Substituted aminothiazoles as DGKzeta inhibitors for immune activation

Abstract

The present invention covers aminothiazole compounds of general formula (I), in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment and/or prophylaxis of diseases, in particular of diacylglycerol kinase zeta (DGK?) regulated disorders, as a sole agent or in combination with other active ingredients.

Claims

1. A compound having the structure: ##STR00756## or a tautomer, hydrate, or solvate thereof, or a pharmaceutically acceptable salt of any of the foregoing.

2. The compound of claim 1, wherein the compound is ##STR00757## or a tautomer, hydrate, or solvate thereof, or a pharmaceutically acceptable salt of any of the foregoing.

3. The compound of claim 1, wherein the compound is ##STR00758## or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound is ##STR00759##

5. A pharmaceutical composition comprising a compound of claim 2, or a tautomer, hydrate, or solvate thereof, or a pharmaceutically acceptable salt of any of the foregoing, and at least one pharmaceutically acceptable excipient.

6. A pharmaceutical composition comprising a compound of claim 3, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

7. A pharmaceutical composition comprising a compound of claim 4 and at least one pharmaceutically acceptable excipient.

8. A method of treating a disease or condition associated with dysregulated immune responses or aberrant DGK? signaling in a mammal, comprising administering an effective amount of a compound of claim 2, or a tautomer, hydrate, or solvate thereof, or a pharmaceutically acceptable salt of any of the foregoing, to the mammal.

9. The method of claim 8, wherein the mammal is a human.

10. The method of claim 8, wherein the disease is cancer.

11. The method of claim 8, wherein the disease is non-small cell lung cancer, gastric adenocarcinoma, cancer of the gastroesophageal junction, clear cell renal cell carcinoma, or melanoma.

12. The method of claim 8, wherein the disease is non-small cell lung cancer.

13. The method of claim 8, wherein the disease is gastric adenocarcinoma.

14. The method of claim 8, wherein the disease is cancer of the gastroesophageal junction.

15. The method of claim 8, wherein the disease is clear cell renal cell carcinoma.

16. The method of claim 8, wherein the disease is melanoma.

17. A method of treating a disease or condition associated with dysregulated immune responses or aberrant DGK? signaling in a mammal, comprising administering an effective amount of a compound of claim 3, or a pharmaceutically acceptable salt thereof, to the mammal.

18. The method of claim 17, wherein the compound is ##STR00760##

19. The method of claim 17, wherein the mammal is a human.

20. The method of claim 17, wherein the disease is cancer.

21. The method of claim 17, wherein the disease is non-small cell lung cancer, gastric adenocarcinoma, cancer of the gastroesophageal junction, clear cell renal cell carcinoma, or melanoma.

22. The method of claim 17, wherein the disease is non-small cell lung cancer.

23. The method of claim 17, wherein the disease is gastric adenocarcinoma.

24. The method of claim 17, wherein the disease is cancer of the gastroesophageal junction.

25. The method of claim 17, wherein the disease is clear cell renal cell carcinoma.

26. The method of claim 17, wherein the disease is melanoma.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1: DGKz_hu_1 encoding human DGK? M1 to V928 plus N-terminal Flag-Tag, as described under SEQ ID No. 1.

(2) FIG. 2: SIINFEKL amino acid sequence, as described under SEQ ID No. 2.

(3) FIG. 3: OVA-30 peptide sequence, as described under SEQ ID No. 3.

(4) FIG. 4: FLAG-Tag, as described under SEQ ID No. 4.

(5) FIG. 5: Kozak sequence for translation initiation, as described under SEQ ID No. 5.

(6) FIG. 6: 50% thermal ellipsoids of Example 49.2, Molecule 1. F171 and F151 represents the two refined positions for the 180? disorder over the C13-C16 axis.

(7) FIG. 7: 50% thermal ellipsoids of Example 59.1, Molecule 1

(8) FIG. 8: 50% thermal ellipsoids of Example 61.2, Molecule 1

(9) FIG. 9: 50% thermal ellipsoids of Example 62.2, Molecule 1

EXPERIMENTAL SECTIONGENERAL PART

(10) NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. The multiplicities are stated according to the signal form which appears in the spectrum, NMR-spectroscopic effects of a higher order were not taken into consideration. Multiplicity of the NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, br=broad signal, m=multiplet. NMR signals: shift in [ppm]. Combinations of multiplicity could be e.g. dd=doublet from doublet.

(11) Chemical names were generated using software programs such as the ACD/Name batch version 14.05 from ACD/Labs and BioVia Draw 2019 Version 19.1 NET, and chemical names were adapted if needed. In some cases generally accepted names of commercially available reagents were used in place of chemical names generated using abovementioned software programs.

(12) All reagents the synthesis of which is not described in the experimental part were purchased commercially, or said reagents are known compounds or can be formed from known compounds by known methods by a person skilled in the art.

(13) Table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.

(14) TABLE-US-00001 TABLE 1 Abbreviations CDCl.sub.3 deuterochloroform DAD diode array detector SQD single quadrupole detector Azura UVD single variable wavelength UV detector for HPLC DMF N,N-dimethylformamide DMSO-d6 deuterated dimethyl sulphoxide DMSO dimethyl sulphoxide ELSD evaporative light scattering detector ESIpos electrospray ionization positive Expl. example HATU (7-aza-1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate HPLC high-pressure liquid chromatography LC-MS liquid chromatography coupled with mass spectrometry mL milliliter min minute(s) MTBE methyl tert-butyl ether RP-HPLC reverse-phase high-pressure liquid chromatography Rt retention time rt room temperature sat. saturated THF tetrahydrofurane EtOAc ethyl acetate TLC thin layer chromatography rac racemic ?M micromolar M molar UPLC Ultra high performance chromatography UPLC-MS Ultra high performance chromatography coupled with mass spectrometry BEH ethylene bridged hybrid CSH charged surface hybrid UV ultra violet CAS-RN chemical abstracts service registry number NMR nuclear magnetic resonance MHz Megahertz

(15) Analytical UPLC-MS Standard Procedures

(16) Method 1/Acidic

(17) Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50?2.1 mm; eluent A: water+0.1 vol % formic acid, eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60? C.; injection: 2 ?L; DAD scan: 210-400 nm; ELSD

(18) Method 2/Basic

(19) Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50?2.1 mm; eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60? C.; injection: 2 ?L; DAD scan: 210-400 nm; ELSD

(20) Method 3/Basic

(21) Instrument: Waters Acquity UPLC-MS SingleQuad; Column: Acquity UPLC CSH C18 1.7 ?m 50?2.1 mm; eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60? C.; DAD scan: 210-400 nm.

(22) Optical Rotation

(23) Optical rotations were measured with a JASCO Polarimeter 2000 using the solvent and concentration stated in each case at 20? C., wavelength 589 nm, integration time 10 s, layer thickness 100 mm.

(24) Compound PurificationGeneral

(25) The example compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartridges KP-Sil? or KP-NH? in combination with a Biotage autopurifier system (SP4? or Isolera Four?) and eluents such as gradients of hexane/ethyl acetate or dichloromethane/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier system equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

(26) In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

(27) Specific methods are described below, and in the respective protocols describing the preparations of example compounds and intermediates.

(28) Preparative HPLC

(29) Instrument: pump: Labomatic HD-3000, head HDK 280, low pressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 ?m, 125?30 mm; eluent; gradient; UV-Detection. Eluent solvent A: water+0.1 vol % formic acid (99%; acidic) or 0.2 vol % aqueous ammonia (32%, basic), solvent B: acetonitrile; flow 150 mL/min.

(30) Gradients:

(31) Method A: 0.00-0.50 min 1% B, 0.50-6.00 min 1-25% B, 6.00-6.10 min 25-100% B, 6.10-8.00 min 100% B

(32) Method B: 0.00-0.50 min 10% B, 0.50-6.00 min 10-50% B, 6.00-6.10 min 50-100% B, 6.10-8.00 min 100% B

(33) Method C: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B, 6.00-6.10 min 55-100% B, 6.10-8.00 min 100% B

(34) Method D: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B, 6.00-6.10 min 70-100% B, 6.10-8.00 min 100% B

(35) Method E: 0.00-0.50 min 40% B, 0.50-6.00 min 40-80% B, 6.00-6.10 min 80-100% B, 6.10-8.00 min 100% B

(36) Method F:

(37) Instrument: Waters autopurification system; column: Waters CSH C18 5? 100?30 mm; eluent A: water+0.1 Vol-% aqueous ammonia (32%), eluent B: acetonitrile, DAD scan: 210-400 nm; MS Instrument: QDA (Waters); Collector-Trigger: DAD-MS flow rate: 60 mL/min

(38) Chiral HPLC and Stereochemistry Assignments

(39) Separations of stereoisomeric mixtures, such as racemic compounds, by chiral HPLC can result in the isolation of single stereoisomers without known configuration of the respective stereogenic centres in the isolated isomers. In the following, the full chemical names of all such separated isomers obtained from an isomeric mixture, including (R) and (S) configurations, are listed in alphabetical order together with all respective intermediate or example numbers, followed by the individual isomers with data on their analytics, isolation and yield, followed by descriptors such as (enantiomer 1), (stereoisomer 2), and the like. Likewise, example compounds obtained from starting materials being single stereoisomers of unknown absolute configuration are disclosed herein in an analogous fashion. The order of the full chemical names (including (R) and (S) configurations) cannot be construed as to encode for any correlation to the individual intermediate or example numbers.

(40) Preparative Flash Chromatography

(41) Instrument: Biotage Isolera Four; pump: Dual-Piston; flow rate: 1 to 200 mL/min; internal detector: 200-400 nm (variable UV detector); solvent inlets: 4; cartridges: Biotage SNAP Ultra?, sizes: 10 g, 25 g, 50 g, 100 g, 340 g, media: Biotage? HP-Sphere25 micron spherical silica, resolution: minimum 7000 N/m (plates per meter) typical 10 000 N/m; solvent A: hexane, solvent B: ethyl acetate, solvent C: dichlormethane, solvent D: ethanol; solvent E: methanol; UV collection modes: single/dual/?-All wavelengths (variable UV); fractionation modes: volume, threshold, threshold with volume, low slope, medium slope, custom slope or via external detection

(42) Method X: gradient with solvent A and B, ?-all

(43) Method Y: gradient with solvent C and D, ?-all

(44) Method Z: gradient with solvent C and E, ?-all

(45) The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.

(46) The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

EXPERIMENTAL SECTIONPREPARATION OF INTERMEDIATES

(47) Intermediate 1

1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethan-1-one

(48) ##STR00134##

(49) 1-(4-Hydroxyphenyl)ethan-1-one (2.00 g, 14.7 mmol) was provided in dichloromethane (25 mL) at 0? C. 4-dimethylaminopyridine (100 mg, 819 ?mol; CAS-RN 1122-58-3) and imidazole (2.00 g, 29.4 mmol; CAS-RN 288-32-4) were added. To the mixture was added dropwise a solution of tert-butyl(chloro)dimethylsilane (3.32 g, 22.0 mmol) dichloromethane. The reaction mixture was stirred for 2 h at rt. The mixture was poured into aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate gradient 0-10%) to give 3.7 g (96% yield) of the title compound.

(50) .sup.1H-NMR (400 MHz, CHLOROFORM-d): ? ppm=0.23 (s, 6H), 0.99 (s, 9H), 2.55 (s, 3H), 6.85-6.89 (m, 2H), 7.86-7.90 (m, 2H)

(51) Intermediate 2

tert-butyl(dimethyl)(4-{1-[(trimethylsilyl)oxy]ethenyl}phenoxy)silane

(52) ##STR00135##

(53) Lithium diisopropylamide solution in tetrahydrofurane (1.5 mL, 2.0 M, 3.0 mmol; CAS-RN 4111-54-0) was provided under argon at ?70? C., and 1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethan-1-one (500 mg, 2.00 mmol, Intermediate 1) was added. The mixture was allowed to warm to 0? C. and was stirred for 30 min at 0? C. Chlorotrimethylsilane (1.6 mL, 13 mmol; CAS-RN 75-77-4) was added and the reaction mixture was stirred for 4 h at rt. The mixture was poured into water/brine and extracted with methyl tert-butylether. The combined organic layer was washed with brine, dried and concentrated under reduced pressure to give 700 mg (98% yield) of the title compound as a yellow oil.

(54) .sup.1H-NMR (400 MHz, CHLOROFORM-d): ? ppm=0.07 (s, 9H), 0.77-0.82 (m, 15H), 4.13-4.15 (m, 1H), 4.60 (d, J=1.77 Hz, 1H), 6.57-6.61 (m, 2H), 7.24-7.29 (m, 2H).

(55) Intermediate 3

2-bromo-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethan-1-one

(56) ##STR00136##

(57) Tert-butyl(dimethyl)(4-{1-[(trimethylsilyl)oxy]ethenyl}phenoxy)silane (695 mg, 2.15 mmol; Intermediate 2) was provided at 0? C. in tetrahydrofurane (57 mL) and N-bromosuccinimide (460 mg, 2.59 mmol; CAS-RN 128-08-5) was added. The reaction mixture was stirred overnight at rt. The mixture was treated with water/brine and extracted with ethyl acetate. The combined organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexane/ethyl acetate gradient 0-10%) to give 460 mg (62% yield) of the title compound.

(58) .sup.1H-NMR (400 MHz, CHLOROFORM-d): ? ppm=0.24-0.26 (m, 6H), 0.99 (s, 9H), 4.40 (s, 2H), 6.90 (d, J=8.87 Hz, 2H), 7.91 (d, J=8.87 Hz, 2H).

