4-aryl-N-phenyl-1,3,5-triazin-2-amines containing a sulfoximine group

Abstract

The present invention relates to 4-aryl-N-phenyl-1,3,5-triazin-2-amines containing a sulfoximine group of general formula (I) or (Ia) 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) or (Ia). ##STR00001##

Claims

1. The compound (rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine or a salt, solvate, or salt of a solvate thereof.

2. The compound ()-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine or a salt, solvate, or salt of a solvate thereof.

3. The compound (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine or a salt, solvate, or salt of a solvate thereof.

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

5. A pharmaceutical composition comprising a compound according to claim 2 in combination with an inert, nontoxic, pharmaceutically suitable adjuvant.

6. A pharmaceutical composition comprising a compound according to claim 3 in combination with an inert, nontoxic, pharmaceutically suitable adjuvant.

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

8. A pharmaceutical combination comprising a compound according to claim 2 in combination with at least one or more further active ingredients.

9. A pharmaceutical combination comprising a compound according to claim 3 in combination with at least one or more further active ingredients.

10. A method for the treatment of non-small cell lung carcinoma, prostate carcinoma, cervical carcinoma, colorectal carcinoma, or melanoma comprising administering to a patient in need thereof a compound according to claim 1.

11. A method for the treatment of non-small cell lung carcinoma, prostate carcinoma, cervical carcinoma, colorectal carcinoma, or melanoma comprising administering to a patient in need thereof a compound according to claim 2.

12. A method for the treatment of non-small cell lung carcinoma, prostate carcinoma, cervical carcinoma, colorectal carcinoma, or melanoma comprising administering to a patient in need thereof a compound according to claim 3.

Description

PREPARATIVE EXAMPLES

Syntheses of Compounds

(1) The syntheses of the inventive disubstituted triazines according to the present invention is preferably carried out according to one of the general synthetic sequences, shown in schemes 1, 2, 3 or 4 below:

(2) Scheme 1:

(3) ##STR00068## ##STR00069##

(4) In the first step 2,4-dichloro-1,3,5-triazine (1) is reacted with suitable anilines (2) to give the corresponding 4-chloro-N-phenyl-1,3,5-triazin-2-amines (3). The reaction is carried out with one equivalent of the aniline (2) in an inert solvent like DMF, THF, DME, dioxane or an alcohol like isopropanol, or mixtures of such solvents. Preferably, the reaction is carried out at a temperature below 0 C. in such a way that the reaction mixture is kept homogenous. Preferred conditions use an additional base like triethylamine or N,N-diisopropylethylamine.

(5) In the second step the intermediate 4-chloro-N-phenyl-1,3,5-triazin-2-amine (3) is reacted with a boronic acid derivative R.sup.2B(OR).sub.2 (4) to give compounds of formula (5). The boronic acid derivative (4) may be a boronic acid (RH) or an ester of the boronic acid, e.g. its isopropyl ester (RCH(CH.sub.3).sub.2), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (RRC(CH.sub.3).sub.2C(CH.sub.3).sub.2).

(6) The coupling reaction is catalyzed by Pd catalysts, e.g. by Pd(0) catalysts like 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 like 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)Cl2].

(7) The reaction is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF or isopropanol with water and in the presence of a base like aqueous potassium carbonate, aqueous sodium bicarbonate or potassium phosphate.

(8) Deprotection of compounds of formula (5) gives the corresponding N-unprotected sulfoximines of formula (6). The deprotection is preferably carried out with sodium ethanolate in ethanol at 60 C.

(9) N-unprotected sulfoximines of formula (6) may be reacted to give N-functionalized derivatives of formula (I).

(10) Scheme 2

(11) Another synthesis route to N-unprotected sulfoximines of formula (6) is shown in Scheme 2.

(12) ##STR00070##

(13) In the first step 2,4-dichloro-1,3,5-triazine (1) is reacted with suitable anilines of formula (13) to give the corresponding 4-chloro-N-phenyl-1,3,5-triazin-2-amines of formula (14). The reaction is carried out with one equivalent of the aniline (13) in an inert solvent like DMF, THF, DME, dioxane or an alcohol like isopropanol, or mixtures of such solvents. Preferably, the reaction is carried out at a temperature below 0 C. in such a way that the reaction mixture is kept homogenous. Preferred conditions use an additional base like triethylamine or N,N-diisopropylethylamine.

(14) In the second step the intermediate 4-chloro-N-phenyl-1,3,5-triazin-2-amine of formula (14) is reacted with a boronic acid derivative R.sup.2B(OR).sub.2 (4) to give compounds of formula (15). The boronic acid derivative (4) may be a boronic acid (RH) or an ester of the boronic acid, e.g. its isopropyl ester (RCH(CH.sub.3).sub.2), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (RRC(CH.sub.3).sub.2C(CH.sub.3).sub.2).

(15) The coupling reaction is catalyzed by Pd catalysts, e.g. by Pd(0) catalysts like 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 like 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].

(16) The reaction is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like aqueous potassium carbonate, aqueous sodium bicarbonate or potassium phosphate.

(17) Finally, the compound of formula (15) is reacted with sodium azide in trichloromethane and sulfuric acid at 45 C. to give the N-unprotected sulfoximine of formula (6) (see for example: a) H. R. Bentley et al, J. Chem. Soc. 1952, 1572; b) C. R. Johnson et al, J. Am. Chem. Soc. 1970, 92, 6594; c) Satzinger et al, Angew. Chem. 1971, 83, 83).

(18) Scheme 3

(19) Another synthesis route to N-cyanosulfoximines of formula (20), which can also be converted to unprotected sulfoximines of formula (6), is shown in Scheme 3.

(20) ##STR00071## ##STR00072##

(21) In the first step 2,4-dichloro-1,3,5-triazine (1) is reacted with suitable anilines of formula (16) to give the corresponding 4-chloro-N-phenyl-1,3,5-triazin-2-amines of formula (17). The reaction is carried out with one equivalent of the aniline of formula (2) in an inert solvent like DMF, THF, DME, dioxane or an alcohol like isopropanol, or mixtures of such solvents. Preferably, the reaction is carried out at a temperature below 0 C. in such a way that the reaction mixture is kept homogenous. Preferred conditions use an additional base like triethylamine or N,N-diisopropylethylamine.

(22) In the second step the intermediate 4-chloro-N-phenyl-1,3,5-triazin-2-amine of formula (17) is reacted with a boronic acid derivative R.sup.2B(OR).sub.2 (4) to give compounds of formula (18). The boronic acid derivative (4) may be a boronic acid (RH) or an ester of the boronic acid, e.g. its isopropyl ester (RCH(CH.sub.3).sub.2), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (RRC(CH3)2-C(CH3)2-).

(23) The coupling reaction is catalyzed by Pd catalysts, e.g. by Pd(0) catalysts like 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 like 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].

(24) The reaction is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like aqueous potassium carbonate, aqueous sodium bicarbonate or potassium phosphate.

(25) In the next step, the sulfide of formula (18) is reacted with cyanogen amine as a nitrogen source to give the corresponding N-cyanosulfilimine of formula (19). Preferably, the reaction is carried out using NBS and potassium tert-butoxide in methanol at room temperature (see for example: a) C. Bolm et al, Org. Lett. 2007, 9, 3809). Even more preferred is the use of iodobenzenediacetate in DCM at room temperature (see for example: a) J. M. Babcock, US 2009/0023782).

(26) Finally, N-cyanosulfilimine of formula (19) is oxidized to the corresponding N-cyanosulfoximine of formula (20). The reaction is preferably carried out using mCPBA and potassium carbonate in ethanol at room temperature (see for example: a) C. Bolm et al, Org. Lett. 2007, 9, 3809). Even more preferred is the use of potassium permanganate in acetone at 50 C. (see for example: a) C. Bolm et al, Adv. Synth. Catal. 2010, 352, 309).

(27) The N-cyano group of compound (20) is cleaved upon treatment with TFAA affording the corresponding N-trifluoroacetylsulfoximine which is converted into the NH-free sulfoximine of formula (6) by methanolysis of the trifluoroacetyl moiety (see for example: C. Bolm et al, Org. Lett. 2007, 9(19), 3809).

(28) Scheme 4:

(29) Another synthesis route to N-unprotected sulfoximines of formula (6) is shown in Scheme 4.

(30) ##STR00073##

(31) In the first step the intermediate 4-chloro-N-phenyl-1,3,5-triazin-2-amine (3) is reacted with a suitable ortho-fluorine boronic acid derivative of formula (21) to give a compound of formula (22). The boronic acid derivative of formula (21) may be a boronic acid (RH) or an ester of the boronic acid, e.g. its isopropyl ester (RCH(CH.sub.3).sub.2), or an ester derived from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (RRC(CH.sub.3).sub.2C(CH.sub.3).sub.2).

(32) The coupling reaction is catalyzed by Pd catalysts, e.g. by Pd(0) catalysts like 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 like 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].

(33) The reaction is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like aqueous potassium carbonate, aqueous sodium bicarbonate or potassium phosphate.

(34) In the second step the ortho-flourine of the substituent in 4-position of the compound of formula (22) is replaced by a suitable alkoxy group. OR.sup.8. The reaction is preferably carried out by adding at least two equivalents of sodium hydride to a solution of compound (22) in alcohol (23) to give the desired N-unprotected sulfoximines of formula (6). The reactions are run at a temperature of 60 C. or in the temperature range between 50 C. and 70 C.

(35) Preparation of Compounds:

(36) Abbreviations Used in the Description of the Chemistry and in the Examples that Follow are:

(37) CDCl.sub.3 (deuterated chloroform); cHex (cyclohexane); DCM (dichloromethane); DIPEA (di-iso-propylethylamine); DME (1,2-dimethoxyethane), DMF (dimethylformamide); DMSO (dimethyl sulfoxide); eq (equivalent); ES (electrospray); EtOAc (ethyl acetate); EtOH (ethanol); iPrOH (isopropanol); mCPBA (meta-chloroperoxybenzoic acid), MeOH (methanol); MS (mass spectrometry); NBS (N-bromosuccinimide), NMR (nuclear magnetic resonance); Pd(dppf)Cl.sub.2 ([1,1-bis(diphenylphosphino)ferrocene]dichloro palladium(II) complex with dichloromethane); iPrOH (isopropanol); RT (room temperature); sat. aq. (saturated aqueous); SiO.sub.2 (silica gel); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran).

(38) The IUPAC names of the examples were generated using the program ACD/Name batch version 12.01 from ACD LABS.

Example 1

(rac)-Ethyl [(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]carbamate

(39) ##STR00074##
Preparation of Intermediate 1.1:

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

(40) ##STR00075##

(41) 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) 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 brine and extracted with ethyl acetate (2). The combined organic phases were washed with water, dried (sodium sulfate), filtered and concentrated to give the desired product (32.2 g) that was used without further purification.

(42) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.18 (m, 1H), 8.11 (m, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 3.75 (s, 2H), 2.01 (s, 3H).

(43) Preparation of Intermediate 1.2:

(rac)-1-[(Methylsulfinyl)methyl]-3-nitrobenzene

(44) ##STR00076##

(45) Iron(III)chloride (0.55 g; 3.4 mmol) was added to a solution of 1-[(methylsulfanyl)methyl]-3-nitrobenzene (21.6 g; 117.9 mmol) in acetonitrile (280 mL) and the batch was stirred at room temperature for 10 minutes. Periodic acid (28.8 g; 126.1 mmol) was added under stirring in one portion and the temperature was kept below 30 C. by cooling. The batch was stirred at room temperature for 90 minutes before it was added to a stirred solution of sodium thiosulfate pentahydrate (163 g; 660 mmol) in ice water (1500 mL). The batch was saturated with solid sodium chloride and extracted with THF (2). The combined organic phases were washed with brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by chromatography (DCM/ethanol 95:5) to give the desired product (16.6 g; 83.1 mmol).

(46) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.21 (m, 1H), 8.17 (m, 1H), 7.67 (m, 1H), 7.58 (m, 1H), 4.10 (d, 1H), 3.97 (d, 1H), 2.53 (s, 3H).

(47) Preparation of Intermediate 1.3:

(rac)-2,2,2-Trifluoro-N-[methyl(3-nitrobenzyl)oxido-6-sulfanylidene]acetamide

(48) ##STR00077##

(49) To a suspension of (rac)-1-[(methylsulfinyl)methyl]-3-nitrobenzene (16.6 g; 83.1 mmol), trifluoroacetamide (18.8 g; 166.1 mmol), magnesium oxide (13.4 g; 332.3 mmol) and rhodium(II)-acetat dimer (1.7 g; 8.3 mmol) in DCM (2290 mL) was added iodobenzene diacetate (40.1 g; 124.6 mmol) at room temperature. The batch was stirred for 16 hours at room temperature, filtered and concentrated. The residue was purified by chromatography (DCM/ethanol 97:3) to give the desired product (25.6 g; 82.4 mmol).

(50) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.36 (m, 1H), 8.31 (m, 1H), 7.80 (m, 1H), 7.69 (m, 1H), 4.91 (d, 1H), 4.79 (d, 1H), 3.28 (s, 3H).

(51) Preparation of Intermediate 1.4:

(rac)-1-[(S-Methylsulfonimidoyl)methyl]-3-nitrobenzene

(52) ##STR00078##

(53) Potassium carbonate (56.9 g; 411.8 mmol) was added to a solution of (rac)-2,2,2-trifluoro-N-[methyl(3-nitrobenzyl)oxido-.sup.6-sulfanylidene]acetamide (25.6 g; 82.4 mmol) in methanol (1768 mL) at room temperature. The batch was stirred for 1 hour at room temperature before it was diluted with ethyl acetate and brine. After extraction with ethyl acetate (2) the combined organic phases were dried (sodium sulfate), filtered and concentrated to give the desired product (13.9 g; 65.1 mmol).

(54) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.29 (m, 2H), 7.79 (m, 1H), 7.63 (m, 1H), 4.47 (d, 1H), 4.34 (d, 1H), 2.99 (s, 3H), 2.66 (br, 1H).

(55) Preparation of Intermediate 1.5:

(rac)-Ethyl [methyl(3-nitrobenzyl)oxido-6-sulfanylidene]carbamate

(56) ##STR00079##

(57) Ethyl chlorocarbonate (8.1 mL; 84.6 mmol) was added dropwise to a stirred solution of (rac)-1-[(S-methylsulfonimidoyl)methyl]-3-nitrobenzene (13.9 g; 65.1 mmol) in pyridine (615 mL) at 0 C. The batch was slowly warmed to room temperature. After 24 hours the batch was concentrated and the residue was dissolved in ethyl acetate and washed with brine. The organic phase was filtered using a Whatman filter and concentrated to give the desired product (19.7 g) that was used without further purification.

(58) .sup.1H NMR (400 MHz, d.sub.6-CDCl.sub.3, 300K) =8.30 (m, 2H), 7.81 (m, 1H), 7.64 (m, 1H), 4.88 (d, 1H), 4.79 (d, 1H), 4.18 (q, 2H), 3.07 (s, 3H), 1.31 (tr, 3H).

(59) Preparation of Intermediate 1.6:

(rac)-Ethyl [(3-aminobenzyl)(methyl)oxido-6-sulfanylidene]carbamate

(60) ##STR00080##

(61) Titanium(III)chloride solution (about 15% in about 10% hydrochloric acid, 118 mL; Merck Schuchardt OHG) was added to a stirred solution of (rac)-ethyl [methyl(3-nitrobenzyl)oxido-.sup.6-sulfanylidene]carbamate (5.0 g; 17.5 mmol) in THF (220 mL) at room temperature. The batch was stirred for 18 hours. By adding 2N sodium hydroxide solution the pH value of the reaction mixture, that was cooled with an ice bath, was raised to 8. The batch was saturated with solid sodium chloride and extracted with ethyl acetate (3). The combined organic phases were washed with brine, dried (sodium sulfate), filtered and concentrated to give the desired product (4.2 g) that was used without further purification.

(62) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =7.00 (m, 1H), 6.53 (m, 3H), 5.18 (br, 2H), 4.62 (s, 2H), 3.95 (m, 2H), 3.08 (s, 3H). 1.13 (tr, 3H).

(63) Preparation of Intermediate 1.7:

(rac)-Ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-6-sulfanylidene]-carbamate

(64) ##STR00081##

(65) DIPEA (3.1 mL; 17.8 mmol) was added to a stirred solution of 2,4-dichloro-1,3,5-triazine (1.34 g; 8.9 mmol) in THF/i-PrOH (1:1; 18 mL) at 40 C. Then a solution of (rac)-ethyl [(3-aminobenzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (2.29 g; 8.9 mmol) in THF/i-PrOH (1:1; 9 mL) was added at this temperature. Under stirring the temperature of the reaction mixture was slowly raised over 3 hours to 0 C. The batch was concentrated to give the crude product (4.9 g) that was used without further purification.

(66) TABLE-US-00002 System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Column: Acquity UPLC BEH C18 1.7 50 2.1 mm Solvent: A1 = H.sub.2O + 0.1% HCOOH B1 = Acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Temperatuer: 60 C. Injektion: 2.0 l Detection: DAD scan range 210-400 nm -> Peaktable ELSD Method: MS ESI+, ESI Switch A1 + B1 = C:\MassLynx\Mass_160_1000.flp Retention: 0.88 min MS(ES+): m/z = 370 [M + H]
Preparation of End Product:

(67) A batch with crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (400 mg), (4-fluoro-2-methoxyphenyl)boronic acid (276 mg; 1.62 mmol; Aldrich) and tetrakis(triphenylphosphin)palladium(0) (187 mg; 0.16 mmol) in 1,2-dimethoxyethane (5.0 mL) and 2M solution of potassium carbonate (1.1 mL) was degassed using argon. The batch was stirred under argon for 80 minutes at 100 C. After cooling the batch was diluted with ethyl acetate and washed with brine. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM/ethanol 95:5) to give the desired product (178 mg; 0.39 mmol).

(68) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.94 (m, 1H), 7.84 (s, 1H), 7.74 (br, 1H), 7.53 (s, 1H), 7.42 (m, 1H), 7.16 (m, 1H), 6.77 (m, 2H), 4.74 (m, 2H), 4.17 (q, 2H), 3.93 (s, 3H), 3.00 (s, 3H), 1.30 (tr, 3H).

Example 2

(rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(69) ##STR00082##

(70) A freshly prepared 1.5M solution of sodium ethanolate in ethanol (2.9 mL; 4.35 mmol) was added under argon to a solution of (rac)-ethyl [(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}-benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (500 mg; 1.09 mmol) in ethanol (18.5 mL). The batch was stirred at 60 C. for 2 hours. Further 1.5M solution of sodium ethanolate in ethanol (2.9 mL; 4.35 mmol) was added and the batch was stirred for additional 5 hours at 60 C. After cooling the batch was diluted with brine and extracted with ethyl acetate (3). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM/ethanol 9:1) to give the desired product (378 mg; 0.98 mmol).

(71) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.95 (m, 1H), 7.77 (m, 2H), 7.55 (s, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 6.75 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H), 2.71 (s, 1H).

Alternative preparation of Example 2 ((rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methyl-sulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine)

(72) Preparation of Intermediate 2.1:

(rac)-4-Chloro-N-{3-[(methylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine

(73) ##STR00083##

(74) Intermediate 2.1 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using (rac)-3-[(methylsulfinyl)methyl]aniline (UkrOrgSynthesis Ltd.).

(75) TABLE-US-00003 System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Column: Acquity UPLC BEH C18 1.7 50 2.1 mm Solvent: A2 = H.sub.2O + 0.2% NH.sub.3 B1 = Acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Temperature: 60 C. Injektion: 2.0 l Detection: DAD scan range 210-400 nm -> Peaktable ELSD Method: MS ESI+, ESI Switch A2 + B1 = C:\MassLynx\NH3_Mass_100_1000.olp System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Retention 1.13 min MS(ES): m/z = 283 [M + H]
Preparation of Intermediate 2.2:

(rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(methylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine

(76) ##STR00084##

(77) Intermediate 2.2 was prepared under similar conditions as described in the preparation of Example 42 using crude (rac)-4-chloro-N-{3-[(methylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by column chromatography (DCM/EtOH 95:5) to give the desired product.

(78) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.95 (br, 1H), 7.74 (br, 1H), 7.65 (s, 1H), 7.40 (m, 2H), 7.05 (m, 1H), 6.77 (m, 2H), 4.07 (d, 1H), 3.95 (m, 4H), 2.49 (s, 3H).

(79) Preparation of End Product

(80) Concentrated sulfuric acid (2.5 mL) was added dropwise to a stirred batch of sodium azide (0.61 g; 9.4 mmol) and ((rac)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(methylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine (1.75 g; 4.7 mmol) in trichloromethane (8.0 mL) at 0 C. The batch was stirred for 18 hours at 45 C. While cooling in an ice bath the batch was cautiously diluted with ice water. The batch was further diluted with saturated sodium chloride solution and THF before solid sodium bicarbonate was added under stirring to neutralize the acid. The batch was extracted with THF (3). The combined organic phases were washed with saturated sodium chloride solution, dried (Na.sub.2SO.sub.4), filtered and concentrated to give the desired product (1.79 g; 4.6 mmol).

(81) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.95 (m, 1H), 7.77 (m, 2H), 7.55 (s, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 6.75 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H), 2.71 (s, 1H).

Example 3 and 4

()-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine (enantiomer 1) and (+)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)-methyl]phenyl}-1,3,5-triazin-2-amine (enantiomer 2)

(82) (rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine (see example 2) was separated into the enantiomers by preparative HPLC.

(83) TABLE-US-00004 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IC 5 m 250 20 mm Solvent: Hexane/Ethanol 60:40 + 0.1% Diethylamine Flow: 40 mL/min Solution: 2600 mg/44 mL EtOH/DMSO 2:1 Injektion: 55 0.8 mL Temperature: RT Detection: UV 254 nm Retention purity time in min in % Optical rotation index Example 3 13.4-15.6 98.3 5.2 +/ 0.31 Enantiomer 1 (c = 1.0000 g/100 mL CHCl.sub.3) 20 C. or 17.9 +/ 0.48 (c = 1.0000 g/100 mL DMSO) 20 C. Example 4 15.6-17.8 95.5 2.3 +/ 0.06 Enantiomer 2 (c = 1.0000 g/100 mL CHCl.sub.3) 20 C. or 14.0 +/ 0.40 (c = 1.0000 g/100 mL DMSO) 20 C. Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.80 (s, 1H), 7.95 (m, 1H), 7.77 (m, 2H), 7.55 (s, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 6.75 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H), 2.71 (s, 1H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.80 (s, 1H), 7.95 (m, 1H), 7.77 (m, 2H), 7.55 (s, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 6.75 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H), 2.71 (s, 1H).

(84) Due to its negative optical rotation index in chloroform Enantiomer 1 is also referred to as ()-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine. Enantiomer 2 is also referred to as (+)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)-methyl]phenyl}-1,3,5-triazin-2-amine.

Example 5

(rac)-Ethyl {[3-({4-[2-(benzyloxy)-4-fluorophenyl]-1,3,5-triazin-2-yl}amino)benzyl](methyl)oxido-6-sulfanylidene}carbamate

(85) ##STR00085##

(86) Example 5 was prepared under similar conditions as described in the preparation of Example 1 using crude (rac)-ethyl[{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and [2-(benzyloxy)-4-fluorophenyl]boronic acid (ABCR GmbH & Co. KG).

