (m, 1H), 4.24-4.34 (m, 2H), 4.45-4.54 (m, 2H), 5.88-5.96 (m, 1H), 6.30-6.36 (m, 1H), 6.58-6.67 (m, 1H), 6.91-7.02 (m, 1H), 7.07-7.19 (m, 2H), 8.20-8.31 (m, 1H), 8.68-8.77 (m, 1H), 9.84-9.92 (m, 1H).

Example 7

(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13-oxa-5,7,18,25-tetraazatetracyclo[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

(236) ##STR00065##

Preparation of Intermediate 7.1

(rac)-5-{[tert-butyl(diphenyl)silyl]oxy}pentan-2-ol

(237) ##STR00066##

(238) To a solution of (rac)-pentane-1,4-diol (5.00 g) in DMF (53 mL) at 0° C. was sequentially added imidazole (3.92 g) and tert-butyl(chloro)diphenylsilane (12 mL) and the mixture was stirred at room temperature for 22 h. The reaction was stopped by the addition of water and the mixture was extracted with hexanes. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated to yield the title compound (12.9 g).

(239) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=0.97-1.04 (m, 12H), 1.31-1.43 (m, 2H), 1.46-1.66 (m, 2H), 3.51-3.60 (m, 1H), 3.60-3.67 (m, 2H), 4.31-4.38 (m, 1H), 7.40-7.48 (m, 6H), 7.58-7.64 (m, 4H).

Preparation of Intermediate 7.2

(rac)-tert-butyl{[4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentyl]oxy}diphenylsilane

(240) ##STR00067##

(241) To a solution of 3-[(methylsulfanyl)methyl]-5-nitrophenol (1.57 g, prepared according to WO2015/155197 A1), (rac)-5-{[tert-butyl(diphenyl)silyl]oxy}pentan-2-ol (3.24 g) and triphenylphosphine (2.27 g) at 0° C. was slowly added diisopropylazo dicarboxylate (1.7 mL) and the mixture was stirred for 2 h at room temperature. The mixture was concentrated and the crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (3.74 g).

(242) LC-MS (method a): R.sub.t=1.84 min; MS (ESIpos): m/z=524 [M+H].sup.+

(243) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=0.95 (s, 9H), 1.21-1.28 (m, 3H), 1.58-1.77 (m, 4H), 1.92-1.97 (m, 3H), 3.64-3.73 (m, 2H), 3.73-3.80 (m, 2H), 4.57-4.68 (m, 1H), 7.28-7.34 (m, 1H), 7.38-7.48 (m, 6H), 7.52-7.55 (m, 1H), 7.55-7.64 (m, 4H), 7.73-7.78 (m, 1H).

Preparation of Intermediate 7.3

(rac)-4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentan-1-ol

(244) ##STR00068##

(245) To a solution of (rac)-tert-butyl{[4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentyl]oxy}diphenylsilane (1.18 g) in THF (110 mL) at room temperature was added tetra-n-butylammonium fluoride solution (1M in THF, 4.5 mL) and the mixture was stirred for 3.5 h. The mixture was concentrated and the crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (542 mg) that was contaminated by some impurities and used without further purification.

(246) LC-MS (method a): R.sub.t=1.17 min; MS (ESIpos): m/z=286 [M+H].sup.+

(247) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.23-1.28 (m, 3H), 1.44-1.77 (m, 4H), 1.96 (s, 3H), 3.37-3.46 (m, 2H), 3.77-3.83 (m, 2H), 4.42-4.49 (m, 1H), 4.58-4.67 (m, 1H), 7.31-7.35 (m, 1H), 7.53-7.57 (m, 1H), 7.71-7.76 (m, 1H).

Preparation of Intermediate 7.4

(rac)-4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentanal

(248) ##STR00069##

(249) To a solution of (rac)-4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentan-1-ol (440 mg) in dichloromethane (2.6 mL) at room temperature was added Dess-Martin periodinane (654 mg) and the mixture was stirred for 2.5 h. The mixture was diluted with diethyl ether and water/saturated aqueous sodium thiosulphate solution/saturated aqueous sodium bicarbonate solution (v/v/v=1/1/1) and the mixture was vigorously stirred for 16 h to obtain two clear layers. The organic layer was separated, dried and concentrated to yield the title compound (518 mg) that was used without further purification.

