FLUORINATED BENZOFURANYL-PYRIMIDINE DERIVATIVES CONTAINING A SULFOXIMINE GROUP

Abstract

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

##STR00001##

Claims

1: A compound of general formula (I) ##STR00110## wherein R.sup.1 represents a group selected from the group consisting of C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-heterocyclyl-, phenyl-, heteroaryl-, phenyl-C.sub.1-C.sub.3-alkyl-, and heteroaryl-C.sub.1-C.sub.3-alkyl-, wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, 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 represents the group ##STR00111## R.sup.3, R.sup.4 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, —SF.sub.5, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(O)R.sup.9, —C(O)OR.sup.9, —S(O).sub.2R.sup.9, —C(O)NR.sup.10R.sup.11, —P(O)(OR.sup.2).sub.2, —CH.sub.2OP(OR.sup.12).sub.2, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, and heteroaryl-, wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, or heteroaryl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.6, R.sup.7 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, a fluoro atom, a chloro atom, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.8a, R.sup.8b represent, independently from each other, a group selected from the group consisting of a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.9 represents a group selected from the group consisting of C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.3-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, and heteroaryl-, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.10, R.sup.11 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, and heteroaryl-, wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, or heteroaryl- group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; or R.sup.10 and R.sup.11, together with the nitrogen atom they are attached to, form a cyclic amine; and R.sup.12 represents a group selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl- and benzyl-; and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof.

2: The compound of general formula (I) according to claim 1, wherein R.sup.1 represents a group selected from the group consisting of C.sub.1-C.sub.6-alkyl- and C.sub.3-C.sub.5-cycloalkyl-, wherein said group is optionally substituted with one substituent selected from the group consisting of hydroxy, halo-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 represents the group ##STR00112## R.sup.3 represents a hydrogen atom, a fluoro atom, a chloro atom, a —SF.sub.5 group, a C.sub.1-C.sub.3-alkyl- group, or a fluoro-C.sub.1-C.sub.3-alkyl- group; R.sup.4 represents a hydrogen atom or a fluoro atom; R.sup.5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(O)R.sup.9, —C(O)OR.sup.9, —S(O).sub.2R.sup.9, —C(O)NR.sup.10R.sup.11, —P(O)(OR.sup.12).sub.2, —CH.sub.2OP(OR.sup.12).sub.2, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, and heteroaryl-, wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, or heteroaryl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.6, R.sup.7 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, a fluoro atom, a chloro atom, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.8a, R.sup.8b represent, independently from each other, a group selected from the group consisting of a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.9 represents a group selected from the group consisting of C.sub.1-C.sub.6-alkyl-, halo-C.sub.1-C.sub.3-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, and heteroaryl-, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C.sub.1-C.sub.3-alkyl-, and C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.10, R.sup.11 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, benzyl-, phenyl-, and heteroaryl-, wherein said C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, benzyl-, phenyl-, 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.10 and R.sup.11, together with the nitrogen atom they are attached to, form a cyclic amine; and R.sup.12 represents a group selected from the group consisting of a hydrogen atom and C.sub.1-C.sub.2-alkyl-; and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof.

3: The compound of general formula (I) according to claim 1, wherein R.sup.1 represents a group selected from the group consisting of C.sub.1-C.sub.6-alkyl- and C.sub.3-C.sub.5-cycloalkyl-, wherein said group is optionally substituted with one substituent selected from the group consisting of hydroxy, C.sub.1-C.sub.3-alkoxy-, —NH.sub.2, alkylamino-, dialkylamino-, and cyclic amines, —OP(O)(OH).sub.2; R.sup.2 represents the group ##STR00113## R.sup.3 represents a hydrogen atom, a fluoro atom, a chloro atom, a —SF.sub.5 group, a C.sub.1-C.sub.3-alkyl- group, or a fluoro-C.sub.1-C.sub.3-alkyl- group; R.sup.4 represents a hydrogen atom or a fluoro atom; R.sup.5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(O)R.sup.9, —C(O)OR.sup.9, —C(O)NR.sup.10R.sup.11, —P(O)(OR.sup.2).sub.2, —CH.sub.2OP(OR.sup.12).sub.2, and C.sub.1-C.sub.3-alkyl-, wherein said C.sub.1-C.sub.3-alkyl group is optionally substituted with one substituent, selected from the group consisting of —NH.sub.2, alkylamino-, dialkylamino-, and cyclic amines; R.sup.6, R.sup.7 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, a fluoro atom and a chloro atom; R.sup.8a, R.sup.8b represent, independently from each other, a group selected from the group consisting of a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, methyl-, methoxy-, halomethyl-, and fluoromethoxy-; R.sup.9 represents a group selected from the group consisting of C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-, and benzyl- group, the phenyl- group of which is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of halogen, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, —NH.sub.2, alkylamino-, and dialkylamino-; R.sup.10, R.sup.11 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.3-alkyl-, and benzyl-; or R.sup.10 and R.sup.11, together with the nitrogen atom they are attached to, form a cyclic amine; and R.sup.12 represents a group selected from a hydrogen atom and methyl-; and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof.

4: The compound of general formula (I) according to claim 1, wherein R.sup.1 represents a C.sub.1-C.sub.6-alkyl- group, wherein said group is optionally substituted with one substituent, selected from the group consisting of C.sub.1-C.sub.3-alkoxy, —NH.sub.2, alkylamino-, dialkylamino-, and cyclic amines; R.sup.2 represents the group ##STR00114## R.sup.3 represents a hydrogen atom, a fluoro atom, a chloro atom, a —SF.sub.5 group, a methyl- group, an ethyl- group, or a trifluoromethyl- group; R.sup.4 represents a hydrogen atom or a fluoro atom; R.sup.5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(O)R.sup.9, —C(O)OR.sup.9, and —C(O)NR.sup.10R.sup.11; R.sup.6, R.sup.7 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, a fluoro atom, and a chloro atom; R.sup.9 represents a C.sub.1-C.sub.3-alkyl- group, a benzyl- group, or trifluoromethyl-; and R.sup.10, R.sup.11 represent, independently from each other, a group selected from the group consisting of a hydrogen atom and C.sub.1-C.sub.2-alkyl-; and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof.

5: The compound of general formula (I) according to claim 1, wherein R.sup.1 represents a C.sub.1-C.sub.3-alkyl- group; R.sup.2 represents the group ##STR00115## R.sup.3 represents a hydrogen atom, a fluoro atom, a methyl- group, or a —SF.sub.5 group; R.sup.4 represents a hydrogen atom; R.sup.5 represents a group selected from the group consisting of a hydrogen atom, cyano, —C(O)R.sup.9, —C(O)OR.sup.9, and —C(O)NR.sup.10R.sup.11; R.sup.6 represents a group selected from the group consisting of a hydrogen atom and a fluoro atom, R.sup.7 represents a hydrogen atom; R.sup.9 represents a methyl- group, an ethyl- group, or a trifluoromethyl- group; R.sup.10 represents a C.sub.1-C.sub.2-alkyl- group; and R.sup.11 represents a hydrogen atom; and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof.