(59) LC-MS (method 2): R.sub.t=1.58 min; MS (ESIpos): m/z=329.2 [M+H].sup.+

(60) Intermediate 4

[4-amino-2-(4-methoxy-2-methyl-anilino)thiazol-5-yl]-phenyl-methanone

(61) ##STR00137##

(62) 1-Isothiocyanato-4-methoxy-2-methylbenzene (225.1 mg, 1.26 mmol) was dissolved in acetonitrile (25 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (190 mg, 1.26 mmol) and cyanamide (63.4 mg, 1.51 mmol). After stirring for 45 min at rt further 1,8-diazabicyclo(5.4.0)undec-7-ene (96 mg, 0.62 mmol) and 2-bromo-1-phenylethanone (225 mg, 1.26 mmol) were added. The reaction mixture was stirred at rt overnight. The suspension was treated with water and the precipitate was isolated by filtration, washed with water and some ethyl acetate and dried by lyophilization to give 351 mg (78% yield) of the title compound.

(63) .sup.1H-NMR: (400 MHz, DMSO-d6): ? ppm=2.19 (s, 3H), 3.74 (s, 3H), 6.78 (dd, J=8.62, 2.79 Hz, 1H), 6.88 (d, J=2.79 Hz, 1H), 7.26 (d, J=8.62 Hz, 1H), 7.34-7.47 (m, 3H), 7.50-7.62 (m, 2H), 7.75-8.52 (m, 2H), 9.90-10.16 (br s, 1H).

(64) LC-MS (method 2) Rt=1.09 min; MS (ESIpos): m/z=340.1 [M+H].sup.+

(65) The following intermediates were prepared from commercial starting materials stated in Table 2, below, using the procedure as for Intermediate 4, followed by purification by chromatography if needed. If no purification is specified, the respective title compound was isolated as crude product.

(66) The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (methods X, Y or Z depending on polarity) if necessary. In case of a missing precipitation, the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and evaporated to dryness. The crude product was purified by chromatography as stated in Table 2.