(250) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295K) δ/ppm=1.24-1.31 (m, 3H), 1.84-2.00 (m, 5H), 2.54-2.61 (m, 2H), 3.73-3.83 (m, 2H), 4.57-4.67 (m, 1H), 7.32-7.34 (m, 1H), 7.56-7.59 (m, 1H), 7.75-7.77 (m, 1H), 9.66-9.72 (m, 1H)

Preparation of Intermediate 7.5

(rac)-5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoro-N-[4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentyl]aniline

(251) ##STR00070##

(252) To a suspension of 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoroaniline (439 mg, see Intermediate 1.6) and (rac)-4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentanal (515 mg, 1.82 mmol) in 1,2-dichloroethane (13 mL) was added acetic acid (8.3 mL) followed by sodium triacetoxyborohydride (1.16 g) and the mixture was stirred for 4.5 h at room temperature. The reaction was stopped by the addition of saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (282 mg) that was contaminated by some impurities and used without further purification.

(253) LC-MS (method a): R.sub.t=1.59 min; MS (ESIpos): m/z=509 [M+H].sup.+

Preparation of Intermediate 7.6

(rac)-N-[4-{3-amino-5-[(methylsulfanyl)methyl]phenoxy}pentyl]-5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoroaniline

(254) ##STR00071##

(255) To a solution of (rac)-5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoro-N-[4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentyl]aniline (280 mg) in methanol (8.9 mL) and THF (2.7 mL) was added platinum (1%) and vanadium (2%) on activated carbon (54 mg). The mixture was purged with hydrogen gas (1 atm) and stirred for 2 h. Additional platinum (1%) and vanadium (2%) on activated carbon (54 mg) was added and the mixture was stirred for 2 h under an atmosphere of hydrogen and 16 h under an atmosphere of nitrogen. Additional platinum (1%) and vanadium (2%) on activated carbon (54 mg) was added and the mixture was stirred for 2 h under an atmosphere of hydrogen. The mixture was filtered over a pad of celite and the filter cake was washed with methanol and THF. The filtrate was concentrated to yield the title compound (224 mg) that was contaminated by some impurities used without further purification.

(256) LC-MS (method a): R.sub.t=1.42 min; MS (ESIpos): m/z=479 [M+H].sup.+

Example 7—Preparation of the End Product

(257) A degassed suspension of (rac)-N-[4-{3-amino-5-[(methylsulfanyl)methyl]phenoxy}pentyl]-5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoroaniline (180 mg, 376 μmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (31 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (18 mg) and potassium phosphate (399 mg) in toluene (16 mL) and N-methylpyrrolidone (1.6 mL) was stirred at 130° C. for 2.5 h. The mixture was allowed to cool to room temperature, diluted with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (63 mg).

(258) LC-MS (method a): R.sub.t=1.51 min; MS (ESIpos): m/z=443 [M+H].sup.+

(259) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.20-1.26 (m, 3H), 1.45-1.62 (m, 3H), 1.99 (s, 4H), 3.07-3.26 (m, 2H), 3.56-3.64 (m, 2H), 4.43-4.56 (m, 1H), 5.99-6.08 (m, 1H), 6.61-6.67 (m, 1H), 6.76-6.82 (m, 1H), 7.13-7.27 (m, 2H), 7.56-7.64 (m, 1H), 7.90-7.95 (m, 1H), 8.55-8.61 (m, 1H), 9.71-9.77 (m, 1H).

Example 8

(rac)-3,20-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13-oxa-5,7,18,25-tetraazatetracyclo[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

(260) ##STR00072##

Preparation of Intermediate 8.1

(rac)-tert-butyl{[4-{3-[(methylsulfonyl)methyl]-5-nitrophenoxy}pentyl]oxy}diphenylsilane

(261) ##STR00073##

(262) To a solution of (rac)-tert-butyl{[4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentyl]oxy}diphenylsilane (2.50 g, see Intermediate 7.2) in dichloromethane (46 mL) at 0° C. was added 3-chloroperbenzoic acid (2.35 g, 77% purity) and the mixture was stirred for 45 min. The reaction was stopped by the addition of saturated aqueous sodium thiosulfate solution and the mixture was stirred for 1 h. The mixture was partitioned between dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated to yield the title compound (3.89 g) that was contaminated by impurities and used without further purification.