(87) The batch was purified by preparative HPLC.

(88) TABLE-US-00005 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(89) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.94 (m, 1H), 7.82 (s, 1H), 7.65 (m, 1H), 7.44 (m, 3H), 7.31 (m, 4H), 7.12 (m, 1H), 6.80 (m, 2H), 5.20 (s, 2H), 4.66 (s, 2H), 4.16 (q, 2H), 2.96 (s, 3H), 1.30 (tr, 3H).

Example 6

(rac)-4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(90) ##STR00086##

(91) Example 6 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl {[3-({4-[2-(benzyloxy)-4-fluorophenyl]-1,3,5-triazin-2-yl}amino)benzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate. The batch was purified by column chromatography (DCM/EtOH 95:5).

(92) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.95 (m, 1H), 7.70 (m, 2H), 7.50 (s, 1H), 7.44 (m, 2H), 7.32 (m, 4H), 7.12 (m, 1H), 6.79 (m, 2H), 5.20 (s, 2H), 4.33 (d, 1H), 4.21 (d, 1H), 2.92 (s, 3H), 2.69 (s, 1H).

Example 7 and 8

()-4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine (enantiomer 1) and (+)-4-[2-(benzyloxy)-4-fluorophenyl]-N-{3-[(S-methylsulfonimidoyl)-methyl]phenyl}-1,3,5-triazin-2-amine (enantiomer 2)

(93) (rac)-4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC.

(94) TABLE-US-00006 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IC 5 m 250 30 mm Solvent: Hexane/Ethanol 50:50 + 0.1% Diethylamine Flow: 30 mL/min Solution: 52 mg/1.5 mL EtOH/MeOH 1:1 Injektion: 2 0.75 mL Temperature: RT Detection: UV 254 nm Retention purity time in min in % Optical rotation index Example 7 12.0-13.5 >99.9 7.1 +/ 0.11 Enantiomer 1 (c = 1.0000 g/100 mL CHCl.sub.3) 20 C. Example 8 13.5-15.3 98.2 3.5 +/ 0.08 Enantiomer 2 (c = 1.0000 g/100 mL CHCl.sub.3) 20 C. Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.82 (s, 1H), 7.95 (m, 1H), 7.70 (m, 2H), 7.50 (s, 1H), 7.44 (m, 2H), 7.32 (m, 4H), 7.12 (m, 1H), 6.79 (m, 2H), 5.20 (s, 2H), 4.33 (d, 1H), 4.21 (d, 1H), 2.92 (s, 3H), 2.69 (s, 1H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.82 (s, 1H), 7.95 (m, 1H), 7.70 (m, 2H), 7.50 (s, 1H), 7.44 (m, 2H), 7.32 (m, 4H), 7.12 (m, 1H), 6.79 (m, 2H), 5.20 (s, 2H), 4.33 (d, 1H), 4.21 (d, 1H), 2.92 (s, 3H), 2.69 (s, 1H).

Example 9

(rac)-Ethyl [(3-{[4-(4,5-difluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]carbamate

(95) ##STR00087##

(96) Example 9 was prepared under similar conditions as described in the preparation of Example 1 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and (4,5-difluoro-2-methoxyphenyl)boronic acid (Aldrich). The batch was purified by column chromatography (DCM/EtOH 95:5).

(97) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.82 (m, 3H), 7.46 (m, 2H), 7.18 (m, 1H), 6.87 (m, 1H), 4.74 (m, 2H), 4.17 (q, 2H), 3.92 (s, 3H), 3.01 (s, 3H), 1.31 (tr, 3H).

Example 10

(rac)-4-(4,5-Difluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}1,3,5-triazin-2-amine

(98) ##STR00088##

(99) Example 10 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl[(3-{[4-(4,5-difluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate. The batch was purified by preparative HPLC.

(100) TABLE-US-00007 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% NH.sub.3 B = Acetonitrile Gradient: 0-1 min 15% B, 1-8 min 15-60% B Flow: 50 mL/min Solution: 48 mg/2 mL DMSO Injektion: 2 1 mL Temperature: RT Detection: DAD scan range 210-400 nm MS ESI+, scan range 160-1000 m/z ELSD Retention 7.57-8.00 min

(101) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.78 (m, 3H), 7.54 (s, 1H), 7.42 (m, 1H), 7.17 (m, 1H), 6.86 (m, 1H), 4.40 (d, 1H), 4.27 (d, 1H), 3.91 (s, 3H), 2.96 (s, 3H), 2.72 (s, 1H).

Example 11

(rac)-Ethyl [(3-{[4-(4-chloro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]carbamate

(102) ##STR00089##

(103) Example 11 was prepared under similar conditions as described in the preparation of Example 1 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]-carbamate and (4-chloro-2-methoxyphenyl)boronic acid (ABCR GmbH & Co. KG). The batch was purified by preparative HPLC.

(104) TABLE-US-00008 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(105) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.85 (m, 2H), 7.75 (br, 1H), 7.57 (m, 1H), 7.42 (m, 1H), 7.17 (m, 1H), 7.04 (m, 2H), 4.73 (m, 2H), 4.16 (q, 2H), 3.93 (s, 3H), 2.99 (s, 3H), 1.30 (tr, 3H).

Example 12

(rac)-4-(4-Chloro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(106) ##STR00090##

(107) Example 12 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl[(3-{[4-(4-chloro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate. The batch was purified by preparative HPLC.

(108) TABLE-US-00009 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(109) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.80 (m, 4H), 7.39 (m, 1H), 7.15 (m, 1H), 7.03 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H). 2.39 (br, 1H).

Example 13 and 14

Enantiomers of 4-(4-Chloro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(110) (rac)-4-(4-Chloro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC.

(111) TABLE-US-00010 System: Agilent: Prep 1200, 2 Prep Pump, DLA, MWD, Prep FC Column: Chiralpak IC 5 m 250 20 mm Solvent: Ethanol/Methanol 65:35 + 0.1% DEA Flow: 12 mL/min Solution: 34 mg/1.5 mL MeOH/DMSO 2:1 Injektion: 5 0.3 mL Temperature: RT Detection: MWD 254 nm Retention time in min purity in % Example 13 7.8-8.4 >99.9 Enantiomer 1 Example 14 8.4-9.4 >95% Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.80 (s, 1H), 7.80 (m, 4H), 7.39 (m, 1H), 7.15 (m, 1H), 7.03 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H). 2.39 (br, 1H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.80 (s, 1H), 7.80 (m, 4H), 7.39 (m, 1H), 7.15 (m, 1H), 7.03 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H). 2.39 (br, 1H).

Example 15

(rac)-1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]-3-methylurea

(112) ##STR00091##

(113) Isocyanatomethane (7.6 l; 0.13 mmol) was added to a solution of (rac)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.13 mmol) in DMF (2.0 ml) and triethylamine (18.0 l; 0.13 mmol) at room temperature. The batch was stirred for 5 hours before further isocyanatomethane (3.8 l; 0.07 mmol) was added. After 72 hours the batch was diluted with sodium bicarbonate and extracted with ethyl acetate (2). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (34 mg; 0.08 mmol)

(114) TABLE-US-00011 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(115) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.80 (m, 4H), 7.41 (m, 1H), 7.17 (m, 1H), 6.78 (m, 2H), 5.04 (br, 1H), 4.83 (d, 1H), 4.64 (d, 1H), 3.94 (s, 3H), 3.00 (s, 3H), 2.78 (d, 3H).

Example 16 and 17

()-1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]-3-methylurea (enantiomer 1) and (+)-1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]-3-methylurea (enantiomer 2)

(116) (rac)-1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]-3-methylurea was separated into the enantiomers by preparative HPLC.

(117) TABLE-US-00012 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IA 5 m 250 30 mm Solvent: Ethanol/Methanol 50:50 Flow: 30 mL/min Temperature: RT Solution: 26 mg/1.5 mL EtOH/MeOH 1:1 Injektion: 1 1.5 mL Detection: UV 254 nm Retention purity time in min in % Optical rotation index Example 16 27.5-35.5 98.9 25.1 +/ 0.19 Enantiomer 1 (c = 1.0000 g/100 mL CHCl.sub.3) 20 C. Example 17 37.0-50.3 99.2 18.7 +/ 0.10 Enantiomer 2 (c = 1.0000 g/100 mL CHCl.sub.3) 20 C. Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.81 (s, 1H), 7.80 (m, 4H), 7.41 (m, 1H), 7.17 (m, 1H), 6.78 (m, 2H), 5.04 (br, 1H), 4.83 (d, 1H), 4.64 (d, 1H), 3.94 (s, 3H), 3.00 (s, 3H), 2.78 (d, 3H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.81 (s, 1H), 7.80 (m, 4H), 7.41 (m, 1H), 7.17 (m, 1H), 6.78 (m, 2H), 5.04 (br, 1H), 4.83 (d, 1H), 4.64 (d, 1H), 3.94 (s, 3H), 3.00 (s, 3H), 2.78 (d, 3H).

Example 18

(rac)-Ethyl [(3-{[4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)-oxido-6-sulfanylidene]carbamate

(118) ##STR00092##

(119) Example 18 was prepared under similar conditions as described in the preparation of Example 1 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and (2,2-difluoro-1,3-benzodioxol-4-yl)boronic acid (Combi Blocks Inc.). The batch was purified by preparative HPLC.

(120) TABLE-US-00013 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(121) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.86 (s, 1H), 8.12 (m, 1H), 7.82 (m, 1H), 7.48 (m, 3H), 7.24 (m, 3H), 4.76 (m, 2H), 4.17 (q, 2H), 3.02 (s, 3H), 1.31 (tr, 3H).

Example 19

(rac)-4-(2,2-Difluoro-1,3-benzodioxol-4-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}1,3,5-triazin-2-amine

(122) ##STR00093##

(123) Example 19 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl [(3-{[4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate. The batch was purified by column chromatography (DCM/EtOH 95:5).

(124) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 8.13 (m, 1H), 7.87 (m, 2H), 7.52 (br, 1H), 7.45 (m, 1H), 7.22 (m, 3H), 4.44 (d, 1H), 4.29 (d, 1H), 2.97 (s, 3H), 2.70 (s, 1H).

Example 20

(rac)-Ethyl [(3-{[4-(5-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]carbamate

(125) ##STR00094##

(126) Example 20 was prepared under similar conditions as described in the preparation of Example 1 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and (5-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.

(127) TABLE-US-00014 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(128) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 7.84 (m, 1H), 7.73 (br, 1H), 7.60 (m, 1H), 7.51 (s, 1H), 7.43 (m, 1H), 7.19 (m, 2H), 7.00 (m, 1H), 4.74 (m, 2H), 4.18 (q, 2H), 3.91 (s, 3H), 3.00 (s, 3H), 1.30 (tr, 3H).

Example 21

(rac)-4-(5-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(129) ##STR00095##

(130) Example 21 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl [(3-{[4-(5-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate. The batch was purified by column chromatography (DCM/EtOH 95:5).

(131) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 7.73 (m, 2H), 7.63 (m, 1H), 7.43 (m, 2H), 7.19 (m, 2H), 7.02 (m, 1H), 4.38 (d, 1H), 4.28 (d, 1H), 3.91 (s, 3H), 2.95 (s, 3H), 2.70 (br, 1H).

Example 22 and 23

Enantiomers of 4-(5-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(132) (rac)-4-(5-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC:

(133) TABLE-US-00015 System: Agilent: Prep 1200, 2 Prep Pump, DLA, MWD, Prep FC Column: Chiralcel OJ-H 5 m 250 20 mm Solvent: Ethanol/methanol 50:50 + 0.1% DEA Flow: 16 mL/min Temperature: RT Solution: 57 mg/0.6 mL EtOH/MeOH 1:1 Injektion: 2 0.3 mL Detection: MWD 254 nm Retention time in min purity in % Example 22 6.1-7.2 >99% Enantiomer 1 Example 23 8.6-10.2 >99% Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.84 (s, 1H), 7.73 (m, 2H), 7.63 (m, 1H), 7.43 (m, 2H), 7.19 (m, 2H), 7.02 (m, 1H), 4.38 (d, 1H), 4.28 (d, 1H), 3.91 (s, 3H), 2.95 (s, 3H), 2.70 (br, 1H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.84 (s, 1H), 7.73 (m, 2H), 7.63 (m, 1H), 7.43 (m, 2H), 7.19 (m, 2H), 7.02 (m, 1H), 4.38 (d, 1H), 4.28 (d, 1H), 3.91 (s, 3H), 2.95 (s, 3H), 2.70 (br, 1H).

Example 24

(rac)-N-[(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]acetamide

(134) ##STR00096##

(135) Acetyl chloride (10.1 l; 0.14 mmol) was added to a solution of (rac)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.13 mmol) in DCM (1.5 ml) and triethylamine (45.0 l; 0.32 mmol) at 0 C. The ice bath was removed and the batch was stirred for 23 hours before further acetyl chloride (4.0 l; 0.06 mmol) was added. After 24 hours additional acetyl chloride (5.0 l; 0.07 mmol) was added and the batch was stirred for 3 hours before it was diluted with water and extracted with ethyl acetate (2). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (35 mg; 0.08 mmol).

(136) TABLE-US-00016 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(137) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.95 (m, 1H), 7.78 (m, 2H), 7.56 (m, 1H), 7.42 (m, 1H), 7.16 (m, 1H), 6.79 (m, 2H), 4.78 (d, 1H), 4.65 (d, 1H), 3.94 (s, 3H), 3.03 (s, 3H), 2.12 (s, 3H).

Example 25

(rac)-Ethyl [(3-{[4-(2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]carbamate

(138) ##STR00097##

(139) Example 25 was prepared under similar conditions as described in the preparation of Example 1 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and (2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.

(140) TABLE-US-00017 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(141) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.85 (m, 2H), 7.71 (m, 1H), 7.56 (s, 1H), 7.48 (m, 1H), 7.42 (m, 1H), 7.17 (m, 1H), 7.07 (m, 2H), 4.73 (s, 2H), 4.17 (q, 2H), 3.93 (s, 3H), 2.98 (s, 3H), 1.30 (tr, 3H).

Example 26

(rac)-4-(2-Methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(142) ##STR00098##

(143) Example 26 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl[(3-{[4-(2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]-carbamate. After aqueous work up no further purification was necessary.

(144) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.83 (s, 1H), 7.86 (m, 1H), 7.75 (m, 2H), 7.54 (s, 1H), 7.49 (m, 1H), 7.41 (m, 1H), 7.16 (m, 1H), 7.05 (m, 2H), 4.38 (d, 1H), 4.26 (d, 1H), 3.93 (s, 3H), 2.94 (s, 3H). 2.70 (s, 1H).

Example 27 and 28

(145) Enantiomers of 4-(2-Methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine(rac)-4-(2-Methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC:

(146) TABLE-US-00018 System: Agilent: Prep 1200, 2 Prep Pump, DLA, MWD, Prep FC Column: Chiralcel OJ-H 5 m 250 20 mm Solvent: Ethanol/methanol 50:50 + 0.1% DEA Flow: 16 mL/min Temperature: RT Solution: 59 mg/0.6 mL EtOH Injektion: 2 0.3 mL Detection: MWD 254 nm Retention time in min purity in % Example 27 11.7-12.2 >99% Enantiomer 1 Example 28 7.5-7.9 >99% Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.83 (s, 1H), 7.86 (m, 1H), 7.75 (m, 2H), 7.54 (s, 1H), 7.49 (m, 1H), 7.41 (m, 1H), 7.16 (m, 1H), 7.05 (m, 2H), 4.38 (d, 1H), 4.26 (d, 1H), 3.93 (s, 3H), 2.94 (s, 3H). 2.70 (s, 1H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.83 (s, 1H), 7.86 (m, 1H), 7.75 (m, 2H), 7.54 (s, 1H), 7.49 (m, 1H), 7.41 (m, 1H), 7.16 (m, 1H), 7.05 (m, 2H), 4.38 (d, 1H), 4.26 (d, 1H), 3.93 (s, 3H), 2.94 (s, 3H). 2.70 (s, 1H).

Example 29

(rac)-Ethyl [(3-{[4-(3,4-dihydro-2H-chromen-8-yl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]carbamate

(147) ##STR00099##

(148) Example 29 was prepared under similar conditions as described in the preparation of Example 1 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and 3,4-dihydro-2H-chromen-8-ylboronic acid (Parkway Scientific LLC). The batch was purified by preparative HPLC.

(149) TABLE-US-00019 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(150) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 7.85 (m, 1H), 7.74 (br, 1H), 7.65 (m, 1H), 7.42 (m, 2H), 7.19 (m, 2H), 6.94 (m, 1H), 4.73 (s, 2H), 4.30 (tr, 2H), 4.17 (q, 2H), 2.98 (s, 3H), 2.89 (tr, 2H), 2.10 (m, 2H), 1.31 (tr, 3H).

Example 30

(rac)-4-(3,4-Dihydro-2H-chromen-8-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(151) ##STR00100##

(152) Example 30 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl[(3-{[4-(3,4-dihydro-2H-chromen-8-yl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate. After aqueous work up no further purification was necessary.

(153) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.83 (s, 1H), 7.74 (m, 3H), 7.49 (br, 1H), 7.40 (m, 1H), 7.17 (m, 2H), 6.94 (m, 1H), 4.30 (m, 4H), 2.94 (s, 3H), 2.88 (tr, 2H), 2.69 (s, 1H), 2.10 (m, 2H).

Example 31 and 32

(154) Enantiomers of 4-(3,4-dihydro-2H-chromen-8-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine(rac)-4-(3,4-Dihydro-2H-chromen-8-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC.

(155) TABLE-US-00020 System: Agilent: Prep 1200, 2 Prep Pump, DLA, MWD, Prep FC Column: Chiralcel OJ-H 5 m 250 20 mm Solvent: Ethanol/methanol 50:50 + 0.1% DEA Flow: 16 mL/min Temperature: RT Solution: 46 mg/0.6 mL MeOH Injektion: 2 0.3 mL Detection: MWD 254 nm Retention time in min purity in % Example 31 7.0-8.1 >99% Enantiomer 1 Example 32 10.0-11.3 >99% Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.83 (s, 1H), 7.74 (m, 3H), 7.49 (br, 1H), 7.40 (m, 1H), 7.17 (m, 2H), 6.94 (m, 1H), 4.30 (m, 4H), 2.94 (s, 3H), 2.88 (tr, 2H), 2.69 (s, 1H), 2.10 (m, 2H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.83 (s, 1H), 7.74 (m, 3H), 7.49 (br, 1H), 7.40 (m, 1H), 7.17 (m, 2H), 6.94 (m, 1H), 4.30 (m, 4H), 2.94 (s, 3H), 2.88 (tr, 2H), 2.69 (s, 1H), 2.10 (m, 2H).

Example 33

(rac)-Ethyl [(3-{[4-(2,3-dihydro-1-benzofuran-7-yl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]carbamate

(156) ##STR00101##

(157) Example 33 was prepared under similar conditions as described in the preparation of Example 1 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and (2,3-dihydro-1-benzofuran-7-yl)boronic acid (ChemBridge Corporation). The batch was purified by preparative HPLC.

(158) TABLE-US-00021 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(159) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.85 (s, 1H), 8.10 (m, 1H), 7.96 (s, 1H), 7.75 (m, 1H), 7.42 (m, 3H), 7.18 (m, 1H), 6.98 (m, 1H), 4.80 (tr, 2H), 4.76 (s, 2H), 4.17 (q, 2H), 3.29 (tr, 2H), 3.01 (s, 3H), 1.31 (tr, 3H).

Example 34

(rac)-4-(2,3-Dihydro-1-benzofuran-7-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(160) ##STR00102##

(161) Example 34 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl[(3-{[4-(2,3-dihydro-1-benzofuran-7-yl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate. After aqueous work up no further purification was necessary.

(162) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.85 (s, 1H), 8.11 (m, 1H), 7.87 (s, 1H), 7.76 (br, 1H), 7.44 (m, 2H), 7.39 (m, 1H), 7.17 (m, 1H), 6.98 (m, 1H), 4.81 (tr, 2H), 4.40 (d, 1H), 4.30 (d, 1H), 3.29 (tr, 2H), 2.95 (s, 3H), 2.72 (s, 1H).

Example 35 and 36

Enantiomers of 4-(2,3-dihydro-1-benzofuran-7-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(163) (rac)-4-(2,3-Dihydro-1-benzofuran-7-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC.

(164) TABLE-US-00022 System: Agilent: Prep 1200, 2 x Prep Pump, DLA, MWD, Prep FC Column: Chiralpak IA 5 m 250 20 mm Solvent: Ethanol/Methanol 50:50 + 0.1% DEA Flow: 15 mL/min Temperature: RT Solution: 74 mg/0.9 mL DMSO Injektion: 3 0.3 mL Detection: MWD 254 nm Retention time in min purity in % Example 35 9.1-10.5 >97% Enantiomer 1 Example 36 10.8-15.8 >95% Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.85 (s, 1H), 8.11 (m, 1H), 7.87 (s, 1H), 7.76 (br, 1H), 7.44 (m, 2H), 7.39 (m, 1H), 7.17 (m, 1H), 6.98 (m, 1H), 4.81 (tr, 2H), 4.40 (d, 1H), 4.30 (d, 1H), 3.29 (tr, 2H), 2.95 (s, 3H), 2.72 (s, 1H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.85 (s, 1H), 8.11 (m, 1H), 7.87 (s, 1H), 7.76 (br, 1H), 7.44 (m, 2H), 7.39 (m, 1H), 7.17 (m, 1H), 6.98 (m, 1H), 4.81 (tr, 2H), 4.40 (d, 1H), 4.30 (d, 1H), 3.29 (tr, 2H), 2.95 (s, 3H), 2.72 (s, 1H).

Example 37

(rac)-Ethyl [(3-{[4-(2,3-dihydro-1,4-benzodioxin-5-yl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)-oxido-6-sulfanylidene]carbamate

(165) ##STR00103##

(166) Example 37 was prepared under similar conditions as described in the preparation of Example 1 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and 2,3-dihydro-1,4-benzodioxin-5-ylboronic acid (Combi Blocks Inc.). The batch was purified by column chromatography (DCM/EtOH 95:5).

(167) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.85 (s, 1H), 7.87 (s, 1H), 7.71 (m, 1H), 7.48 (m, 2H), 7.42 (m, 1H), 7.17 (m, 1H), 7.04 (m, 1H), 6.95 (m, 1H), 4.74 (m, 2H), 4.37 (m, 4H), 4.17 (q, 2H), 3.00 (s, 3H), 1.31 (tr, 3H).

Example 38

(rac)-4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(168) ##STR00104##

(169) Example 38 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl[(3-{[4-(2,3-dihydro-1,4-benzodioxin-5-yl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate. After aqueous work up no further purification was necessary.

(170) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 7.75 (m, 2H), 7.56 (s, 1H), 7.49 (m, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 7.04 (m, 1H), 6.94 (m, 1H), 4.38 (m, 5H), 4.26 (d, 1H), 2.95 (s, 3H), 2.72 (s, 1H).

Example 39 and 40

(171) Enantiomers of 4-(2,3-dihydro-1,4-benzodioxin-5-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine(rac)-4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC.