(67) TABLE-US-00002 TABLE 2 Intermediates 5-77 Inter- mediate Chemical structure Starting number Compound name materials Analytics/purification/yield 5 4-isothiocyanato- N,N- dimethylaniline; 2-bromo-1- phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 2.87 (s, 6 H), 6.72 (d, J = 9.13 Hz, 2 H), 7.30 (br d, J = 8.36 Hz, 2 H), 7.38- 7.51 (m, 3 H), 7.61 (dd, J = 7.48, 2.15 Hz, 2 H), 7.82- 8.55 (m, 2 H), 10.32-10.58 (br s, 1 H). LC-MS (method 1) Rt = 1.00 min; MS (ESIpos): m/z = 339.3 [4-amino-2-[4-(dimethylamino)anilino]thiazol-5-yl]- [M + H].sup.+ phenyl-methanone RP-HPLC (method C, acidic) 10% yield 6 1-isopropoxy-4- isothiocyanatobenzene; 2-bromo-1- phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.24 (d, J = 6.08 Hz, 6 H), 4.56 (spt, J = 6.04 Hz, 1 H), 6.88-6.95 (m, 2 H), 7.42- 7.49 (m, 5 H), 7.61-7.67 (m, 2 H), 7.89-8.41 (m, 2 H), 10.57-10.61 (br s, 1 H). LC-MS (method 1) Rt = 1.24 min; MS (ESIpos): m/z = 354.8 [M + H].sup.+ [4-amino-2-(4-isopropoxyanilino)thiazol-5-yl]- RP-HPLC (method D, acidic) phenyl-methanone 66% yield 7 0 1,3,5-trifluoro-2- isothiocyanatobenzene; 2-bromo-1- phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.38 (m, 2 H), 7.43-7.52 (m, 3 H), 7.63 (m, 2 H), 7.97-8.42 (m, 2 H), 10.22- 10.38 (br s, 1 H). LC-MS (method 2) Rt = 0.81 min; MS (ESIpos): m/z = 350.5 [M + H].sup.+ RP-HPLC (method C, basic) 68% yield [4-amino-2-(2,4,6-trifluoroanilino)thiazol-5-yl]- phenyl-methanone 8 2-bromo-4-fluoro-1- isothiocyanatobenzene; 2-bromo-1- phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.33 (td, J = 8.55, 2.91 Hz, 1 H), 7.39-7.51 (m, 3 H), 7.61 (dd, J = 7.48, 1.90 Hz, 2 H), 7.66-7.75 (m, 2 H), 7.96- 8.45 (m, 2 H), 10.20-10.49 (br s, 1 H). LC-MS (method 2) Rt = 0.81 min; MS (ESIpos): m/z = 350.5 [M + H].sup.+ RP-HPLC (method C, basic) [4-amino-2-(2-bromo-4-fluoro- 33% yield anilino)thiazol-5-yl]-phenyl-methanone 9 1-fluoro-4- isothiocyanatobenzene; 2-chloro-1-(6- methylpyridin-3- yl)ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 2.52 (s, 3 H), 7.22 (t, J = 8.87 Hz, 2 H), 7.36 (d, J = 7.86 Hz, 1 H), 7.60-7.67 (m, 2 H), 7.92 (dd, J = 7.86, 2.28 Hz, 1 H), 8.14-8.48 (m, 2 H), 8.72 (d, J = 2.03 Hz, 1 H), 10.87 (s, 1 H). LC-MS (method 2) Rt = 0.86 min; MS (ESIpos): m/z = 329.2 [M + H].sup.+ 72% yield [4-amino-2-(4-fluoroanilino)thiazol- 5-yl]-(6-methyl-3-pyridyl)methanone 10 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(4- pyridyl)ethanone; hydrobromide (1:1) .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.20-7.26 (m, 2 H), 7.54-7.59 (m, 1 H), 7.56- 7.58 (m, 1 H), 7.60-7.67 (m, 2 H), 8.27-8.47 (m, 2 H), 8.70 (d, J = 5.83 Hz, 2 H), 10.83- 11.02 (br s, 1 H). LC-MS (method 2) Rt = 0.77 min; MS (ESIpos): m/z = 315.1 [M + H].sup.+ 76% yield [4-amino-2-(4-fluoroanilino)thiazol- 5-yl]-(4-pyridyl)methanone 11 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(2- fluorophenyl)ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.21 (t, J = 8.87 Hz, 2 H), 7.24-7.31 (m, 2 H), 7.44-7.53 (m, 2 H), 7.55- 7.63 (m, 2 H), 8.16 (br s, 2 H), 10.79 (s, 1 H). LC-MS (method 2) Rt = 0.97 min; MS (ESIpos): m/z = 332.3 [M + H].sup.+ [4-amino-2-(4-fluoroanilino)thiazol- 92% yield 5-yl]-(2-fluorophenyl)methanone 12 4- isothiocyanatobenzonitrile; 2-bromo-1- phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.45-7.52 (m, 3 H), 7.68 (dd, J = 7.73, 1.65 Hz, 2 H), 7.81 (s, 4 H), 8.17-8.40 (m, 2 H), 11.08-11.35 (br s, 1 H). LC-MS (method 2) Rt = 0.92 min; MS (ESIpos): m/z = 321.1 [M + H].sup.+ 56% yield 4-[(4-amino-5-benzoyl-thiazol-2- yl)amino]benzonitrile 13 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[4-chloro-3- (trifluoromethyl)phenyl] ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.22 (t, J = 8.87 Hz, 2 H), 7.66 (br d, J = 4.06 Hz, 2 H), 7.87 (s, 1 H), 7.95- 8.01 (m, 1 H), 8.07 (s, 1 H), 8.28-8.49 (m, 2H), 10.90- 10.96 (br s, 1 H). LC-MS (method 2) Rt = 1.26 min; MS (ESIpos): m/z = 416.2 [M + H].sup.+ RP-HPLC (method D, basic) 31% yield [4-amino-2-(4-fluoroanilino)thiazol-5-yl]- [4-chloro-3-(trifluoromethyl)phenyl]methanone 14 2-chloro-4-fluoro-1- isothiocyanatobenzene; 2-bromo-1-phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.25-7.31 (m, 1 H), 7.41-7.50 (m, 3 H), 7.58 (dd, J = 8.49, 2.91 Hz, 1 H), 7.60-7.66 (m, 2 H), 7.81 (dd, J = 9.12, 5.83 Hz, 1 H), 8.17 (br s, 2 H), 10.36 (br s, 1 H). LC-MS (method 2) Rt = 1.00 min; MS (ESIpos): m/z = 348.5 [M + H].sup.+ RP-HPLC (method C, basic) [4-amino-2-(2-chloro-4-fluoro- 67% yield anilino)thiazol-5-yl]-phenyl-methanone 15 1-fluoro-4- isothiocyanatobenzene; 3-(bromoacetyl) benzonitrile .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.22 (t, J = 8.87 Hz, 2 H), 7.61-7.66 (m, 2 H), 7.69 (t, J = 7.98 Hz, 1 H), 7.97 (dd, J = 7.86, 1.77 Hz, 2 H), 8.06 (t, J = 1.52 Hz, 1 H), 8.33 (br s, 2 H), 10.81-10.97 (m, 1H). LC-MS (method 2) Rt = 0.97 min; MS (ESIpos): m/z = 339.2 [M + H].sup.+ 78% yield 3-[4-amino-2-(4-fluoroanilino) thiazole-5-carbonyl]benzonitrile 16 2-chloro-4- isothiocyanato-N,N- dimethylaniline; 2-bromo-1- phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 2.68 (s, 6 H), 7.14 (d, J = 8.87 Hz, 1 H), 7.34 (dd, J = 8.62, 2.53 Hz, 1 H), 7.42-7.50 (m, 3 H), 7.60- 7.69 (m, 2 H), 7.69-7.74 (m, 1 H), 8.22 (br s, 2 H), 10.58 (br s, 1 H). LC-MS (method 2) Rt = 1.14 min; MS (ESIpos): m/z = 373.2 [M + H].sup.+ [4-amino-2-[3-chloro-4-(dimethylamino) RP-HPLC (method D, basic) anilino]thiazol-5-yl]-phenyl-methanone 66% yield 17 0 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(6- methoxypyridin-3-yl) ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.91 (s, 3 H), 6.91 (dd, J = 8.49, 0.63 Hz, 1 H), 7.19-7.26 (m, 2 H), 7.62- 7.66 (m. 2 H), 7.98 (dd, J = 8.62, 2.53 Hz, 1 H), 8.24 (br s, 2 H), 8.51 (dd, J = 2.53, 0.76 Hz, 1 H), 10.85 (br s, 1 H). LC-MS (method 1) Rt = 1.09 min; MS (ESIpos): m/z = 345.2 [M + H].sup.+ 72% yield [4-amino-2-(4-fluoroanilino)thiazol- 5-yl]-(6-methoxy-3-pyridyl)methanone 18 1-fluoro-4- isothiocyanatobenzene; 4-(bromoacetyl)- N-methylbenzamide LC-MS (method 2) Rt = 0.79 min; MS (ESIpos): m/z = 371.2 [M + H].sup.+ RP-HPLC (method C, basic) 31% yield 4-[4-amino-2-(4-fluoroanilino) thiazole-5-carbonyl]-N-methyl-benzamide 19 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(3- fluorophenyl)ethanone LC-MS (method 2) Rt = 1.03 min; MS (ESIpos): m/z = 332.2 [M + H].sup.+ RP-HPLC (method D, basic) 13% yield [4-amino-2-(4-fluoroanilino)thiazol- 5-yl]-(3-fluorophenyl)methanone 20 2-chloro-4- isothiocyanato-1- methoxybenzene; 2-bromo-1- phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.83 (s, 3 H), 7.15 (d, J = 8.87 Hz, 1 H), 7.41 (dd, J = 8.87. 2.79 Hz, 1 H), 7.44-7.51 (m, 3 H), 7.62- 7.69 (m, 2 H), 7.82 (d, J = 2.03 Hz, 1 H), 8.27 (br s, 2 H), 10.71 (s, 1 H). LC-MS (method 2) Rt = 0.98 min; MS (ESIpos): m/z = 360.2 [M + H].sup.+ [4-amino-2-(3-chloro-4-methoxy- 39% yield anilino)thiazol-5-yl]-phenyl-methanone 21 1-isothiocyanato-4- methoxybenzene; 2-bromo-1-(4- fluorophenyl)thanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.74 (s, 3 H), 6.94 (d, J = 8.87 Hz, 2 H), 7.28 (t, J = 8.87 Hz, 2 H), 7.45 (br d, J = 8.62 Hz, 2 H), 7.67-7.73 (m, 2 H), 7.89-8.50 (m, 2 H), 10.64 (br s, 1 H). LC-MS (method 2) Rt = 1.09 min; MS (ESIpos): m/z = 344.5 [M + H].sup.+ preparative flash chromatography (method Y, 1-10%) [4-amino-2-(4-methoxyanilino) 66% yield thiazol-5-yl]-(4-fluorophenyl)methanone 22 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1- [4-(methylsulfonyl) phenyl]ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.28 (s, 3 H), 7.22 (t, J = 8.87 Hz, 2 H), 7.60- 7.65 (m, 2 H), 7.88 (d, J = 8.62 Hz, 2 H), 8.00-8.04 (m, 2 H), 8.31 (br s, 2 H), 9.20 (s, 1 H). LC-MS (method 2) Rt = 0.83 min; MS (ESIpos): m/z = 392.2 [M + H].sup.+ 92% yield [4-amino-2-(4-fluoroanilino)thiazol-5-yl]-(4- methylsulfonylphenyl)methanone 23 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1- [4-(1H-imidazol-1- yl)phenyl]ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.14-7.15 (m, 1 H), 7.22 (t, J = 8.87 Hz, 2 H), 7.58-7.69 (m, 2 H), 7.75- 7.82 (m, 4 H), 7.84 (t, J = 1.39 Hz, 1 H), 8.00-8.56 (m, 2 H), 8.37 (t, J = 1.14 Hz, 1 H), 10.84 (br s, 1 H). LC-MS (method 2) Rt = 0.88 min; MS (ESIpos): m/z = 380.2 [M + H].sup.+ RP-HPLC (method C, basic) 16% yield [4-amino-2-(4-fluoroanilino)thiazol- 5-yl]-(4-imidazol-1-ylphenyl)methanone 24 1-fluoro-4- isothiocyanatobenzene; 4-(bromoacetyl)-2- fluorobenzonitrile .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.22 (t, J = 8.87 Hz, 2 H), 7.58-7.63 (m, 2 H), 7.65 (dd, J = 7.98, 1.39 Hz, 1 H), 7.72 (dd, J = 9.76, 1.39 Hz, 1 H), 8.04 (dd, J = 7.86, 6.59 Hz, 1 H), 8.39 (br s, 2 H), 10.92 (br s, 1 H). LC-MS (method 2) Rt = 0.92 min; MS (ESIpos): m/z = 357.2 [M + H].sup.+ RP-HPLC (method C, basic) 5% yield 4-[4-amino-2-(4-fluoroanilino) thiazole-5-carbonyl]-2-fluoro-benzonitrile 25 1-fluoro-4- isothiocyanatobenzene; 4-(bromoacetyl)-3- fluorobenzonitrile .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.23 (t, J = 8.87 Hz, 2 H), 7.60-7.67 (m, 3 H), 7.73 (dd, J = 9.89, 1.27 Hz, 1 H), 8.05 (dd, J = 7.86, 6.59 Hz, 1 H), 8.41 (br s, 2 H), 10.94 (br s, 1 H). LC-MS (method 2) Rt = 0.92 min; MS (ESIpos): m/z = 357.2 [M + H].sup.+ RP-HPLC (method D, acidic) 13% yield 4-[4-amino-2-(4-fluoroanilino) thiazole-5-carbonyl]-3-fluoro-benzonitrile 26 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(2-fluoro-4- methoxyphenyl)ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.81 (s, 3 H), 6.83 (dd, J = 8.49, 2.41 Hz, 1 H), 6.89 (dd, J = 12.29, 2.41 Hz, 1 H), 7.21 (t, J = 8.87 Hz, 2 H), 7.42 (t, J = 8.49 Hz, 1 H), 7.56- 7.63 (m, 2 H), 7.99-8.17 (br s, 2 H), 10.77 (br s, 1 H). LC-MS (method 1) Rt = 1.13 min; MS (ESIpos): m/z = 362.4 [M + H].sup.+ 81% yield [4-amino-2-(4-fluoroanilino)thiazol-5-yl]- (2-fluoro-4-methoxy-phenyl)methanone 27 0 1-isothiocyanato-4- (trifluoromethoxy) benzene; 2-bromo-1- phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.38 (d, J = 8.36 Hz, 2 H), 7.45-7.52 (m, 3 H), 7.67 (dd, J = 7.60, 1.77 Hz, 2 H), 7.74 (d, J = 9.13 Hz, 2 H), 8.03-8.37 (br s, 2 H), 10.94 (br s, 1 H). LC-MS (method 1) Rt = 1.13 min; MS (ESIpos): m/z = 380.5 [M + H].sup.+ [4-amino-2-[4-(trifluoromethoxy) preparative flash chromatography anilino]thiazol-5-yl]-phenyl-methanone (method X, 25-90%) 21% yield 28 1-fluoro-4- isothiocyanatobenzene; 2-chloro-1-(3,4- difluorophenyl)ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.22 (t, J = 8.87 Hz, 2 H), 7.52-7.58 (m, 2 H), 7.61-7.73 (m, 3 H), 8.06- 8.52 (br s, 2 H), 10.87 (br s, 1 H). LC-MS (method 2) Rt = 1.13 min; MS (ESIpos): m/z = 350.2 [M + H].sup.