(263) LC-MS (method a): R.sub.t=1.72 min; MS (ESIpos): m/z=557 [M+H].sup.+

Preparation of Intermediate 8.2

(rac)-4-{3-[(methylsulfonyl)methyl]-5-nitrophenoxy}pentan-1-ol

(264) ##STR00074##

(265) To a solution of (rac)-tert-butyl{[4-{3-[(methylsulfonyl)methyl]-5-nitrophenoxy}pentyl]oxy}diphenylsilane (3.89 g) in THF (330 mL) at 0° C. was added tetra-n-butylammonium fluoride solution (1M in THF, 14 mL) and the mixture was stirred for 2.5 h at this temperature and for 20 h at room temperature. The mixture was concentrated and the crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) to yield the title compound (1.44 g) that was contaminated by some impurities and used without further purification.

(266) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.26-1.32 (m, 3H), 1.46-1.77 (m, 4H), 2.93-2.99 (m, 3H), 3.39-3.46 (m, 2H), 4.41-4.49 (m, 1H), 4.58-4.70 (m, 3H), 4.64-4.67 (m, 2H), 7.39-7.46 (m, 1H), 7.67-7.74 (m, 1H), 7.83-7.88 (m, 1H).

Preparation of Intermediate 8.3

(rac)-4-{3-[(methylsulfonyl)methyl]-5-nitrophenoxy}pentanal

(267) ##STR00075##

(268) To a solution of (rac)-4-{3-[(methylsulfonyl)methyl]-5-nitrophenoxy}pentan-1-ol (1.00 g, 3.15 mmol) in dichloromethane (5.2 mL) at room temperature was added Dess-Martin periodinane (4.01 g) and the mixture was stirred for 2.5 h. The mixture was diluted with diethyl ether and water/saturated aqueous sodium thiosulphate solution/saturated aqueous sodium bicarbonate solution (v/v/v=1/1/1) and the mixture was vigorously stirred for 16 h to obtain two clear layers. The organic layer was separated, dried and concentrated to yield the title compound (1.64 g) that was contaminated by impurities used without further purification.

Preparation of Intermediate 8.4

(rac)-5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoro-N-[4-{3-[(methylsulfonyl)methyl]-5-nitrophenoxy}pentyl]aniline

(269) ##STR00076##

(270) To a suspension of 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoroaniline (1.05 g, see Intermediate 1.6) and (rac)-4-{3-[(methylsulfonyl)methyl]-5-nitrophenoxy}pentanal (1.64 g) in 1,2-dichloroethane (31 mL) was added acetic acid (20 mL), followed by sodium triacetoxyborohydride (2.76 g), and the mixture was stirred for 6 h at room temperature. The reaction was stopped by the addition of saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/ethyl acetate) and to yield the title compound (616 mg).

(271) LC-MS (method a): R.sub.t=1.39 min; MS (ESIpos): m/z=541 [M+H].sup.+

(272) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.27-1.33 (m, 3H), 1.69-1.83 (m, 4H), 2.91-2.96 (m, 3H), 3.13-3.23 (m, 2H), 4.58-4.65 (m, 2H), 4.65-4.72 (m, 1H), 5.82-5.94 (m, 1H), 7.20-7.27 (m, 2H), 7.29-7.35 (m, 1H), 7.39-7.45 (m, 1H), 7.66-7.70 (m, 1H), 7.83-7.89 (m, 1H), 8.86-8.93 (m, 1H).