(172) TABLE-US-00023 System: Agilent: Prep 1200, 2 Prep Pump, DLA, MWD, Prep FC Column: Chiralcel OJ-H 5 m 250 20 mm Solvent: Ethanol/methanol 50:50 + 0.1% DEA Flow: 16 mL/min Temperature: RT Solution: 140 mg/1.5 mL MeOH Injektion: 5 0.3 mL Detection: MWD 254 nm Retention time in min purity in % Example 39 7.5-9.0 >99% Enantiomer 1 Example 40 9.4-11.3 >98% Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.84 (s, 1H), 7.75 (m, 2H), 7.56 (s, 1H), 7.49 (m, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 7.04 (m, 1H), 6.94 (m, 1H), 4.38 (m, 5H), 4.26 (d, 1H), 2.95 (s, 3H), 2.72 (s, 1H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.84 (s, 1H), 7.75 (m, 2H), 7.56 (s, 1H), 7.49 (m, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 7.04 (m, 1H), 6.94 (m, 1H), 4.38 (m, 5H), 4.26 (d, 1H), 2.95 (s, 3H), 2.72 (s, 1H).

Example 41

(rac)-N-{3-[(N,S-Dimethylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine

(173) ##STR00105##

(174) Formaldehyde (17.9 l; 0.65 mmol) was added to a solution of (rac)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.13 mmol) in formic acid (1.0 ml) at room temperature. The batch was stirred at 80 C. for 24 hours. After cooling the batch was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate (2). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (5 mg; 0.01 mmol).

(175) TABLE-US-00024 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% NH.sub.3 B = MeOH Gradient: 0-1 min 15% B, 1-8 min 15-60% B, 8-8.1 min 60-100% B, 8.1-10 min 100% B Flow: 50 mL/min Temperature: RT Solution: 59 mg/4.5 mL DMSO Injektion: 9 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 5.6-5.8 min

(176) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.94 (m, 1H), 7.71 (m, 2H), 7.58 (m, 1H), 7.40 (m, 1H), 7.13 (m, 1H), 6.75 (m, 2H), 4.33 (s, 2H), 3.93 (s, 3H), 2.86 (s, 3H), 2.74 (s, 3H).

Example 42

(rac)-Ethyl [{3-[(4-{2-[(4-fluorobenzyl)oxy]phenyl}-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-6-sulfanylidene]carbamate

(177) ##STR00106##

(178) A batch with crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate (400 mg), {2-[(4-fluorobenzyl)oxy]phenyl}boronic acid (266 mg; 1.08 mmol; Aldrich Chemical Company Inc.) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (132 mg; 0.16 mmol) in 1,2-dimethoxyethane (2.5 mL) and 2M solution of potassium carbonate (1.1 mL) was degassed using argon. The batch was stirred under argon for 90 minutes at 100 C. After cooling the batch was diluted with DCM. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM/ethanol 95:5) to give the desired product (134 mg; 0.25 mmol).

(179) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 7.86 (m, 2H), 7.62 (m, 1H), 7.42 (m, 5H), 7.12 (m, 3H), 7.09 (m, 2H), 5.16 (s, 2H), 4.67 (s, 2H), 4.16 (q, 2H), 2.95 (s, 3H), 1.30 (tr, 3H).

Example 43

(rac)-4-{2-[(4-Fluorobenzyl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(180) ##STR00107##

(181) Example 43 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl[{3-[(4-{2-[(4-fluorobenzyl)oxy]phenyl}-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate. After aqueous work up no further purification was necessary.

(182) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.83 (s, 1H), 7.87 (m, 1H), 7.76 (s, 1H), 7.68 (m, 1H), 7.42 (m, 5H), 7.04 (m, 5H), 5.16 (s, 2H), 4.34 (d, 1H), 4.22 (d, 1H), 2.92 (s, 3H), 2.70 (s, 1H).

Example 44

(rac)-N-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]methanesulfonamide

(183) ##STR00108##

(184) Methanesulfonyl chloride (12.0 l; 0.16 mmol) was added to a solution of (rac)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine (50.0 mg; 0.13 mmol), triethylamine (21.6 l; 0.16 mmol) and 4-dimethylaminopyridine (1.6 mg; 0.01 mmol) in DCM (2.0 ml) at room temperature. The batch was stirred for 23 hours before additional methanesulfonyl chloride (8.0 l; 0.10 mmol) was added. After 23 hours additional methanesulfonyl chloride (8.0 l; 0.10 mmol) was added. After 24 hours additional methanesulfonyl chloride (12.0 l; 0.16 mmol) was added. Finally, after 48 hours additional methanesulfonyl chloride (20.0 l; 0.26 mmol) was added and the batch was stirred for 2 additional hours. The batch was diluted with aqueous water and extracted with DCM (2). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (21 mg; 0.05 mmol).

(185) TABLE-US-00025 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(186) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.94 (m, 1H), 7.82 (m, 3H), 7.43 (m, 1H), 7.21 (m, 1H), 6.76 (m, 2H), 4.74 (s, 2H), 3.92 (s, 3H), 3.14 (s, 3H), 3.06 (s, 3H).

Example 45

(rac)-Ethyl [(3-{[4-(3-chloro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]carbamate

(187) ##STR00109##

(188) Example 45 was prepared under similar conditions as described in the preparation of Example 42 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and (3-chloro-2-methoxyphenyl)boronic acid (Aalen Chemical Co., Ltd.). The batch was purified by preparative HPLC.

(189) TABLE-US-00026 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(190) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.85 (s, 1H), 7.97 (s, 1H), 7.81 (m, 1H), 7.58 (m, 3H), 7.43 (m, 1H), 7.18 (m, 2H), 4.75 (m, 2H), 4.17 (q, 2H), 3.87 (s, 3H), 3.02 (s, 3H), 1.30 (tr, 3H).

Example 46

(rac)-Ethyl {[3-({4-[5-fluoro-2-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-1,3,5-triazin-2-yl}-amino)benzyl](methyl)oxido-6-sulfanylidene}carbamate

(191) ##STR00110##

(192) Example 46 was prepared under similar conditions as described in the preparation of Example 42 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]-carbamate and [5-fluoro-2-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]boronic acid (FCH Group Company). The batch was purified by preparative HPLC.

(193) TABLE-US-00027 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(194) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.83 (s, 1H), 7.89 (br, 1H), 7.70 (m, 3H), 7.43 (m, 1H), 7.15 (m, 2H), 6.93 (m, 1H), 4.74 (m, 2H), 4.18 (q, 2H), 3.96 (m, 4H), 3.41 (m, 2H), 3.01 (s, 3H), 2.02 (br, 1H), 1.64 (m, 4H). 1.31 (tr, 3H).

Example 47

(rac)-Ethyl [methyl(oxido)(3-{[4-(2-phenoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)-6-sulfanylidene]carbamate

(195) ##STR00111##

(196) Example 47 was prepared under similar conditions as described in the preparation of Example 42 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]-carbamate and (2-phenoxyphenyl)boronic acid (ABCR GmbH & CO. KG). The batch was purified by preparative HPLC.

(197) TABLE-US-00028 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(198) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.35 (s, 1H), 8.72 (s, 1H), 7.89 (m, 2H), 7.65 (br, 1H), 7.52 (m, 1H), 7.26 (m, 4H), 7.03 (m, 3H), 6.89 (m, 2H), 4.78 (s, 2H), 3.93 (q, 2H), 3.12 (s, 3H), 1.09 (tr, 3H).

Example 48

(rac)-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]cyanamide

(199) ##STR00112##
Preparation of Intermediate 48.1:

4-Chloro-N-{3-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine

(200) ##STR00113##

(201) Intermediate 48.1 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using 3-[(methylsulfanyl)methyl]aniline (UkrOrgSynthesis Ltd.).

(202) TABLE-US-00029 System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Column: Acquity UPLC BEH C18 1.7 50 2.1 mm Solvent: A2 = H.sub.2O + 0.2% NH.sub.3 B1 = Acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Temperatuer: 60 C. Injektion: 2.0 l Detection: DAD scan range 210-400 nm > Peaktable ELSD Method: MS ESI+, ESI Switch A2 + B1 = C:\MassLynx\Mass_160_1000_BasicReport.flp System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Retention 1.13 min MS(ES): m/z = 268 [M + H]
Preparation of Intermediate 48.2:

4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine

(203) ##STR00114##

(204) Intermediate 48.2 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by column chromatography (DCM/EtOH 95:5) to give the desired product.

(205) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.97 (br, 1H), 7.83 (m, 2H), 7.50 (s, 1H), 7.31 (m, 1H), 7.07 (m, 1H), 6.77 (m, 2H), 3.93 (s, 3H), 3.69 (s, 2H), 2.02 (s, 3H).

(206) Preparation of Intermediate 48.3:

(rac)-[(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)-6-sulfanylidene]cyanamide

(207) ##STR00115##

(208) 2-Bromo-1H-isoindole-1,3(2H)-dione (150 mg; 0.84 mmol) was added to a solution of 4-(4-fluoro-2-methoxyphenyl)-N-{3-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine (200 mg; 0.56 mmol), cyanamide (31 mg; 0.73 mmol) and potassium 2-methylpropan-2-olate (76 mg; 0.67 mmol) in methanol (3.0 ml) at room temperature. The batch was stirred for 2 hours before it was diluted with aqueous sodium thiosulfate solution and extracted with DCM (2). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product.

(209) TABLE-US-00030 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(210) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.94 (m, 2H), 7.76 (m, 2H), 7.40 (m, 1H), 7.08 (m, 1H), 6.77 (m, 2H), 4.41 (d, 1H), 4.20 (d, 1H), 3.92 (s, 3H), 2.74 (s, 3H).

(211) Preparation of End Product:

(212) Potassium carbonate (84 mg; 0.61 mmol) and 3-chlorobenzenecarboperoxoic acid (75 mg; 0.30 mmol) were added to a stirred solution of (rac)-[(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)-.sup.6-sulfanylidene]cyanamide (80 mg; 0.20 mmol) in ethanol (2.0 ml) at 0 C. The ice bath was removed and the batch was slowly warmed to room temperature. The batch was stirred for 22 hours at room temperature. The batch was diluted with aqueous sodium chloride solution and extracted with ethyl acetate (2) and DCM (1). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (10 mg; 0.03 mmol).

(213) TABLE-US-00031 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IA 5 m 250 30 mm Solvent: Methanol + 0.1% diethylamine Flow: 40 mL/min Temperature: RT Solution: 55 mg/2 mL DMSO/MeOH 1:1 Injektion: 4 0.5 mL Detection: UV 280 nm Retention: 8.0-10.3 min

(214) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 7.93 (m, 2H), 7.76 (m, 1H), 7.48 (m, 2H), 7.19 (m, 1H), 6.79 (m, 2H), 4.63 (m, 2H), 3.94 (s, 3H), 3.04 (s, 3H).

Example 49 and 50

Enantiomers of [(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]cyanamide

(215) (rac)-[(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]cyanamide was separated into the enantiomers by preparative HPLC:

(216) TABLE-US-00032 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IA 5 m 250 20 mm Solvent: Ethanol 100 (v/v) Flow: 20 mL/min Temperature: RT Solution: 48 mg/1.2 mL DCM/MeOH 1:1 Injektion: 2 0.6 mL Detection: UV 254 nm Retention time in min purity in % Example 49 5.9 >99 Enantiomer 1 Example 50 9.5 >99 Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.84 (s, 1H), 7.93 (m, 2H), 7.76 (m, 1H), 7.48 (m, 2H), 7.19 (m, 1H), 6.79 (m, 2H), 4.63 (m, 2H), 3.94 (s, 3H), 3.04 (s, 3H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.84 (s, 1H), 7.93 (m, 2H), 7.76 (m, 1H), 7.48 (m, 2H), 7.19 (m, 1H), 6.79 (m, 2H), 4.63 (m, 2H), 3.94 (s, 3H), 3.04 (s, 3H).

Example 51

(rac)-Ethyl [(3-fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)-oxido-6-sulfanylidene]carbamate

(217) ##STR00116##
Preparation of Intermediate 51.1:

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

(218) ##STR00117##

(219) Intermediate 51.1 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).

(220) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.00 (m, 1H), 7.82 (m, 1H), 7.44 (m, 1H), 3.74 (s, 2H), 2.03 (s, 3H).

(221) Preparation of Intermediate 51.2:

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

(222) ##STR00118##

(223) Intermediate 51.2 was prepared under similar conditions as described in the preparation of Intermediate 1.2 using 1-fluoro-3-[(methylsulfanyl)methyl]-5-nitrobenzene.

(224) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =8.06 (m, 2H), 7.63 (m, 1H), 4.32 (d, 1H), 4.08 (d, 1H), 2.45 (s, 3H).

(225) Preparation of Intermediate 51.3:

(rac)-2,2,2-trifluoro-N-[(3-fluoro-5-nitrobenzyl)(methyl)oxido-6-sulfanylidene]acetamide

(226) ##STR00119##

(227) Intermediate 51.3 was prepared under similar conditions as described in the preparation of Intermediate 1.3 using (rac)-1-fluoro-3-[(methylsulfinyl)methyl]-5-nitrobenzene.

(228) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.13 (m, 1H) 8.07 (m, 1H), 7.56 (m, 1H), 4.92 (d, 1H), 4.76 (d, 1H), 3.33 (s, 3H).

(229) Preparation of Intermediate 51.4:

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

(230) ##STR00120##

(231) Intermediate 51.4 was prepared under similar conditions as described in the preparation of Intermediate 1.4 using (rac)-2,2,2-trifluoro-N-[(3-fluoro-5-nitrobenzyl)(methyl)oxido-.sup.6-sulfanylidene]acetamide.

(232) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.19 (m, 1H), 8.08 (m, 1H), 7.76 (m, 1H), 4.60 (d, 1H), 4.49 (d, 1H), 3.85 (s, 1H), 2.79 (s, 3H).

(233) Preparation of Intermediate 51.5:

(rac)-Ethyl [(3-fluoro-5-nitrobenzyl)(methyl)oxido-6-sulfanylidene]carbamate

(234) ##STR00121##

(235) Intermediate 51.5 was prepared under similar conditions as described in the preparation of Intermediate 1.5 using (rac)-1-fluoro-3-[(S-methylsulfonimidoyl)methyl]-5-nitrobenzene.

(236) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.11 (m, 1H), 8.02 (m, 1H), 7.57 (m, 1H), 4.90 (d, 1H), 4.759 (d, 1H), 4.18 (q, 2H), 3.12 (s, 3H), 1.31 (tr, 3H).

(237) Preparation of Intermediate 51.6:

(rac)-Ethyl [(3-amino-5-fluorobenzyl)(methyl)oxido-6-sulfanylidene]carbamate

(238) ##STR00122##

(239) Intermediate 51.6 was prepared under similar conditions as described in the preparation of Intermediate 1.6 using (rac)-ethyl [(3-fluoro-5-nitrobenzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate.

(240) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =6.49 (m, 3H), 4.58 (m, 2H), 4.17 (q, 2H), 3.91 (s, 2H), 3.00 (s, 3H), 1.31 (tr, 3H).

(241) Preparation of Intermediate 51.7:

(rac)-Ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]-5-fluorobenzyl}(methyl)oxido-6-sulfanylidene]carbamate

(242) ##STR00123##

(243) Intermediate 51.7 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using (rac)-ethyl [(3-amino-5-fluorobenzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate.

(244) TABLE-US-00033 System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Column: Acquity UPLC BEH C18 1.7 50 2.1 mm Solvent: A1 = H.sub.2O + 0.1% HCOOH B1 = Acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Temperatuer: 60 C. Injektion: 2.0 l Detection: DAD scan range 210-400 nm -> Peaktable ELSD Method: MS ESI+, ESI Switch A1 + B1 = C:\MassLynx\NH3_Mass_100_1000.olp Retention: 0.94 min MS(ES+): m/z = 388 [M + H]
Preparation of End Product:

(245) Example 51 was prepared under similar conditions as described in the preparation of Example 42 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]-5-fluorobenzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by preparative HPLC.

(246) TABLE-US-00034 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H2O + 0.1% HCOOH B = Acetonitril Gradient: 0-1 min 30% B, 1-8 min 30-70% B Flow: 50 mL/min Temperature: RT Solution: 664 mg/7 mL acetone Injektion: 7 1 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 1.12 min

(247) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.65 (s, 1H), 8.86 (s, 1H), 8.32 (br, 1H), 8.00 (br, 1H), 7.48 (br, 1H), 7.12 (m, 1H), 6.98 (m, 1H), 6.92 (m, 1H), 4.87 (m, 2H), 3.98 (m, 2H), 3.92 (s, 3H), 3.22 (s, 3H), 1.15 (tr, 3H).

Example 52

(rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(248) ##STR00124##

(249) Example 52 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl[(3-fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate.

(250) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.79 (s, 1H), 8.10 (br, 2H), 7.92 (br, 1H), 7.20 (br, 1H), 6.85 (m, 1H), 6.76 (m, 2H), 4.36 (d, 1H), 4.22 (s, 1H), 3.95 (s, 3H), 3.01 (s, 3H).

Example 53 and 54

Enantiomers of 4-(4-Fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(251) (rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC:

(252) TABLE-US-00035 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IC 5 m 250 30 mm Solvent: Hexane/ethanol 70:30 (v/v) Flow: 40 mL/min Temperature: RT Solution 1860 mg/10.8 mL THF/DMSO 9:1 Injection 36 0.3 mL Detection: UV 280 nm Retention time in min purity in % Example 53 13.7-15.4 99.8 Enantiomer 1 Example 54 15.4-17.2 95.4 Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.79 (s, 1H), 8.10 (br, 2H), 7.92 (br, 1H), 7.20 (br, 1H), 6.85 (m, 1H), 6.76 (m, 2H), 4.36 (d, 1H), 4.22 (s, 1H), 3.95 (s, 3H), 3.01 (s, 3H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.79 (s, 1H), 8.10 (br, 2H), 7.92 (br, 1H), 7.20 (br, 1H), 6.85 (m, 1H), 6.76 (m, 2H), 4.36 (d, 1H), 4.22 (s, 1H), 3.95 (s, 3H), 3.01 (s, 3H).

Example 55

(rac)-4-[2-(Cyclohexylmethoxy)-4-fluorophenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(253) ##STR00125##
Preparation of Intermediate 55.1:

(rac)-Ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]carbamate

(254) ##STR00126##

(255) Intermediate 55.1 was prepared under similar conditions as described in the preparation of Example 42 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]-5-fluorobenzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and (2,4-difluorophenyl)boronic acid (Aldrich Chemical Company Inc.). The batch was purified by column chromatography (DCM/EtOH 95:5).

(256) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 8.31 (m, 1H), 8.05 (br, 1H), 7.61 (m, 1H), 7.45 (m, 2H), 7.21 (m, 1H), 7.00 (m, 2H), 4.76 (dd, 2H), 4.17 (q, 2H), 3.02 (s, 3H), 1.31 (tr, 3H).

(257) Preparation of End Product:

(258) Sodium hydride (60%; 3.2 mg; 0.08 mmol) was added under stirring to a solution of (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (30.0 mg; 0.07 mmol) in cyclohexylmethanol (0.5 ml) at room temperature. The batch was stirred under argon at 50 C. for 2 hours before additional sodium hydride (60%; 2.7 mg; 0.07 mmol) was added. After 20 hours additional sodium hydride (60%; 2.7 mg; 0.07 mmol) was added and the batch was stirred for further 5 hours. After cooling, the batch was diluted with ethyl acetate and diluted sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The desired product (10 mg; 0.02 mmol) was isolated by preparative HPLC.

(259) TABLE-US-00036 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(260) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.83 (s, 1H), 7.88 (m, 1H), 7.84 (br, 1H), 7.72 (br, 1H), 7.44 (m, 1H), 7.36 (s, 1H), 7.19 (m, 1H), 6.77 (m, 2H), 4.43 (d, 1H), 4.28 (d, 1H), 3.85 (d, 2H), 2.98 (s, 3H), 2.73 (br, 1H), 1.78 (m, 6H), 1.15 (m, 5H).

Example 56

(rac)-4-{4-Fluoro-2-[(4-fluorobenzyl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(261) ##STR00127##

(262) Example 56. was prepared under similar conditions as described in the preparation of Example 55 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (4-fluorophenyl)methanol.

(263) TABLE-US-00037 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Methanol Gradient: 0-1 min 50% B, 1-8 min 50-90% B, 8-8.1 min 90-100% B, 8.1-10 min 100% B Flow: 50 mL/min Temperature: RT Solution: 620 mg/4.5 mL DMSO Injektion: 9 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 5.0-5.6 min

(264) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.95 (m, 1H), 7.75 (br, 1H), 7.68 (m, 1H), 7.38 (m, 4H), 7.13 (m, 1H), 7.01 (m, 2H), 6.80 (m, 2H), 5.15 (s, 2H), 4.36 (d, 1H), 4.22 (d, 1H), 2.93 (s, 3H), 2.68 (br, 1H).

Example 56.a and 56.b

(265) Enantiomers of 4-{4-fluoro-2-[(4-fluorobenzyl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine(rac)-4-{4-Fluoro-2-[(4-fluorobenzyl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC:

(266) TABLE-US-00038 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IA 5 m 250 30 mm Solvent: Ethanol/methanol 50:50 (v/v) Flow: 30 mL/min Temperature: RT Solution: 190 mg/3 mL EtOH/MeOH Injektion: 2 1.5 mL Detection: UV 280 nm Retention time in min purity in % Example 56.a 17.2-23.5 >99.9 Enantiomer 1 Example 56.b 35.8-52.5 99.3 Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.81 (s, 1H), 7.95 (m, 1H), 7.75 (br, 1H), 7.68 (m, 1H), 7.38 (m, 4H), 7.13 (m, 1H), 7.01 (m, 2H), 6.80 (m, 2H), 5.15 (s, 2H), 4.36 (d, 1H), 4.22 (d, 1H), 2.93 (s, 3H), 2.68 (br, 1H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.81 (s, 1H), 7.95 (m, 1H), 7.75 (br, 1H), 7.68 (m, 1H), 7.38 (m, 4H), 7.13 (m, 1H), 7.01 (m, 2H), 6.80 (m, 2H), 5.15 (s, 2H), 4.36 (d, 1H), 4.22 (d, 1H), 2.93 (s, 3H), 2.68 (br, 1H).

Example 57

(rac)-4-{4-Fluoro-2-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)-methyl]phenyl}-1,3,5-triazin-2-amine

(267) ##STR00128##

(268) Example 57. was prepared under similar conditions as described in the preparation of Example 55 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and 2-(tetrahydro-2H-pyran-4-yl)ethanol.

(269) TABLE-US-00039 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Methanol Gradient: 0-1 min 50% B, 1-8 min 50-90% B, 8-8.1 min 90-100% B, 8.1-10 min 100% B Flow: 50 mL/min Temperature: RT Solution: 603 mg/4.5 mL DMSO Injektion: 9 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 3.8-4.2 min

(270) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.78 (m, 3H), 7.49 (s, 1H), 7.42 (m, 1H), 7.16 (m, 1H), 6.76 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 4.10 (tr, 2H), 3.91 (m, 2H), 3.32 (m, 2H), 2.95 (s, 3H), 2.71 (br, 1H), 1.75 (m, 3H), 1.33 (m, 4H).

Example 58

(rac)-4-(4-Fluoro-2-methoxyphenyl)-N-(3-{[S-(tetrahydro-2H-pyran-4-yl)sulfonimidoyl]methyl}-phenyl)-1,3,5-triazin-2-amine

(271) ##STR00129##
Preparation of Intermediate 58.1:

(rac)-4-Chloro-N-{3-[(tetrahydro-2H-pyran-4-ylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine

(272) ##STR00130##

(273) Intermediate 58.1 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using (rac)-3-[(tetrahydro-2H-pyran-4-ylsulfinyl)methyl]aniline (UkrOrgSynthesis Ltd.).