+ RP-HPLC (method D, basic) 34% yield [4-amino-2-(4-fluoroanilino)thiazol- 5-yl]-(3,4-difluorophenyl)methanone 29 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(3,4- dichlorophenyl)ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.19 (t, J = 8.87 Hz, 2 H), 7.56 (br s, 2 H), 7.63 (dd, J = 8.36, 2.03 Hz, 1 H), 7.73 (d, J = 8.36 Hz, 1 H), 7.84 (d, J = 1.77 Hz, 1 H), 8.03-8.58 (m, 2 H), 10.83 (br s, 1 H). LC-MS (method 2) Rt = 1.22 min; MS (ESIneg): m/z = 380.3 [M ? H].sup.+ RP-HPLC (method D, basic) 32% yield [4-amino-2-(4-fluoroanilino)thiazol- 5-yl]-(3,4-dichlorophenyl)methanone 30 1-isothiocyanato-4- (trifluoromethoxy) benzene; 2-bromo-1- (4-fluorophenyl)ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.31 (t, J = 8.87 Hz, 2 H), 7.37 (d, J = 8.36 Hz, 2 H), 7.70-7.77 (m, 4 H), 8.07- 8.34 (br s, 2 H), 10.98 (br s, 1 H). LC-MS (method 2) Rt = 1.20 min; MS (ESIpos): m/z = 398.2 [M + H].sup.+ 89% yield [4-amino-2-[4-(trifluoromethoxy)anilino]thiazol- 5-yl]-(4-fluorophenyl)methanone 31 1-isothiocyanato-4- (trifluoromethyl) benzene; 2-bromo-1- phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.45-7.52 (m, 3 H), 7.66-7.73 (m, 4 H), 7.83 (br d, J = 8.36 Hz, 2 H), 8.24 (br s, 2 H), 11.13 (br s, 1 H). LC-MS (method 2) Rt = 1.14 min; MS (ESIpos): m/z = 364.2 [M + H].sup.+ 85% yield [4-amino-2-[4-(trifluoromethyl)anilino]thiazol-5- yl]-phenyl-methanone 32 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[6- (trifluoromethyl)pyridin- 3-yl]ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.22 (t, J = 8.87 Hz, 2 H), 7.55-7.64 (m, 2 H), 8.02 (d, J = 7.86 Hz, 1 H), 8.39 (br s, 1 H), 8.29 (dd, J = 7.86, 1.77 Hz, 2 H), 8.99 (d, J = 1.77 Hz, 1 H), 10.95 (br s, 1 H). LC-MS (method 2) Rt = 1.03 min; MS (ESIpos): m/z = 383.1 [M + H].sup.+ RP-HPLC (method C, basic) 97% yield [4-amino-2-(4-fluoroanilino)thiazol-5-yl]- [6-(trifluoromethyl)-3-pyridyl]methanone 33 4-chloro-2-fluoro-1- isothiocyanatobenzene; 2-bromo-1-phenylethanone LC-MS (method 2) Rt = 0.97 min; MS (ESIpos): m/z = 348.2 [M + H].sup.+ 94% yield [4-amino-2-(4-chloro-2-fluoro- anilino)thiazol-5-yl]-phenyl-methanone 34 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1- (2,3-dihydro-1H- inden-5-yl)ethanone LC-MS (method 2) Rt = 1.25 min; MS (ESIpos): m/z = 354.5 [M + H].sup.+ 89% yield [4-amino-2-(4-fluoroanilino)thiazol- 5-yl]-indan-5-yl-methanone 35 1,2-difluoro-4- isothiocyanatobenzene; 2-bromo-1-phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6); ? ppm = 7.21-7.28 (m, 1 H), 7.38-7.54 (m, 4 H), 7.63- 7.72 (m, 2 H), 7.90-8.02 (m, 1 H), 8.10-8.46 (br s, 2 H), 10.86-11.07 (br s, 1 H). LC-MS (method 2) Rt = 1.05 min; MS (ESIpos): m/z = 332.2 [M + H].sup.+ 76% yield [4-amino-2-(3,4-difluoroanilino) thiazol-5-yl]-phenyl-methanone 36 1-fluoro-4- isothiocyanatobenzene; 4-(bromoacetyl)benzonitrile .sup.1H-NMR (400 MHz, DMSO- d6); ? ppm = 7.22 (t, J = 8.87 Hz, 2 H), 7.62 (br dd, J = 8.87, 4.82 Hz, 2 H), 7.80 (d, J = 8.36 Hz, 2 H), 7.95 (d, J = 1.00 Hz, 2 H), 8.32 (br s, 2 H), 10.84- 10.95 (br s, 1 H). LC-MS (method 2) Rt = 0.97 min; MS (ESIpos): m/z = 339.2 [M + H].sup.+ 84% yield 4-[4-amino-2-(4-fluoroanilino) thiazole-5-carbonyl]benzonitrile 37 0 1-chloro-4- isothiocyanatobenzene; 2-bromo-1- phenylethanone LC-MS (method 1) Rt = 1.23 min; MS (ESIneg): m/z = 328.3 100% yield [4-amino-2-(4-chloroanilino)thiazol- 5-yl]-phenyl-methanone 38 1,2-dichloro-4- isothiocyanatobenzene; 2-bromo-1- phenylethanone LC-MS (method 1) Rt = 1.32 min; MS (ESIneg): m/z = 362.3 [M ? H].sup.+ preparative flash chromatography (method X, 10-80%) 65% yield [4-amino-2-(3,4-dichloroanilino) thiazol-5-yl]-phenyl-methanone 39 1-chloro-2-fluoro-4- isothiocyanatobenzene; 2-bromo-1-phenylethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.28 (br dt, J = 8.87, 1.27 Hz, 1 H), 7.45- 7.57 (m, 4 H), 7.68 (dd, J = 7.60, 1.77 Hz, 2 H), 7.99 (dd, J = 11.91, 2.03 Hz, 1 H), 8.27 (br s, 2 H), 11.07 (br s, 1 H). LC-MS (method 2) Rt = 1.04 min; MS (ESIpos): m/z = 348.1 [M + H].sup.+ [4-amino-2-(4-chloro-3-fluoro- 67% yield anilino)thiazol-5-yl]-phenyl-methanone 40 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(4- chlorophenyl)ethanone LC-MS (method 2) Rt = 1.12 min; MS (ESIpos): m/z = 348.1 [M + H].sup.+ 94% yield [4-amino-2-(4-chloroanilino)thiazol- 5-yl]-(4-fluorophenyl)methanone 41 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(4- chlorophenyl)ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.21 (t, J = 8.87 Hz, 2 H), 7.54 (d, J = 8.62 Hz, 2 H), 7.62 (br dd, J = 8.87, 5.07 Hz, 2 H), 7.68 (d, J = 8.62 Hz, 2 H), 8.28 (br s, 2 H), 10.83 (br s, 1 H). LC-MS (method 1) Rt = 1.25 min; MS (ESIneg): m/z = 346.3 [M ? H].sup.+ preparative flash chromatography (method Y, [4-amino-2-(4-fluoroanilino)thiazol- 0-15% 5-yl]-(4-chlorophenyl)methanone 53% yield 42 1-fluoro-4- isothiocyanatobenzene; ethyl 2-[4-(bromoacetyl) phenoxy]-2- methylpropanoate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.15 (t, J = 7.10 Hz, 3 H), 1.56 (s, 6 H), 4.17 (q, J = 7.10 Hz, 2 H), 6.78 (d, J = 8.87 Hz, 2 H), 7.12 (t, J = 8.87 Hz, 2 H), 7.34-7.51 (br s, 2 H), 7.58 (d, J = 8.62 Hz, 2 H), 7.62-8.80 (m, 2 H), 9.78- 10.70 (m, 1 H). LC-MS (method 2) Rt = 1.25 min; MS (ESIpos): m/z = 444.3 [M + H].sup.+ 93% yield ethyl 2-[4-[4-amino-2-(4-fluoroanilino)thiazole-5- carbonyl]phenoxy]-2-methyl-propanoate 43 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[4- (trifluoromethoxy)phenyl] ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.21 (t, J = 8.87 Hz, 2 H), 7.46 (dd, J = 8.74, 0.89 Hz, 2 H), 7.55-7.66 (m, 2 H), 7.79 (d, J = 8.87 Hz, 2 H), 8.36 (br s, 2 H), 10.77 (br s, 1H). LC-MS (method 2) Rt = 1.21 min; MS (ESIpos): m/z = 398.1 [M + H].sup.+ RP-HPLC (method D, basic) 50% yield [4-amino-2-(4-fluoroanilino)thiazol-5-yl]-[4- (trifluoromethoxy)phenyl]methanone 44 1-chloro-4- isothiocyanatobenzene; 2-bromo-1-(4- chlorophenyl)ethanone LC-MS (method 2) Rt = 1.19 min; MS (ESIpos): m/z = 364.1 [M + H].sup.+ 87% yield [4-amino-2-(4-chloroanillno)thiazol- 5-yl]-(4-chlorophenyl)methanone 45 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1- [4-(trifluoromethyl) phenyl]ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.22 (t, J = 8.87 Hz, 2 H), 7.61-7.65 (m, 2 H), 7.85 (s, 4 H), 8.36 (br s, 2 H), 10.88 (br s, 1 H). LC-MS (method 2) Rt = 1.15 min; MS (ESIpos): m/z = 382.2 [M + H].sup.+ 66% yield [4-amino-2-(4-fluoroanilino)thiazol-5-yl]- [4-(trifluoromethyl)phenyl]methanone 46 1-isothiocyanato-4- (trifluoromethyl)benzene; 2-bromo-1- [4-(difluoromethoxy) phenyl]ethanone LC-MS (method 2) Rt = 1.15 min; MS (ESIpos): m/z = 430.2 [M + H].sup.+ 87% yield [4-amino-2-[4-(trifluoromethyl)anilino]thiazol-5-yl]- [4-(difluoromethoxy)phenyl]methanone 47 0 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1- [4-(difluoromethoxy) phenyl]ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.34 (t, J = 74.50 Hz, 1 H), 7.17-7.31 (m, 4 H), 7.61 (br dd, J = 8.62, 4.82 Hz, 2 H), 7.73 (d, J = 8.62 Hz, 2 H), 8.23 (br s, 2 H), 10.82 (br s, 1H). LC-MS (method 2) Rt = 1.11 min; MS (ESIpos): m/z = 380.4 [M + H].sup.+ RP-HPLC (method D, basic) 94% yield [4-amino-2-(4-fluoroanilino)thiazol- 5-yl]-[4-(difluoromethoxy)phenyl]methanone 48 phenylisothiocyanate; 2-bromo-4- hydroxyacetophenone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 6.78 (d, 2 H), 7.04 (t 1 H), 7.33 (d, 2H), 7.54 (d, 2 H), 7.57 (d, 2 H), 8.06 (br s, 2 H), 9.95 (br s, 1 H), 10.68 (br s, 1 H) LC-MS (method 2) Rt = 0.61 min; MS (ESIpos): m/z = 312 [M + H].sup.+ preparative flash (4-amino-2-anilino-thiazol-5-yl)-(4- chromatography (ethyl hydroxyphenyl)methanone acetate/heptane 4/1) 80% yield 49 4-chloro-2-fluoro-1- isothiocyanatobenzene; 2-bromo-1- [4-(difluoromethoxy) phenyl]ethanone LC-MS (method 2) Rt = 1.00 min; MS (ESIpos): m/z = 414.2 [M + H].sup.+ quantitave yield [4-amino-2-(4-chloro-2-fluoro-anilino)thiazol-5-yl]-[4- (difluoromethoxy)phenyl]methanone 50 1-chloro-4- isothiocyanatobenzene; 2-bromo-1-[4- (difluoromethoxy) phenyl]ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.35 (t, J = 74.77 Hz, 1 H), 7.26 (d, J = 8.62 Hz, 2 H), 7.42 (d, J = 8.87 Hz, 1 H), 7.66 (d, J = 8.87 Hz, 2 H), 7.75 (d, J = 8.62 Hz, 2 H), 8.26 (br s, 2 H), 10.92 (br s, 1 H). LC-MS (method 2) Rt = 1.19 min; MS (ESIpos): m/z = 396.2 [M + H].sup.+ RP-HPLC (method D, acidic) quantitative yield [4-amino-2-(4-chloroanilino)thiazol-5-yl]-[4- (difluoromethoxy)phenyl]methanone 51 1-chloro-2-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[4- (difluoromethoxy) phenyl]ethanone LC-MS (method 2) Rt = 1.08 min; MS (ESIpos): m/z = 414.2 [M + H].sup.+ 95% yield [4-amino-2-(4-chloro-3-fluoro-anilino)thiazol-5-yl]-[4- (difluoromethoxy)phenyl]methanone 52 1,2-difluoro-4- isothiocyanatobenzene; 2-bromo-1- [4-(difluoromethoxy) phenyl]ethanone .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.35 (t, J = 76.04 Hz, 1 H), 7.27 (br d, J = 8.62 Hz, 3 H), 7.39-7.48 (m, 1 H), 7.75 (d, J = 8.87 Hz, 2 H), 7.97 (ddd, J = 12.99, 7.29, 2.28 Hz, 1 H), 8.27 (br s, 2 H), 10.99 (br s, 1 H). LC-MS (method 2) Rt = 1.06 min; MS (ESIpos): m/z = 398.2 [M + H].sup.+ 87% yield [4-amino-2-(3,4-difluoroanilino)thiazol-5-yl]-[4- (difluoromethoxy)phenyl]methanone 53 2-bromo-1- (pyridin-4-yl) ethan-1-one salt with hydrogen bromide; 1,2-difluoro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.22-7.28 (m, 1 H), 7.39-7.47 (m, 1 H), 7.56- 7.59 (m, 2 H), 7.91-7.99 (m, 1 H), 8.39 (td, J = 6.46, 2.79 Hz, 1 H), 8.36-8.44 (m, 1 H), 8.68- 8.74 (m, 2 H), 10.78-11.25 (m, 1 H). LC-MS (method 1) Rt = 0.89 min; MS (ESIpos): m/z = 333.1 [M + H].sup.+ RP-HPLC (method C, acidic) [4-amino-2-(3,4-difluoroanilino)-1,3- 76% yield thiazol-5-yl](pyridin-4-yl)methanone 54 2-bromo-1-(4- methoxyphenyl) ethan-1-one; 1,2-difluoro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.82 (s, 3 H), 7.02 (d, J = 8.87 Hz, 2 H), 7.22- 7.28 (m, 1 H), 7.38-7.47 (m, 1 H), 7.68 (d, J = 8.87 Hz, 2 H), 7.91-8.03 (m, 1 H), 8.19 (br s, 2 H), 10.81-11.06 (m, 1 H). LC-MS (method 2) Rt = 1.07 min; MS (ESIpos): m/z = 362.1 [M + H].sup.