6: The compound of general formula (I) according to claim 1, wherein R.sup.2 represents the group ##STR00116## and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof.

7: The compound of general formula (I) according to claim 1, wherein R.sup.5 represents a group selected from the group consisting of a hydrogen atom and a cyano group; and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof.

8: The compound of general formula (I) according to claim 1, wherein R.sup.3 represents a hydrogen atom, a fluoro atom, a methyl- group, or a —SF.sub.5 group; and R.sup.4 represents a hydrogen atom; and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof.

9: The compound of general formula (I) according to claim 1, wherein R.sup.1 represents a methyl- group; R.sup.2 represents the group ##STR00117## R.sup.3 represents a hydrogen atom, a fluoro atom, a methyl- group, or a —SF.sub.5 group; R.sup.4 represents a hydrogen atom; R.sup.5 represents a group selected from the group consisting of a hydrogen atom and a cyano group; and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof.

10: The compound according to claim 1, which is selected from the group consisting of: (rac)-[(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)oxido-λ.sup.6-sulfanylidene]cyanamide; [(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)oxido-λ.sup.6-sulfanylidene]cyanamide; Enantiomer 1; [(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)oxido-λ.sup.6-sulfanylidene]cyanamide; Enantiomer 2; (rac)-5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3- [(S-methylsulfonimidoyl)-methyl]phenyl}-pyrimidin-2-amine; 5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-[(S-methylsulfonimidoyl)-methyl]-phenyl}-pyrimidin-2-amine; Enantiomer 1; 5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-[(S-methylsulfonimidoyl)-methyl]-phenyl}-pyrimidin-2-amine; Enantiomer 2; (rac)-[(3-Fluoro-5-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)-oxido-λ.sup.6-sulfanylidene]cyanamide; [(3-Fluoro-5-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)-oxido-λ.sup.6-sulfanylidene]cyanamide; Enantiomer 1; [(3-Fluoro-5-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)-oxido-λ.sup.6-sulfanylidene]cyanamide; Enantiomer 2; (rac)-5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-fluoro-5- [(S-methylsulfonimidoyl)-methyl]-phenyl}-pyrimidin-2-amine; 5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-fluoro-5- [(S-methylsulfonimidoyl)-methyl]-phenyl}-pyrimidin-2-amine; Enantiomer 1; 5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-fluoro-5- [(S-methylsulfonimidoyl)-methyl]-phenyl}-pyrimidin-2-amine; Enantiomer 2; (rac)-[(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-methylbenzyl)-(methyl)oxido-λ.sup.6-sulfanylidene]cyanamide; [(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-methylbenzyl)-(methyl)oxido-λ.sup.6-sulfanylidene]cyanamide; Enantiomer 1; [(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-methylbenzyl)-(methyl)oxido-λ.sup.6-sulfanylidene]cyanamide; Enantiomer 2; (rac)-5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-methyl-5- [(S-methylsulfonimidoyl)-methyl]phenyl}pyrimidin-2-amine; (rac)- {[3-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-(pentafluoro-λ.sup.6-sulfanyl)benzyl](methyl)oxido-λ.sup.6-sulfanylidene}cyanamide; and (rac)-5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]-5-(pentafluoro-λ.sup.6-sulfanyl)phenyl}pyrimidin-2-amine; and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof.

11-12. (canceled)

13: A method for the treatment or prophylaxis of a hyper-proliferative disorder, virally induced infectious disease, or cardiovascular disease, comprising administering to a subject in need thereof an effective amount of the compound of general formula (I) according to claim 1, or an enantiomer, diastereomer, salt, solvate, or a salt of a solvate thereof.

14: A method for the treatment or prophylaxis of lung carcinoma, prostate carcinoma, cervical carcinoma, colorectal carcinoma, melanoma, ovarian carcinoma, or leukemia, comprising administering to a subject in need thereof an effective amount of the compound of general formula (I) according to claim 1, or an enantiomer, diastereomer, salt, solvate, or a salt of a solvate thereof.

15: A method for the treatment or prophylaxis of non-small cell lung carcinoma, hormone-independent human prostate carcinoma, cervical carcinoma, multidrug-resistant human cervical carcinoma, colorectal carcinoma, melanoma, ovarian carcinoma, or acute myeloid leukemia, comprising administering to a subject in need thereof an effective amount of the compound of general formula (I) according to claim 1, or an enantiomer, diastereomer, salt, solvate, or a salt of a solvate thereof.

16: A pharmaceutical combination comprising the compound of general formula (I) according to claim 1, or an enantiomer, diastereomer, salt, solvate, or a salt of a solvate thereof, in combination with at least one or more further active ingredients.

17: A pharmaceutical composition comprising the compound of general formula (I) according to claim 1, or an enantiomer, diastereomer, salt, solvate, or a salt of a solvate thereof, in combination with an inert, nontoxic, pharmaceutically suitable adjuvant.

18: A method for the treatment or prophylaxis of a hyper-proliferative disorder, virally induced infectious disease, or cardiovascular disease, comprising administering to a subject in need thereof the pharmaceutical combination according to claim 16.

19: A method for the treatment or prophylaxis of a hyper-proliferative disorder, virally induced infectious disease, or cardiovascular disease, comprising administering to a subject in need thereof the pharmaceutical combination according to claim 17.

20: A compound of general formula (6) ##STR00118## wherein R, R.sup.2, R.sup.3 and R.sup.4 are as defined according to claim 1 for the compounds of general formula (I), and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof.

21: Use of a compound of general formula (6) ##STR00119## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined according to claim 1 for the compounds of general formula (I), and the enantiomers, diastereomers, salts, solvates, or salts of solvates thereof, for the preparation of a compound of general formula (I) as defined according to claim 1.

Description

EXAMPLE 1

(rac)-[(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)oxido-λ.SUP.6.-sulfanylidene]cyanamide

[0502] ##STR00021##

Preparation of Intermediate 1.1

1-[(Methylsulfanyl)methyl]-3-nitrobenzene

[0503] ##STR00022##

[0504] Sodium methanethiolate (13.5 g; 192 mmol) was added in two portions to a stirred solution of 1-(chloromethyl)-3-nitrobenzene (30.0 g; 175 mmol; Aldrich Chemical Company Inc.) in ethanol (360 mL) at −15° C. The cold bath was removed and the batch was stirred at room temperature for 3 hours. The batch was diluted with saturated aqueous sodium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried (sodium sulfate), filtered and concentrated to give the desired product (32.2 g) that was used without further purification.