(274) TABLE-US-00040 System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Column: Acquity UPLC BEH C18 1.7 50 2.1 mm Solvent: A2 = H.sub.2O + 0.2% NH.sub.3 B1 = Acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Temperatuer: 60 C. Injektion: 2.0 l Detection: DAD scan range 210-400 nm > Peaktable ELSD Method: MS ESI+, ESI Switch A2 + B1 = C:\MassLynx\NH3_Mass_100_1000.olp Retention 0.81 min MS(ES): m/z = 351 [M H]
Preparation of Intermediate 58.2:

(rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(tetrahydro-2H-pyran-4-ylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine

(275) ##STR00131##

(276) Intermediate 58.2 was prepared under similar conditions as described in the preparation of Example 42 using crude (rac)-4-chloro-N-{3-[(tetrahydro-2H-pyran-4-ylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by column chromatography (DCM/EtOH 95:5) to give the desired product.

(277) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.96 (m, 1H), 7.70 (m, 2H), 7.40 (m, 2H), 7.06 (m, 1H), 6.78 (m, 2H), 4.03 (m, 7H), 3.39 (m, 2H), 2.73 (m, 1H), 1.83 (m, 4H).

(278) Preparation and End Product

(279) Example 58 was prepared under similar conditions as described in the alternative preparation of Example 2 using (rac)-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(tetrahydro-2H-pyran-4-ylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine, sodium azide, sulfuric acid and trichloromethane.

(280) TABLE-US-00041 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% Vol. HCOOH (99%) B = Acetonitrile Gradient: 0-1 min 10% B, 1-8 min 10-45% B Flow: 50 mL/min Temperature: RT Solution: 200 mg/2 mL DMSO Injektion: 2 1 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 6.5-6.9 min

(281) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.97 (br, 1H), 7.76 (m, 2H), 7.53 (s, 1H), 7.41 (m, 1H), 7.16 (m, 1H), 6.77 (m, 2H), 4.31 (d, 1H), 4.09 (m, 3H), 3.93 (s, 3H), 3.36 (m, 2H), 3.15 (m, 1H), 2.61 (s, 1H), 2.01 (m, 4H).

Example 59

(rac)-N-{4-Chloro-3-[(S-methylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine

(282) ##STR00132##
Preparation of Intermediate 59.1:

(rac)-4-Chloro-N-{4-chloro-3-[(methylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine

(283) ##STR00133##

(284) Intermediate 59.1 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using (rac)-4-chloro-3-[(methylsulfinyl)methyl]aniline (UkrOrgSynthesis Ltd.).

(285) TABLE-US-00042 System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Column: Acquity UPLC BEH C18 1.7 50 2.1 mm Solvent: A2 = H.sub.2O + 0.2% NH.sub.3 B1 = Acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Temperatuer: 60 C. Injektion: 2.0 l Detection: DAD scan range 210-400 nm > Peaktable ELSD Method: MS ESI+, ESI Switch A2 + B1 = C:\MassLynx\NH3_Mass_100_1000.olp System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001 Retention 0.85 min MS(ES): m/z = 317 [M + H]
Preparation of Intermediate 59.2:

(rac)-N-{4-Chloro-3-[(methylsulfinyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine

(286) ##STR00134##

(287) Intermediate 59.2 was prepared under similar conditions as described in the preparation of Example 42 using crude (rac)-4-chloro-N-{4-chloro-3-[(methylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by column chromatography (DCM/EtOH 95:5) to give the desired product.

(288) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.85 (m, 3H), 7.64 (m, 1H), 7.39 (m, 1H), 6.76 (m, 2H), 4.19 (d, 1H), 4.13 (d, 1H), 3.93 (s, 3H), 2.57 (s, 3H),

(289) Preparation of End Product

(290) Example 59 was prepared under similar conditions as described in the alternative preparation of Example 2 using ((rac)-N-{4-chloro-3-[(methylsulfinyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine, sodium azide, sulfuric acid and trichloromethane.

(291) TABLE-US-00043 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% Vol. NH.sub.3 (32%) B = Acetonitrile Gradient: 0-1 min 15% B, 1-8 min 15-60% B Flow: 50 mL/min Temperature: RT Solution: 55 mg/1 mL DMSO/MeOH 1:1 Injektion: 1 1 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 6.2-6.5 min

(292) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.87 (m, 3H), 7.57 (s, 1H), 7.42 (m, 1H), 6.78 (m, 2H), 4.60 (d, 1H), 4.51 (d, 1H), 3.93 (s, 3H), 2.97 (s, 3H), 2.84 (s, 1H).

Example 59.a and 59.b

(293) Enantiomers of N-{4-Chloro-3-[(S-methylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine(rac)-N-{4-Chloro-3-[(S-methylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC:

(294) TABLE-US-00044 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IA 5 m 250 20 mm Solvent: Methanol 100 (v/v) Flow: 20 mL/min Temperature: RT Solution: 14 mg/1 mL DCM/MeOH 1:1 Injektion: 2 0.5 mL Detection: UV 280 nm Retention time in min purity in % Example 59.a 5.3 98.7 Enantiomer 1 Example 59.b 7.3 96.8 Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.80 (s, 1H), 7.87 (m, 3H), 7.57 (s, 1H), 7.42 (m, 1H), 6.78 (m, 2H), 4.60 (d, 1H), 4.51 (d, 1H), 3.93 (s, 3H), 2.97 (s, 3H), 2.84 (s, 1H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.80 (s, 1H), 7.87 (m, 3H), 7.57 (s, 1H), 7.42 (m, 1H), 6.78 (m, 2H), 4.60 (d, 1H), 4.51 (d, 1H), 3.93 (s, 3H), 2.97 (s, 3H), 2.84 (s, 1H).

Example 60

(rac)-Ethyl [{3-[(4-{2-[(3,4-dichlorobenzyl)oxy]phenyl}-1,3,5-triazin-2-yl)amino]benzyl}(methyl)-oxido-6-sulfanylidene]carbamate

(295) ##STR00135##

(296) Example 60 was prepared under similar conditions as described in the preparation of Example 42 using crude (rac)-ethyl [{3-[(4-chloro-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate and {2-[(3,4-dichlorobenzyl)oxy]phenyl}boronic acid (Combi Blocks Inc.). The batch was purified by preparative HPLC.

(297) TABLE-US-00045 System: Agilent: Prep 1200, 2 Prep Pump, DLA, MWD, ELSD, Prep FC Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% NH.sub.3 B = Acetonitrile Gradient: 0-17.5 min 40-80% B; 17.5-20 min 80-100% B Flow: 38 mL/min Temperature: RT Solution: 120 mg/1.6 mL DMSO/ACN 1:1 Injektion: 2 0.8 mL Detection: MWD 210 nm Retention: 12.2-13.3 min

(298) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.87 (s, 1H), 7.91 (m, 1H), 7.85 (s, 1H), 7.66 (m, 2H), 7.46 (m, 2H), 7.38 (m, 2H), 7.22 (m, 1H), 7.15 (m, 2H), 7.06 (m, 1H), 5.15 (s, 2H), 4.70 (s, 2H), 4.16 (q, 2H), 2.97 (s, 3H), 1.30 (tr, 3H).

Example 61

(rac)-4-{2-[(3,4-Dichlorobenzyl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(299) ##STR00136##

(300) Example 61 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl[{3-[(4-{2-[(3,4-dichlorobenzyl)oxy]phenyl}-1,3,5-triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6-sulfanylidene]carbamate. After aqueous work up no further purification was necessary.

(301) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.87 (s, 1H), 7.93 (m, 1H), 7.78 (s, 1H), 7.70 (m, 2H), 7.48 (m, 1H), 7.36 (m, 3H), 7.24 (m, 1H), 7.14 (m, 2H), 7.06 (m, 1H), 5.15 (s, 2H), 4.37 (d, 1H), 4.25 (d, 1H), 2.93 (s, 3H), 2.68 (s, 1H),

Example 62

(rac)-4-(4-Fluoro-2-{[(2H5)phenyl(2H2)methyl]oxy}phenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(302) ##STR00137##

(303) Example 62 was prepared under similar conditions as described in the preparation of Example 55 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (.sup.2H.sub.5)phenyl(.sup.2H.sub.2)methanol (Aldrich Chemical Company Inc). The batch was purified by preparative HPLC.

(304) TABLE-US-00046 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(305) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.94 (m, 1H), 7.68 (m, 3H), 7.32 (br, 1H), 7.11 (m, 1H), 6.79 (m, 2H), 4.33 (d, 1H), 4.21 (d, 1H), 2.92 (s, 3H).

Example 63

4-[2-(1-Cyclopentylethoxy)-4-fluorophenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine, mixture of all 4 stereoisomers

(306) ##STR00138##

(307) Example 63. was prepared under similar conditions as described in the preparation of Example 55 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (rac)-1-cyclopentylethanol (ChemSampCo, Inc.).

(308) TABLE-US-00047 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(309) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.78 (s, 1H), 7.76 (m, 3H), 7.54 (s, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 6.72 (m, 2H), 4.39 (d, 1H), 4.24 (m, 2H), 2.95 (s, 3H), 2.70 (br, 1H), 2.09 (m, 1H), 1.47 (m, 11H).

Example 64

(rac)-N-{3-Chloro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine

(310) ##STR00139##
Preparation of Intermediate 64.1:

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

(311) ##STR00140##

(312) A suspension of 3-bromomethyl-1-chloro-5-nitrobenzene (10.0 g) in ethanol (200 mL) at 20 C. was treated with sodiummethanethiolate (3.3 g) in 3 portions, during 3 hours the temperature was increased from 20 C. to room temperature. Then brine was added, extracted with ethyl acetate (3), the combined organic phases were washed with water to neutrality, dried with sodium sulfate, filtered and concentrated. The title compound (8.6 g) was thus obtained and used without further purification.

(313) Preparation of Intermediate 64.2:

1-Chloro-3-[(methylsulfinyl)methyl]-5-nitrobenzene

(314) ##STR00141##

(315) To a solution of 1-chloro-3-[(methylsulfanyl)methyl]-5-nitrobenzene (4.3 g) in methanol (340 mL) water (18.7 mL) and sodium periodat (4.4 g) was added and stirred for 24 hours at room temperature. Then the reaction mixture was concentrated under reduced pressure to 30% of the volume, diluted with water, extracted with ethyl acetate (3), washed with disodium sulfurothioate and brine, dried with sodium sulfate, filtered and concentrated. The title compound (4.5 g) was thus obtained and used without further purification.

(316) .sup.1H-NMR (600 MHz, CDCl.sub.3): 0=8.23 (t, 1H), 8.08 (t, 1H), 7.67 (t, 1H), 4.07 (d, 1H), 3.92 (d, 1H), 2.57 (s, 3H).

(317) Preparation of Intermediate 64.3:

3-Chloro-5-[(methylsulfinyl)methyl]aniline

(318) ##STR00142##

(319) A solution of 1-chloro-3-[(methylsulfinyl)methyl]-5-nitrobenzene (4.4 g) in methanol (40 mL) and water (11.6 mL) was treated with ammoniumchloride (5.1 g), cooled to 0 C., treated with portions of zinc powder (6.2 g) and stirred for 5 hours at room temperature. The reaction mixture was filtered over cellite, washed with THF/ethyl acetate, washed with brine, dried with sodium sulfate and condensed to dryness.

(320) Crystallization of the crude product (4.9 g) from diethyl ether furnished the pure title compound (3.4 g).

(321) .sup.1H-NMR (600 MHz, CDCl.sub.3): =6.63 (m, 2H), 6.49 (m, 1H), 3.90 (d, 1H), 3.80 (m, 3H), 2.48 (s, 3H).

(322) Preparation of Intermediate 64.4:

4-Chloro-N-{3-chloro-5-[(methylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine

(323) ##STR00143##

(324) A solution of 2,4-dichloro-triazine (250 mg) in THF (2.2 mL) and 2-propanol (2.2 mL) at 40 C. was treated with N,N-diisopropylethylamine (0.55 mL) and 3-chloro-5-[(methylsulfinyl)methyl]aniline (322.6 mg) an then stirred and gradually warmed from 40 C. to 0 C. for 3 hours. The reaction mixture was then concentrated in vacuo to give the crude title compound (934 mg) which was used without further purification.

(325) Preparation of Intermediate 64.5:

N-{3-Chloro-5-[(methylsulfinyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine

(326) ##STR00144##

(327) A solution of 4-chloro-N-{3-chloro-5-[(methylsulfinyl)methyl]phenyl}-1,3,5-triazin-2-amine (934 mg) in 1,2-dimethoxyethane (5.2 mL) and a 2 M solution of sodium carbonate (1.6 mL) is treated with 4-fluoro-2-methoxyphenylboronic acid (269 mg) and Pd(dppf)Cl.sub.2 (129 mg) and then heated for 3 hours at 100 C. The reaction mixture was then allowed to cool to room temperature, taken up in ethyl acetate (100 mL) and water (50 mL), washed with saturated brine, dried over sodium sulfate, and condensed in vacuo to give the crude product that was purified by flash column chromatography on SiO.sub.2 with DCM/acetone (5%-60%) to give analytically pure product (340 mg).

(328) .sup.1H-NMR (500 MHz, CDCl.sub.3): =8.83 (s, 1H), 8.18 (br. s., 1H), 7.99 (br. s., 1H), 7.33 (br. s., 1H), 7.64 (s, 1H), 7.02 (s, 1H), 6.78 (m, 2H), 3.96 (m, 5H), 2.53 (s, 3H).

(329) Preparation of End Product:

(330) To a solution of N-{3-chloro-5-[(methylsulfinyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine (75 mg) in chloroform (0.8 mL) sodiumazide (48.4 mg) was added and treated at 0 C. dropwise with conc. sulfuric acid (0.35 mL) and stirred for 48 hours in a sealed tube. Then the reaction mixture was poured into ice water, alkalized with sodium bicarbonate, extracted with ethyl acetate/THF (9:1), washed, dried over sodium sulfate and evaporated to dryness.

(331) The crude product was purified by flash column chromatography on SiO.sub.2 with DCM/ethanol (0%-5%) to give the desired product (42 mg).

(332) .sup.1H-NMR (600 MHz, CDCl.sub.3): =8.81 (s, 1H), 7.99 (m, 3H), 7.41 (br, 1H), 7.10 (m, 1H), 6.76 (m, 2H), 4.35 (d, 1H), 4.20 (d, 1H), 3.94 (s, 3H), 3.01 (s, 3H).

Example 65

(rac)-4-[4-Fluoro-2-(3,3,3-trifluoropropoxy)phenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(333) ##STR00145##

(334) Sodium hydride (60%; 26.8 mg; 0.67 mmol) was added under stirring to a solution of (rac)-ethyl[(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate (75.0 mg; 0.17 mmol) in 3,3,3-trifluoropropan-1-ol (0.5 ml; ABCR GmbH & CO. KG) at room temperature. The batch was stirred under argon at 70 C. for 19 hours. After UPLC MS check, additional sodium hydride (60%; 13.4 mg; 0.34 mmol) was added and the batch was stirred for additional 22 hours at 70 C. After cooling, the batch was diluted with ethyl acetate and saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The desired product (12 mg; 0.03 mmol) was isolated by preparative HPLC.

(335) TABLE-US-00048 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% Vol. HCOOH (99%) B = methanol Gradient: 0-1 min 20% B, 1-8 min 20-90% B Flow: 50 mL/min Temperature: RT Solution: 59 mg/2 mL DMSO/MeOH 1:1 Injektion: 1 2 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z Retention: 6.5-6.9 min

(336) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.78 (s, 1H), 7.88 (m, 1H), 7.71 (m, 3H), 7.39 (m, 1H), 7.15 (m, 1H), 6.82 (m, 1H), 6.73 (m, 1H), 4.39 (d, 1H), 4.25 (m, 3H), 2.96 (s, 3H), 2.60 (m, 3H),

Example 66

(rac)-4-[4-Fluoro-2-(pyridin-3-ylmethoxy)phenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(337) ##STR00146##

(338) Example 66 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and pyridin-3-ylmethanol (Aldrich Chemical Company Inc.). The desired product was isolated by preparative HPLC.

(339) TABLE-US-00049 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% Vol. NH.sub.3 (32%) B = Methanol Gradient: 0-1 min 30% B, 1-8 min 30-70% B Flow: 50 mL/min Temperature: RT Solution: 233 mg/2.3 mL DMSO/MeOH 1:1 Injektion: 3 0.75 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 6.3-6.7 min

(340) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 8.76 (br, 1H), 8.55 (m, 1H), 7.98 (m, 1H), 7.77 (m, 2H), 7.69 (m, 1H), 7.39 (m, 2H), 7.28 (m, 1H), 7.14 (m, 1H), 6.82 (m, 2H), 5.20 (s, 2H), 4.37 (d, 1H), 4.23 (d, 1H), 2.94 (s, 3H), 2.70 (br, 1H).

Example 67

(rac)-4-[4-Fluoro-2-(pyridin-2-ylmethoxy)phenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(341) ##STR00147##

(342) Example 67. was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and pyridin-2-ylmethanol (Aldrich Chemical Company Inc.). The desired product was isolated by preparative HPLC.

(343) TABLE-US-00050 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% Vol. NH.sub.3 (32%) B = Methanol Gradient: 0-1 min 30% B, 1-8 min 30-70% B Flow: 50 mL/min Temperature: RT Solution: 139 mg/1.5 mL DMSO/MeOH 1:1 Injektion: 2 0.75 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 6.7-7.0 min

(344) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.85 (s, 1H), 8.59 (m, 1H), 8.00 (m, 1H), 7.75 (m, 2H), 7.63 (m, 2H), 7.51 (br, 1H), 7.36 (m, 1H), 7.21 (m, 1H), 7.13 (m, 1H), 6.81 (m, 2H), 5.32 (s, 2H), 4.37 (d, 1H), 4.23 (d, 1H), 2.95 (s, 3H), 2.68 (s, 1H).

Example 68

(rac)-4-[4-Fluoro-2-(pyridin-4-ylmethoxy)phenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(345) ##STR00148##

(346) Example 68. was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and pyridin-4-ylmethanol (Aldrich Chemical Company Inc.). The desired product was isolated by preparative HPLC.

(347) TABLE-US-00051 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% Vol. NH.sub.3 (32%) B = Methanol Gradient: 0-1 min 30% B, 1-8 min 30-70% B Flow: 50 mL/min Temperature: RT Solution: 123 mg/1.5 mL DMSO/MeOH 1:1 Injektion: 2 0.75 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 6.5-6.8 min

(348) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.85 (s, 1H), 8.57 (br, 2H), 8.01 (m, 1H), 7.77 (br, 1H), 7.70 (br, 1H), 7.36 (m, 4H), 7.13 (m, 1H), 6.85 (m, 1H), 6.75 (m, 1H), 5.20 (s, 2H), 4.37 (d, 1H), 4.22 (d, 1H), 2.94 (s, 3H), 2.70 (br, 1H).

Example 69

4-{4-Fluoro-2-[1-(4-fluorophenyl)ethoxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine, mixture of 4 stereoisomers

(349) ##STR00149##

(350) Example 69 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (rac)-1-(4-fluorophenyl)ethanol (Aldrich Chemical Company Inc.). The desired product was isolated by preparative HPLC.

(351) TABLE-US-00052 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% NH.sub.3 B = Acetonitrile Gradient: 0-1 min 30% B, 1-8 min 30-70% B, 8-8.1 min 70-100% B, 8.1-10 min 100% B Flow: 50 mL/min Temperature: RT Solution: 187 mg/4 mL DMSO Injektion: 4 1 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 5.8-6.2 min

(352) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.83 (s, 1H), 7.78 (m, 3H), 7.48 (br, 1H), 7.34 (m, 3H), 7.15 (m, 1H), 6.99 (m, 2H), 6.73 (m, 1H), 6.58 (m, 1H), 5.32 (q, 1H), 4.38 (d, 1H), 4.25 (d, 1H), 2.95 (s, 3H), 1.59 (d, 3H).

Example 70

(rac)-[(3-Fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-6-sulfanylidene]cyanamide

(353) ##STR00150##
Preparation of Intermediate 70.1:

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

(354) ##STR00151##

(355) Intermediate 70.1 was prepared under similar conditions as described in the preparation of Intermediate 1.6 using 1-fluoro-3-[(methylsulfanyl)methyl]-5-nitrobenzene.

(356) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =6.42 (m, 2H), 6.26 (m, 1H), 3.74 (br, 2H), 3.55 (s, 2H), 2.01 (s, 3H).

(357) Preparation of Intermediate 70.2:

4-Chloro-N-{3-fluoro-5-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine

(358) ##STR00152##

(359) Intermediate 70.2 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using 3-fluoro-5-[(methylsulfanyl)methyl]aniline.

(360) TABLE-US-00053 System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, QD 3001 Column: Acquity UPLC BEH C18 1.7 50 2.1 mm Solvent: A2 = H.sub.2O + 0.2% NH.sub.3 B1 = Acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Temperatuer: 60 C. Injektion: 2.0 l Detection: DAD scan range 210-400 nm -> Peaktable ELSD Method: MS ESI+, ESI Switch A2 + B1 = C:\MassLynx\Mass_100_1000_BasicReport.flp Retention 1.20 min MS(ES): m/z = 285 [M + H]
Preparation of Intermediate 70.3:

4-(4-Fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine

(361) ##STR00153##

(362) Intermediate 70.3 was prepared under similar conditions as described in the preparation of Example 42 using crude 4-chloro-N-{3-fluoro-5-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by chromatography (hexane/ethyl acetate 6:4) and finally recrystallized from ethyl acetate to give the desired product.

(363) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.47 (s, 1H), 8.81 (s, 1H), 7.95 (br, 2H), 7.38 (br, 1H), 7.09 (m, 1H), 6.89 (m, 1H), 6.81 (m, 1H), 3.87 (s, 3H), 3.64 (s, 2H), 1.94 (s, 3H).

(364) Preparation of Intermediate 70.4:

(rac)-[(3-Fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl-4-sulfanylidene]cyanamide

(365) ##STR00154##

(366) A mixture of 4-(4-fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine (500 mg; 1.33 mmol), cyanamide (112 mg; 2.67 mmol) and bis(acetyloxy)(phenyl)-.sup.3-iodane (473 mg; 1.47 mmol) in DCM (7.5 ml) was stirred at a temperature between 0-5 C. for 3 hours. The batch was concentrated and the residue was purified by chromatography (DCM/EtOH 92:8) to give the desired product (494 mg; 1.19 mmol).

(367) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 8.06 (br, 2H), 7.79 (s, 1H), 7.24 (m, 1H), 6.80 (m, 3H), 4.40 (d, 1H), 4.15 (d, 1H), 3.98 (s, 3H), 2.80 (s, 3H).

(368) Preparation of End Product:

(369) At room temperature sodium metaperiodate (380 mg; 1.774 mmol) was dissolved in water (4.5 ml). DCM (6.0 ml) and ruthenium(III)chloride (2 mg; 0.009 mmol) were added under stirring. A suspension of (rac)-[(3-fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl-.sup.4-sulfanylidene]cyanamide (490 mg; 1.183 mmol) in DCM (8.0 ml) was added dropwise and the batch was stirred at room temperature. After 18 hours additional ruthenium(III)chloride (2 mg; 0.009 mmol) was added and the batch was stirred for 5 hours. Finally, further ruthenium(III)chloride (2 mg; 0.009 mmol) was added and the batch was stirred over night. The batch was filtered and the fitrate was extracted with DCM (3). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM/EtOH 9:1) to give the desired product (146 mg; 0.340 mmol).