+ 92% yield [4-amino-2-(3,4-difluoroanilino)-1,3- thiazol-5-yl](4-methoxyphenyl)methanone 55 2-bromo-1- (6-methoxypyridin-3- yl)ethan-1-one; 1,2-difluoro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 2.54 (s, 3 H), 6.92 (dd, J = 8.62, 0.51 Hz, 1 H), 7.28 (br s, 1 H), 7.40-7.49 (m, 1 H), 7.94-8.03 (m, 2 H), 8.18-8.36 (m, 2 H), 8.53 (dd, J = 2.53, 0.76 Hz, 1 H), 10.98- 11.04 (m, 1 H). LC-MS (method 2) Rt = 0.92 min; MS (ESIpos): m/z = 363.2 [M + H].sup.+ 77% yield [4-amino-2-(3,4-difluoroanilino)-1,3- thiazol-5-yl](6-methoxypyridin-3-yl)methanone 56 2-bromo-1-[6- (trifluoromethyl)pyridin- 3-yl]ethan-1-one; 1,2-difluoro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.21-7.27 (m, 1 H), 7.38-7.47 (m, 1 H), 7.87- 7.98 (m, 1 H), 8.03 (d, J = 8.36 Hz, 1 H), 8.31 (dd, J = 8.11, 2.03 Hz, 1 H), 8.33-8.52 (m, 2 H), 9.00 (d, J = 1.52 Hz, 1 H), 11.04-11.24 (m, 1 H). LC-MS (method 2) Rt = 0.96 min; MS (ESIpos): m/z = 401.3 [M + H].sup.+ 74% yield [4-amino-2-(3,4-difluoroanilino)-1,3-thiazol-5-yl][6- (trifluoromethyl)pyridin-3-yl]methanone 57 0 2-bromo-1-(pyridin-4- yl)ethan-1-one salt with hydrogen bromide; 1-chloro-2-fluoro-4- isothiocyanatobenzene LC-MS (method 2) Rt = 0.77 min; MS (ESIpos): m/z = 349.1 [M + H].sup.+ 69% yield [4-amino-2-(4-chloro-3-fluoroanilino)-1,3- thiazol-5-yl](pyridin-4-yl)methanone 58 2-bromo-1-(pyridin-4- yl)ethan-1-one salt with hydrogen bromide; 1-chloro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.78 (d, J = 12.42 Hz, 1 H), 4.08 (d, J = 12.17 Hz, 1 H), 7.18-7.23 (m, 2 H), 7.31- 7.36 (m, 2 H), 7.56-7.60 (m, 2 H), 8.39 (s, 1 H), 8.48-8.55 (m, 2 H). LC-MS (method 2) Rt = 0.84 min; MS (ESIpos): m/z = 331.1 [M + H].sup.+ 57% yield [4-amino-2-(4-chloroanilino)-1,3- thiazol-5-yl](pyridin-4-yl)methanone 59 2-bromo-1-(4- methoxyphenyl) ethan-1-one; 1-chloro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.82 (s, 3 H), 7.01 (d, J = 8.87 Hz, 2 H), 7.38- 7.43 (m, 2 H), 7.61-7.70 (m, 4 H), 8.03-8.27 (m, 2 H), 10.78- 10.92 (m, 1 H). LC-MS (method 2) Rt = 1.15 min; MS (ESIpos): m/z = 360.1 [M + H].sup.+ 94% yield [4-amino-2-(4-chloroanilino)-1,3- thiazol-5-yl](4-methoxyphenyl)methanone 60 2-bromo-1-(4- methoxyphenyl) ethan-1-one; 1-chloro-2-fluoro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.82 (s, 3 H), 6.99-7.03 (m, 2 H), 7.25 (dd, J = 8.74, 1.65 Hz, 1 H), 7.51 (t J = 8.74 Hz, 1 H), 7.68 (d, J = 8.87 Hz, 2 H), 7.95 (br d, J = 12.17 Hz, 1 H), 8.06-8.29 (m, 2 H), 10.92-11.16 (m, 1H). LC-MS (method 2) Rt = 1.15 min; MS (ESIpos): m/z = 378.1 [M + H].sup.+ [4-amino-2-(4-chloro-3-fluoroanilino)- 80% yield 1,3-thiazol-5-yl](4-methoxyphenyl)methanone 61 2-bromo-1- phenylethan-1-one; isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.08 (t, J = 7.60 Hz, 1 H), 7.36 (t, J = 7.86 Hz, 2 H), 7.44-7.51 (m, 3 H), 7.61 (d, J = 7.86 Hz, 2 H), 7.64-7.69 (m, 2 H), 8.21 (br s, 2 H), 10.78 (br s, 1 H). LC-MS (method 2) Rt = 1.05 min; MS (ESIpos): m/z = 296.4 [M + H].sup.+ (4-amino-2-anilino-1,3-thiazol-5- 14% yield yl)(phenyl)methanone 62 2-bromo-1- phenylethan-1-one; 1-fluoro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.21 (t, J = 8.87 Hz, 2 H), 7.43-7.52 (m, 3 H), 7.59-7.69 (m, 4 H), 8.22 (br s, 2 H), 10.79 (br s, 1 H). LC-MS (method 2) Rt = 1.04 min; MS (ESIpos): m/z = 314.4 [M + H].sup.+ preparative flash chromatography (method Z, 0-1%) [4-amino-2-(4-fluoroanilino)-1,3- 78% yield thiazol-5-yl](phenyl)methanone 63 2-bromo-1-(4- methoxyphenyl) ethan-1-one; 1-fluoro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.81 (s, 3 H), 7.01 (d, J = 8.87 Hz, 2 H), 7.21 (t, J = 8.87 Hz, 2 H), 7.66 (d, J = 8.87 Hz, 4 H), 8.15 (br s, 2 H), 10.77 (br s, 1 H). LC-MS (method 2) Rt = 1.09 min; MS (ESIpos): m/z = 344.4 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 57% yield [4-amino-2-(4-fluoroanilino)-1,3- thiazol-5-yl](4-methoxyphenyl)methanone 64 2-bromo-1-(4- methylphenyl) ethan-1-one; 1-fluoro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 2.35 (s, 3 H), 7.21 (t, J = 8.87 Hz, 2 H), 7.27 (d, J = 7.86 Hz, 2 H), 7.57 (d, J = 8.11 Hz, 2 H), 7.63 (dd, J = 9.13, 4.82 Hz, 2 H), 8.19 (br s, 2 H), 10.77 (s, 1 H). LC-MS (method 2) Rt = 1.14 min; MS (ESIpos): m/z = 328.4 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) [4-amino-2-(4-fluoroanilino)-1,3- 47% yield thiazol-5-yl](4-methylphenyl)methanone 65 2-bromo-1- (4-fluorophenyl) ethan-1-one; 1-fluoro-4- isothiocyanatobenzene .sup.1H NMR (400 MHz, DMSO- d6): ? ppm = 7.21 (t, J = 8.87 Hz, 2 H), 7.30 (t, J = 8.87 Hz, 2 H), 7.62 (dd, J = 8.87, 4.82 Hz, 2 H), 7.73 (dd, J = 8.74, 5.45 Hz, 2 H), 8.22 (br s, 2 H), 10.82 (br s, 1 H). LC-MS (method 2) Rt = 1.05 min; MS (ESIpos): m/z = 332.4 [M + H].sup.+ preparative flash chromatography (method Z, 0-2%) [4-amino-2-(4-fluoroanilino)-1,3- 66% yield thiazol-5-yl](4-fluorophenyl)methanone 66 2-bromo-1- phenylethan-1-one; 2,4-difluoro-1- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.09-7.17 (m, 1 H), 7.39 (ddd, J = 11.15, 8.74, 2.91 Hz, 1 H), 7.43-7.50 (m, 3 H), 7.62-7.65 (m, 2 H), 8.01 (br td, J = 9.12, 6.34 Hz, 1 H), 8.08-8.39 (m, 2H), 10.50 (br s, 1 H). LC-MS (method 2) Rt = 0.88 min; MS (ESIpos): m/z = 332.4 [M + H].sup.+ preparative flash [4-amino-2-(2,4-difluoroanilino)-1,3- chromatography (method Z, 0-3%) thiazol-5-yl](phenyl)methanone 71% yield 67 00 2-bromo-1- phenylethan-1-one; 1-isothiocyanato-4- methoxybenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.70-3.76 (m, 3 H), 6.92-6.96 (m, 2 H), 7.42- 7.50 (m, 5 H), 7.60-7.66 (m, 2 H), 7.93-8.48 (m, 2 H), 10.60 (br s, 1 H). LC-MS (method 2) Rt = 1.04 min; MS (ESIpos): m/z = 326.4 [M + H].sup.+ preparative flash [4-amino-2-(4-methoxyanilino)-1,3- chromatography (method Z, 0-1%) thiazol-5-yl](phenyl)methanone 76% yield 68 01 2-bromo-1-(4-{[tert- butyl(dimethyl)silyl]oxy} phenyl)ethan-1-one (Intermediate 3); 1-fluoro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 0.23 (s, 6 H), 0.96 (s, 9 H), 6.92 (d, J = 8.62 Hz, 2 H), 7.21 (t, J = 8.87 Hz, 2 H), 7.59-7.66 (m, 4 H), 8.15 (br s, 2 H), 10.76 (br s, 1 H). LC-MS (method 2) Rt = 1.56 min; MS (ESIpos): m/z = 444.2 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 27% yield [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl] (4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)methanone 69 02 2-bromo-1- phenylethan-1-one; 1-isothiocyanato-4- methylbenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 2.27 (s, 3 H), 7.16 (d, J = 8.11 Hz, 2 H), 7.44- 7.49 (m, 5 H), 7.63-7.67 (m, 2 H), 7.93-8.63 (m, 2 H), 10.69 (br s, 1 H). LC-MS (method 2) Rt = 1.15 min; MS (ESIpos): m/z = 310.5 [M + H].sup.+ preparative flash [4-amino-2-(4-methylanilino)-1,3- chromatography (method Z, 0-3%) thiazol-5-yl](phenyl)methanone 67% yield 70 03 2-bromo-1- phenylethan-1-one; 1-fluoro-3- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 6.85-6.93 (m, 1 H), 7.27 (ddd, J = 8.24, 2.03, 0.89 Hz, 1 H), 7.38 (td, J = 8.17, 6.72 Hz, 1 H), 7.45-7.53 (m, 3 H), 7.66-7.70 (m, 2 H), 7.76 (dt, J = 11.66, 2.15 Hz, 1 H), 8.26 (br s, 2 H), 10.96 (s, 1 H). LC-MS (method 2) Rt = 1.07 min; MS (ESIpos): m/z = 314.4 [4-amino-2-(3-fluoroanilino)-1,3- [M + H].sup.+ thiazol-5-yl](phenyl)methanone preparative flash chromatography (method Z, 0-3%) 53% yield 71 04 2-bromo-1- phenylethan-1-one; 1-fluoro-2- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.15-7.25 (m, 2 H), 7.27-7.34 (m, 1 H), 7.43- 7.51 (m, 3 H), 7.62-7.68 (m, 2 H), 8.04-8.11 (m, 1 H), 8.10- 8.32 (m, 2 H), 10.54 (s, 1 H). LC-MS (method 2) Rt = 0.96 min; MS (ESIpos): m/z = 314.5 [M + H].sup.+ preparative flash chromatography (method Z, 0-1%) [4-amino-2-(2-fluoroanilino)-1,3- 36% yield thiazol-5-yl](phenyl)methanone 72 05 2-bromo-1- phenylethan-1-one; 1-isothiocyanato-3- methylbenzene .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 2.30 (s, 3 H), 6.91 (br d, J = 7.35 Hz, 1 H), 7.24 (br t, J = 7.73 Hz, 1 H), 7.38 (br s, 1 H), 7.41-7.54 (m, 4 H), 7.62-7.68 (m, 2 H), 8.20 (br s, 2 H), 10.70 (br s, 1 H). LC-MS (method 2) Rt = 1.15 min; MS (ESIpos): m/z = 310.5 [M + H].sup.+ [4-amino-2-(3-methylanilino)-1,3- preparative flash thiazol-5-yl](phenyl)methanone chromatography (method Z, 0-3%) 53% yield 73 06 2-bromo-1- phenylethan-1-one; 1-isothiocyanato- 2-methylbenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 2.23 (s, 3 H), 7.14-7.26 (m, 2 H), 7.27- 7.31 (m, 1 H), 7.38-7.52 (m, 4 H), 7.57-7.62 (m, 2 H), 8.15 (br s, 2 H), 10.18 (br s, 1 H). LC-MS (method 2) Rt = 1.10 min; MS (ESIpos): m/z = 310.5 [M + H].sup.+ preparative flash chromatography (method Z, 0-1%) [4-amino-2-(2-methylanilino)-1,3- 60% yield thiazol-5-yl](phenyl)methanone 74 07 2-bromo-1- phenylethan-1-one; 4-isothiocyanato-1- methyl-1H-pyrazole .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 3.81 (s, 3 H), 7.41-7.52 (m, 4 H), 7.58- 7.66 (m, 2 H), 7.90 (s, 1 H), 7.94-8.50 (m, 2 H), 10.44- 10.57 (m, 1 H). LC-MS (method 2) Rt = 0.78 min; MS (ESIpos): m/z = 300.5 [M + H].sup.+ preparative flash {4-amino-2-[(1-methyl-1H-pyrazol- chromatography (method Z, 0-1%) 4-yl)amino]-1,3-thiazol-5-yl}(phenyl)methanone 58% yield 75 08 2-bromo-1-phenylethan- 1-one; 3-isothiocyanatopyridine .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.37-7.42 (m, 1 H), 7.45-7.53 (m, 3 H), 7.65- 7.69 (m, 2 H), 8.12 (br ddd, J = 8.36, 2.53, 1.52 Hz, 1 H), 8.16-8.39 (m, 2 H), 8.28 (dd, J = 4.69, 1.39 Hz, 1 H), 8.81 (d, J = 2.53 Hz, 1 H), 10.95 (br s, 1H). LC-MS (method 2) Rt = 0.70 min; MS (ESIpos): m/z = 297.4 {4-amino-2-[(pyridin-3-yl)amino]- [M + H].sup.+ 1,3-thiazol-5-yl](phenyl)methanone preparative flash chromatography (method Z, 0-3%) 23% yield 76 09 2-bromo-1-(4- bromophenyl)ethan- 1-one; 1-fluoro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 7.21 (t, J = 8.87 Hz, 2 H), 7.56-7.65 (m, 4 H), 7.66-7.70 (m, 2 H), 8.26 (br s, 2 H), 10.85 (br s, 1 H). LC-MS (method 2) Rt = 1.19 min; MS (ESIpos): m/z = 392.3 [M + H].sup.+ preparative flash chromatography (method Z, 0-1%) 77% yield [4-amino-2-(4-fluoroanilino)-1,3- thiazol-5-yl](4-bromophenyl)methanone 77 0 1-[4-(benzyloxy) phenyl]-2- bromoethan-1-one; 1-fluoro-4- isothiocyanatobenzene .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 5.17 (s, 2 H), 7.09 (d, J = 8.87 Hz, 2 H), 7.21 (t, J = 8.87 Hz, 2 H), 7.31-7.37 (m, 1 H), 7.41 (t, J = 7.35 Hz, 2 H), 7.45-7.49 (m, 2 H), 7.60- 7.69 (m, 4 H), 7.96-8.34 (m, 2 H), 10.71-10.79 (m, 1 H). LC-MS (method 2) Rt = 1.30 min; MS (ESIpos): m/z = 420.2 [M + H].sup.+ 87% yield [4-amino-2-(4-fluoroanilino)-1,3- thiazol-5-yl][4-(benzyloxy)phenyl]methanone