Preparation of Intermediate 8.5

(rac)-N-[(4-{3-amino-5-[(methylsulfonyl)methyl]phenoxy}pentyl]-5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoroaniline

(273) ##STR00077##

(274) To a solution of (rac)-5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoro-N-[(4-{3-[(methylsulfonyl)methyl]-5-nitrophenoxy}pentyl]aniline (610 mg) in methanol (27 mL) and THF (2.7 mL) was added platinum (1%) and vanadium (2%) on activated carbon (110 mg). The mixture was purged with hydrogen gas (1 atm) and stirred for 3 h. Additional was added platinum (1%) and vanadium (2%) on activated carbon (110 mg) was added and the mixture was stirred under an atmosphere of hydrogen gas for 2 h. The mixture was filtered over a pad of Celite. The filter cake was washed with methanol and THF and the filtrate was concentrated to yield the title compound (529 mg) that was contaminated by impurities and used without further purification.

(275) LC-MS (method a): R.sub.t=1.23 min; MS (ESIpos): m/z=511 [M+H].sup.+

(276) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.19-1.26 (m, 3H), 1.58-1.78 (m, 4H), 2.83-2.87 (m, 3H), 3.09-3.20 (m, 2H), 4.15-4.23 (m, 2H), 4.28-4.38 (m, 1H), 5.08-5.19 (m, 2H), 5.83-5.90 (m, 1H), 6.09-6.17 (m, 3H), 7.21-7.27 (m, 2H), 7.29-7.36 (m, 1H), 8.88-8.93 (m, 1H).

Example 8—Preparation of the End Product

(277) A degassed suspension of (rac)-N-[4-{3-amino-5-[(methylsulfonyl)methyl]phenoxy}pentyl]-5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoroaniline (420 mg), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct (68 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (39 mg) and potassium phosphate (872 mg) in toluene (35 mL) and N-methylpyrrolidone (3.5 mL) was stirred at 130° C. for 16 h. The mixture was allowed to cool to room temperature and combined with a smaller reaction batch (100 mg (rac)-N-[4-{3-amino-5-[(methylsulfonyl)methyl]phenoxy}pentyl]-5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluoroaniline). The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was suspended in dichloromethane. The precipitate was filtered off and dried to yield the title compound (225 mg).

(278) LC-MS (method a): R.sub.t=1.27 min; MS (ESIpos): m/z=475 [M+H].sup.+

(279) .sup.1H NMR (400 MHz, DMSO-d.sub.6, 295 K) δ/ppm=1.19-1.28 (m, 3H), 1.42-1.64 (m, 3H), 1.91-2.03 (m, 1H), 2.89-2.98 (m, 3H), 3.07-3.29 (m, 2H), 4.32-4.47 (m, 2H), 4.47-4.57 (m, 1H), 5.98-6.08 (m, 1H), 6.71-6.77 (m, 1H), 6.83-6.92 (m, 1H), 7.11-7.27 (m, 2H), 7.54-7.65 (m, 1H), 8.00-8.09 (m, 1H), 8.55-8.63 (m, 1H), 9.82-9.94 (m, 1H).

Examples 9 and 10

Enantiomers of 3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13-oxa-5,7,18,25-tetraazatetracyclo[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

(280) ##STR00078##

(281) (rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13-oxa-5,7,18,25-tetraazatetracyclo[17.3.1.1.sup.2,6.1.sup.8,1.sup.2]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene (4.98 g) was separated into the single enantiomers by preparative chiral HPLC.

(282) TABLE-US-00003 System: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000 Column: Chiralpak IG, 5 μm 250 × 30 mm Solvent: DCM/EtOH 95:5 Flow: 50 mL/min Temperature: Room temperature Solution: 4.98 g in 100 mL DCM/DMSO 4:1 Injection: 100 × 1 mL Detection: UV 254 nm Retention purity time in min in % yield Example 9 3.0-4.2 98.9% 1690 mg Enantiomer 1 Example 10 4.0-6.2 99.3% 1670 mg Enantiomer 2