(370) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.66 (s, 1H), 8.83 (s, 1H), 8.27 (br, 1H), 7.93 (br, 1H), 7.47 (br, 1H), 7.09 (m, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 4.99 (m, 2H), 3.87 (s, 3H), 3.38 (s, 3H).

Example 71 and 72

Enantiomers of (rac)-[(3-fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)-(methyl)oxido-6-sulfanylidene]cyanamide

(371) (rac)-[(3-Fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]cyanamide was separated into the enantiomers by preparative HPLC.

(372) TABLE-US-00054 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IA 5 m 250 30 mm Solvent: Ethanol/methanol 50:50 (v/v) Flow: 30 mL/min Temperature: RT Solution: 143 mg/3.3 mL EtOH/MeOH/DMSO 1.5:1.5:0.3 Injektion: 3 1.1 mL Detection: UV 254 nm Retention time in min purity in % Example 71 11.8-15.2 >99.9 Enantiomer 1 Example 72 15.2-25.1 96.9 Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) = 10.66 (s, 1H), 8.83 (s, 1H), 8.27 (br, 1H), 7.93 (br, 1H), 7.47 (br, 1H), 7.09 (m, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 4.99 (m, 2H), 3.87 (s, 3H), 3.38 (s, 3H). Enantiomer 2: .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) = 10.66 (s, 1H), 8.83 (s, 1H), 8.27 (br, 1H), 7.93 (br, 1H), 7.47 (br, 1H), 7.09 (m, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 4.99 (m, 2H), 3.87 (s, 3H), 3.38 (s, 3H).

Example 73

(rac)-4-[2-(But-2-yn-1-yloxy)-4-fluorophenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(373) ##STR00155##

(374) Example 73 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and but-2-yn-1-ol (Aldrich Chemical Company Inc.). The compound was purified by chromatography (DCM/EtOH 97:3).

(375) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.79 (s, 1H), 7.96 (m, 1H), 7.80 (m, 2H), 7.60 (m, 1H), 7.41 (m, 1H), 7.15 (m, 1H), 6.96 (m, 1H), 6.80 (m, 1H), 4.79 (d, 2H), 4.42 (d, 1H), 4.29 (d, 1H), 2.95 (s, 3H), 2.72 (br, 1H), 1.85 (tr, 3H).

Example 74 and 75

Enantiomers of 4-[2-(but-2-yn-1-yloxy)-4-fluorophenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(376) (rac)-4-[2-(But-2-yn-1-yloxy)-4-fluorophenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC.

(377) TABLE-US-00055 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IC 5 m 250 30 mm Solvent: Hexan/ethanol 70:30 (v/v) Flow: 40 mL/min Temperature: RT Solution: 360 mg/6 mL EtOH/MeOH/DCM Injektion: 5 1.2 mL Detection: UV 280 nm Retention time in min purity in % Example 74 20.4-23.8 99.9 Enantiomer 1 Example 75 24.1-28.1 98.9 Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.79 (s, 1H), 7.96 (m, 1H), 7.80 (m, 2H), 7.60 (m, 1H), 7.41 (m, 1H), 7.15 (m, 1H), 6.96 (m, 1H), 6.80 (m, 1H), 4.79 (d, 2H), 4.42 (d, 1H), 4.29 (d, 1H), 2.95 (s, 3H), 2.72 (br, 1H), 1.85 (tr, 3H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.79 (s, 1H), 7.96 (m, 1H), 7.80 (m, 2H), 7.60 (m, 1H), 7.41 (m, 1H), 7.15 (m, 1H), 6.96 (m, 1H), 6.80 (m, 1H), 4.79 (d, 2H), 4.42 (d, 1H), 4.29 (d, 1H), 2.95 (s, 3H), 2.72 (br, 1H), 1.85 (tr, 3H).

Example 76

(rac)-4-[2-(2-Cyclopropylethoxy)-4-fluorophenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(378) ##STR00156##

(379) Example 76. was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and 2-cyclopropylethanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(380) TABLE-US-00056 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% NH.sub.3 B = Acetonitrile Gradient: 0-8 min 30-70% B Flow: 50 mL/min Temperature: RT Solution: 87 mg/2 mL DMSO Injektion: 4 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 5.1-5.4 min

(381) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.79 (s, 1H), 7.85 (m, 1H), 7.73 (m, 2H), 7.50 (br, 1H), 7.40 (m, 1H), 7.16 (m, 1H), 6.75 (m, 2H), 4.39 (d, 1H), 4.25 (d, 1H), 4.11 (tr, 2H), 2.95 (s, 3H), 2.71 (s, 1H), 1.67 (m, 2H), 0.79 (m, 1H), 0.43 (m, 2H), 0.07 (m, 2H).

Example 77

(rac)-4-[4-Fluoro-2-(prop-2-yn-1-yloxy)phenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(382) ##STR00157##

(383) Example 77. was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and prop-2-yn-1-ol (Aldrich Chemical Company Inc.). The compound was purified by chromatography (DCM/EtOH 97:3).

(384) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.98 (m, 1H), 7.76 (m, 2H), 7.62 (br, 1H), 7.42 (m, 1H), 7.15 (m, 1H), 6.93 (m, 1H), 6.64 (m, 1H), 4.82 (d, 2H), 4.42 (d, 1H), 4.28 (d, 1H), 2.96 (s, 3H), 2.72 (s, 1H), 2.60 (br, 1H).

Example 78 and 79

Enantiomers of 4-[4-fluoro-2-(prop-2-yn-1-yloxy)phenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(385) (rac)-4-[4-Fluoro-2-(prop-2-yn-1-yloxy)phenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC.

(386) TABLE-US-00057 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IC 5 m 250 30 mm Solvent: Hexane/ethanol 70:30 (v/v) Flow: 40 mL/min Temperature: RT Solution: 228 mg/3 mL EtOH/MeOH Injektion: 3 1.0 mL Detection: UV 280 nm Retention time in min purity in % Example 78 19.1-22.9 98.7 Enantiomer 1 Example 79 22.9-27.8 98.7 Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.80 (s, 1H), 7.98 (m, 1H), 7.76 (m, 2H), 7.62 (br, 1H), 7.42 (m, 1H), 7.15 (m, 1H), 6.93 (m, 1H), 6.64 (m, 1H), 4.82 (d, 2H), 4.42 (d, 1H), 4.28 (d, 1H), 2.96 (s, 3H), 2.72 (s, 1H), 2.60 (br, 1H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.80 (s, 1H), 7.98 (m, 1H), 7.76 (m, 2H), 7.62 (br, 1H), 7.42 (m, 1H), 7.15 (m, 1H), 6.93 (m, 1H), 6.64 (m, 1H), 4.82 (d, 2H), 4.42 (d, 1H), 4.28 (d, 1H), 2.96 (s, 3H), 2.72 (s, 1H), 2.60 (br, 1H).

Example 80

(rac)-4-{2-[(3,4-Difluorobenzyl)oxy]-4-fluorophenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(387) ##STR00158##

(388) Example 80 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (3,4-difluorophenyl)methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(389) TABLE-US-00058 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% Vol. HCOOH (99%) B = Acetonitrile Gradient: 0-8 min 15-60% B Flow: 50 mL/min Temperature: RT Solution: 238 mg/3.9 mL DMSO/MeOH 1:1 Injektion: 3 1.3 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 8.0-8.5 min

(390) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.96 (m, 1H), 7.69 (m, 3H), 7.33 (m, 2H), 7.09 (m, 3H), 6.83 (m, 2H), 5.25 (s, 2H), 4.37 (d, 1H), 4.23 (d, 1H), 2.95 (s, 3H), 2.70 (br, 1H),

Example 81

(rac)-4-[4-Fluoro-2-(1,3-thiazol-5-ylmethoxy)phenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(391) ##STR00159##

(392) Example 81 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and 1,3-thiazol-5-ylmethanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(393) TABLE-US-00059 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-8 min 15-60% B Flow: 50 mL/min Temperature: RT Solution: 579 mg/3.5 mL DMSO Injektion: 7 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 5.0-5.2 min

(394) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.79 (m, 2H), 7.96 (m, 1H), 7.88 (m, 1H), 7.74 (br, 1H), 7.68 (m, 1H), 7.51 (br, 1H), 7.37 (m, 1H), 7.14 (m, 1H), 6.86 (m, 2H), 5.37 (s, 2H), 4.38 (d, 1H), 4.23 (d, 1H), 2.95 (s, 3H).

Example 82

(rac)-4-{4-Fluoro-2-[(2-fluoropyridin-4-yl)methoxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)-methyl]phenyl}-1,3,5-triazin-2-amine

(395) ##STR00160##

(396) Example 82 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (2-fluoropyridin-4-yl)methanol (Activate Scientific GmbH). The desired product was isolated by preparative HPLC.

(397) TABLE-US-00060 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-8 min 15-60% B Flow: 50 mL/min Temperature: RT Solution: 312 mg/3 mL DMSO Injektion: 6 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 5.7-6.0 min

(398) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.85 (s, 1H), 8.17 (m, 1H), 8.04 (m, 1H), 7.76 (br, 1H), 7.70 (m, 1H), 7.61 (br, 1H), 7.36 (br, 1H), 7.22 (m, 2H), 7.13 (m, 1H), 6.86 (m, 1H), 6.74 (m, 1H), 5.20 (s, 2H), 4.37 (d, 1H), 4.24 (d, 1H), 2.95 (s, 3H), 2.73 (br, 1H).

Example 83 and 84

Enantiomers of 4-{4-fluoro-2-[(2-fluoropyridin-4-yl)methoxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(399) (rac)-4-{4-Fluoro-2-[(2-fluoropyridin-4-yl)methoxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC.

(400) TABLE-US-00061 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IA 5 m 250 30 mm Solvent: Ethanol 100% Flow: 25 mL/min Temperature: RT Solution: 67 mg/4 mL EtOH/MeOH Injektion: 1 4.0 mL Detection: UV 254 nm Retention time in min purity in % Example 83 19.0-31.0 99.7 Enantiomer 1 Example 84 42.0-65.0 99.1 Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.85 (s, 1H), 8.17 (m, 1H), 8.04 (m, 1H), 7.76 (br, 1H), 7.70 (m, 1H), 7.61 (br, 1H), 7.36 (br, 1H), 7.22 (m, 2H), 7.13 (m, 1H), 6.86 (m, 1H), 6.74 (m, 1H), 5.20 (s, 2H), 4.37 (d, 1H), 4.24 (d, 1H), 2.95 (s, 3H), 2.73 (br, 1H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.85 (s, 1H), 8.17 (m, 1H), 8.04 (m, 1H), 7.76 (br, 1H), 7.70 (m, 1H), 7.61 (br, 1H), 7.36 (br, 1H), 7.22 (m, 2H), 7.13 (m, 1H), 6.86 (m, 1H), 6.74 (m, 1H), 5.20 (s, 2H), 4.37 (d, 1H), 4.24 (d, 1H), 2.95 (s, 3H), 2.73 (br, 1H).

Example 85

(rac)-4-[4-Fluoro-2-(prop-2-en-1-yloxy)phenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(401) ##STR00161##

(402) Example 85 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and prop-2-en-1-ol (Aldrich Chemical Company Inc.). The desired product was isolated by preparative HPLC.

(403) TABLE-US-00062 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-8 min 30-70% B Flow: 50 mL/min Temperature: RT Solution: 50 mg/2.5 mL DMSO Injektion: 5 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 3.2-3.4 min

(404) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.92 (m, 1H), 7.75 (m, 2H), 7.49 (s, 1H), 7.40 (m, 1H), 7.16 (m, 1H), 6.76 (m, 2H), 6.03 (m, 1H), 5.46 (m, 1H), 5.28 (m, 1H), 4.85 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 2.94 (s, 3H), 2.70 (br, 1H).

Example 86

(rac)-4-(4-Fluoro-2-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-N-{3-[(S-methylsulfonimidoyl)-methyl]phenyl}-1,3,5-triazin-2-amine

(405) ##STR00162##

(406) Example 86 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and [4-(trifluoromethyl)phenyl]methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(407) TABLE-US-00063 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% NH.sub.3 B = Acetonitrile Gradient: 0-8 min 30-70% B Flow: 50 mL/min Temperature: RT Solution: 389 mg/4.5 mL DMSO Injektion: 9 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 6.2-6.6 min

(408) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.99 (m, 1H), 7.90 (br, 1H), 7.60 (m, 5H), 7.45 (m, 1H), 7.34 (m, 1H), 7.13 (m, 1H), 6.81 (m, 2H), 5.22 (s, 2H), 4.36 (d, 1H), 4.23 (d, 1H), 2.94 (s, 3H), 2.73 (br, 1H).

Example 87

(rac)-4-{2-[(4-Chlorobenzyl)oxy]-4-fluorophenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(409) ##STR00163##

(410) Example 87 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (4-chlorophenyl)methanol (Aldrich Chemical Company Inc). The desired product was isolated by preparative HPLC.

(411) TABLE-US-00064 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(412) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.94 (s, 1H), 7.99 (m, 1H), 7.75 (m, 2H), 7.34 (m, 6H), 7.16 (m, 1H), 6.82 (m, 2H), 5.18 (s, 2H), 4.39 (d, 1H), 4.25 (d, 1H), 2.96 (s, 3H), 2.70 (br, 1H).

Example 88

(rac)-4-(2-Ethoxy-4-fluorophenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(413) ##STR00164##

(414) Example 88 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and ethanol. The desired product was isolated by preparative HPLC.

(415) TABLE-US-00065 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% NH.sub.3 B = Acetonitrile Gradient: 0-8 min 15-60% B Flow: 50 mL/min Temperature: RT Solution: 129 mg/3 mL DMSO Injektion: 6 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 5.8-6.2 min

(416) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.83 (s, 1H), 7.81 (m, 3H), 7.53 (s, 1H), 7.43 (m, 1H), 7.18 (m, 1H), 6.78 (m, 2H), 4.41 (d, 1H), 4.28 (d, 1H), 4.16 (q, 2H), 2.97 (s, 3H), 2.73 (s, 1H), 1.44 (tr, 3H).

Example 89

(rac)-4-(4-Fluoro-2-{[3-fluoro-5-(trifluoromethyl)benzyl]oxy}phenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(417) ##STR00165##

(418) Example 89 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and [3-fluoro-5-(trifluoromethyl)phenyl]methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(419) TABLE-US-00066 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(420) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 8.04 (s, 1H), 7.77 (br, 1H), 7.67 (m, 2H), 7.42 (m, 3H), 7.26 (m, 1H), 7.15 (m, 1H), 6.83 (m, 2H), 5.21 (s, 2H), 4.38 (d, 1H), 4.25 (d, 1H), 2.95 (s, 3H).

Example 90

(rac)-4-{4-Fluoro-2-[(3-fluorobenzyl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(421) ##STR00166##

(422) Example 90 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (3-fluorophenyl)methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(423) TABLE-US-00067 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(424) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.86 (s, 1H), 8.02 (m, 1H), 7.75 (m, 2H), 7.54 (s, 1H), 7.35 (m, 3H), 7.18 (m, 2H), 7.01 (m, 1H), 6.82 (m, 2H), 5.21 (s, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 2.96 (s, 3H).

Example 91

(rac)-4-(4-Fluoro-2-propoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(425) ##STR00167##

(426) Example 91 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and propan-1-ol. The desired product was isolated by preparative HPLC.

(427) TABLE-US-00068 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% NH.sub.3 B = Acetonitrile Gradient: 0-8 min 30-70% B Flow: 50 mL/min Temperature: RT Solution: 126 mg/4 mL DMSO Injektion: 8 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 6.6-6.9 min

(428) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.85 (m, 1H), 7.75 (m, 2H), 7.42 (m, 2H), 7.16 (m, 1H), 8.74 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 4.01 (tr, 2H), 2.95 (s, 3H), 2.70 (s, 1H), 1.81 (m, 2H), 1.00 (tr, 3H).

Example 92

(rac)-4-{2-[(3-Chlorobenzyl)oxy]-4-fluorophenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(429) ##STR00168##

(430) Example 92 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (3-chlorophenyl)methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(431) TABLE-US-00069 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% NH.sub.3 B = Acetonitrile Gradient: 0-8 min 30-70% B Flow: 50 mL/min Temperature: RT Solution: 233 mg/3 mL DMSO Injektion: 6 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 5.9-6.2 min

(432) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 8.00 (m, 1H), 7.68 (m, 3H), 7.53 (s, 1H), 7.35 (m, 1H), 7.26 (m, 3H), 7.14 (m, 1H), 6.81 (m, 2H), 5.16 (s, 2H), 4.36 (d, 1H), 4.23 (d, 1H), 2.94 (s, 3H), 2.70 (br, 1H).

Example 93

(rac)-4-[4-Fluoro-2-(1,2-oxazol-3-ylmethoxy)phenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(433) ##STR00169##

(434) Example 93 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and 1,2-oxazol-3-ylmethanol (UkrOrgSynthesis Ltd.). The desired product was isolated by preparative HPLC.

(435) TABLE-US-00070 System: Agilent: Prep 1200, 2 Prep Pump, DLA, MWD, Prep FC, Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% TFA B = Methanol Gradient: 0-17.5 min 25-55% B, 17.5-20 min 55-100% B Flow: 38 mL/min Temperature: RT Solution: 29 mg/0.8 mL DMSO Injektion: 1 0.8 mL Detection: UV 210 nm Retention: 8.3-10.2 min

(436) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.41 (s, 1H), 8.80 (m, 2H), 7.80 (m, 3H), 7.37 (m, 1H), 7.18 (m, 2H), 6.94 (m, 1H), 6.55 (br, 1H), 5.33 (s, 2H), 4.99 (m, 2H), 3.37 (s, 3H).

Example 94

(rac)-4-{2-[(3-Chloro-5-fluorobenzyl)oxy]-4-fluorophenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(437) ##STR00170##

(438) Example 94 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (3-chloro-5-fluorophenyl)methanol (Apollo Scientific Ltd.). The desired product was isolated by preparative HPLC.

(439) TABLE-US-00071 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(440) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.85 (s, 1H), 8.03 (m, 1H), 7.77 (s, 1H), 7.69 (m, 1H), 7.46 (m, 1H), 7.37 (m, 2H), 7.16 (m, 2H), 7.01 (m, 1H), 6.85 (m, 1H), 6.76 (m, 1H), 5.14 (s, 2H), 4.38 (d, 1H), 4.24 (d, 1H), 2.95 (s, 3H).

Example 95

(rac)-4-[2-(2,2-Difluoroethoxy)-4-fluorophenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(441) ##STR00171##

(442) Example 95 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and 2,2-difluoroethanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(443) TABLE-US-00072 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% NH.sub.3 B = Acetonitrile Gradient: 0-8 min 15-50% B Flow: 50 mL/min Temperature: RT Solution: 68 mg/3 mL DMSO/MeOH 1:1 Injektion: 3 1 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 6.18-6.54 min

(444) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.95 (m, 1H), 7.77 (br, 1H), 7.69 (m, 1H), 7.43 (m, 1H), 7.34 (br, 1H), 7.18 (m, 1H), 6.88 (m, 1H), 6.76 (m, 1H), 6.05 (m, 1H), 4.40 (d, 1H), 4.27 (m, 3H), 2.95 (s, 3H), 2.68 (s, 1H).

Example 96

(rac)-4-{4-Fluoro-2-[(4-fluoro-3-methylbenzyl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(445) ##STR00172##

(446) Example 96 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (4-fluoro-3-methylphenyl)methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(447) TABLE-US-00073 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(448) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.94 (m, 1H), 7.70 (m, 2H), 7.51 (br, 1H), 7.32 (m, 2H), 7.20 (m, 1H), 7.13 (m, 1H), 6.94 (m, 1H), 6.79 (m, 2H), 5.11 (s, 2H), 4.35 (d, 1H), 4.33 (d, 1H), 2.93 (s, 3H), 2.61 (s, 1H), 2.23 (s, 3H).

Example 97

(rac)-4-{2-[(3-Chloro-4-fluorobenzyl)oxy]-4-fluorophenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(449) ##STR00173##

(450) Example 97 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (3-chloro-4-fluorophenyl)methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(451) TABLE-US-00074 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(452) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 8.00 (m, 1H), 7.76 (br, 1H), 7.69 (m, 2H), 7.48 (br, 1H), 7.36 (m, 1H), 7.27 (m, 1H), 7.11 (m, 2H), 6.79 (m, 2H), 5.12 (s, 2H), 4.37 (d, 1H), 4.24 (d, 1H), 2.95 (s, 3H), 2.71 (br, 1H).

Example 98

(rac)-3-({5-Fluoro-2-[4-({3-[(S-methylsulfonimidoyl)methyl]phenyl}amino)-1,3,5-triazin-2-yl]-phenoxy}methyl)benzonitrile

(453) ##STR00174##

(454) Example 98 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and 3-(hydroxymethyl)benzonitrile (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(455) TABLE-US-00075 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% NH.sub.3 B = Acetonitrile Gradient: 0-8 min 30-70% B Flow: 50 mL/min Temperature: RT Solution: 473 mg/4.5 mL DMSO Injektion: 9 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 4.7-4.9 min

(456) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.35 (s, 1H), 8.83 (s, 1H), 7.85 (m, 6H), 7.53 (br, 1H), 7.28 (br, 1H), 7.16 (m, 1H), 7.11 (br, 1H), 6.95 (m, 1H), 5.32 (s, 2H), 4.32 (br, 2H), 3.55 (s, 1H), 2.79 (s, 3H).

Example 99

(rac)-4-{4-Fluoro-2-[(2-methylprop-2-en-1-yl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(457) ##STR00175##

(458) Example 99 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and 2-methylprop-2-en-1-ol (Aldrich Chemical Company Inc). The desired product was isolated by preparative HPLC.

(459) TABLE-US-00076 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(460) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.83 (s, 1H), 7.94 (m, 1H), 7.76 (m, 2H), 7.55 (br, 1H), 7.42 (m, 1H), 7.18 (m, 1H), 6.78 (m, 2H), 5.18 (br, 1H), 5.01 (br, 1H), 4.55 (s, 2H), 4.41 (d, 1H), 4.28 (d, 1H), 2.97 (s, 3H), 2.70 (br, 1H). 1.82 (s, 3H).

Example 100

(rac)-4-[4-Fluoro-2-(4,4,4-trifluorobutoxy)phenyl]-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(461) ##STR00176##

(462) Example 100 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and 4,4,4-trifluorobutan-1-ol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(463) TABLE-US-00077 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(464) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.82 (s, 1H), 7.95 (m, 1H), 7.80 (br, 1H), 7.70 (m, 1H), 7.46 (m, 2H), 7.19 (m, 1H), 6.82 (m, 1H), 6.73 (m, 1H), 4.42 (d, 1H), 4.29 (d, 1H), 4.12 (tr, 2H), 2.98 (s, 3H), 2.74 (br, 1H), 2.38 (m, 2H), 2.07 (m, 2H).