(68) Intermediate 78

[4-(difluoromethoxy)phenyl][2-(4-fluoroanilino)-4-methyl-1,3-thiazol-5-yl]methanone

(69) ##STR00211##

(70) 1-Fluoro-4-isothiocyanatobenzene (116 mg, 0.755 mmol) was dissolved in acetonitrile (7.5 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (100 mg, 0.66 mmol) and ethanimidamide (salt with hydrogen chloride) (86 mg, 0.91 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (70 mg, 0.47 mmol) and 2-bromo-1-[4-(difluoromethoxy)phenyl]ethan-1-one (200 mg, 0.755 mmol) were added. The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC (method D, basic) to give 72 mg (25% yield) of the title compound.

(71) LC-MS (method 2) Rt=1.30 min; MS (ESIpos): m/z=379.4 [M+H].sup.+

(72) Intermediate 79

[2-(3,4-difluoroanilino)-4-methyl-1,3-thiazol-5-yl][4-(difluoromethoxy)phenyl]methanone

(73) ##STR00212##

(74) 1,2-difluoro-4-isothiocyanatobenzene (129 mg, 0.755 mmol) was dissolved in acetonitrile (7.5 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (100 mg, 0.66 mmol) and ethanimidamide (salt with hydrogen chloride) (86 mg, 0.91 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (70 mg, 0.47 mmol) and 2-bromo-1-[4-(difluoromethoxy)phenyl]ethan-1-one (200 mg, 0.755 mmol) were added. The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC (method E, basic) to give 31 mg (10% yield) of the title compound.

(75) LC-MS (method 2) Rt=1.36 min; MS (ESIpos): m/z=397.3 [M+H].sup.+

(76) Intermediate 80

ethyl 2-[4-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]phenoxy]acetate

(77) ##STR00213##

(78) 1-fluoro-4-isothiocyanatobenzene (8.91 g, 58.20 mmol) was dissolved in acetonitrile (450 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (8.86 g, 58.20 mmol) and cyanamide (2.94 g, 69.82 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (4.43 g, 29.07 mmol) and ethyl [4-(bromoacetyl)phenoxy]acetate (17.52 g, 58.20 mmol) were added. The reaction mixture was stirred at rt overnight. The suspension was treated with water and the precipitate was isolated by filtration, washed with water and dried by lyophilization to give 18.54 g (77% yield) of the title compound.

(79) .sup.1H-NMR (500 MHz, DMSO-d6): ? ppm=1.22 (t, J=7.09 Hz, 3H), 4.18 (q, J=7.25 Hz, 2H), 4.86 (s, 2H), 7.00 (d, J=9.14 Hz, 2H), 7.21 (t, J=9.14 Hz, 2H), 7.61-7.67 (m, 4H), 8.21 (br s, 2H), 10.77 (s, 1H).

(80) LC-MS (method 2) Rt=1.09 min; MS (ESIpos): m/z=416.3 [M+H].sup.+

(81) Intermediate 81

[2-(4-fluoroanilino)-4-methyl-thiazol-5-yl]-phenyl-methanone

(82) ##STR00214##

(83) 1-fluoro-4-isothiocyanatobenzene (77 mg, 0.50 mmol) was solved in acetonitrile (5 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (77 mg, 0.50 mmol) and ethanimidamide (salt with hydrogen chloride) (57 mg, 0.60 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (38 mg, 0.25 mmol) and 2-bromo-1-phenylethanone (100 mg, 0.50 mmol) were added. The reaction mixture was stirred at rt overnight. The solution was filtrated and purified by RP-HPLC (method D, basic). The title compound was isolated by lyophilization (53 mg, 33% yield).

(84) .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm=2.28 (s, 3H), 7.18 (t, J=8.87 Hz, 2H), 7.51 (d, J=7.86 Hz, 2H), 7.53-7.58 (m, 3H), 7.63-7.67 (m, 2H), 10.67 (br s, 1H).

(85) LC-MS (method 2) Rt=1.22 min; MS (ESIpos): m/z=313.1 [M+H].sup.+

(86) Intermediate 82

rac-2-[4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]-2-methyl-propanoic acid

(87) ##STR00215##

(88) Rac-ethyl 2-[4-[4-amino-2-(N-[2-amino-1-methyl-2-oxo-ethyl]-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]-2-methyl-propanoate (180 mg, 349 ?mol, example 39) was dissolved in THF (1.8 ml), cooled to 0? C., and an aqueous solution of sodium hydroxide (350 ?l, 1.0 M, 350 ?mol) was added. The reaction mixture was stirred overnight at rt. Additional aqueous solution of sodium hydroxide (1.04 mmol) was added and the mixture was stirred for 3 days at rt. The reaction mixture was treated with water, and aqueous solution of hydrochloric acid (1 M) was added to adjust the pH to 5 and afterwards it was extracted three times with dichloromethane. The organic layer was concentrated under reduced pressure to give 36 mg (21% yield) of the title compound.

(89) The aqueous layer was adjusted to pH 3 by addition of aqueous hydrochloric acid (1 M), the formed precipitate was isolated by filtration, washed with water and dried by lyophilization to give 90 mg (53% yield) of the title compound.

(90) .sup.1H NMR (400 MHz, DMSO-d.sub.6): ? ppm=1.15 (d, J=7.35 Hz, 3H), 1.51 (s, 6H), 4.94-5.14 (m, 1H), 6.73-6.79 (m, 2H), 7.22-7.26 (m, 1H), 7.30-7.37 (m, 2H), 7.42-7.47 (m, 2H), 7.58 (br s, 1H), 7.64 (dd, J=8.87, 5.07 Hz, 2H), 7.77-8.44 (m, 2H), 12.81-13.47 (m, 1H)

(91) LC-MS (method 1) Rt=1.00 min; MS (ESIpos): m/z=487.5 [M+H].sup.+

(92) Intermediate 83

tert-butyl N-(4-amino-5-benzoyl-thiazol-2-yl)-N-phenyl-carbamate

(93) ##STR00216##

(94) (4-amino-2-anilino-1,3-thiazol-5-yl)(phenyl)methanone (100 mg, 339 ?mol, Intermediate 61) was provided in dichloromethane at rt. N,N-diisopropylethylamine (180 ?l, 1.0 mmol; CAS-RN 7087-68-5), 4-(dimethylamino)pyridine (8 mg, 67.7 ?mol; CAS-RN 1122-58-3) and di-tert-butyl dicarbonate (81 mg, 372 ?mol; CAS-RN 24424-99-5) was added. The reaction mixture was stirred for 3 h at rt. The mixture was diluted with dichloromethane, washed with brine, dried and evaporated to give 120 mg (95% purity, 85% yield) of the title compound.

(95) .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm=1.32 (s, 9H), 7.35-7.44 (m, 3H), 7.45-7.51 (m, 2H), 7.52-7.58 (m, 3H), 7.69-7.73 (m, 2H), 7.94 (s, 2H).

(96) The following intermediates were prepared from the starting materials stated in Table 3, below, using the procedure as for Intermediate 83.

(97) The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (methods X, Y or Z depending on polarity) after precipitation, extraction or filtration of the reaction mixture if necessary.