[0505] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.18 (m, 1H), 8.11 (m, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 3.75 (s, 2H), 2.01 (s, 3H).

Preparation of Intermediate 1.2

3- [(Methylsulfanyl)methyl]aniline

[0506] ##STR00023##

[0507] Titanium(III)chloride solution (approx. 15%) in approx. 10% aqueous hydrochloric acid (389 mL; Merck Schuchardt OHG) was added to a stirred solution of 1-[(methylsulfanyl)methyl]-3-nitrobenzene (10.5 g; 57.3 mmol; Intermediate 1.1) in THF (680 mL) at room temperature and the batch was stirred for 45 hours. By adding 1N sodium hydroxide solution the pH value of the reaction mixture was raised to 7 before the batch was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexanes/ethyl acetate) to give the desired product (6.56 g; 40.67 mmol).

[0508] .sup.1H NMR (400 MHz, DMSO-d6) δ=6.93 (t, 1H), 6.50 (t, 1H), 6.46-6.39 (m, 2H), 5.01 (s, 2H), 3.52 (s, 2H), 1.95 (s, 3H).

Preparation of Intermediate 1.3

2-Chloro-5-fluoro-4-(4-fluoro-1-benzofuran-7-yl) pyrimidine

[0509] ##STR00024##

[0510] A mixture of 2,4-dichloro-5-fluoropyrimidine (818 mg; 4.90 mmol; Aldrich Chemical Company Inc.), (4-fluoro-1-benzofuran-7-yl)boronic acid (1 g; 5.39 mmol; ABCR GmbH & CO. KG) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II)-dichlormethane (400.2 mg; 0.49 mmol) and 2 M aqueous solution of potassium carbonate (7.35 mL) in 1,2-dimethoxyethane (25.4 mL) was degassed using argon. The batch was stirred under an atmosphere of argon for 90 minutes at ambient temperature. The batch was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (hexanes/ethyl acetate) to give the desired product (834 mg; 3.13 mmol).

[0511] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=9.06 (d, 1H), 8.21 (d, 1H), 7.78 (dd, 1H), 7.38-7.32 (m, 1H), 7.25 (d, 1H).

Preparation of Intermediate 1.4

5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3- [(methylsulfanyl)methyl]phenyl}pyrimidin-2-amine

[0512] ##STR00025##

[0513] A mixture of 2-chloro-5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidine (517 mg; 1.94 mmol; intermediate 1.3), 3-[(methylsulfanyl)methyl]aniline (625 mg; 3.88 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct (120 mg; 0.145 mmol; ABCR GmbH & CO. KG) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (70 mg; 0.145 mmol; Aldrich Chemical Company Inc.) and potassium phosphate (2.06 g; 9.69 mmol) in toluene (43.9 ml) and NMP (3.4 mL) was stirred at 130° C. for 3 hours. After cooling, the batch was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 2:1) to give the title compound (523 mg; 1.35 mmol).

[0514] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=9.85 (s, 1H), 8.71 (d, 1H), 8.20 (d, 1H), 7.81 (t, 1H), 7.77 (dd, 1H), 7.67-7.61 (m, 1H), 7.33 (dd, 1H), 7.25-7.18 (m, 2H), 6.89 (d, 1H), 3.64 (s, 2H), 1.94 (s, 3H).

Preparation of Intermediate 1.5

(rac)-[(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)-λ.SUP.4.-sulfanylidene]-cyanamide

[0515] ##STR00026##

[0516] Iodobenzene diacetate (517 mg; 1.57 mmol) was added to a stirred solution of 5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-[(methylsulfanyl)methyl]phenyl}pyrimidin-2-amine (590 mg; 1.43 mmol; intermediate 1.4) and cyanamide (121 mg; 2.86 mmol) in DCM (16.3 mL) at 0° C. The batch was stirred for 2.5 hours at this temperature before it was purified by column chromatography on silica gel (hexanes/ethyl acetate) to give the title compound (585 mg; 1.38 mmol).

[0517] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=10.02 (s, 1H), 8.72 (d, 1H), 8.21 (d, 1H), 7.87 (s, 1H), 7.83-7.76 (m, 2H), 7.38-7.30 (m, 2H), 7.23 (d, 1H), 7.01 (d, 1H), 4.50-4.21 (m, 2H), 2.84 (s, 3H).

[0518] Preparation of End Product:

[0519] Potassium permanganate (368 mg; 2.28 mmol) was added to a stirred solution of (rac)-[(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)-2.sup.4-sulfanylidene]-cyanamide (483 mg; 1.14 mmol; intermediate 1.5) in acetone (24.4 mL) at RT. The batch was stirred at 50° C. for one hour. The batch was concentrated and the residue was purified by column chromatography on silica gel (hexanes/ethyl acetate) to give the desired product (267 mg; 0.59 mmol).

[0520] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=10.03 (s, 1H), 8.72 (d, 1H), 8.20 (d, 1H), 7.91 (t, 1H), 7.85 (dd, 1H), 7.78 (dd, 1H), 7.40-7.29 (m, 2H), 7.23 (d, 1H), 7.07 (d, 1H), 5.00-4.88 (m, 2H), 3.35 (s, 3H).

EXAMPLES 2 AND 3

Enantiomers of [(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)oxido-λ.SUP.6.-sulfanylidene]cyanamide

[0521] ##STR00027##

[0522] (rac)- [(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)oxido-λ.sup.6-sulfanylidene]cyanamide (219 mg) was separated into the enantiomers by chiral preparative HPLC.

TABLE-US-00001 System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC Column: Chiralpak IC 5 μm 250 × 30 mm Solvent: ethyl acetate/hexanes 50:50 (v/v) Flow: 40 mL/min Temperature: 25° C. Solution: 219 mg/4 mL ethyl acetate Injection: 8 × 0.5 mL Detection: UV 280 nm Retention time in min Amount purity in % Example 2 7.4-8.3 88 mg 99 Enantiomer 1 Example 3 10.6-11.9 91 mg 99 Enantiomer 2

EXAMPLE 4

(rac)-5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-[(S-methylsulfonimidoyl)-methyl]phenyl}-pyrimidin-2-amine

[0523] ##STR00028##

[0524] To a stirred solution of (rac)-[(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-benzyl)(methyl)oxido-λ.sup.6-sulfanylidene]cyanamide (360 mg; 0.81 mmol; example 1) in DCM (37 mL) at 0° C., TFAA (0.344 mL; 2.43 mmol) was added. The mixture was allowed to react at RT for 2 hours. The reaction mixture was concentrated, re-dissolved in MeOH (5.9 mL) and treated with potassium carbonate (560 mg; 4.05 mmol). The mixture was allowed to react at RT for 18 hours. The reaction mixture was diluted with ethyl acetate and THF and washed with saturated aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/MeOH) to give the title compound (152 mg; 0.37 mmol).