Example 101

(rac)-4-{4-Fluoro-2-[(2,3,5-trifluorobenzyl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(465) ##STR00177##

(466) Example 101 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (2,3,5-trifluorophenyl)methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(467) TABLE-US-00078 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(468) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.87 (s, 1H), 8.07 (m, 1H), 7.80 (s, 1H), 7.72 (m, 1H), 7.40 (m, 3H), 7.18 (m, 1H), 6.89 (m, 3H), 5.26 (s, 2H), 4.42 (d, 1H), 4.28 (d, 1H), 2.98 (s, 3H), 2.71 (br, 1H).

Example 102

(rac)-4-{2-[(2Z)-But-2-en-1-yloxy]-4-fluorophenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine

(469) ##STR00178##

(470) Example 102 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (2Z)-but-2-en-1-ol (ChemSampCo, Inc.). The desired product was isolated by preparative HPLC.

(471) TABLE-US-00079 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(472) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.89 (m, 1H), 7.76 (m, 2H), 7.57 (br, 1H), 7.39 (m, 1H), 7.15 (m, 1H), 6.75 (m, 2H), 5.70 (m, 2H), 4.72 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 2.95 (s, 3H), 2.71 (br, 1H). 1.73 (d, 3H).

Example 103

(rac)-4-{4-Fluoro-2-[(2,4,5-trifluorobenzyl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(473) ##STR00179##

(474) Example 103 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (2,4,5-trifluorophenyl)methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(475) TABLE-US-00080 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(476) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 8.03 (m, 1H), 7.77 (br, 1H), 7.65 (m, 2H), 7.48 (br, 1H), 7.39 (m, 1H), 7.15 (m, 1H), 6.94 (m, 1H), 6.83 (m, 2H), 5.17 (s, 2H), 4.39 (d, 1H), 4.25 (d, 1H), 2.96 (s, 3H), 2.70 (br, 1H).

Example 104

(rac)-4-{4-Fluoro-2-[(3,4,5-trifluorobenzyl)oxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)methyl]-phenyl}-1,3,5-triazin-2-amine

(477) ##STR00180##

(478) Example 104 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and (3,4,5-trifluorophenyl)methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.

(479) TABLE-US-00081 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonirile Gradient: 0-8 min 30-70% B Flow: 50 mL/min Temperature: RT Solution: 431 mg/4 mL DMSO Injektion: 8 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 5.6-6.0 min

(480) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.84 (s, 1H), 8.02 (m, 1H), 7.77 (br, 1H), 7.69 (m, 1H), 7.39 (m, 2H), 7.17 (m, 3H), 6.85 (m, 1H), 6.74 (m, 1H), 5.10 (s, 2H), 4.39 (d, 1H), 4.25 (d, 1H), 2.95 (s, 3H). 2.69 (br, 1H).

Example 105

(rac)-[(2,3-Difluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)-oxido-6-sulfanylidene]cyanamide

(481) ##STR00181##
Preparation of Intermediate 105.1:

(2,3-Difluoro-5-nitrophenyl)methanol

(482) ##STR00182##

(483) Borane-tetrahydrofuran complex (1.0M solution in THF; 177 mL) was added under stirring to an ice-cold solution of 2,3-difluoro-5-nitrobenzoic acid (9.0 g; 44.3 mmol; Butt Park Ltd.) in THF (85 mL). The ice bath was removed and the batch was stirred for 18 hours at room temperature. The batch was cautiously diluted with methanol under stirring at 0 C. Ethyl acetate was added and the batch was washed with aqueous 1 M solution of sodium hydroxide and half-concentrated aqueous sodium chloride solution. The organic phase was dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 1:1) to give the desired product (8.2 g; 43.3 mmol).

(484) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.26 (m, 1H), 8.03 (m, 1H), 4.89 (s, 2H), 2.13 (br, 1H).

(485) Preparation of Intermediate 105.2:

(5-Amino-2,3-difluorophenyl)methanol

(486) ##STR00183##

(487) Intermediate 105.2 was prepared under similar conditions as described in the preparation of Intermediate 1.6 using. (2,3-difluoro-5-nitrophenyl)methanol.

(488) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =6.46 (m, 1H), 6.39 (m, 1H), 4.67 (s, 2H), 3.02 (br, 3H).

(489) Preparation of Intermediate 105.3:

3-(Chloromethyl)-4,5-difluoroaniline

(490) ##STR00184##

(491) Thionylchloride (7.7 g; 64.9 mmol) was added dropwise under stirring to a water-cooled solution of (5-amino-2,3-difluorophenyl)methanol (4.1 g; 26.0 mmol) in DCM (78 ml) and 1-methylpyrrolidin-2-one (11 ml). The batch was stirred at room temperature for 18 hours before it was diluted with ice-water, aqueous sodium bicarbonate solution and brine. The batch was stirred for 2 hours at room temperature and finally it was extracted with ethyl acetate (2). The combined organic phases were filtered using a Whatman filter and concentrated to give the crude product (6.5 g) that was used without further purification.

(492) Preparation of Intermediate 105.4:

3,4-Difluoro-5-[(methylsulfanyl)methyl]aniline

(493) ##STR00185##

(494) Intermediate 105.4 was prepared under similar conditions as described in the preparation of Intermediate 1.1 using crude 3-(chloromethyl)-4,5-difluoroaniline. The batch was purified by chromatography (hexane/ethyl acetate 1:1).

(495) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =6.35 (m, 2H), 3.62 (br, 4H), 2.99 (s, 3H).

(496) Preparation of Intermediate 105.5:

4-Chloro-N-{3,4-difluoro-5-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine

(497) ##STR00186##

(498) Intermediate 105.5 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using 3,4-difluoro-5-[(methylsulfanyl)methyl]aniline.

(499) TABLE-US-00082 System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD Column: Acquity UPLC BEH C18 1.7 50 2.1 mm Solvent: A1 = H2O + 0.1% Vol. HCOOH (99%) A2 = H2O + 0.2% Vol. NH3 (32%) B1 = Acetonitril Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Temperatuer: 60 C. Injektion: 2.0 l Detection: DAD scan range 210-400 nm > Peaktable ELSD Method: MS ESI+, ESI Switch A2 + B1 = C:\MassLynx\NH3_Mass_100_1000.olp Retention 1.19 min MS(ES): m/z = 303 [M + H]
Preparation of Intermediate 105.6:

N-{3,4-Difluoro-5-[(methylsulfanyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine

(500) ##STR00187##

(501) Intermediate 105.6 was prepared under similar conditions as described in the preparation of Example 42 using crude 4-chloro-N-{3,4-difluoro-5-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by chromatography (hexane/ethyl acetate 1:1) to give the desired product.

(502) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 8.15 (br, 2H), 7.35 (m, 1H), 7.08 (br, 1H), 6.78 (m, 2H), 3.98 (s, 3H), 3.73 (s, 2H), 2.08 (s, 3H).

(503) Preparation of Intermediate 105.7:

(rac)-[(2,3-Difluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)-4-sulfanylidene]cyanamide

(504) ##STR00188##

(505) Bis(acetyloxy)(phenyl)-.sup.3-iodane (469 mg; 1.46 mmol) was added to a stirred solution of N-{3,4-difluoro-5-[(methylsulfanyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine (520 mg; 1.33 mmol) and cyanamide (111 mg; 2.65 mmol) in DCM (7.5 ml) at 0 C. The batch was stirred at this temperature for 4 hours. The batch was concentrated and the residue was purified by chromatography (DCM/EtOH 8:2) to give the desired product (300 mg; 0.69 mmol).

(506) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 8.49 (br, 1H), 8.06 (br, 1H), 7.87 (br, 1H), 7.22 (br, 1H), 6.79 (m, 2H), 4.34 (m, 2H), 3.96 (s, 3H), 2.86 (s, 3H).

(507) Preparation of End Product:

(508) Potassium permanganate (217 mg; 1.37 mmol) was added under stirring to a solution of (rac)-[(2,3-difluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)-.sup.4-sulfanylidene]-cyanamide (297 mg; 0.69 mmol) in acetone (6.9 mL) at room temperature. The batch was stirred at 50 C. for 1 hour. The batch was concentrated and the residue was purified by chromatography (DCM/EtOH 9:1) to give the desired product (153 mg; 0.34 mmol).

(509) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.62 (s, 1H), 8.81 (s, 1H), 8.55 (br, 1H), 7.96 (br, 1H), 7.43 (br, 1H), 7.08 (m, 1H), 6.89 (m, 1H), 5.06 (m, 2H), 3.87 (s, 3H), 3.50 (s, 3H).

Example 106

(rac)-N-{3,4-Difluoro-5-[(S-methylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine

(510) ##STR00189##

(511) Trifluoroacetic anhydride (0.32 mL; 0.90 mmol) was added under stirring to an ice-cooled suspension of (rac)-[(2,3-difluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]cyanamide (134 mg; 0.30 mmol) in DCM (13 mL). The batch was stirred for 2 hours at room temperature before it was concentrated in vacuo. The residue was taken up in methanol (2.1 mL) and potassium carbonate (206 mg; 1.49 mmol) was added under stirring at room temperature. After 2 hours the batch was diluted with ethyl acetate and THF. The batch was washed with aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated in vacuo. The residue was purified by chromatography (DCM/EtOH 9:1) to give the desired product (68 mg; 0.16 mmol).

(512) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.78 (s, 1H), 8.49 (br, 1H), 8.08 (br, 1H), 7.69 (br, 1H), 7.18 (br, 1H), 6.78 (m, 2H), 4.46 (d, 1H), 4.38 (d, 1H), 3.94 (s, 3H), 3.03 (s, 3H).

Example 107

(rac)-[Ethyl(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)oxido-6-sulfanylidene]cyanamide

(513) ##STR00190##
Preparation of Intermediate 107.1:

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

(514) ##STR00191##

(515) Intermediate 107.1 was prepared under similar conditions as described in the preparation of Intermediate 1.1 using 1-(chloromethyl)-3-nitrobenzene and sodium ethanethiolate.

(516) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.19 (m, 1H), 8.11 (m, 1H), 7.67 (m, 1H), 7.49 (m, 1H), 3.80 (s, 2H), 2.45 (q, 2H), 1.25 (tr, 3H).

(517) Preparation of Intermediate 107.2:

3-[(Ethylsulfanyl)methyl]aniline

(518) ##STR00192##

(519) Intermediate 107.2 was prepared under similar conditions as described in the preparation of Intermediate 1.6 using 1-[(ethylsulfanyl)methyl]-3-nitrobenzene.

(520) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =7.09 (m, 1H), 6.68 (m, 2H), 6.57 (m, 1H), 3.63 (s, 2H), 3.42 (br, 2H), 2.45 (q, 2H), 1.23 (tr, 3H).

(521) Preparation of Intermediate 107.3:

4-Chloro-N-{3-[(ethylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine

(522) ##STR00193##

(523) Intermediate 107.3 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using 3-[(ethylsulfanyl)methyl]aniline.

(524) TABLE-US-00083 System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD Column: Acquity UPLC BEH C18 1.7 50 2.1 mm Solvent: A1 = H.sub.2O + 0.1% Vol. HCOOH (99%) A2 = H.sub.2O + 0.2% Vol. NH.sub.3 (32%) B1 = Acetonitrile Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Temperatuer: 60 C. Injektion: 2.0 l Detection: DAD scan range 210-400 nm -> Peaktable ELSD Method: MS ESI+, ESI Switch A2 + B1 = C:\MassLynx\NH3_Mass_100_1000.olp Retention 1.22 min MS (ES): m/z = 281 [M + H]
Preparation of Intermediate 107.4:

N-{3-[(Ethylsulfanyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine

(525) ##STR00194##

(526) Intermediate 107.4 was prepared under similar conditions as described in the preparation of Example 42 using crude 4-chloro-N-{3-[(ethylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc.). The batch was purified by column chromatography (hexane/ethyl acetate 1:1) to give the desired product.

(527) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.80 (s, 1H), 7.98 (br, 1H), 7.62 (m, 2H), 7.46 (br, 1H), 7.31 (m, 1H), 7.08 (m, 1H), 6.76 (m, 2H), 3.93 (s, 3H), 3.73 (s, 2H), 2.46 (q, 2H), 1.23 (tr, 3H).

(528) Preparation of Intermediate 107.5:

(rac)-[Ethyl(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl-1-sulfanylidene]-cyanamide

(529) ##STR00195##

(530) Intermediate 107.5 was prepared under similar conditions as described in the preparation of Intermediate 105.7 using N-{3-[(ethylsulfanyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine.

(531) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.63 (s, 1H), 7.95 (m, 1H), 7.75 (m, 3H), 7.42 (m, 1H), 7.10 (m, 1H), 6.79 (m, 2H), 4.37 (d, 1H), 4.18 (d, 1H), 3.94 (s, 3H), 3.11 (m, 1H), 2.89 (m, 1H), 1.43 (tr, 3H).

(532) Preparation of End Product:

(533) Example 107 was prepared under similar conditions as described in the preparation of Example 105 using (rac)-[ethyl(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl-.sup.4-sulfanylidene]-cyanamide.

(534) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.85 (s, 1H), 7.95 (m, 2H), 7.75 (br, 1H), 7.66 (m, 1H), 7.45 (m, 1H), 7.18 (m, 1H), 6.79 (m, 2H), 4.60 (m, 2H), 3.94 (s, 3H), 3.16 (q, 2H), 1.44 (tr, 3H).

Example 108

(rac)-N-{3-[(S-ethylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine

(535) ##STR00196##

(536) Example 108 was prepared under similar conditions as described in the preparation of Example 106 using (rac)-[ethyl(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)oxido-.sup.6-sulfanylidene]cyanamide.

(537) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.96 (m, 1H), 7.78 (m, 2H), 7.41 (m, 2H), 7.16 (m, 1H), 6.78 (m, 2H), 4.33 (d, 1H), 4.18 (d, 1H), 3.94 (s, 3H), 3.04 (q, 2H), 1.43 (tr, 3H).

Example 109 and 110

Enantiomers of N-{3-[(S-ethylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine

(538) (rac)-N-{3-[(S-ethylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine was separated into the enantiomers by preparative HPLC:

(539) TABLE-US-00084 System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Column: Chiralpak IC 5 m 250 30 mm Solvent: Hexane/ethanol 70:30 (v/v) Flow: 50 mL/min Temperature: RT Solution: 205 mg/4.9 mL DCM/MeOH Injektion: 7 0.7 mL Detection: UV 280 nm Retention time in min purity in % Example 17.8-19.2 >99.9 109 Enantiomer 1 Example 19.2-21.6 96.5 110 Enantiomer 2 Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.81 (s, 1H), 7.96 (m, 1H), 7.78 (m, 2H), 7.41 (m, 2H), 7.16 (m, 1H), 6.78 (m, 2H), 4.33 (d, 1H), 4.18 (d, 1H), 3.94 (s, 3H), 3.04 (q, 2H), 1.43 (tr, 3H). Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) = 8.81 (s, 1H), 7.96 (m, 1H), 7.78 (m, 2H), 7.41 (m, 2H), 7.16 (m, 1H), 6.78 (m, 2H), 4.33 (d, 1H), 4.18 (d, 1H), 3.94 (s, 3H), 3.04 (q, 2H), 1.43 (tr, 3H).

(540) Enantiomer 1: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.96 (m, 1H), 7.78 (m, 2H), 7.41 (m, 2H), 7.16 (m, 1H), 6.78 (m, 2H), 4.33 (d, 1H), 4.18 (d, 1H), 3.94 (s, 3H), 3.04 (q, 2H), 1.43 (tr, 3H).

(541) Enantiomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.81 (s, 1H), 7.96 (m, 1H), 7.78 (m, 2H), 7.41 (m, 2H), 7.16 (m, 1H), 6.78 (m, 2H), 4.33 (d, 1H), 4.18 (d, 1H), 3.94 (s, 3H), 3.04 (q, 2H), 1.43 (tr, 3H).

Example 111

(rac)-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}-5-methylbenzyl)(methyl)oxido-6-sulfanylidene]cyanamide

(542) ##STR00197##
Preparation of Intermediate 111.1:

3-(Chloromethyl)-5-methylaniline

(543) ##STR00198##

(544) Thionylchloride (15.3 g; 128.5 mmol) was added dropwise under stirring to an ice-cooled solution of (3-amino-5-methylphenyl)methanol (6.3 g; 42.8 mmol; GLSyntech, LLC) in DCM (140 ml). The batch was stirred at room temperature for 18 hours before it was concentrated in vacuo. The residue was taken up in DCM and concentrated once more in vacuo to give the crude product that was used without further purification.

(545) Preparation of Intermediate 111.2:

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

(546) ##STR00199##

(547) Intermediate 111.2 was prepared under similar conditions as described in the preparation of Intermediate 1.1 using crude 3-(chloromethyl)-5-methylaniline. The batch was purified by chromatography (hexane/ethyl acetate 6:4).

(548) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =6.26 (m, 1H), 6.21 (m, 2H), 3.43 (s, 2H), 2.07 (s, 3H), 1.89 (s, 3H).

(549) Preparation of Intermediate 111.3:

4-Chloro-N-{3-methyl-5-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine

(550) ##STR00200##

(551) Intermediate 111.3 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using 3-methyl-5-[(methylsulfanyl)methyl]aniline. The crude product was purified by chromatography (hexane/ethylacetate 2:1) to give the desired product.

(552) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.63 (s, 1H), 8.59 (br, 1H), 7.37 (br, 1H), 7.30 (m, 1H), 6.87 (br, 1H), 3.60 (s, 2H), 2.25 (s, 3H), 1.95 (s, 3H).

(553) Preparation of Intermediate 111.4:

4-(4-Fluoro-2-methoxyphenyl)-N-{3-methyl-5-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine

(554) ##STR00201##

(555) Intermediate 111.4 was prepared under similar conditions as described in the preparation of Example 42 using 4-chloro-N-{3-methyl-5-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by chromatography (hexane/ethyl acetate 1:1) to give the desired product.

(556) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.17 (s, 1H), 8.75 (s, 1H), 7.78 (br, 1H), 7.52 (m, 2H), 7.05 (m, 1H), 6.87 (m, 1H), 6.79 (m, 1H), 3.84 (s, 3H), 3.59 (s, 2H), 2.25 (s, 3H), 1.93 (s, 3H).

(557) Preparation of Intermediate 111.5:

(rac)-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}-5-methylbenzyl)(methyl)-4-sulfanylidene]cyanamide

(558) ##STR00202##

(559) Intermediate 111.5 was prepared under similar conditions as described in the preparation of Example 105.7 using 4-(4-fluoro-2-methoxyphenyl)-N-{3-methyl-5-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine. The batch was purified by preparative HPLC.

(560) TABLE-US-00085 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(561) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.32 (s, 1H), 8.77 (s, 1H), 7.68 (m, 3H), 7.07 (m, 1H), 6.87 (m, 2H), 4.39 (d, 1H), 4.20 (d, 1H), 3.84 (s, 3H), 2.81 (s, 3H), 2.29 (s, 3H).

(562) Preparation of End Product:

(563) Example 111 was prepared under similar conditions as described in the preparation of Example 105 using (rac)-[(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}-5-methylbenzyl)(methyl)-.sup.4-sulfanylidene]cyanamide The batch was purified by preparative HPLC.

(564) TABLE-US-00086 System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.1% HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max. 2.5 mL DMSO o. DMF Injektion: 1 2.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z

(565) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.34 (s, 1H), 8.77 (s, 1H), 7.76 (br, 2H), 7.62 (m, 1H), 7.07 (m, 1H), 6.96 (m, 1H), 6.87 (m, 1H), 4.89 (m, 2H), 3.83 (s, 3H), 3.34 (s, 3H), 2.30 (s, 3H).

Example 112

(rac)-2-({5-Fluoro-2-[4-({3-[(S-methylsulfonimidoyl)methyl]phenyl}amino)-1,3,5-triazin-2-yl]phenoxy}methyl)prop-2-en-1-ol

(566) ##STR00203##

(567) Example 112 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate and 2-methylidenepropane-1,3-diol (Aldrich Chemical Company Inc.).

(568) TABLE-US-00087 System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBrigde C18 5 m 100 30 mm Solvent: A = H.sub.2O + 0.2% Vol. NH.sub.3 (32%) B = Acetonitrile Gradient: 0-8 min 20-30% B Flow: 50 mL/min Temperature: RT Solution: 40 mg/1.5 mL DMSO/MeOH 1:1 Injektion: 3 0.5 mL Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Retention: 7.2-7.8 min

(569) .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) =8.77 (s, 1H), 8.53 (br, 1H), 8.36 (br, 1H), 7.81 (s, 1H), 7.64 (m, 1H), 7.42 (m, 1H), 7.18 (m, 1H), 6.83 (m, 1H), 6.76 (m, 1H), 5.29 (m, 2H), 4.78 (s, 2H), 4.40 (m, 3H), 4.28 (m, 1H), 2.97 (s, 3H).

Example 113

(rac)-[Cyclopropyl(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}benzyl)oxido-6-sulfanylidene]cyanamide

(570) ##STR00204##
Preparation of Intermediate 113.1:

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

(571) ##STR00205##

(572) Sulfur (3.63 g; 25.0 mmol) was added portionswise to a stirred 0.5 M solution of bromo(cyclopropyl)magnesium in THF (50.0 ml; 25.0 mmol). The batch was stirred at 50 C. for 1 hour and then cooled to 0 C. Lithium tetrahydridoaluminate(1-) (522 mg; 13.8 mmol) was cautiously added under stirring. The batch was stirred for 30 minutes at 50 C. and cooled to 0 C. again. Water (2 ml) was cautiously added under stirring. Finally, sulfuric acid (5%; 100 ml) was cautiously added and the batch was stirred for 10 minutes. The organic phase was separated and the aqueous phase was extracted with diethyl ether (2). The combined organic phases were washed with saturated aqueous ammonium chloride solution (2), aqueous sodium bicarbonate solution (5%, 2), water (2) and saturated aqueous sodium chloride solution (2). The organic phase was dried (Na.sub.2SO.sub.4) and filtered before it was slowly added to a stirred batch of 1-(chloromethyl)-3-nitrobenzene (2.15 g; 12.5 mmol) and potassium carbonate (2.59 g; 18.8 mmol) in DMF (40 ml). The batch was stirred at 85 C. over night. After cooling, the batch was filtered over celite and concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water (2) and saturated aqueous sodium chloride solution (2). The organic phase was dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 8:2) to give the desired product (2.38 g; 11.4 mmol).

(573) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =8.16 (m, 1H), 8.06 (m, 1H), 7.75 (m, 1H), 7.56 (m, 1H), 3.90 (s, 2H), 1.72 (m, 1H), 0.77 (m, 2H), 0.39 (m, 2H).

(574) Preparation of Intermediate 113.2:

3-[(Cyclopropylsulfanyl)methyl]aniline

(575) ##STR00206##

(576) Intermediate 113.2 was prepared under similar conditions as described in the preparation of Intermediate 1.6 using 1-[(cyclopropylsulfanyl)methyl]-3-nitrobenzene. The batch was purified by chromatography.

(577) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =6.89 (m, 1H), 6.49 (m, 1H), 6.38 (m, 2H), 4.96 (s, 2H), 3.56 (s, 2H), 1.75 (m, 1H), 0.78 (m, 2H), 0.42 (m, 2H).

(578) Preparation of Intermediate 113.3:

4-Chloro-N-{3-[(cyclopropylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine

(579) ##STR00207##

(580) Intermediate 113.3 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using 3-[(cyclopropylsulfanyl)methyl]aniline. The crude product was purified by chromatography (hexane/ethylacetate 4:1) to give the desired product.