(98) TABLE-US-00003 TABLE 3 Intermediates 84-96 Intermediate Chemical structure Starting number Compound name materials Analytics/purification/yield 84 Intermediate 62; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.34 (s, 9 H), 7.31 (t, J = 8.87 Hz, 2 H), 7.44- 7.48 (m, 2 H), 7.50-7.59 (m, 3 H), 7.68-7.74 (m, 2 H), 7.93 (s, 2 H). 91% yield tert-butyl N-(4-amino-5-benzoyl- thiazol-2-yl)-N-(4- fluorophenyl)carbamate 85 Intermediate 63; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.35 (s, 9 H), 3.84 (s, 3 H), 7.05-7.10 (m, 2 H), 7.31 (t, J = 8.74 Hz, 2 H), 7.46 (dd, J = 8.87, 5.07 Hz, 2 H), 7.73 (d, J = 8.87 Hz, 2 H), 7.86 (s, 2 H). 94% yield tert-butyl N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-N- (4-fluorophenyl)carbamate 86 Intermediate 64; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.34 (s, 9 H), 2.39 (s, 3 H), 7.31 (s, 4 H), 7.44-7.48 (m, 2 H), 7.61 (s, 2 H), 7.89 (s, 2 H). 79% yield tert-butyl N-[4-amino-5-(4- methylbenzoyl)thiazol-2-yl]-N-(4- fluorophenyl)carbamate 87 0 Intermediate 65; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.34 (s, 9 H), 7.31 (t, J = 8.87 Hz, 2 H), 7.37 (t, J = 9.00 Hz, 2 H), 7.46 (dd, J = 9.12, 5.07 Hz, 2 H), 7.79 (dd, J = 8.87, 5.58 Hz, 2 H), 7.95 (s, 2 H). quantitative yield tert-butyl N-[4-amino-5-(4- fluorobenzoyl)thiazol-2-yl]-N-(4- fluorophenyl)carbamate 88 Intermediate 66; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.35 (s, 9 H), 7.22-7.27 (m, 1 H), 7.49- 7.57 (m, 4 H), 7.67-7.74 (m, 3 H), 7.95 (s, 2 H). 69% yield tert-butyl N-(4-amino-5-benzoyl- thiazol-2-yl)-N-(2,4- difluorophenyl)carbamate 89 Intermediate 67; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.34 (s, 9 H), 3.80 (s, 3 H), 6.98-7.02 (m, 2 H), 7.25-7.30 (m, 2 H), 7.50- 7.58 (m, 3 H), 7.68-7.74 (m, 2 H), 7.93 (s, 2 H). 91% yield tert-butyl N-(4-amino-5-benzoyl- thiazol-2-yl)-N-(4- methoxyphenyl)carbamate 90 Intermediate 68; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 0.25 (s, 6 H), 0.96-0.99 (m, 9 H), 1.35 (s, 9 H), 6.99 (d, J = 8.62 Hz, 2 H), 7.28-7.34 (m, 2 H), 7.46 (dd, J = 8.87, 5.07 Hz, 2 H), 7.69 (d, J = 8.87 Hz, 2 H), 7.88 (s, 2 H). 92% yield tert-butyl N-[4-amino-5-[4-[tert- butyl(dimethyl)silyl]oxybenzoyl] thiazol-2-yl]-N-(4- fluorophenyl)carbamate 91 Intermediate 69; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6: ? ppm = 1.33 (s, 9 H), 2.36 (s, 3 H), 7.25 (d, J = 9.38 Hz, 4 H), 7.54 (s, 3 H), 7.69- 7.74 (m, 2 H), 7.93 (s, 2 H). 85% yield tert-butyl N-(4-amino-5-benzoyl- thiazol-2-yl)-N-(p-tolyl)carbamate 92 Intermediate 70; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.34 (s, 9 H), 7.22-7.32 (m, 2 H), 7.43 (br dt, J = 9.76, 2.22 Hz, 1 H), 7.48- 7.60 (m, 4 H), 7.69-7.74 (m, 2 H), 7.95 (s, 2 H). 99% yield tert-butyl N-(4-amino-5-benzoyl- thiazol-2-yl)-N-(3- fluorophenyl)carbamate 93 Intermediate 71; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6: ? ppm = 1.34 (s, 9 H), 7.33 (td, J = 7.67, 1.39 Hz, 1 H), 7.41 (ddd, J = 10.01, 8.49, 1.27 Hz, 1 H), 7.47-7.60 (m, 5 H), 7.70-7.75 (m, 2 H), 7.95 (s, 2 H). 88% yield tert-butyl N-(4-amino-5-benzoyl- thiazol-2-yl)-N-(2- fluorophenyl)carbamate 94 Intermediate 74; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.39 (s, 9 H), 3.85 (s, 3 H), 7.49-7.57 (m, 4 H), 7.68-7.73 (m, 2 H), 7.92 (s, 1 H), 7.98 (s, 2 H). 89% yield tert-butyl N-(4-amino-5-benzoyl- thiazol-2-yl)-N-(1-methylpyrazol-4- yl)carbamate 95 Intermediate 75; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.34 (s, 9 H), 7.49-7.61 (m, 4 H), 7.68- 7.75 (m, 2 H), 7.90-7.97 (m, 3 H), 8.60 (dd, J = 4.56, 1.52 Hz, 1 H), 8.63 (dd, J = 2.54, 0.51 Hz, 1 H). LC-MS (method 2) Rt = 1.24 min; MS (ESIpos): m/z = 397.5 [M + H].sup.+ 85% yield tert-butyl N-(4-amino-5-benzoyl- thiazol-2-yl)-N-(3- pyridyl)carbamate 96 Intermediate 76; di-tert-butyl dicarbonate .sup.1H-NMR (400 MHz, DMSO- d6): ? ppm = 1.34 (s, 9 H), 7.31 (t, J = 8.74 Hz, 2 H), 7.44- 7.48 (m, 2 H), 7.64-7.68 (m, 2 H), 7.73-7.77 (m, 2 H), 7.98 (s, 2 H). LC-MS (method 2) Rt = 1.53 min; MS (ESIpos): m/z = 492.5 [M + H].sup.+ preparative flash chromatography (method Z, 0- 3%) 92% yield tert-butyl N-[4-amino-5-(4- bromobenzoyl)thiazol-2-yl]-N-(4- fluorophenyl)carbamate

(99) Intermediate 97

2-bromo-1-[4-(methoxymethoxy)phenyl]ethan-1-one

(100) ##STR00230##

(101) 4-Hydroxyphenacyl bromide (2.50 g, 11.6 mmol) was provided in THF (50 mL). To this was added sodium hydride (511 mg, 60% in mineral oil, 12.8 mmol), and the suspension was stirred at rt for 1 h, after which time chloromethyl methyl ether (1.1 mL, 13.9 mmol) was added dropwise. The suspension was stirred at rt for 72 h. The reaction was stopped by the addition of a saturated aqueous solution of ammonium chloride and extracted with dichloromethane. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum to give a brown oil. The residue was purified by normal phase column chromatography (10-80% EtOAc in heptane) to give 1.161 g (39% yield) of the title compound as a light yellow oil.

(102) .sup.1H-NMR (CDCl3, 400 MHz): ? ppm=3.48 (s, 3H); 4.40 (s, 2H); 5.23 (s, 2H); 7.09 (d, 2H); 7.96 (d, 2H)

(103) LC-MS (method 2): Rt=0.79 min; MS(ESIpos) m/z=260 [M+H].sup.+

(104) Intermediate 98

(4-amino-2-anilino-1,3-thiazol-5-yl)[4-(methoxymethoxy)phenyl]methanone

(105) ##STR00231##

(106) Dry acetonitrile (65 mL) was provided and phenyl isothiocyanate (350 ?l, 2.9 mmol; CAS-RN 103-72-0), cyanamide (146 mg, 3.47 mmol; CAS-RN 420-04-2) and 1,8-diazabicyclo[5.4.0]undec-7-en (0.75 mL, 5.1 mmol; CAS-RN 6674-22-2) were added and the solution was stirred at rt for 45 min, after which time more 1,8-diazabicyclo(5.4.0)undec-7-ene (0.75 mL, 5.1 mmol) was added, followed by 2-bromo-1-[4-(methoxymethoxy)phenyl]ethan-1-one (750 mg, 2.89 mmol in 10 mL acetonitrile; Intermediate 97). The solution was stirred at rt for 1.5 h. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organics were washed with brine, and silica was added. The suspension was concentrated under vacuum. The residue was purified by normal phase column chromatography (10-80% EtOAc in heptane) to give 669 mg (65% yield) of the title compound as a yellow solid.

(107) LC-MS (method 2): Rt=0.81 min; MS(ESIpos) m/z=356 [M+H].sup.+

(108) .sup.1H-NMR (CDCl3, 400 MHz): ? ppm=3.49 (s, 3H); 5.20 (s, 2H); 7.05 (d, 2H); 7.19 (t, 1H); 7.33-7.43 (m, 4H); 7.73 (d, 2H); 8.46 (br s, 1H); NH2 not observed.

(109) Intermediate 99

[4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl][4-(methoxymethoxy)phenyl]methanone

(110) ##STR00232##

(111) Dry acetonitrile (25 mL) was provided and 4-fluorophenyl isothiocyanate (296 mg, 1.93 mmol), cyanamide (97.4 mg, 2.32 mmol; CAS-RN 420-04-2) and 1,8-diazabicyclo(5.4.0)undec-7-ene (0.5 mL, 3.4 mmol; CAS-RN 6674-22-2) were added and the solution was stirred at rt for 45 min, after which time more 1,8-diazabicyclo(5.4.0)undec-7-ene (0.5 mL, 3.4 mmol)) was added, followed by 2-bromo-1-[4-(methoxymethoxy)phenyl]ethan-1-one (500 mg, 1.93 mmol in 10 mL acetonitrile; Intermediate 98). The solution was stirred at rt for 18 h. The mixture was evaporated to dryness under vacuum, partitioned between water and ethyl acetate and extracted into ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and brine, then dried over magnesium sulfate before being filtered. Silica was added and the suspension was evaporated. This was purified by normal phase column chromatography (15-100% EtOAc in heptane) to give 620 mg (72% yield) of the title compound.

(112) .sup.1H-NMR (DMSO-d6, 400 MHz): ? ppm=3.43 (s, 3H); 5.29 (s, 2H); 7.12 (d, 2H); 7.25 (2H, t); 7.64-7.72 (m, 4H); 8.20 (br s, 2H); 10.79 (s, 1H).

(113) LC-MS (method 2): Rt=0.81 min; MS(ESIpos) m/z=374 [M+H].sup.+

(114) Intermediate 100

rac-2-[4-[4-amino-2-(N-[2-amino-1-methyl-2-oxo-ethyl]-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]acetic acid

(115) ##STR00233##

(116) To a solution of rac-ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate (24 mg, 0.05 mmol; Example 81) in tetrahydrofurane (2 mL) was added aqueous sodium hydroxide solution (0.1 mL, 1 M). The reaction mixture was stirred overnight at rt.

(117) The reaction mixture was diluted with water, aqueous hydrochloride acid (1 M) was added dropwise to adjust the pH to 3 and afterwards the mixture was extracted with dichloromethane. The organic layer was washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The residue was dissolved in acetonitrile/water (1:1) and dried by lyophilization to give 15 mg (63% yield) of the title compound.

(118) .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm=1.16 (d, J=7.35 Hz, 3H), 4.68 (s, 2H), 5.05 (br q, J=7.44 Hz, 1H), 6.89 (d, J=8.87 Hz, 2H), 7.24 (s, 1H), 7.33 (t, J=8.74 Hz, 2H), 7.47 (d, J=8.87 Hz, 2H), 7.58 (s, 1H), 7.64 (dd, J=8.87, 5.07 Hz, 2H), 8.08 (br s, 2H), 13.02 (br s, 1H).

(119) LC-MS (method 1) Rt=0.87 min; MS (ESIpos): m/z=459.5 [M+H].sup.+

(120) Intermediates 100.1 and 100.2:

(R)-2-[4-[4-amino-2-(N-[2-amino-1-methyl-2-oxo-ethyl]-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]acetic acid and (S)-2-[4-[4-amino-2-(N-[2-amino-1-methyl-2-oxo-ethyl]-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]acetic acid

(121) Intermediate 100.1

2-[4-[4-amino-2-(N-[2-amino-1-methyl-2-oxo-ethyl]-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]acetic acid (enantiomer 1)

(122) ##STR00234##

(123) To an ice cooled solution of ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate (enantiomer 1) (2.50 g, 5.14 mmol, Example 81.1) in tetrahydrofurane (26.3 mL) was added aqueous sodium hydroxide solution (5.1 mL, 1 M). The mixture was stirred overnight at rt.

(124) The reaction mixture was diluted with water, aqueous hydrochloride acid (1 M) was added dropwise to adjust the pH to 3 and afterwards the mixture was treated with dichloromethane. The resulting precipitate was isolated by filtration, washed with water and some dichloromethane and dried by lyophilization to give 1.48 g (62% yield) of the title compound.

(125) Intermediate 100.2

2-[4-[4-amino-2-(N-[2-amino-1-methyl-2-oxo-ethyl]-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]acetic acid (enantiomer 2)

(126) ##STR00235##

(127) To an ice cooled solution of ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate (enantiomer 2) (2.60 g, 5.34 mmol; Example 81.2) in tetrahydrofurane (27.3 mL) was added aqueous sodium hydroxide solution (5.3 mL, 1 M). The mixture was stirred overnight at rt.

(128) The reaction mixture was diluted with water, aqueous hydrochloride acid (1 M) was added dropwise to adjust the pH to 3 and afterwards the mixture was treated with dichloromethane.

(129) The resulting precipitate was isolated by filtration, washed with water and some dichloromethane and dried by lyophilization to give 0.95 g (37% yield) of the title compound.

(130) The organic layer of the filtrate was separated, washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness to give further 695 mg (28% yield) of the title compound.

(131) The following Intermediates were prepared from commercial starting materials stated in Table 4, below, using the procedure as for Intermediate 4, followed by purification by chromatography if needed. If no purification is specified, the respective title compound was isolated as crude product.

(132) The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (methods X, Y or Z depending on polarity) if necessary. In case of a missing precipitation, the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and evaporated to dryness. The crude product was purified by chromatography as stated in Table 4.