[0525] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=9.91 (s, 1H), 8.71 (d, 1H), 8.21 (d, 1H), 7.84 (s, 1H), 7.81-7.72 (m, 2H), 7.37-7.26 (m, 2H), 7.23 (d, 1H), 7.02 (d, 1H), 4.37-4.24 (m, 2H), 3.53 (s, 1H), 2.77 (s, 3H).

EXAMPLES 5 AND 6

Enantiomers of 5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-[(S-methylsulfonimidoyl)-methyl]-phenyl}-pyrimidin-2-amine

[0526] ##STR00029##

[0527] (rac)-5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-[(S-methylsulfonimidoyl)-methyl]-phenyl}-pyrimidin-2-amine (147 mg) was separated into the enantiomers by chiral preparative HPLC.

TABLE-US-00002 System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC Column: Chiralpak ID 5 μm 250 × 30 mm Solvent: hexane/ethanol/diethylamine 70:30:0.1 (v/v/v) Flow: 45 mL/min Temperature: RT Solution: 147 mg/2.1 mL DCM Injection: 3 × 0.7 mL Detection: UV 280 nm Retention time in min Amount purity in % Example 5 18.2-21.1 min 50 mg 97.9 Enantiomer 1 Example 6 21.1-25.7 min 60 mg 98.5 Enantiomer 2

EXAMPLE 7

(rac)- [(3-Fluoro-5-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)-oxido-λ.SUP.6.-sulfanylidene]cyanamide

[0528] ##STR00030##

Preparation of Intermediate 7.1

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

[0529] ##STR00031##

[0530] Intermediate 7.1 was prepared under similar conditions as described in the preparation of Intermediate 1.1 using 1-(chloromethyl)-3-fluoro-5-nitrobenzene (Hansa Fine Chemicals GmbH, Germany, CAS #1214344-25-8).

[0531] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=8.08 (s, 1H), 7.98 (dt, 1H), 7.70 (dt, 1H), 3.86 (s, 2H), 1.97 (s, 3H).

Preparation of Intermediate 7.2

3-Fluoro-5-[(methylsulfanyl)methyl]aniline

[0532] ##STR00032##

[0533] Intermediate 7.2 was prepared under similar conditions as described in the preparation of Intermediate 1.2 using 1-fluoro-3-[(methylsulfanyl)methyl]-5-nitrobenzene (Intermediate 7.1).

[0534] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=6.32 (t, 1H), 6.24-6.15 (m, 2H), 5.38 (s, 2H), 3.52 (s, 2H), 1.97-1.92 (m, 3H).

Preparation of Intermediate 7.3

5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-fluoro-5-[(methylsulfanyl)methyl]phenyl}pyrimidin-2-amine

[0535] ##STR00033##

[0536] Intermediate 7.3 was prepared under similar conditions as described in the preparation of Intermediate 1.4 using 2-chloro-5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidine (1 g; 3.75 mmol; Intermediate 1.3) and 3-fluoro-5-[(methylsulfanyl)methyl]aniline (1.14 g; 6.56 mmol; intermediate 7.2). The residue was purified by column chromatography on silica gel (hexanes/ethyl acetate) to give the title compound (1.19 g; 2.96 mmol).

[0537] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=10.10 (s, 1H), 8.76 (d, 1H), 8.18 (d, 1H), 7.81-7.71 (m, 2H), 7.52 (s, 1H), 7.34 (dd, 1H), 7.24 (d, 1H), 6.75-6.69 (m, 1H), 3.64 (s, 2H), 1.96 (s, 3H).

Preparation of Intermediate 7.4

(rac)- [(3-Fluoro-5-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-benzyl)(methyl)-λ.SUP.4.-sulfanylidene]cyanamide

[0538] ##STR00034##

[0539] Intermediate 7.4 was prepared under similar conditions as described in the preparation of Intermediate 1.5 using 5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-fluoro-5-[(methylsulfanyl)methyl]-phenyl}-pyrimidin-2-amine (Intermediate 7.3). The batch was purified by column chromatography on silica gel (DCM/MeOH) to give the title compound (1.69 g; 3.71 mmol).

[0540] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=10.29 (s, 1H), 8.78 (d, 1H), 8.19 (d, 1H), 7.93 (dt, 1H), 7.80 (dd, 1H), 7.57 (s, 1H), 7.40-7.31 (m, 1H), 7.24 (d, 1H), 6.84 (dd, 1H), 4.50-4.21 (m, 2H), 2.85 (s, 3H).

[0541] Preparation of End Product:

[0542] Example 7 was prepared under similar conditions as described in the preparation of Example 1 using (rac)-[(3-fluoro-5-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)-λ.sup.4-sulfanylidene]cyanamide (1.68 g; 3.69 mmol; Intermediate 7.4). The batch was purified by column chromatography on silica gel (hexanes/ethyl acetate) to give the title compound (1.01 g; 2.07 mmol).

[0543] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=10.30 (s, 1H), 8.78 (d, 1H), 8.18 (d, 1H), 7.99 (dt, 1H), 7.80 (dd, 1H), 7.62 (s, 1H), 7.34 (dd, 1H), 7.24 (d, 1H), 6.92-6.87 (m, 1H), 5.04-4.93 (m, 2H), 3.39 (s, 3H).

EXAMPLES 8 AND 9

Enantiomers of [(3-Fluoro-5-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)-oxido-λ.SUP.6.-sulfanylidene]cyanamide

[0544] ##STR00035##

[0545] (rac)-[(3-Fluoro-5-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)-oxido-λ.sup.6-sulfanylidene]cyanamide (162 mg) was separated into the enantiomers by chiral preparative HPLC.

TABLE-US-00003 System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC Column: Chiralpak ID 5 μm 250 × 20 mm Solvent: hexane/2-propanol/diethylamine 70:30:0.1 (v/v/v) Flow: 30 mL/min Temperature: RT Solution: 162 mg/2.5 mL DMF/DCM Injection: 5 × 0.5 mL Detection: UV 280 nm Retention time in min Amount purity in % Example 8 16.9-24.2 55 mg 98.9 Enantiomer 1 Example 9 25.2-32.6 45 mg 95.2 Enantiomer 2

EXAMPLE 10

(rac)-5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-fluoro-5- [(S-methylsulfonimidoyl)-methyl]-phenyl}-pyrimidin-2-amine

[0546] ##STR00036##

[0547] Example 10 was prepared under similar conditions as described in the preparation of Example 4 using (rac)- [(3-fluoro-5-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}benzyl)(methyl)-oxido-λ.sup.6-sulfanylidene]cyanamide (784 mg; 1.61 mmol; Example 7). The batch was purified by column chromatography on silica gel (ethyl acetate/MeOH) to give the title compound (272 mg; 0.62 mmol).