(581) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.69 (s, 1H), 8.59 (br, 1H), 7.59 (br, 1H), 7.48 (m, 1H), 7.27 (m, 1H), 7.05 (m, 1H), 3.72 (s, 2H), 1.76 (m, 1H), 0.80 (m, 2H), 0.44 (m, 2H).

(582) Preparation of Intermediate 113.4:

N-{3-[(Cyclopropylsulfanyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine

(583) ##STR00208##

(584) Intermediate 113.4 was prepared under similar conditions as described in the preparation of Example 42 using 4-chloro-N-{3-[(cyclopropylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by chromatography (hexane/ethyl acetate 2:1) to give the desired product.

(585) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.24 (s, 1H), 8.75 (s, 1H), 7.75 (m, 3H), 7.25 (m, 1H), 7.07 (m, 1H), 6.99 (m, 1H), 6.86 (m, 1H), 3.84 (s, 3H), 3.72 (s, 2H), 1.74 (m, 1H), 0.75 (m, 2H), 0.42 (m, 2H).

(586) Preparation of Intermediate 113.5:

(rac)-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}-5-methylbenzyl)(methyl)-4-sulfanylidene]cyanamide

(587) ##STR00209##

(588) Intermediate 113.5 was prepared under similar conditions as described in the preparation of Example 105.7 using N-{3-[(cyclopropylsulfanyl)methyl]phenyl}-4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine. The batch was purified by chromatography (ethyl acetate/methanol 9:1).

(589) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.38 (s, 1H), 8.78 (s, 1H), 7.63 (m, 3H), 7.37 (m, 1H), 7.14 (m, 1H), 7.06 (m 1H), 6.88 (m, 1H), 4.53 (d, 1H), 4.38 (d, 1H), 3.85 (s, 3H), 2.70 (m, 1H), 1.07 (m, 3H), 0.84 (m, 1H).

(590) Preparation of End Product:

(591) Example 113 was prepared under similar conditions as described in the preparation of Example 105 using (rac)-[(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}-5-methylbenzyl)(methyl)-.sup.4-sulfanylidene]cyanamide The batch was purified by chromatography (gradient: ethyl acetate/hexanes 4:1.fwdarw.ethyl acetate).

(592) .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) =10.44 (s, 1H), 8.81 (s, 1H), 7.93 (m, 3H), 7.43 (m, 1H), 7.20 (m, 1H), 7.10 (m, 1H), 6.91 (m, 1H), 5.01 (m, 2H), 3.88 (br, 3H), 2.97 (m, 1H), 1.18 (m, 3H), 0.90 (m, 1H).

(593) The following Table 1 provides an overview on the compounds of the invention:

(594) Table 1

(595) TABLE-US-00088 TABLE 1 Compound No. Structure Nomenclature 1 0 (rac)-Ethyl [(3-{[4-(4-fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 2 (rac)-4-(4-Fluoro-2-methoxyphenyl)- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 3 ()-4-(4-Fluoro-2-methoxyphenyl)-N- {3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 4 (+)-4-(4-Fluoro-2-methoxyphenyl)-N- {3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine: enantiomer 2 5 (rac)-Ethyl {[3-({4-[2-(benzyloxy)-4- fluorophenyl]-1,3,5-triazin-2- yl}amino)benzyl](methyl)oxido-.sup.6- sulfanylidene}carbamate 6 (rac)-4-[2-(Benzyloxy)-4- fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl] phenyl}- 1,3,5-triazin-2-amine 7 ()-4-[2-(Benzyloxy)-4-fluorophenyl]- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine: enantiomer 1 8 (+)-4-[2-(Benzyloxy)-4- fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 9 (rac)-Ethyl [(3-{[4-(4,5-difluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 10 (rac)-4-(4,5-Difluoro-2- methoxyphenyl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 11 0 (rac)-Ethyl [(3-{[4-(4-chloro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 12 (rac) 4-(4-Chloro-2-methoxyphenyl)- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 13 4-(4-Chloro-2-methoxyphenyl)-N-{3- [(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 14 4-(4-Chloro-2-methoxyphenyl)-N-{3- [(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 15 (rac)-1-[(3-{[4-(4-Fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]-3-methylurea 16 ()-1-[(3-{[4-(4-Fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]-3-methylurea; enantiomer 1 17 (+)-1-[(3-{[4-(4-Fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]-3-methylurea; enantiomer 2 18 (rac)-Ethyl [(3-{[4-(2,2-difluoro-1,3- benzodioxol-4-yl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 19 (rac)-4-(2,2-Difluoro-1,3- benzodioxol-4-yl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 20 (rac)-Ethyl [(3-{[4-(5-fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 21 0 (rac)-4-(5-Fluoro-2-methoxyphenyl)- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 22 4-(5-Fluoro-2-methoxyplienyl)-N-{3- [(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 23 4-(5-Fluoro-2-methoxyphenyl)-N-{3- [(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 24 (rac)-N-[(3-{[4-(4-fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]acetamide 25 (rac)-Ethyl [(3-{[4-(2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 26 (rac)-4-(2-Methoxyphenyl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 27 4-(2-Methoxyphenyl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 28 4-(2-Methoxyphenyl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 29 (rac)-Ethyl [(3-{[4-(3,4-dihydro-2H- chromen-8-yl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 30 (rac)-4-(3,4-Dihydro-2H-chromen-8 - yl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 31 0 4-(3,4-Dihydro-2H-chromen-8-yl)-N- {3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 32 4-(3,4-Dihydro-2H-chromen-8-yl)-N- {3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 33 (rac)-Ethyl [(3-{[4-(2,3-dihydro-1- benzofuran-7-yl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 34 (rac)-4-(2,3-Dihydro-1-benzofuran-7- yl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 35 4-(2,3-Dihydro-1-benzofuran-7-yl)- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 36 4-(2,3-Dihydro-1-benzofuran-7-yl)- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 37 (rac)-Ethyl [(3-{[4-(2,3-dihydro-1,4- benzodioxin-5-yl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxide-.sup.6- sulfanylidene]carbamate 38 (rac)-4-(2,3-Dihydro-1,4- benzodioxin-5-yl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 39 4-(2,3-Dihydro-1,4-benzodioxin-5- yl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 40 4-(2,3-Dihydro-1,4-benzodioxin-5- yl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 41 0 (rac)-N-{3-[(N,S- Dimethylsulfonimidoyl)methyl]phenyl}- 4-(4-fluoro-2-methoxyphenyl)- 1,3,5-triazin-2-amine 42 (rac)-Ethyl[{3-[(4-{2-[(4- fluorobenzyl)oxy]phenyl}-1,3,5- triazin-2- yl)amino]benzyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 43 (rac)-4-{2-[(4- Fluorobenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 44 (rac)-N-[(3-{[4-(4-Fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]methanesulfonamide 45 (rac)-Ethyl [(3-{[4-(3-chloro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 46 (rac)-Ethyl {[3-({4-[5-fluoro-2- (tetrahydro-2H-pyran-4- ylmethoxy)phenyl]-1,3,5-triazin-2- yl}amino)benzyl](methyl)oxido-.sup.6- sulfanylidene}carbamate 47 (rac)-Ethyl [methyl(oxido)(3-{[4-(2- phenoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)-.sup.6- sulfanylidene]carbamate 48 (rac)-[(3-{[4-(4-fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]cyanamide 49 [(3-{[4-(4-fluoro-2-methoxyphenyl)- 1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]cyanamide; enantiomer 1 50 [(3-{[4-(4-fluoro-2-methoxyphenyl)- 1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]cyanamide; enantiomer 2 51 0 (rac)-Ethyl [(3-fluoro-5-{[4-(4-fluoro- 2-methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 52 (rac)-4-(4-Fluoro-2-methoxyphenyl)- N-{3-fluoro-5-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 53 4-(4-Fluoro-2-methoxyphenyl)-N-{3- fluoro-5-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 54 4-(4-Fluoro-2-methoxyphenyl)-N-{3- fluoro-5-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 55 (rac)-4-[2-(Cyclohexylmethoxy)-4- fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 56 (rac)-4-{4-Fluoro-2-[(4- fluorobenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 56.a 4-{4-Fluoro-2-[(4- fluorobenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 56.b 4-{4-Fluoro-2-[(4- fluorobenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 57 (rac)-4-{4-Fluoro-2-[2-(tetrahydro- 2H-pyran-4-yl)ethoxy]phenyl}-N-{3- [(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 58 (rac)-4-(4-Fluoro-2-methoxyphenyl)- N-(3-{[S-(tetrahydro-2H-pyran-4- yl)sulfonimidoyl]methyl}phenyl)- 1,3,5-triazin-2-amine 59 0 (rac)-N-{4-Chloro-3-[(S- methylsulfonimidoyl)methyl]phenyl}- 4-(4-fluoro-2-methoxyphenyl)-1,3,5- triazin-2-amine 59.a N-{4-Chloro-3-[(S- methylsulfonimidoyl)methyl]phenyl}- 4-(4-fluoro-2-methoxyphenyl)-1,3,5- triazin-2-amine; enantiomer 1 59.b N-{4-Chloro-3-[(S- methylsulfonimidoyl)methyl]phenyl}- 4-(4-fluoro-2-methoxyphenyl)-1,3,5- triazin-2-amine; enantiomer 2 60 (rac)-Ethyl [{3-[(4-{2-[(3,4- dichlorobenzyl)oxy]phenyl}-1,3,5- triazin-2- yl)amino]benzyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 61 (rac)-4-{2-[(3,4- Dichlorobenzyl)oxy]phenyl}-N-{3- [(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 62 (rac)-4-(4-Fluoro-2- {[(.sup.2H.sub.5)phenyl(.sup.2H.sub.2)methyl]oxy}phenyl)- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 63 4-[2-(1-cyclopentylethoxy)-4- fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine, mixture of all 4 stereoisomers 64 (rac)-N-{3-Chloro-5-[(S- methylsulfonimidoyl)methyl]phenyl}- 4-(4-fluoro-2-methoxyphenyl)-1,3,5- triazin-2-amine 65 (rac)-4-[4-Fluoro-2-(3,3,3- trifluoropropoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 66 (rac)-4-[4-Fluoro-2-(pyridin-3- ylmethoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 67 0 (rac)-4-[4-Fluoro-2-(pyridin-2- ylmethoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 68 (rac)-4-[4-Fluoro-2-(pyridin-4- ylmethoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 69 4-{4-Fluoro-2-[1-(4- fluorophenyl)ethoxy]phenyl}-N-{3- [(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine, mixture of 4 stereoisomers 70 (rac)-[(3-Fluoro-5-{[4-(4-fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl-.sup.6- sulfanylidene]cyanamide 71 [(3-Fluoro-5-{[4-(4-fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl-.sup.6- sulfanylidene]cyanamide; enantiomer 1 72 [(3-Fluoro-5-{[4-(4-fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl-.sup.6- sulfanylidene]cyanamide; enantiomer 2 73 (rac)-4-[2-(But-2-yn-1-yloxy)-4- fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 74 4-[2-(But-2-yn-1-yloxy)-4- fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 75 4-[2-(But-2-yn-1-yloxy)-4- fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 76 (rac)-4-[2-(2-Cyclopropylethoxy)-4- fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 77 0 (rac)-4-[4-Fluoro-2-(prop-2-yn-1- yloxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 78 4-[4-Fluoro-2-(prop-2-yn-1- yloxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 79 4-[4-Fluoro-2-(prop-2-yn-1- yloxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 80 (rac)-4-{2-[(3,4-Difluorobenzyl)oxy]- 4-fluorophenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 81 (rac)-4-[4-Fluoro-2-(1,3-thiazol-5- ylmethoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 82 (rac)-4-{4-Fluoro-2-[(2-fluoropyridin- 4-yl)methoxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazm-2-amine 83 4-{4-Fluoro-2-[(2-fluoropyridin-4- yl)methoxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 84 4-{4-Fluoro-2-[(2-fluoropyridin-4- yl)methoxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 85 (rac)-4-[4-Fluoro-2-(prop-2-en-1- yloxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 86 (rac)-4-(4-Fluoro-2-{[4- (trifluoromethyl)benzyl]oxy}phenyl)- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 87 00 (rac)-4-{2-[(4-Chlorobenzyl)oxy]-4- fluorophenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 88 01 (rac)-4-(2-Ethoxy-4-fluorophenyl)-N- {3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 89 02 (rac)-4-(4-Fluoro-2-{[3-fluoro-5- (trifluoromethyl)benzyl]oxy}phenyl)- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazm-2-amine 90 03 (rac)-4-{4-Fluoro-2-[(3- fluorobenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 91 04 (rac)-4-(4-Fluoro-2-propoxyphenyl)- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 92 05 (rac)-4-{2-[(3-Chlorobenzyl)oxy]-4- fluorophenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 93 06 (rac)-4-[4-Fluoro-2-(1,2-oxazol-3- ylmethoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 94 07 (rac)-4-{2-[(3-Chloro-5- fluorobenzyl)oxy]-4-fluorophenyl}- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 95 08 (rac)-4-[2-(2,2-Difluoroethoxy)-4- fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 96 09 (rac)-4-{4-Fluoro-2-[(4-fluoro-3- methylbenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 97 0 (rac)-4-{2-[(3-Chloro-4- fluorobenzyl)oxy]-4-fluorophenyl}- N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 98 (rac)-3-({5-Fluoro-2-[4-({3-[(S- methylsulfonimidoyl)methyl]phenyl} amino)-1,3,5-triazin-2- yl]phenoxy}methyl)benzonitrile 99 (rac)-4-{4-Fluoro-2-[(2-methylprop- 2-en-1-yl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 100 (rac)-4-[4-Fluoro-2-(4,4,4- trifluorobutoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 101 (rac)-4-{4-Fluoro-2-[(2,3,5- trifluorobenzyl)oxy]phenyl}-N-{3- [(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 102 (rac)-4-{2-[(2Z)-But-2-en-1-yloxy]-4- fluorophenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 103 (rac)-4-{4-Fluoro-2-[(2,4,5- trifluorobenzyl)oxy]phenyl}-N-{3- [(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 104 (rac)-4-{4-Fluoro-2-[(3,4,5- trifluorobenzyl)oxy]phenyl}-N-{3- [(S- methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 105 (rac)-[(2,3-Difluoro-5-{[4-(4-fluoro- 2-methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]cyanamide 106 (rac)-N-{3,4-Difluoro-5-[(S- methylsulfonimidoyl)methyl]phenyl}- 4-(4-fluoro-2-methoxyphenyl)-1,3,5- triazin-2-amine 107 0 (rac)-[Ethyl(3-{[4-(4-fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)oxido-.sup.6- sulfanylidene]cyanamide 108 (rac)-N-{3-[(S- ethylsulfonimidoyl)methyl]phenyl}- 4-(4-fluoro-2-methoxyphenyl)-1,3,5- triazin-2-amine 109 N-{3-[(S- ethylsulfonimidoyl)methyl]phenyl}- 4-(4-fluoro-2-methoxyphenyl)-1,3,5- triazin-2-amine; enantiomer 1 110 N-{3-[(S- ethylsulfonimidoyl)methyl]phenyl}- 4-(4-fluoro-2-methoxyphenyl)-1,3,5- triazin-2-amine; enantiomer 2 111 (rac)-[(3-{[4-(4-Fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}-5- methylbenzyl)(methyl)oxido-.sup.6- sulfanylidene]cyanamide 112 (rac)-2-({5-Fluoro-2-[4-({3-[(S- methylsulfonimidoyl)methyl]phenyl} amino)-1,3,5-triazin-2- yl]phenoxy}methyl)prop-2-en-1-ol 113 (rac)-[Cyclopropyl(3-{[4-(4-fluoro-2- methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)oxido-.sup.6- sulfanylidene]cyanamide
Results:

(596) TABLE-US-00089 TABLE 2 Inhibition of 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 or M, n.t. means that the compounds have not been tested in this assay. {circle around (1)} Nomenclature {circle around (2)} {circle around (3)} 1 (rac)-Ethyl [(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 16 nM 2200 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate 2 (rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S- 25 nM 2100 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 3 ()-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S- 16 nM 1700 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 4 (+)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S- 13 nM 1300 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 5 Ethyl {[3-({4-[2-(benzyloxy)-4-fluorophenyl]-1,3,5-triazin-2- 4 nM 250 nM yl}amino)benzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate 6 4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(S- 3 nM 220 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 9 (rac)-Ethyl [(3-{[4-(4,5-difluoro-2-methoxyphenyl)-1,3,5- 8 nM 690 nM triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 10 (rac)-4-(4,5-Difluoro-2-methoxyphenyl)-N-{3-[(S- 28 nM 1300 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 11 (rac)-Ethyl [(3-{[4-(4-chloro-2-methoxyphenyl)-1,3,5-triazin- 23 nM 5500 nM 2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate 12 (rac) 4-(4-Chloro-2-methoxyphenyl)-N-{3-[(S- 74 nM 6800 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 13 4-(4-Chloro-2-methoxyphenyl)-N-{3-[(S- 93 nM 9500 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 14 4-(4-Chloro-2-methoxyphenyl)-N-{3-[(S- 160 nM 13000 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 15 (rac)-1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 7 nM 930 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]-3- methylurea 16 1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 19 nM 1100 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]-3- methylurea; enantiomer 1 17 1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 14 nM 1200 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]-3- methylurea; enantiomer 2 18 (rac)-Ethyl [(3-{[4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1,3,5- 33 nM 3900 nM triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 19 (rac)-4-(2,2-Difluoro-1,3-benzodioxol-4-yl)-N-{3-[(S- 59 nM 2100 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 20 (rac)-Ethyl [(3-{[4-(5-fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 22 nM 2000 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate 21 (rac)-4-(5-Fluoro-2-methoxyphenyl)-N-{3-[(S- 56 nM 3500 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 22 4-(5-Fluoro-2-methoxyphenyl)-N-{3-[(S- 91 nM 2800 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 23 4-(5-Fluoro-2-methoxyphenyl)-N-{3-[(S- 110 nM 5600 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 24 (rac)-N-[(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 11 nM 1800 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]acetamide 25 (rac)-Ethyl [(3-{[4-(2-methoxyphenyl)-1,3,5-triazin-2- 28 nM 6300 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate 26 (rac)-4-(2-Methoxyphenyl)-N-{3-[(S- 35 nM 4600 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 27 4-(2-Methoxyphenyl)-N-{3-[(S- 100 nM 7600 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 28 4-(2-Methoxyphenyl)-N-{3-[(S- 89 nM 5900 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 29 (rac)-Ethyl [(3-{[4-(3,4-dihydro-2H-chromen-8-yl)-1,3,5- 13 nM 1200 nM triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 30 (rac)-4-(3,4-Dihydro-2H-chromen-8-yl)-N-{3-[(S- 21 nM 940 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 31 4-(3,4-Dihydro-2H-chromen-8-yl)-N-{3-[(S- 22 nM 670 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 32 4-(3,4-Dihydro-2H-chromen-8-yl)-N-{3-[(S- 40 nM 1600 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 33 (rac)-Ethyl [(3-{[4-(2,3-dihydro-1-benzofuran-7-yl)-1,3,5- 21 nM 3100 nM triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 34 (rac)-4-(2,3-Dihydro-1-benzofuran-7-yl)-N-{3-[(S- 68 nM 2200 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 35 4-(2,3-Dihydro-1-benzofuran-7-yl)-N-{3-[(S- 64 nM 3100 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 36 4-(2,3-Dihydro-1-benzofuran-7-yl)-N-{3-[(S- 50 nM 2900 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 37 (rac)-Ethyl [(3-{[4-(2,3-dihydro-1,4-benzodioxin-5-yl)-1,3,5- 9 nM 2300 nM triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 38 (rac)-4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-N-{3-[(S- 14 nM 1600 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 39 4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-N-{3-[(S- 29 nM 1500 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 40 4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-N-{3-[(S- 25 nM 1800 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 41 (rac)-N-{3-[(N,S-Dimethylsulfonimidoyl)methyl]phenyl}-4-(4- 36 nM 2600 nM fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine 42 (rac)-Ethyl [{3-[(4-{2-[(4-fluorobenzyl)oxy]phenyl}-1,3,5- 5 nM 1600 nM triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 43 (rac)-4-{2-[(4-Fluorobenzyl)oxy]phenyl}-N-{3-[(S- 9 nM 1900 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 44 (rac)-N-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 20 nM 1800 nM yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]methanesulfonamide 45 (rac)-Ethyl [(3-{[4-(3-chloro-2-methoxyphenyl)-1,3,5-triazin- 820 nM 9000 nM 2-yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]carbamate 46 (rac)-Ethyl {[3-({4-[5-fluoro-2-(tetrahydro-2H-pyran-4- 120 nM 11000 nM ylmethoxy)phenyl]-1,3,5-triazin-2- yl}amino)benzyl](methyl)oxido-.sup.6-sulfanylidene}carbamate 47 (rac)-Ethyl [methyl(oxido)(3-{[4-(2-phenoxyphenyl)-1,3,5- 35 nM 6500 nM triazin-2-yl]amino}benzyl)-.sup.6-sulfanylidene]carbamate 48 (rac)-[(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 13 nM 630 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]cyanamide 49 [(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 7 nM 650 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]cyanamide; enantiomer 1 50 [(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 7 nM 430 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]cyanamide; enantiomer 2 51 (rac)-Ethyl [(3-fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5- 10 nM 430 nM triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 52 (rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S- 17 nM 1000 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 53 4-(4-Fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S- 16 nM 540 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 54 4-(4-Fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S- 16 nM 850 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 55 (rac)-4-[2-(Cyclohexylmethoxy)-4-fluorophenyl]-N-{3-[(S- 10 nM 2200 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 56 (rac)-4-{4-Fluoro-2-[(4-fluorobenzyl)oxy]phenyl}-N-{3-[(S- 6 nM 410 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 56.a 4-{4-Fluoro-2-[(4-fluorobenzyl)oxy]phenyl}-N-{3-[(S- 4 nM 560 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 56.b 4-{4-Fluoro-2-[(4-fluorobenzyl)oxy]phenyl}-N-{3-[(S- 5 nM 560 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 57 (rac)-4-{4-Fluoro-2-[2-(tetrahydro-2H-pyran-4- 370 nM 8300 nM yl)ethoxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 58 (rac)-4-(4-Fluoro-2-methoxyphenyl)-N-(3-{[S-(tetrahydro-2H- 89 nM 5200 nM pyran-4-yl)sulfonimidoyl]methyl}phenyl)-1,3,5-triazin-2- amine 59 (rac)-N-{4-Chloro-3-[(S-methylsulfonimidoyl)methyl]phenyl}- 26 nM 1400 nM 4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine 59.a N-{4-Chloro-3-[(S-methylsulfonimidoyl)methyl]phenyl}-4-(4- 25 nM 2900 nM fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine; enantiomer 1 59.b N-{4-Chloro-3-[(S-methylsulfonimidoyl)methyl]phenyl}-4-(4- 33 nM 1800 nM fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine; enantiomer 2 60 (rac)-Ethyl [{3-[(4-{2-[(3,4-dichlorobenzyl)oxy]phenyl}-1,3,5- 13 nM 3300 nM triazin-2-yl)amino]benzyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 61 (rac)-4-{2-[(3,4-Dichlorobenzyl)oxy]phenyl}-N-{3-[(S- 15 nM 1200 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 62 (rac)-4-(4-Fluoro-2-{[(.sup.2H.sub.5)phenyl(.sup.2H.sub.2)methyl]oxy}phenyl)-N- 7 nM 220 nM {3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2- amine 63 4-[2-(1-cyclopentylethoxy)-4-fluorophenyl]-N-{3-[(S- 99 nM n.t. methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine, mixture of all 4 stereoisomers 64 (rac)-N-{3-Chloro-5-[(S-methylsulfonimidoyl)methyl]phenyl}- 15 nM 250 nM 4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine 65 (rac)-4-[4-Fluoro-2-(3,3,3-trifluoropropoxy)phenyl]-N-{3-[(S- 79 nM 6000 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 66 (rac)-4-[4-Fluoro-2-(pyridin-3-ylmethoxy)phenyl]-N-{3-[(S- 24 nM 1600 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 67 (rac)-4-[4-Fluoro-2-(pyridin-2-ylmethoxy)phenyl]-N-{3-[(S- 97 nM 6900 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 68 (rac)-4-[4-Fluoro-2-(pyridin-4-ylmethoxy)phenyl]-N-{3-[(S- 14 nM 1500 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 69 4-{4-Fluoro-2-[1-(4-fluorophenyl)ethoxy]phenyl}-N-{3-[(S- 22 nM 3500 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine, mixture of 4 stereoisomers 70 (rac)-[(3-Fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5- 6 nM 180 nM triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]cyanamide 71 [(3-Fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 6 nM 230 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]cyanamide; enantiomer 1 72 [(3-Fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 5 nM 240 nM yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]cyanamide; enantiomer 2 73 (rac)-4-[2-(But-2-yn-1-yloxy)-4-fluorophenyl]-N-{3-[(S- 8 nM 820 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 74 4-[2-(But-2-yn-1-yloxy)-4-fluorophenyl]-N-{3-[(S- 3 nM 590 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 75 4-[2-(But-2-yn-1-yloxy)-4-fluorophenyl]-N-{3-[(S- 4 nM 450 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 76 (rac)-4-[2-(2-Cyclopropylethoxy)-4-fluorophenyl]-N-{3-[(S- 30 nM 3200 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 77 (rac)-4-[4-Fluoro-2-(prop-2-yn-1-yloxy)phenyl]-N-{3-[(S- 15 nM 1600 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 78 4-[4-Fluoro-2-(prop-2-yn-1-yloxy)phenyl]-N-{3-[(S- 9 nM 580 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 79 4-[4-Fluoro-2-(prop-2-yn-1-yloxy)phenyl]-N-{3-[(S- 5 nM 440 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 80 (rac)-4-{2-[(3,4-Difluorobenzyl)oxy]-4-fluorophenyl}-N-{3- 13 nM 1000 nM [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 81 (rac)-4-[4-Fluoro-2-(1,3-thiazol-5-ylmethoxy)phenyl]-N-{3- 23 nM 1500 nM [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 82 (rac)-4-{4-Fluoro-2-[(2-fluoropyridin-4-yl)methoxy]phenyl}- 7 nM 360 nM N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2- amine 83 4-{4-Fluoro-2-[(2-fluoropyridin-4-yl)methoxy]phenyl}-N-{3- 2 nM 270 nM [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2- amine; enantiomer 1 84 4-{4-Fluoro-2-[(2-fluoropyridin-4-yl)methoxy]phenyl}-N-{3- 3 nM 220 nM [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2- amine; enantiomer 2 85 (rac)-4-[4-Fluoro-2-(prop-2-en-1-yloxy)phenyl]-N-{3-[(S- 9 nM 380 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 86 (rac)-4-(4-Fluoro-2-{[4-(trifluoromethyl)benzyl]oxy}phenyl)- 8 nM 1400 nM N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2- amine 87 (rac)-4-{2-[(4-Chlorobenzyl)oxy]-4-fluorophenyl}-N-{3-[(S- 3 nM 680 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 88 (rac)-4-(2-Ethoxy-4-fluorophenyl)-N-{3-[(S- 11 nM 1300 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 89 (rac)-4-(4-Fluoro-2-{[3-fluoro-5- 4 nM 280 nM (trifluoromethyl)benzyl]oxy}phenyl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 90 (rac)-4-{4-Fluoro-2-[(3-fluorobenzyl)oxy]phenyl}-N-{3-[(S- 2 nM 260 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 91 (rac)-4-(4-Fluoro-2-propoxyphenyl)-N-{3-[(S- 29 nM 2300 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 92 (rac)-4-{2-[(3-Chlorobenzyl)oxy]-4-fluorophenyl}-N-{3-[(S- 4 nM 250 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 93 (rac)-4-[4-Fluoro-2-(1,2-oxazol-3-ylmethoxy)phenyl]-N-{3- 7 nM 2000 nM [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 94 (rac)-4-{2-[(3-Chloro-5-fluorobenzyl)oxy]-4-fluorophenyl}-N- 3 nM 230 nM {3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2- amine 95 (rac)-4-[2-(2,2-Difluoroethoxy)-4-fluorophenyl]-N-{3-[(S- 21 nM 1800 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 96 (rac)-4-{4-Fluoro-2-[(4-fluoro-3-methylbenzyl)oxy]phenyl}-N- 3 nM 350 nM {3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2- amine 97 (rac)-4-{2-[(3-Chloro-4-fluorobenzyl)oxy]-4-fluorophenyl}-N- 3 nM 200 nM {3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2- amine 98 (rac)-3-({5-Fluoro-2-[4-({3-[(S- 3 nM 180 nM methylsulfonimidoyl)methyl]phenyl}amino)-1,3,5-triazin-2- yl]phenoxy}methyl)benzonitrile 99 (rac)-4-{4-Fluoro-2-[(2-methylprop-2-en-1-yl)oxy]phenyl}-N- 2 nM 250 nM {3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2- amine 100 (rac)-4-[4-Fluoro-2-(4,4,4-trifluorobutoxy)phenyl]-N-{3-[(S- 6 nM 1300 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 101 (rac)-4-{4-Fluoro-2-[(2,3,5-trifluorobenzyl)oxy]phenyl}-N-{3- 4 nM 500 nM [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 102 (rac)-4-{2-[(2Z)-But-2-en-1-yloxy]-4-fluorophenyl}-N-{3-[(S- 7 nM 800 nM methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 103 (rac)-4-{4-Fluoro-2-[(2,4,5-trifluorobenzyl)oxy]phenyl}-N-{3- 7 nM 1200 nM [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 104 (rac)-4-{4-Fluoro-2-[(3,4,5-trifluorobenzyl)oxy]phenyl}-N-{3- 2 nM 54 nM [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 105 (rac)-[(2,3-Difluoro-5-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5- 3 nM 140 nM triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]cyanamide 106 (rac)-N-{3,4-Difluoro-5-[(S- 7 nM 400 nM methylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2- methoxyphenyl)-1,3,5-triazin-2-amine 107 (rac)-[Ethyl(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 4 nM 360 nM yl]amino}benzyl)oxido-.sup.6-sulfanylidene]cyanamide 108 (rac)-N-{3-[(S-ethylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro- 8 nM 1000 nM 2-methoxyphenyl)-1,3,5-triazin-2-amine 109 N-{3-[(S-ethylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2- 24 780 methoxyphenyl)-1,3,5-triazin-2-amine; enantiomer 1 110 N-{3-[(S-ethylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro-2- 9 1100 methoxyphenyl)-1,3,5-triazin-2-amine; enantiomer 2 111 (rac)-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 3 nM 250 nM yl]amino}-5-methylbenzyl)(methyl)oxido-.sup.6- sulfanylidene]cyanamide 112 (rac)-2-({5-Fluoro-2-[4-({3-[(S- 4 nM 730 nM methylsulfonimidoyl)methyl]phenyl}amino)-1,3,5-triazin-2- yl]phenoxy}methyl)prop-2-en-1-ol 113 (rac)-[Cyclopropyl(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5- 2 nM 300 nM triazin-2-yl]amino}benzyl)oxido-.sup.6-sulfanylidene]cyanamide {circle around (1)}: Compound Number {circle around (2)}: CDK9 CDK9/CycT1 kinase assay as described under Method 1. of Materials and Methods {circle around (3)}: CDK2 CDK2/CycE kinase assay as described under Method 2. of Materials and Methods

(597) TABLE-US-00090 TABLE 3 Inhibition of proliferation of HeLa, HeLa/MaTu/ADR, NCI-H460, DU145, Caco-2 and B16F10 cells by compounds according to the present invention. Determined as described above (Method 3. of Materials and Methods section). {circle around (1)} Nomenclature {circle around (2)} {circle around (3)} {circle around (4)} {circle around (5)} {circle around (6)} {circle around (7)} 1 (rac)-Ethyl [(3-{[4-(4-fluoro-2-methoxyphenyl)- 1000 380 360 390 390 360 1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido- .sup.6-sulfanylidene]carbamate 2 (rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S- 1100 n.t. n.t. n.t. n.t. n.t. methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 3 ()-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S- 1100 400 1300 740 1300 1000 methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine; enantiomer 1 4 (+)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S- 970 440 1200 670 1300 1000 methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine; enantiomer 2 5 Ethyl {[3-({4-[2-(benzyloxy)-4-fluorophenyl]- 100 270 210 260 250 270 1,3,5-triazin-2-yl}amino)benzyl](methyl)oxido- .sup.6-sulfanylidene}carbamate 6 4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(S- <100 200 160 180 270 250 methylsulfonimidoyl)methyl]phenyl}-1,3,5- tiazin-2-amine 9 (rac)-Ethyl [(3-{[4-(4,5-difluoro-2- 400 960 980 900 800 1000 methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 10 (rac)-4-(4,5-Difluoro-2-methoxyphenyl)-N-{3- 1100 n.t. n.t. n.t. n.t. n.t. [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 15 (rac)-1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)- 390 940 1000 370 1000 620 1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido- .sup.6-sulfanylidene]-3-methylurea 16 1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5- 950 n.t. n.t. n.t. n.t. n.t. triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]-3-methylurea; enantiomer 1 17 1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5- 580 600 540 580 800 410 triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]-3-methylurea; enantiomer 2 24 (rac)-N-[(3-{[4-(4-fluoro-2-methoxyphenyl)- 490 520 760 680 710 940 1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido- .sup.6-sulfanylidene]acetamide 25 (rac)-Ethyl [(3-{[4-(2-methoxyphenyl)-1,3,5- 1100 n.t. n.t. n.t. n.t. n.t. triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 29 (rac)-Ethyl [(3-{[4-(3,4-dihydro-2H-chromen-8- 510 760 720 540 760 960 yl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 30 (rac)-4-(3,4-Dihydro-2H-chromen-8-yl)-N-{3- 1200 n.t. n.t. n.t. n.t. n.t. [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 37 (rac)-Ethyl[(3-{[4-(2,3-dihydro-1,4- 630 750 920 500 810 720 benzodioxin-5-yl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 39 4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-N-{3-[(S- 1100 n.t. n.t. n.t. n.t. n.t. methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine; enantiomer 1 40 4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-N-{3-[(S- 1100 n.t. n.t. n.t. n.t. n.t. methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine; enantiomer 2 42 (rac)-Ethyl[{3-[(4-{2-[(4- 610 520 370 590 680 680 fluorobenzyl)oxy]phenyl}-1,3,5-triazin-2- yl)amino]benzyl}(methyl)oxido-.sup.6- sulfanylidene]carbamate 43 (rac)-4-{2-[(4-Fluorobenzyl)oxy]phenyl}-N-{3- 590 1100 530 800 1100 800 [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 44 (rac)-N-[(3-{[4-(4-Fluoro-2-methoxyphenyl)- 1000 n.t. n.t. n.t. n.t. n.t. 1,3,5-triazin-2-yl]amino}benzyl)(methyl)oxido- .sup.6-sulfanylidene]methanesulfonamide 48 (rac)-[(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5- 330 400 410 280 420 320 triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]cyanamide 50 [(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5- 260 190 310 140 350 250 triazin-2-yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]cyanamide; enantiomer 2 51 (rac)-Ethyl [(3-fluoro-5-{[4-(4-fluoro-2- 300 240 230 240 290 340 methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]carbamate 52 (rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3- 410 140 650 340 690 550 fluoro-5-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 55 (rac)-4-[2-(Cyclohexylmethoxy)-4- 1000 850 980 990 890 n.t. fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 56 (rac)-4-{4-Fluoro-2-[(4- 370 780 350 370 860 470 fluorobenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 56.a 4-{4-Fluoro-2-[(4-fluorobenzyl)oxy]phenyl}-N- 350 270 340 340 430 340 {3-[(S-methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 56.b 4-{4-Fluoro-2-[(4-fluorobenzyl)oxy]phenyl}-N- 540 540 470 400 540 390 {3-[(S-methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 59 (rac)-N-{4-Chloro-3-[(S- 860 n.t. n.t. n.t. n.t. n.t. methylsulfonimidoyl)methyl]phenyl}-4-(4- fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine 59.a N-{4-Chloro-3-[(S- 1100 n.t. n.t. n.t. n.t. n.t. methylsulfonimidoyl)methyl]phenyl}-4-(4- fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine; enantiomer 1 59.b N-{4-Chloro-3-[(S- 1100 n.t. n.t. n.t. n.t. n.t. methylsulfonimidoyl)methyl]phenyl}-4-(4- fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine; enantiomer 2 64 (rac)-N-{3-Chloro-5-[(S- 400 280 360 290 350 320 methylsulfonimidoyl)methyl]phenyl}-4-(4- fluoro-2-methoxyphenyl)-1,3,5-triazin-2-amine 66 (rac)-4-[4-Fluoro-2-(pyridin-3- 1700 n.t. n.t. n.t. n.t. n.t. ylmethoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 68 (rac)-4-[4-Fluoro-2-(pyridin-4- 410 3000 1100 460 1300 740 ylmethoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 70 (rac)-[(3-Fluoro-5-{[4-(4-fluoro-2- 150 120 230 79 170 130 methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl-.sup.6- sulfanylidene]cyanamide 71 [(3-Fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)- 100 120 160 120 130 110 1,3,5-triazin-2-yl]amino}benzyl)(methyl-.sup.6- sulfanylidene]cyanamide; enantiomer 1 72 [(3-Fluoro-5-{[4-(4-fluoro-2-methoxyphenyl)- 71 120 160 110 190 160 1,3,5-triazin-2-yl]amino}benzyl)(methyl-.sup.6- sulfanylidene]cyanamide; enantiomer 2 73 (rac)-4-[2-(But-2-yn-1-yloxy)-4-fluorophenyl]- 240 280 260 200 300 150 N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 74 4-[2-(But-2-yn-1-yloxy)-4-fluorophenyl]-N-{3- 310 340 330 360 390 340 (S-methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine; enantiomer 1 75 4-[2-(But-2-yn-1-yloxy)-4-fluorophenyl]-N-{3- 260 210 220 170 310 240 [(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine; enantiomer 2 76 (rac)-4-[2-(2-Cyclopropylethoxy)-4- 1100 n.t. n.t. n.t. n.t. n.t. fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 77 (rac)-4-[4-Fluoro-2-(prop-2-yn-1-yloxy)phenyl]- 470 630 560 480 300 520 N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 78 4-[4-Fluoro-2-(prop-2-yn-1-yloxy)phenyl]-N- 650 260 390 370 760 500 {3-[(S-methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 1 79 4-[4-Fluoro-2-(prop-2-yn-1-yloxy)phenyl]-N- 440 350 420 380 390 370 {3-[(S-methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine; enantiomer 2 80 (rac)-4-{2-[(3,4-Difluorobenzyl)oxy]-4- 730 n.t. n.t. n.t. n.t. n.t. fluorophenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 81 (rac)-4-[4-Fluoro-2-(1,3-thiazol-5- 860 n.t. n.t. n.t. n.t. n.t. ylmethoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 82 (rac)-4-{4-Fluoro-2-[(2-fluoropyridin-4- 180 190 180 130 180 150 yl)methoxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 83 4-{4-Fluoro-2-[(2-fluoropyridin-4- 110 640 180 180 210 220 yl)methoxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine; enantiomer 1 84 4-{4-Fluoro-2-[(2-fluoropyridin-4- 120 340 180 180 180 210 yl)methoxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine; enantiomer 2 85 (rac)-4-[4-Fluoro-2-(prop-2-en-1-yloxy)phenyl]- 330 560 230 190 51 280 N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2-amine 86 (rac)-4-(4-Fluoro-2-{[4- 1100 n.t. n.t. n.t. n.t. n.t. (trifluoromethyl)benzyl]oxy}phenyl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 87 (rac)-4-{2-[(4-Chlorobenzyl)oxy]-4- 560 450 570 610 800 590 fluorophenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 88 (rac)-4-(2-Ethoxy-4-fluorophenyl)-N-{3-[(S- 380 700 890 730 780 810 methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 89 (rac)-4-(4-Fluoro-2-{[3-fluoro-5- 470 450 370 420 520 470 (trifluoromethyl)benzyl]oxy}phenyl)-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 90 (rac)-4-{4-Fluoro-2-[(3- 170 100 110 110 80 100 fluorobenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 91 (rac)-4-(4-Fluoro-2-propoxyphenyl)-N-{3-[(S- 1100 n.t. n.t. n.t. n.t. n.t. methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 92 (rac)-4-{2-[(3-Chlorobenzyl)oxy]-4- 470 360 170 380 430 390 fluorophenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 93 (rac)-4-[4-Fluoro-2-(1,2-oxazol-3- 680 n.t. n.t. n.t. n.t. n.t. ylmethoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 94 (rac)-4-{2-[(3-Chloro-5-fluorobenzyl)oxy]-4- 110 190 200 140 220 180 fluorophenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 95 (rac)-4-[2-(2,2-Difluoroethoxy)-4- 1100 n.t. n.t. n.t. n.t. n.t. fluorophenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 96 (rac)-4-{4-Fluoro-2-[(4-fluoro-3- 1000 n.t. n.t. n.t. n.t. n.t. methylbenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 97 (rac)-4-{2-[(3-Chloro-4-fluorobenzyl)oxy]-4- 940 n.t. n.t. n.t. n.t. n.t. fluorophenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 98 (rac)-3-({5-Fluoro-2-[4-({3-[(S- 140 260 120 120 150 130 methylsulfonimidoyl)methyl]phenyl}amino)- 1,3,5-triazin-2-yl]phenoxy} methyl)benzonitrile 99 (rac)-4-{4-Fluoro-2-[(2-methylprop-2-en-1- 120 180 150 120 230 200 yl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 100 (rac)-4-[4-Fluoro-2-(4,4,4- 920 n.t. n.t. n.t. n.t. n.t. trifluorobutoxy)phenyl]-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 101 (rac)-4-{4-Fluoro-2-[(2,3,5- 330 350 360 340 240 340 trifluorobenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 102 (rac)-4-{2-[(2Z)-But-2-en-1-yloxy]-4- 340 140 150 95 160 140 fluorophenyl}-N-{3-[(S-methylsulfonimidoyl) methyl]phenyl}-1,3,5-triazin-2-amine 103 (rac)-4-{4-Fluoro-2-[(2,4,5- 1100 n.t. n.t. n.t. n.t. n.t. trifluorobenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 104 (rac)-4-{4-Fluoro-2-[(3,4,5- 110 240 110 120 150 120 trifluorobenzyl)oxy]phenyl}-N-{3-[(S- methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine 105 (rac)-[(2,3-Difluoro-5-{[4-(4-fluoro-2- 110 71 130 120 81 140 methoxyphenyl)-1,3,5-triazin-2- yl]amino}benzyl)(methyl)oxido-.sup.6- sulfanylidene]cyanamide 107 (rac)-[Ethyl(3-{[4-(4-fluoro-2-methoxyphenyl)- 230 340 450 280 500 300 1,3,5-triazin-2-yl]amino}benzyl)oxido-.sup.6- sulfanylidene]cyanamide 108 (rac)-N-{3-[(S- 1000 n.t. n.t. n.t. n.t. n.t. ethylsulfonimidoyl)methyl]phenyl}-4-(4-fluoro- 2-methoxyphenyl)-1,3,5-triazin-2-amine 111 (rac)-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5- 100 170 270 110 220 130 triazin-2-yl]amino}-5-methylbenzyl) (methyl)oxido-.sup.6-sulfanylidene]cyanamide 112 (rac)-2-({5-Fluoro-2-[4-({3-[(S- 330 390 320 300 350 320 methylsulfonimidoyl)methyl]phenyl}amino)- 1,3,5-triazin-2-yl]phenoxy} methyl)prop-2-en-1- ol 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 this assay. {circle around (1)}: Compound 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

(598) TABLE-US-00091 TABLE 4 Thermodynamic solubility of compounds according to the present invention in water at pH 6.5 as determined by the equilibrium shake flask method described under Method 4. of Materials and Methods. {circle around (1)} Nomenclature {circle around (2)} 3 ()-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S- 601 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 4 (+)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S- 479 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 10 (rac)-4-(4,5-Difluoro-2-methoxyphenyl)-N-{3-[(S- 130 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 16 1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 323 yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]-3-methylurea; enantiomer 1 17 1-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 429 yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]-3-methylurea; enantiomer 2 22 4-(5-Fluoro-2-methoxyphenyl)-N-{3-[(S- 787 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 23 4-(5-Fluoro-2-methoxyphenyl)-N-{3-[(S- 888 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 31 4-(3,4-Dihydro-2H-chromen-8-yl)-N-{3-[(S- 1000 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 32 4-(3,4-Dihydro-2H-chromen-8-yl)-N-{3-[(S- 1000 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 39 4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-N-{3-[(S- 819 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 1 40 4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-N-{3-[(S- 865 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 49 [(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 88 yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]cyanamide; enantiomer 1 50 [(3-{[4-(4-fluoro-2-methoxyphenyl)-1,3,5-triazin-2- 126 yl]amino}benzyl)(methyl)oxido-.sup.6-sulfanylidene]cyanamide; enantiomer 2 54 4-(4-Fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(S- 120 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine; enantiomer 2 73 (rac)-4-[2-(But-2-yn-1-yloxy)-4-fluorophenyl]-N-{3-[(S- 1220 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 77 (rac)-4-[4-Fluoro-2-(prop-2-yn-1-yloxy)phenyl]-N-{3-[(S- 256 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 88 (rac)-4-(2-Ethoxy-4-fluorophenyl)-N-{3-[(S- 884 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine 91 (rac)-4-(4-Fluoro-2-propoxyphenyl)-N-{3-[(S- 104 methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine {circle around (1)}: Compound Number {circle around (2)}: Solubilty in mg/l.

(599) TABLE-US-00092 TABLE 5 Inhibition of Carbonic anhydrase-1 and Carbonic anhydrase-2 as determined by the Carbonic anhydrase Assay described above {circle around (1)} Nomenclature {circle around (2)} {circle around (3)} 3 4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S- >1.0E05 >1.0E05 methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine; enantiomer 1 4 4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S- >1.0E05 >1.0E05 methylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-2-amine; enantiomer 2 {circle around (1)}: Compound Number {circle around (2)}: Inhibition of Carbonic anhydrase-1: the IC.sub.50 (inhibitory concentration at 50% of maximal effect) values are indicated in (mol/l) {circle around (3)} Inhibition of Carbonic anhydrase-2: the IC.sub.50 (inhibitory concentration at 50% of maximal effect) values are indicated in (mol/l)