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

(284) TABLE-US-00004 TABLE 1 Example No. Structure Name of compound 1 (rac)-tert-butyl [{[3,20-difluoro-13-oxa-5,7,18,25- tetraazatetracyclo[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 0 (rac)-3,20-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13-oxa-5,7,18,25- tetraazatetracyclo[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 (rac)-3,19-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13-oxa-5,7,17,24- tetraazatetracyclo[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 4 (rac)-tert-butyl [{[3,21-difluoro-13-oxa-5,7,19,26- tetraazatetracyclo[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 5 (rac)-3,21-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13-oxa-5,7,19,26- tetraazatetracyclo[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 6 (rac)-3,20-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13-oxa-5,7,18,24- tetraazatetracyclo[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 7 (rac)-3,20-difluoro-14-methyl-10- [(methylsulfanyl)methyl]-13-oxa-5,7,18,25- tetraazatetracyclo[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 8 (rac)-3,20-difluoro-14-methyl-10- [(methylsulfonyl)methyl]-13-oxa-5,7,18,25- tetraazatetracyclo[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 Enantiomer 1 of 3,20-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13-oxa-5,7,18,25- tetraazatetracyclo[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 10 Enantiomer 2 of 3,20-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13-oxa-5,7,18,25- tetraazatetracyclo[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

(285) Results:

(286) Table 2: Inhibition for CDK9 and CDK2 of compounds according to the present invention

(287) 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

(288) 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. 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.

(289) TABLE-US-00005 TABLE 2 {circle around (1)} Structure {circle around (2)} {circle around (3)} {circle around (4)} 1 3.4 855 249 2 0 1.8 155 87 3 1.8 829 460 4 1.4 3670 2740 5 1.6 357 216 6 4.0 25 6.3 7 3.9 2980 762 8 0.8 464 606 9 2.3 85 37 10 1.6 130 79

(290) Tables 3a and 3b: Inhibition of proliferation of HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 and MOLM-13 cells by compounds according to the present invention, determined as described under Method 3. of Materials and Methods. All IC.sub.50 (inhibitory concentration at 50% of maximal effect) values are indicated in nM, “n.t.” means that the compounds have not been tested in the respective assay. {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

(291) TABLE-US-00006 TABLE 3a Indications represented by cell lines Cell line Source Indication HeLa ATCC Human cervical tumour HeLa-MaTu-ADR EPO-GmbH Berlin Multidrug-resistant human cervical carcinoma NCI-H460 ATCC Human non-small cell lung carcinoma DU 145 ATCC Hormone-independent human prostate carcinoma Caco-2 ATCC Human colorectal carcinoma B16F10 ATCC Mouse melanoma A2780 ECACC Human ovarian carcinoma MOLM-13 DSMZ Human acute myeloid leukemia

(292) TABLE-US-00007 TABLE 3b Inhibition of proliferation {circle around (1)} Structure {circle around (2)} {circle around (3)} {circle around (4)} {circle around (5)} {circle around (6)} {circle around (7)} {circle around (8)} {circle around (9)} 1 40 46 33 36 70 99 13 7.1 2 00 4.4 5.3 9.2 4.5 8.4 1.2 1.2 2.0 3 01 15 23 25 17 20 25 5.9 5.8 4 02 n.t. n.t. n.t. n.t. n.t. n.t. 31 n.t. 5 03 n.t. n.t. n.t. n.t. n.t. n.t. 3.4 n.t. 6 04 n.t. n.t. n.t. n.t. n.t. n.t. 6.7 n.t. 7 05 n.t. n.t. n.t. n.t. n.t. n.t. 71 n.t. 8 06 n.t. n.t. n.t. n.t. n.t. n.t. 7.7 n.t.

(293) Table 4: 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.

(294) 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).

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

(296) 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.

(297) TABLE-US-00008 TABLE 4 {circle around (1)} Structure {circle around (2)} {circle around (3)} {circle around (4)} 2 07  7.4E−11* <8.0E−5*  >208* 3 08  3.8E−10* 1.2E−3*  13* 5 09 2.2E−10 8.6E−10 7.7E−11 1.2E−10 1.7E−04 1.9E−04 <8.0E−5  1.2E−04 100  90 >208  138 8 0  2.8E−10* 5.0E−4*  33* 9 4.6E−11 2.2E−11 1.5E−11 6.2E−11 1.1E−10 3.1E−11 7.0E−11 5.4E−11 1.7E−4  <8.0E−5  <8.0E−5  <8.0E−5  2.0E−4  <8.00E−5   2.1E−4  1.9E−4  101 >208  >208  >208   84 >208   81  87 10  1.5E−10* 4.5E−4*  37*