[0548] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=10.16 (s, 1H), 8.76 (d, 1H), 8.19 (d, 1H), 7.86 (dt, 1H), 7.79 (dd, 1H), 7.55 (s, 1H), 7.37-7.30 (m, 1H), 7.24 (d, 1H), 6.86 (d, 1H), 4.38-4.27 (m, 2H), 3.65 (s, 1H), 2.80 (s, 3H).

EXAMPLES 11 AND 12

Enantiomers of 5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-fluoro-5-[(S-methylsulfonimidoyl)-methyl]-phenyl}-pyrimidin-2-amine

[0549] ##STR00037##

[0550] (rac)-5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-fluoro-5-[(S-methylsulfonimidoyl)-methyl]-phenyl}-pyrimidin-2-amine (129 mg) was separated into the enantiomers by chiral preparative HPLC.

TABLE-US-00004 System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Gilson: Liquid Handler 215 Column: Chiralpak ID 5 μm 250 × 30 mm Solvent: hexane/ethanol 70:30 (v/v) Flow: 40 mL/min Temperature: RT Solution: 129 mg/9.5 mL DCM/MeOH Injection: 5 × 1.9 mL Detection: UV 280 nm Retention time in min Amount purity in % Example 11 14.5-16.2 55 mg 99 Enantiomer 1 Example 12 16.2-19.0 55 mg 95.6 Enantiomer 2

EXAMPLE 13

(rac)- [(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-methylbenzyl)-(methyl)oxido-λ.SUP.6.-sulfanylidene]cyanamide

[0551] ##STR00038##

Preparation of Intermediate 13.1

3-(Chloromethyl)-5-methylaniline

[0552] ##STR00039##

[0553] To a stirred solution of 3-amino-5-methyl-benzyl alcohol (5 g; 33.9 mmol; GL Syntech LLC, Hatfield, Pa.; CAS #146335-25-3; Behrens et al., Synthesis, 1992, 1235-6) in DCM (140 mL) at 0° C. was added dropwise thionyl chloride (7.4 mL; 102 mmol). The mixture was allowed to react at room temperature overnight. Then, the mixture was concentrated under reduced pressure. The resulting material was dissolved in DCM again and evaporated to dryness to give crude 3-(chloromethyl)-5-methylaniline (7 g).

Preparation of Intermediate 13.2

3-Methyl-5-[(methylsulfanyl)methyl]aniline

[0554] ##STR00040##

[0555] Intermediate 13.2 was prepared under similar conditions as described in the preparation of Intermediate 1.1 using 3-(chloromethyl)-5-methylaniline (Intermediate 13.1).

[0556] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=6.33-6.27 (m, 1H), 6.27-6.21 (m, 2H), 4.95 (s, 2H), 3.47 (s, 2H), 2.12 (s, 3H), 1.94 (s, 3H).

Preparation of Intermediate 13.3

5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-methyl-5-[(methylsulfanyl)methyl]phenyl}pyrimidin-2-amine

[0557] ##STR00041##

[0558] Intermediate 13.3 was prepared under similar conditions as described in the preparation of Intermediate 1.4 using 2-chloro-5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidine (Intermediate 1.3) and 3-methyl-5-[(methylsulfanyl)methyl]aniline (intermediate 13.2). The batch was purified by column chromatography on silica gel (hexanes/ethyl acetate) to give the title compound.

[0559] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=9.77 (s, 1H), 8.71 (d, 1H), 8.20 (d, 1H), 7.76 (dd, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.33 (dd, 1H), 7.23 (d, 1H), 6.71 (s, 1H), 3.59 (s, 2H), 2.25 (s, 3H), 1.94 (s, 3H).

Preparation of Intermediate 13.4

rac- [(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-methylbenzyl)(methyl)-λ.SUP.4.-sulfanylidene]cyanamide

[0560] ##STR00042##

[0561] Intermediate 13.4 was prepared under similar conditions as described in the preparation of Intermediate 1.5 using 5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-methyl-5- [(methylsulfanyl)-methyl]-phenyl}-pyrimidin-2-amine (Intermediate 13.3). The batch was purified by column chromatography on silica gel (hexanes/ethyl acetate).

[0562] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=9.94 (s, 1H), 8.72 (d, 1H), 8.21 (d, 1H), 7.79 (dd, 1H), 7.66 (br. s., 2H), 7.34 (t, 1H), 7.23 (d, 1H), 6.84 (s, 1H), 4.39 (d, 1H), 4.21 (d, 1H), 2.83 (s, 3H), 2.29 (s, 3H).

[0563] Preparation of End Product:

[0564] Example 13 was prepared under similar conditions as described in the preparation of Example 1 using rac- [(3-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-methylbenzyl)(methyl)-λ.sup.4-sulfanylidene]cyanamide (310 mg; 0.71 mmol; Intermediate 13.4). The batch was purified by column chromatography on silica gel (hexane/ethyl acetate) to give the title compound (190 mg; 0.42 mmol).

[0565] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=9.96 (s, 1H), 8.72 (d, 1H), 8.20 (d, 1H), 7.78 (dd, 1H), 7.71 (s, 2H), 7.33 (dd, 1H), 7.23 (d, 1H), 6.89 (s, 1H), 4.95-4.82 (m, 2H), 3.34 (s, 3H), 2.30 (s, 3H).

EXAMPLES 14 AND 15

Enantiomers of [(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-methylbenzyl)-(methyl)oxido-λ.SUP.6.-sulfanylidene]cyanamide

[0566] ##STR00043##

[0567] (rac)- [(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-methylbenzyl)-(methyl)oxido-λ.sup.6-sulfanylidene]cyanamide (67 mg) was separated into the enantiomers by chiral preparative HPLC.

TABLE-US-00005 System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC Column: Chiralpak IC 5 μm 250 × 30 mm Solvent: hexane/ethanol 70/30 (v/v) Flow: 50 mL/min Temperature: RT Solution: 67.5 mg/1.5 mL EtOH/acetone Injection: 3 × 0.5 mL Detection: UV 280 nm Retention time in min Amount purity in % Example 14  8.1-10.3 27 mg >99 Enantiomer 1 Example 15 10.4-12.2 28 mg  96 Enantiomer 2

EXAMPLE 16

(rac)-5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-methyl-5-[(S-methylsulfonimidoyl)-methyl]phenyl}pyrimidin-2-amine

[0568] ##STR00044##

[0569] Example 16 was prepared under similar conditions as described in the preparation of Example 4 using (rac)- [(3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-methylbenzyl)-(methyl)oxido-λ.sup.6-sulfanylidene]cyanamide (112 mg; 0.24 mmol; Example 13). The batch was purified by column chromatography on silica gel (ethyl acetate/MeOH) to give the title compound (46 mg; 0.09 mmol).

[0570] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=9.83 (s, 1H), 8.70 (d, 1H), 8.21 (d, 1H), 7.77 (dd, 1H), 7.62 (d, 2H), 7.32 (dd, 1H), 7.23 (d, 1H), 6.83 (s, 1H), 4.31-4.20 (m, 2H), 3.51 (s, 1H), 2.77 (s, 3H), 2.28 (s, 3H).

EXAMPLE 17

(rac)-{[3-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-(pentafluoro-λ.SUP.6.-sulfanyl)benzyl](methyl)oxido-λ.SUP.6.-sulfanylidene}cyanamide

[0571] ##STR00045##

Preparation of Intermediate 17.1

3-Nitro-5-(pentafluoro-λ.SUP.6.-sulfanyl)benzoic acid

[0572] ##STR00046##

[0573] Nitric acid (100%; 4.1 mL) was added dropwise over 30 minutes to a stirred solution of 3-(pentafluoro-λ.sup.6-sulfanyl)benzoic acid (5.1 g; 20.6 mmol; ABCR GmbH & CO. KG) in sulfuric acid (17.0 mL) at 0° C. The ice bath was removed and the mixture was stirred for 88 hours at room temperature. The batch was cautiously added to ice. The precipitate was separated, washed with water and finally dissolved in ethyl acetate. The organic solution was washed with water, filtered using a Whatman filter and concentrated to give the desired product (4.4 g; 15.0 mmol).

[0574] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.12 (s, 1H), 8.90 (m, 1H), 8.83 (m, 1H, 1H).

Preparation of Intermediate 17.2

[3-Nitro-5-(pentafluoro-λ.SUP.6.-sulfanyl)phenyl]methanol

[0575] ##STR00047##

[0576] To a stirred solution of 3-nitro-5-(pentafluoro-λ.sup.6-sulfanyl)benzoic acid (4.4 g; 15 mmol; Intermediate 17.1) in THF at 0° C. was added a μM solution of borane-tetrahydrofuran complex in THF (60 mL; 60 mmol). The mixture was allowed to react at ambient temperature for 19 hours. Then, MeOH was cautiously added to the stirred mixture while cooling with an ice bath. The batch was diluted with ethyl acetate and washed with aqueous sodium hydroxide solution (1N) and saturated aqueous sodium chloride solution. The organic layer was dried (sodium sulfate), filtered and concentrated to yield the title compound (5.14 g).

[0577] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.54 (s, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 4.92 (d, 2), 2.19 (tr, 1H).

Preparation of Intermediate 17.3

[3-Amino-5-(pentafluoro-λ.SUP.6.-sulfanyl)phenyl]methanol

[0578] ##STR00048##

[0579] Intermediate 17.3 was prepared under similar conditions as described in the preparation of Intermediate 1.2 using [3-nitro-5-(pentafluoro-λ.sup.6-sulfanyl)phenyl]methanol (Intermediate 17.2).

[0580] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.11 (s, 1H), 6.96 (m, 1H), 6.81 (s, 1H), 4.66 (br, 2H), 3.89 (br, 2H).

[0581] Preparation of Intermediate 17.4

3-(Chloromethyl)-5- (pentafluoro-λ.SUP.6.-sulfanyl)aniline

[0582] ##STR00049##

[0583] Intermediate 17.4 was prepared under similar conditions as described in the preparation of Intermediate 13.1 using [3-amino-5-(pentafluoro-λ.sup.6-sulfanyl)phenyl]methanol (Intermediate 17.3).

[0584] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=7.01 (d, 2H), 6.84 (s, 1H), 5.74 (br.), 4.70 (s, 2H).

Preparation of Intermediate 17.5

3-[(Methylsulfanyl)methyl]-5-(pentafluoro-λ.SUP.6.-sulfanyl)aniline

[0585] ##STR00050##

[0586] Intermediate 17.5 was prepared under similar conditions as described in the preparation of Intermediate 1.1 using 3-(chloromethyl)-5-(pentafluoro-λ.sup.6-sulfanyl)aniline (Intermediate 17.4).

[0587] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=6.92 (t, 1H), 6.87 (s, 1H), 6.73 (s, 1H), 5.67 (br. s., 2H), 3.63 (s, 2H), 1.96 (s, 3H).

Preparation of Intermediate 17.6

5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3- [(methylsulfanyl)methyl]-5-(pentafluoro-λ.SUP.6.-sulfanyl)phenyl}pyrimidin-2-amine

[0588] ##STR00051##

[0589] Intermediate 17.6 was prepared under similar conditions as described in the preparation of Intermediate 1.4 using 2-chloro-5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidine (Intermediate 1.3) and 3-[(Methylsulfanyl)methyl]-5-(pentafluoro-λ.sup.6-sulfanyl)aniline (Intermediate 17.5). The batch was purified by column chromatography on silica gel (hexanes/ethyl acetate) to give the title compound.

[0590] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=10.29 (s, 1H), 8.80 (d, 1H), 8.41 (t, 1H), 8.18 (d, 1H), 7.99 (s, 1H), 7.77 (dd, 1H), 7.42-7.38 (m, 1H), 7.36-7.29 (m, 1H), 7.24 (d, 1H), 3.76 (s, 2H), 1.95 (s, 3H).

Preparation of Intermediate 17.7

(rac)-[3-{[5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-(pentafluoro-λ.SUP.6.-sulfanyl)benzyl](methyl)-λ.SUP.4.-sulfanylidene]cyanamide

[0591] ##STR00052##

[0592] Intermediate 17.7 was prepared under similar conditions as described in the preparation of Intermediate 1.5 using 5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-[(methylsulfanyl)methyl]-5-(pentafluoro-λ.sup.6-sulfanyl)phenyl}pyrimidin-2-amine (Intermediate 17.6). The batch was purified by column chromatography on silica gel (ethyl acetate/MeOH).

[0593] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=10.47 (s, 1H), 8.81 (d, 1H), 8.60 (t, 1H), 8.18 (d, 1H), 8.01 (s, 1H), 7.79 (dd, 1H), 7.55 (s, 1H), 7.34 (t, 1H), 7.24 (d, 1H), 4.62-4.32 (m, 2H), 2.87 (s, 3H).

[0594] Preparation of End Product:

[0595] Example 17 was prepared under similar conditions as described in the preparation of Example 1 using (rac)-[3-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-(pentafluoro-λ.sup.6-sulfanyl)benzyl](methyl)-λ.sup.4-sulfanylidene]cyanamide (205 mg; 0.373 mmol; Intermediate 17.7). The batch was purified by chromatography on silica gel (hexanes/ethyl acetate) to give the title compound (120 mg; 0.21 mmol).

[0596] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=10.48 (s, 1H), 8.81 (d, 1H), 8.65 (s, 1H), 8.17 (d, 1H), 8.07 (s, 1H), 7.78 (dd, 1H), 7.59 (s, 1H), 7.33 (t, 1H), 7.23 (d, 1H), 5.18-5.08 (m, 2H), 3.42 (s, 3H).

EXAMPLE 18

(rac)-5-Fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]-5-(pentafluoro-λ.SUP.6.-sulfanyl)phenyl}pyrimidin-2-amine

[0597] ##STR00053##

[0598] Example 18 was prepared under similar conditions as described in the preparation of Example 4 using (rac)- {[3-{[5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)pyrimidin-2-yl]amino}-5-(pentafluoro-λ.sup.6-sulfanyl)-benzyl](methyl)oxido-λ.sup.6-sulfanylidene}cyanamide (107 mg; 0.189 mmol; Example 17). The batch was purified by preparative HPLC to yield the title compound (24 mg; 0.04 mmol).

TABLE-US-00006 System: Waters Aqcuity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3100 Column: Aqcuity BEH C18 1.7 50 × 2.1 mm Solvent: A = H.sub.2O + 0.1% Vol. HCOOH (99%) 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. Solution: 1.0 mg/mL EtOH/MeOH 2:1 Injektion: 2.0 μl Detection: DAD TAC, scan range 210-400 nm MS ESI+, ESI−, scan range 160-1000 m/z ELSD

[0599] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=10.35 (s, 1H), 8.80 (d, 1H), 8.52 (t, 1H), 8.18 (d, 1H), 8.00 (s, 1H), 7.77 (dd, 1H), 7.56 (s, 1H), 7.32 (t, 1H), 7.24 (d, 1H), 4.46 (s, 2H), 3.71 (s, 1H), 2.81 (s, 3H).

[0600] The following Table 1 provides an overview on the compounds described in the example section:

TABLE-US-00007 TABLE 1 Example No. Structure Name of compound 1 [00054] (rac)-[(3-{[5-Fluoro-4-(4-fluoro-1- benzofuran-7-yl)pyrimidin-2- yl]amino}benzyl)(methyl)oxido-λ.sup.6- sulfanylidene]cyanamide 2 [00055] [(3-{[5-Fluoro-4-(4-fluoro-1- benzofuran-7-yl)pyrimidin-2- yl]amino}benzyl)(methyl)oxido-λ.sup.6- sulfanylidene]cyanamide; Enantiomer 1 3 [00056] [(3-{[5-Fluoro-4-(4-fluoro-1- benzofuran-7-yl)pyrimidin-2- yl]amino}benzyl)(methyl)oxido-λ.sup.6- sulfanylidene]cyanamide; Enantiomer 2 4 [00057] (rac)-5-Fluoro-4-(4-fluoro-1- benzofuran-7-yl)-N-{3-[(S- methylsulfonimidoyl)- methyl]phenyl}-pyrimidin-2-amine 5 [00058] 5-Fluoro-4-(4-fluoro-1-benzofuran-7- yl)-N-{3-[(S-methylsulfonimidoyl)- methyl]-phenyl}-pyrimidin-2-amine; Enantiomer 1 6 [00059] 5-Fluoro-4-(4-fluoro-1-benzofuran-7- yl)-N-{3-[(S-methylsulfonimidoyl)- methyl]-phenyl}-pyrimidin-2-amine; Enantiomer 2 7 [00060] (rac)-[(3-Fluoro-5-{[5-fluoro-4-(4- fluoro-1-benzofuran-7-yl)pyrimidin-2- yl]amino}benzyl)(methyl)-oxido-λ.sup.6- sulfanylidene]cyanamide 8 [00061] [(3-Fluoro-5-{[5-fluoro-4-(4-fluoro-1- benzofuran-7-yl)pyrimidin-2- yl]amino}benzyl)(methyl)-oxido-λ.sup.6- sulfanylidene]cyanamide; Enantiomer 1 9 [00062] [(3-Fluoro-5-{[5-fluoro-4-(4-fluoro-1- benzofuran-7-yl)pyrimidin-2- yl]amino}benzyl)(methyl)-oxido-λ.sup.6- sulfanylidene]cyanamide; Enantiomer 2 10 [00063] (rac)-5-Fluoro-4-(4-fluoro-1- benzofuran-7-yl)-N-{3-fluoro-5-[(S- methylsulfonimidoyl)-methyl]- phenyl}-pyrimidin-2-amine 11 [00064] 5-Fluoro-4-(4-fluoro-1-benzofuran-7- yl)-N-{3-fluoro-5-[(S- methylsulfonimidoyl)-methyl]- phenyl}-pyrimidin-2-amine; Enantiomer 1 12 [00065] 5-Fluoro-4-(4-fluoro-1-benzofuran-7- yl)-N-{3-fluoro-5-[(S- methylsulfonimidoyl)-methyl]- phenyl}-pyrimidin-2-amine; Enantiomer 2 13 [00066] (rac)-[(3-{[5-Fluoro-4-(4-fluoro-1- benzofuran-7-yl)pyrimidin-2- yl]amino}-5-methylbenzyl)- (methyl)oxido-λ.sup.6- sulfanylidene]cyanamide 14 [00067] [(3-{[5-Fluoro-4-(4-fluoro-1- benzofuran-7-yl)pyrimidin-2- yl]amino}-5-methylbenzyl)- (methyl)oxido-λ.sup.6- sulfanylidene]cyanamide; Enantiomer 1 15 [00068] [(3-{[5-Fluoro-4-(4-fluoro-1- benzofuran-7-yl)pyrimidin-2- yl]amino}-5-methylbenzyl)- (methyl)oxido-λ.sup.6- sulfanylidene]cyanamide; Enantiomer 2 16 [00069] (rac)-5-Fluoro-4-(4-fluoro-1- benzofuran-7-yl)-N-{3-methyl-5-[(S- methylsulfonimidoyl)- methyl]phenyl}pyrimidin-2-amine 17 [00070] (rac)-{[3-{[5-fluoro-4-(4-fluoro-1- benzofuran-7-yl)pyrimidin-2- yl]amino}-5-(pentafluoro-λ.sup.6- sulfanyl)benzyl](methyl)oxido-λ.sup.6- sulfanylidene}cyanamide 18 [00071] (rac)-5-Fluoro-4-(4-fluoro-1- benzofuran-7-yl)-N-{3-[(S- methylsulfonimidoyl)methyl]-5- (pentafluoro-λ.sup.6- sulfanyl)phenyl}pyrimidin-2-amine

[0601] Results:

[0602] Table 2: Inhibition for CDK9 and CDK2 of compounds according to the present invention 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. [0603] {circle around (1)}: Example Number [0604] {circle around (2)}: CDK9: CDK9/CycT1 kinase assay as described under Method 1a. of Materials and Methods [0605] {circle around (3)}: CDK2: CDK2/CycE kinase assay as described under Method 2a. of Materials and Methods [0606] {circle around (4)}: Selectivity CDK9 over CDK2: IC.sub.50 (CDK2)/IC.sub.50 (CDK9) according to Methods 1a. and 2a. of Materials and Methods [0607] {circle around (5)}: high ATP CDK9: CDK9/CycT1 kinase assay as described under Method 1b. of Materials and Methods [0608] {circle around (6)}: high ATP CDK2: CDK2/CycE kinase assay as described under Method 2b. of Materials and Methods [0609] {circle around (7)}: Selectivity high ATP CDK9 over high ATP CDK2: IC.sub.50 (high ATP CDK2)/IC.sub.50 (high ATP CDK9) according to Methods 1b. and 2b. of Materials and Methods

TABLE-US-00008 TABLE 2 {circle around (1)} Structure {circle around (2)} {circle around (3)} {circle around (4)} {circle around (5)} {circle around (6)} {circle around (7)} 1 [00072] 2.3 75 32 0.9 560 622 (racemic) 2 [00073] 1.4 19 14 1.1 353 321 (Enantiomer 1) 3 [00074] 3.3 45 14 1.0 475 475 (Enantiomer 2) 4 [00075] 4.6 110 24 22 510 23 (racemic) 5 [00076] 3.7 89 24 5.6 802 143 (Enantiomer 1) 6 [00077] 2.6 57 22 3.2 1000 313 (Enantiomer 2) 7 [00078] 4.1 56 14 1.9 652 343 (racemic) 8 [00079] 1.6 62 39 1 812 812 (Enantiomer 1) 9 [00080] 2.1 88 42 3.4 2230 656 (Enantiomer 2) 10 [00081] 3.1 50 16 3.2 1800 563 (racemic) 11 [00082] n.t. 73 n.t. 3.7 913 247 (Enantiomer 1) 12 [00083] 3.1 48 15 0.99 1250 1263 (Enantiomer 2) 13 [00084] n.t. 41 n.t. 0.88 1200 1364 (racemic) 14 [00085] 4.4 65 15 2.2 846 385 (Enantiomer 1) 15 [00086] 2.4 95 40 1.6 835 522 (Enantiomer 2) 16 [00087] 4.9 80 16 6.4 491 77 (racemic) 17 [00088] 8 257 33 7.4 1460 197 (racemic) 18 [00089] 2.9 73 25 4.4 1540 350 (racemic)

[0610] Table 3a and 3b:

[0611] Inhibition of proliferation of HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 and MOLM-13 cells (for corresponding indications see table 3a) by compounds according to the present invention, determined as described under Method 3. of Materials and Methods.

[0612] 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

[0613] {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 Bc6F10 cell proliferation
{circle around (8)}: Inhibition of A2780 cell proliferation
{circle around (9)}: Inhibition of MOLM-13 cell proliferation

[0614] Said cell lines represent the following indications as shown in table 3a:

TABLE-US-00009 TABLE 3a Indications represented by cell lines Cell line Source Indication HeLa ATCC Human cervical tumour HeLa-MaTu-ADR EPO-GmbH Multidrug-resistant human cervical Berlin carcinoma NCI-H460 ATCC Human non-small cell lung carcinoma DU 145 ATCC Hormone-independent human prostate carcinoma Caco-2 ATCC Human colorectal carcinoma B16F10 ATCC Mouse melanoma A2780 ECACC Human ovarian carcinoma MOLM-13 DSMZ Human acute myeloid leukemia

TABLE-US-00010 TABLE 3b Inhibition of cell 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 [00090] 104  134 189 112 110 170 46 83 (racemic) 2 [00091] 100 87 117 54 87 75 55 29 (Enantiomer 1) 3 [00092] 109  118 188 105 144 136 67 47 (Enantiomer 2) 4 [00093] 297  143 181 169 141 211 53  108 (racemic) 5 [00094] 177  190 343 186 230 260 93  115 (Enantiomer 1) 6 [00095] 115 96 314 110 112 185 38  117 (Enantiomer 2) 7 [00096] 50 60 104 51 75 64 23 17 (racemic) 8 [00097] 89 35 119 34 43 56 37 34 (Enantiomer 1) 9 [00098] 31 42 106 34 54 52 19 24 (Enantiomer 2) 10 [00099] 97 n.t. 112 72 104 58 37 37 (racemic) 11 [00100] 31  200 83 41 47 45 32 n.t. (Enantiomer 1) 12 [00101] 30 88 59 62 57 94 35 n.t. (Enantiomer 2) 13 [00102] 40 37 118 86 40 49 34 n.t. (racemic) 14 [00103] 96 57 112 66 61 69 45 75 (Enantiomer 1) 15 [00104] 107  110 121 101 68 114 63 74 (Enantiomer 2) 16 [00105] 46 41 120 106 60 82 35 33 (racemic) 17 [00106] 99 98 192 94 111 118 98 57 (racemic) 18 [00107] 101  116 136 141 152 168 34 30 (racemic)

[0615] Table 4:

[0616] Caco-2 permeation of compounds according to the present invention, determined as described under Method 5. of Materials and Methods.

{circle around (1)}: Example Number

[0617] {circle around (2)}: Concentration of test compound indicated in μM.
{circle around (3)}: P.sub.app A-B (M.sub.ari) indicated in [nm/s]
{circle around (4)}: P.sub.app B-A (M.sub.ari) indicated in [nm/s]
{circle around (5)}: Efflux ratio (Papp B-A/Papp A-B)

TABLE-US-00011 TABLE 4 {circle around (1)} Structure {circle around (2)} {circle around (3)} {circle around (4)} {circle around (5)} 4 [00108] 2 183 104 0.57 (racemic) 6 [00109] 2 221 113 0.51 (Enantiomer 2)