(133) TABLE-US-00004 TABLE 4 Intermediates 101-197 Inter- mediate Chemical structure number Compound name Starting materials Analytics/purification/yield 101 1-fluoro-4- isothiocyanato- benzene; 2-bromo-1-[6- (difluoromethyl)-3- pyridyl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.03 (t, J = 60 Hz, 1 H), 7.23 (t, J = 8.87 Hz, 2 H), 7.64 (dd, J = 9.12, 4.82 Hz, 2 H), 7.81 (d, J = 8.11 Hz, 1 H), 8.22 (dd, J = 7.98, 2.15 Hz, 1 H), 8.35-8.40 (m, 2 H), 8.92 (d, J = 1.52 Hz, 1 H), 10.94 (s, 1 H). LC-MS (method 1) Rt = 1.08 min; MS (ESIpos): m/z = 365.2 [M + H].sup.+ 71% yield [4-amino-2-(4- fluoroanilino)thiazol-5-yl]- [6-(difluoromethyl)-3- pyridyl]methanone 102 2-chloro-1-fluoro-4- isothiocyanato- benzene; 2-bromo- 1-(4- pyridyl)ethanone; hydrobromide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.22 (ddd, J = 8.87, 4.56, 2.53 Hz, 1 H), 7.33-7.37 (m, 1 H), 7.47 (dd, J = 6.84, 2.53 Hz, 1 H), 7.57-7.62 (m, 2 H), 8.41 (s, 1 H), 8.50-8.55 (m, 2 H). LC-MS (method 2) Rt = 0.81 min; MS (ESIpos): m/z = 349.2 [M + H].sup.+ 65% yield [4-amino-2-(3-chloro-4- fluoro-anilino)thiazol-5-yl]- (4-pyridyl) methanone 103 2-chloro-1-fluoro-4- isothiocyanato- benzene; 2-bromo-1-(4- methoxyphenyl) ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 3.79-3.84 (m, 3 H), 7.00 (d, 2 H), 7.32-7.43 (m, 2 H), 7.66 (d, 2 H), 7.88-7.98 (m, 1 H), 8.05- 8.34 (m, 1 H). LC-MS (method 2) Rt = 1.14 min; MS (ESIpos): m/z = 378.3 [M + H].sup.+ 96% yield [4-amino-2-(3-chloro-4- fluoro-anilino)thiazol-5-yl]- 4- methoxyphenyl)methanone 104 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[6- (difluoromethoxy) pyridin-3-yl]ethanone .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ? ppm = 7.15-7.26 (m, 3 H), 7.61- 7.68 (m, 2 H), 7.77 (t, 1H), 8.12- 8.19 (m, 1 H), 8.21-8.40 (m, 2 H), 8.53-8.57 (m, 1 H), 10.90 (br s, 1 H). LC-MS (method 2) Rt = 1.03 min; MS (ESIpos): m/z = 381.2 [M + H].sup.+ 73% yield [4-amino-2-(4- fluoroanilino)thiazol-5-yl]- [6-(difluoromethoxy)-3- pyridyl]methanone 105 0 1,2-difluoro-4- isothiocyanato- benzene; 2-bromo-1-[6- (difluoromethoxy) pyridin-3-yl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.16-7.20 (m, 1 H), 7.24 (brd, J = 8.87 Hz, 1 H), 7.43 (d, J = 10.39 Hz, 1 H), 7.78 (t, J = 72 Hz, 1 H), 7.90-7.94 (m, 1 H), 8.17 (dd, J = 8.36, 2.53 Hz, 1 H), 8.28-8.33 (m, 2 H), 8.56 (d, J =1.77 Hz, 1 H), 11.05 (br s, 1 H). LC-MS (method 2) Rt = 1.02 min; MS (ESIpos): m/z = 399.2 [M + H].sup.+ 63% yield [4-amino-2-(3,4- difluoroanilino)thiazol-5-yl]- [6-(difluoromethoxy)-3- pyridyl]methanone 106 1-chloro-2-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[6- (difluoromethoxy) pyridin-3-yl]ethanone LC-MS (method 2) Rt = 1.03 min; MS (ESIpos): m/z = 415.2 [M + H].sup.+ 57% yield [4-amino-2-(4-chloro-3- fluoro-anilino)thiazol-5-yl]- [6-(difluoromethoxy)-3- pyridyl]methanone 107 1,2-difluoro-4- isothiocyanato- benzene; 1-[4- (benzyloxy)phenyl]- 2-bromoethanone LC-MS (method 2) Rt = 1.29 min; MS (ESIpos): m/z = 438.3 [M + H].sup.+ 71% yield [4-amino-2-(3,4- difluoroanilino)-1,3-thiazol- 5-yl][4- (benzyloxy)phenyl]methanone 108 1-chloro-2-fluoro-4- isothiocyanatobenzene; 1-[4- (benzyloxy)phenyl] 2-bromoethanone LC-MS (method 2) Rt = 1.35 min; MS (ESIpos): m/z = 454.3 [M + H].sup.+ 94% yield [4-amino-2-(4-chloro-3- fluoro-anilino)thiazol-5-yl]- (4- benzyloxyphenyl)methanone 109 1,2-difluoro-4- isothiocyanato- benzene; benzyl N- [4-(2- bromoacetyl)phenyl] carbamate LC-MS (method 2) Rt = 1.18 min; MS (ESIpos): m/z = 481.3 [M + H].sup.+ 78% yield Benzyl (4-{[4-amino-2-(3,4- difluoroanilino)-1,3-thiazol- 5- yl]carbonyl}pheny)carbamate 110 1-fluoro-4- isothiocyanatobenzene; 1-[4- (benzyloxy)phenyl]- 2-bromoethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 5.17 (s, 2 H), 7.06-7.10 (m, 2 H), 7.19-7.23 (m, 2 H), 7.39-7.43 (m, 5 H), 7.62-7.67 (m, 4 H), 8.11-8.15 (m, 2 H), 10.75 (br s, 1 H) LC-MS (method 2) Rt = 1.30 min; MS (ESIpos): m/z = 420.2 [M + H].sup.+ 86% yield [4-amino-2-(4- fluoroanilino)thiazol-5-yl]- (4- benzyloxyphenyl)methanone 111 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(4- iodophenyl)ethanone LC-MS (method 2) Rt = 1.21 min; MS (ESIpos): m/z = 440.1 [M + H].sup.+ 82% yield [4-amino-2-(4- fluoroanilino)thiazol-5-yl]- (4-iodophenyl)methanone 112 1-fluoro-4- isothiocyanatobenzene; 2-[4- (bromoacetyl)phenoxy] ethyl acetate (Intermediate 198) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 3.73 (q, J = 5.15 Hz, 2 H), 4.03-4.07 (m, 2 H), 4.91 (t, J = 5.45 Hz, 1 H), 7.00-7.05 (m, 3 H), 7.19-7.23 (m, 2 H), 7.60- 7.65 (m, 5 H), 8.15-8.19 (m, 2 H), 10.74-10.76 (m, 1 H). LC-MS (method 2) Rt = 1.06 min; MS (ESIpos): m/z = 416.3 [M + H].sup.+ 11% yield 2-[4-[4-amino-2-(4- fluoroanilino)thiazole-5- carbonyl]phenoxy]ethyl acetate 113 1-chloro-2-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(6- methoxy-3- pyridyl)ethanone LC-MS (method 2) Rt = 1.05 min; MS (ESIpos): m/z = 379.2 [M + H].sup.+ 100% yield [4-amino-2-(4-chloro-3- fluoroanilino)-1,3-thiazol-5- yl](6-methoxypyridin-3- yl)methanone 114 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(4- phenoxyphenyl) ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.02-7.06 (m, 2 H), 7.09- 7.13 (m, 2 H), 7.19-7.23 (m, 3 H), 7.43-7.47 (m, 2 H), 7.61- 7.65 (m, 2 H), 7.69-7.71 (m, 2 H), 8.19-8.21 (m, 2 H), 10.77 (br s, 1 H) LC-MS (method 2) Rt = 1.27 min; MS (ESIpos): m/z = 406.2 [M + H].sup.+ 84% yield [4-amino-2-(4- fluoroanilino)thiazol-5-yl]- (4- phenoxyphenyl)methanone 115 0 1-isothiocyanato-4- methoxybenzene; 2- bromo-1-[4- (difluoromethoxy) phenyl]ethanone .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 3.73-3.76 (m, 3 H), 6.93- 6.96 (m, 2 H), 7.22-7.26 (m, 2 H), 7.33 (t, 1 H), 7.45-7.48 (m, 2 H), 7.70-7.73 (m, 2 H), 8.19- 8.21 (m, 2 H), 10.63 (m, 1 H) LC-MS (method 2) Rt = 1.27 min; MS (ESIpos): m/z = 406.2 [M + H].sup.+ 57% yield 4-amino-2-(4- methoxyanilino)thiazol-5- yl]-[4- (difluoromethoxy)phenyl] methanone 116 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(4- nitrophenyl)ethanone LC-MS (method 2) Rt = 0.95 min; MS (ESIpos): m/z = 359.1 [M + H].sup.+ 81% yield [4-amino-2-(4- fluoroanilino)thiazol-5-yl]- (4-nitrophenyl)methanone 117 1-fluoro-4- isothiocyanatobenzene; ethanimidamide acetate (1:1); 2- bromo-1-(4- methoxyphenyl) ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 2.34 (s, 3 H), 3.84 (s, 3 H), 7.05 (m, 2 H), 7.21 (m, 2 H), 7.64 (m, 2 H), 7.71 (m. 2 H), 10.76 (s, 1 H) LC-MS (method 2) Rt = 1.24 min; MS (ESIpos): m/z = 343.2 [M + H].sup.+ 8% yield [2-(4-fluoroanilino)-4- methyl-1,3-thiazol-5-yl](4- methoxyphenyl)methanone 118 1-fluoro-4- isothiocyanatobenzene; N-[4- (bromoacetyl)phenyl] cyclopropanecarbox- amide LC-MS (method 2) Rt = 0.77 min; MS (ESIpos): m/z = 397.3 [M + H].sup.+ 69% yield N-[4-[4-amino-2-(4- fluoroanilino)thiazole-5- carbonyl]phenyl]cyclopropane- carboxamide 119 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[4- (morpholin-4- yl)phenyl]ethanone LC-MS (method 2) Rt = 1.04 min; MS (ESIpos): m/z = 399.2 [M + H].sup.+ 66% yield [4-amino-2-(4- fluoroanilino)thiazol-5-yl]- (4- morpholinophenyl)methanone 120 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-{4- [(1H-pyrazol-1- yl)methyl]phenyl} ethan-1-one, hydrogen bromide LC-MS (method 2) Rt = 1.01 min; MS (ESIpos): m/z = 394.3 [M + H].sup.+ 64% yield [4-amino-2-(4- fluoroanilino)-1,3-thiazol-5- yl][4-(1H-pyrazol-1- ylmethyl)phenyl]methanone 121 1-fluoro-4- isothiocyanatobenzene; 4- (dimethylamino) phenacyl bromide LC-MS (method 2) Rt = 1.16 min; MS (ESIpos): m/z = 357.3 [M + H].sup.+ 86% yield [4-amino-2-(4- fluoroanilino)-1,3-thiazol-5- yl][4- (dimethylamino)phenyl] methanone 122 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[4- (pyrrolidin-1- yl)phenyl]ethanone LC-MS (method 2) Rt = 1.26 min; MS (ESIpos): m/z = 383.2 [M + H].sup.+ 84% yield [4-amino-2-(4- fluoroanilino)thiazol-5-yl]- (4-pyrrolidin-1- ylphenyl)methanone 123 1-(benzyloxy)-4- isothiocyanatobenzene; 2-bromo-1-[4- (difluoromethoxy) phenyl]ethanone LC-MS (method 2) Rt = 1.32 min; MS (ESIpos): m/z = 468.3 [M + H].sup.+ 89% yield [4-amino-2-(4- benzyloxyanilino)thiazol-5- yl]-[4- (difluoromethoxy)phenyl] methanone 124 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[3- (difluoromethoxy) phenyl]ethanone (intermediate 199) LC-MS (method 2) Rt = 1.10 min; MS (ESIpos): m/z = 380.2 [M + H].sup.+ 91% yield [4-amino-2-(4- fluoroanilino)-1,3-thiazol-5- yl][3- (difluoromethoxy)phenyl] methanone 125 0 1,2-difluoro-4- isothiocyanatobenzene; 2-bromo-1- (pyridin-3- yl)ethanone hydrobromide (1:1) LC-MS (method 2) Rt = 0.77 min; MS (ESIpos): m/z = 333.2 [M + H].sup.+ 88% yield [4-amino-2-(3,4- difluoroanilino)-1,3-thiazol- 5-yl](pyridin-3- yl)methanone 126 1-fluoro-4- isothiocyanatobenzene; 4- acetamidophenacyl bromide LC-MS (method 2) Rt = 0.87 min; MS (ESIpos): m/z = 371.3 [M + H].sup.+ 58% yield N-(4-{[4-amino-2-(4- fluoroanilino)-1,3-thiazol-5- yl]carbonyl}phenyl)acetamide 127 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(2- chloropyridin-4- yl)ethanone LC-MS (method 2) Rt = 0.86 min; MS (ESIpos): m/z = 349.2 [M + H].sup.+ 88% yield [4-amino-2-(4- fluoroanilino)-1,3-thiazol-5- yl](2-chloropyridin-4- yl)methanone 128 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(2- methylpyridin-4- yl)ethanone hydrobromide (1:1) LC-MS (method 2) Rt = 0.80 min; MS (ESIpos): m/z = 329.2 [M + H].sup.+ 80% yield [4-amino-2-(4- fluoroanilino)thiazol-5-yl]- (2-methyl-4- pyridyl)methanone 129 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[2- (difluoromethyl)-4- pyridyl]ethanone LC-MS (method 2) Rt = 0.87 min; MS (ESIpos): m/z = 365.2 [M + H].sup.+ 78% yield [4-amino-2-(4- fluoroanilino)-1,3-thiazol-5- yl][2- (difluoromethyl)pyridin-4- yl]methanone 130 4- isothiocyanatopyridine; 2-bromo-1- phenylethanone LC-MS (method 2) Rt = 0.69 min; MS (ESIpos): m/z = 297.2 [M + H].sup.+ 17% yield [4-amino-2-(pyridin-4- ylamino)-1,3-thiazol-5- yl](phenyl)methanone 131 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(2- methoxypyridin-4- yl)ethanone LC-MS (method 2) Rt = 0.91 min; MS (ESIpos): m/z = 345.2 [M + H].sup.+ 80% yield [4-amino-2-(4- fluoroanilino)thiazol-5-yl]- (2-methoxy-4- pyridyl)methanone 132 1-fluoro-4- isothiocyanatobenzene; benzyl N-[4-(2- bromoacetyl)phenyl] carbamate LC-MS (method 2) Rt = 1.20 min; MS (ESIpos): m/z = 463.3 [M + H].sup.+ 72% yield Benzyl (4-{4-amino-2-(4- fluoroanilino)-1,3-thiazol-5- yl]carbonyl}phenyl)carbamate 133 2-fluoro-4- isothiocyanato-1- methoxybenzene; 2- bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.75 (s, 1H), 8.23 (br s, 2H), 7.68-7.75 (m, 1H), 7.64-7.68 (m, 2H), 7.44-7.52 (m, 3H), 7.13- 7.22 (m, 2H), 3.82 (s, 3H). LC-MS (method 2) Rt = 1.08 min MS (ESIpos): m/z = 344.6 [M + H].sup.+ 96% yield [4-amino-2-(3-fluoro-4- methoxyanilino)-1,3- thiazol-5- yl](phenyl)methanone 134 2-fluoro-4- isothiocyanatobenzo- nitrile; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.42 (br s, 1H), 8.28 (br s, 2H), 8.10 (dd, J = 12.5, 1.9 Hz, 1H), 7.86 (dd, J = 8.6, 7.9 Hz, 1H), 7.67-7.72 (m, 2H), 7.46-7.56 (m, 3H), 7.39 (dd, J = 8.6, 2.0 Hz, 1H). LC-MS (method 2) Rt = 0.9 min MS (ESIpos): m/z = 339.5 [M + H].sup.+ 4-[(4-amino-5-benzoyl-1,3- 87% yield thiazol-2-yl)amino]-2- fluorobenzonitrile 135 0 1-bromo-4- isothiocyanatobenzene; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.89 (br s, 1H), 8.22 (br s, 2H), 7.64-7.70 (m, 2H), 7.57-7.64 (m, 2H), 7.44-7.57 (m, 5H). LC-MS (method 2) Rt = 1.18 min MS (ESIpos): m/z = 375.2 [M + H].sup.+ 100% yield [4-amino-2-(4- bromoanilino)-1,3-thiazol- 5-yl](phenyl)methanone 136 2-chloro-1- (difluoromethoxy)-4- isothiocyanatobenzene; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.97 (br s, 1H), 8.26 (br s, 2H), 8.05 (d, J = 2.5 Hz, 1H), 7.64-7.70 (m, 2H), 7.45-7.54 (m, 4H), 7.36 (d, J = 8.9 Hz, 1H), 7.20 (t, J = 73.3 Hz, 1H). LC-MS (method 2) Rt = 1.14 min MS (ESIpos): m/z = 396.3 [M + H].sup.+ 92% yield {4-amino-2-[3-chloro-4- (difluoromethoxy)anilino]- 1,3-thiazol-5- yl}(phenyl)methanone 137 1-ethoxy-4- isothiocyanatobenzene; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.58 (br s, 1H), 7.69-8.55 (m, 2H), 7.60-7.66 (m, 2H), 7.40-7.51 (m, 5H), 6.88-6.95 (m, 2H), 4.00 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H). LC-MS (method 2) Rt = 1.14 min MS (ESIpos): m/z = 340.4 [M + H].sup.+ 100% yield [4-amino-2-(4- ethoxyanilino)-1,3-thiazol- 5-yl](phenyl)methanone 138 5-isothiocyanato- 1,3-benzodioxole; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.64 (s, 1H), 8.20 (br s, 2H), 7.62-7.67 (m, 2H), 7.43-7.52 (m, 3H), 7.32-7.37 (m, 1H), 6.88- 6.95 (m, 2H), 6.02 (s, 2H). LC-MS (method 2) Rt = 0.99 min MS (ESIpos): m/z = 340.2 [M + H].sup.+ 57% yield [4-amino-2-(1,3- benzodioxol-5-ylamino)- 1,3-thiazol-5- yl](phenyl)methanone 139 2,2-difluoro-5- isothiocyanato-1,3- benzodioxole; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.95 (br s, 1H), 8.24 (br s, 2H), 7.94 (d, J = 2.0 Hz, 1H), 7.64-7.69 (m, 2H), 7.45-7.53 (m, 3H), 7.40 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 8.7, 2.2 Hz, 1H). LC-MS (method 2) Rt = 1.17 min MS (ESIpos): m/z = 376.4 [M + H].sup.+ 78% yield {4-amino-2-[(2,2-difluoro- 1,3-benzodioxol-5- yl)amino]-1,3-thiazol-5- yl}(phenyl)methanone 140 1-(difluoromethoxy)- 2-fluoro-4- isothiocyanatobenzene; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.00 (s, 1H), 8.26 (br s, 2H), 7.97 (dd, J = 12.9, 2.5 Hz, 1H), 7.65-7.70 (m, 2H), 7.45-7.54 (m, 3H), 7.33-7.39 (m, 1H), 7.24- 7.29 (m, 1H), 7.18 (t, J = 73.3 Hz, 1H). LC-MS (method 2) Rt = 1.08 min MS (ESIpos): m/z = 380.2 [M + H].sup.+ {4-amino-2-[4- 92% yield (difluoromethoxy)-3- fluoroanilino]-1,3-thiazol-5- yl}(phenyl)methanone 141 1-(benzyloxy)-4- isothiocyanatobenzene; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.61 (br s, 1H), 8.17 (br s, 2H), 7.64 (dd, J = 7.6, 1.8 Hz, 2H), 7.42-7.50 (m, 7H), 7.36-7.42 (m, 2H), 7.30-7.36 (m, 1H), 6.99- 7.04 (m, 2H), 5.09 (s, 2H). LC-MS (method 2) Rt = 1.3 min MS (ESIpos): m/z = 402.4 [M + H].sup.+ 98% yield {4-amino-2-[4- (benzyloxy)anilino]-1,3- thiazol-5- yl}(phenyl)methanone 142 2-chloro-1- (difluoromethoxy)-4- isothiocyanatobenzene; 2-bromo-1-(4- methoxyphenyl) ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.94 (br s, 1H), 8.21 (br s, 2H), 8.06 (d, J = 2.5 Hz, 1H), 7.66-7.71 (m, 2H), 7.48 (dd, J = 8.9, 2.5 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.20 (t, J = 73.8 Hz, 1H), 7.02-7.05 (m, 1H), 7.00-7.02 (m, 1H), 3.82 (s, 3H). LC-MS (method 2) Rt = 1.17 min MS (ESIpos): m/z = 426.2 [M + H].sup.+ 99% yield {4-amino-2-[3-chloro-4- (difluoromethoxy)anilino]- 1,3-thiazol-5-yl}(4- methoxyphenyl)methanone 143 2-chloro-1- (difluoromethoxy)-4- isothiocyanatobenzene; 2-bromo-1-[4- (difluoromethoxy) phenyl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.00 (br s, 1H), 8.14-8.42 (m, 2H), 8.05 (d, J = 2.5 Hz, 1H), 7.73-7.78 (m, 2H), 7.48 (dd, J = 9.0, 2.7 Hz, 1H), 7.38 (d, J = 6.1 Hz, 1H), 7.35 (t, J = 73.8 Hz, 1H), 7.24-7.29 (m, 2H), 7.20 (t, J = 73.3 Hz, 1H). LC-MS (method 2) Rt = 1.15 min MS (ESIpos): m/z = 462.2 [M + H].sup.+ 87% yield {4-amino-2-[3-chloro-4- (difluoromethoxy)anilino]- 1,3-thiazol-5-yl}[4- (difluoromethoxy)phenyl] methanone 144 2-chloro-1- (difluoromethoxy)-4- isothiocyanatobenzene; 2-bromo-1-(4- chlorophenyl)ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.02 (br s, 1H), 8.31 (br s, 2H), 8.05 (d, J = 2.3 Hz, 1H), 7.67-7.72 (m, 2H), 7.53-7.58 (m, 2H), 7.47 (dd, J = 9.0, 2.7 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.20 (t, J = 73.5 Hz, 1H). LC-MS (method 2) Rt = 1.20 min MS (ESIpos): m/z = 430.2 [M + H].sup.+ 100% yield {4-amino-2-[3-chloro-4- (difluoromethoxy)anilino]- 1,3-thiazol-5-yl}(4- chlorophenyl)methanone 145 0 2-chloro-1- (difluoromethoxy)-4- isothiocyanatobenzene; 2-bromo-1-(pyridin- 4-yl)ethanone hydrobromide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.08 (br s, 1H), 8.70-8.74 (m, 2H), 8.42 (br s, 2H), 8.06 (d, J = 2.5 Hz, 1H), 7.56-7.60 (m, 2H), 7.46-7.51 (m, 1H), 7.37 (d, J = 9.1 Hz, 1H), 7.21 (t, J = 73.3 Hz, 1H). LC-MS (method 2) Rt = 0.82 min MS (ESIpos): m/z = 397.2 [M + H].sup.+ 45% yield {4-amino-2-[3-chloro-4- (difluoromethoxy)anilino]- 1,3-thiazol-5-yl}(pyridln-4- yl)methanone 146 2-chloro-1- (difluoromethoxy)-4- isothiocyanatobenzene; 2-bromo-1-[6- (difluoromethoxy) pyridin-3-yl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.07 (br s, 1H), 8.55-8.58 (m, 1H), 8.34 (br s, 2H), 8.18 (dd, J = 8.6, 2.5 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.78 (t, J = 72.5 Hz, 1H), 7.47 (dd, J = 9.0, 2.7 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 7.21 (t, J = 73.5 Hz, 1H), 7.18-7.21 (m, 1H). LC-MS (method 2) Rt = 1.06 min MS (ESIpos): m/z = 463.2 [M + H].sup.+ 92% yield {4-amino-2-[3-chloro-4- (difluoromethoxy)anilino]- 1,3-thiazol-5-yl}[6- (difluoromethoxy)pyridin-3- yl]methanone 147 1-(difluoromethoxy)- 2-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(4- methoxyphenyl) ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.99 (br s, 1H), 8.20 (br s, 2H), 7.97 (dd, J = 13.1, 2.4 Hz, 1H), 7.66-7.71 (m, 2H), 7.33-7.39 (m, 1H), 7.24-7.30 (m, 1H), 7.17 (t, J = 73.3 Hz, 1H), 7.00-7.05 (m, 2H), 3.82 (s, 3H). LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 410.2 [M + H].sup.+ 96% yield {4-amino-2-[4- (difluoromethoxy)-3- fluoroanilino]-1,3-thiazol-5- yl(4- methoxyphenyl)methanone 148 1-(difluoromethoxy)- 2-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(4- chlorophenyl)ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.06 (br s, 1H), 8.30 (br s, 2H), 7.96 (dd, J = 12.9, 2.5 Hz, 1H), 7.68-7.72 (m, 2H), 7.53-7.58 (m, 2H), 7.33-7.39 (m, 1H), 7.24- 7.29 (m, 1H), 7.18 (t, J = 73.3 Hz, 1H). LC-MS (method 2) Rt = 1.18 min MS (ESIpos): m/z = 414.2 [M + H].sup.+ 95% yield {4-amino-2-[4- (difluoromethoxy)-3- fluoroanilino]-1,3-thiazol-5- yl}(4- chlorophenyl)methanone 149 1-(difluoromethoxy)- 2-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[4- (difluoromethoxy) phenyl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.03 (br s, 1H), 8.28 (br s, 2H), 7.96 (dd, J = 12.9, 2.3 Hz, 1H), 7.73-7.78 (m, 2H), 7.32-7.55 (m, 2H), 6.99-7.30 (m, 4H). LC-MS (method 2) Rt = 1.14 min MS (ESIpos): m/z = 446.2 [M + H].sup.+ 88% yield {4-amino-2-[4- (difluoromethoxy)-3- fluoroanilino]-1,3-thiazol-5- yl}[4- (difluoromethoxy)phenyl] methanone 150 1-(difluoromethoxy)- 2-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(pyridin- 4-yl)ethanone hydrobromide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.12 (s, 1H), 8.70-8.74 (m, 2H), 8.41 (br s, 2H), 7.97 (dd, J = 12.9, 2.5 Hz, 1H), 7.57-7.60 (m, 2H), 7.34-7.38 (m, 1H), 7.25-7.30 (m, 1H), 7.18 (t, J = 73.3 Hz,1H). LC-MS (method 2) Rt = 0.8 min MS (ESIpos): m/z = 381.2 [M + H].sup.+ 15% yield {4-amino-2-[4- (difluoromethoxy)-3- fluoroanilino]-1,3-thiazol-5- yl}(pyridin-4-yl)methanone 151 1-(difluoromethoxy)- 2-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[6- (difluoromethoxy) pyridin-3-yl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.02-11.23 (m, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.25-8.41 (m, 2H), 8.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.92-7.98 (m, 1H), 7.78 (t, J = 72.2 Hz, 1H), 7.33-7.40 (m, 1H), 7.24-7.30 (m, 1H), 7.20 (d, J = 9.1 Hz, 1H), 7.18 (t, J = 73.5 Hz, 1H). LC-MS (method 2) Rt = 1.06 min MS (ESIpos): m/z = 447.2 [M + H].sup.+ 86% yield {4-amino-2-[4- (difluoromethoxy)-3- fluoroanilino]-1,3-thiazol-5- yl}[6- (difluoromethoxy)pyridin-3- yl]methanone 152 2-fluoro-4- isothiocyanato-1- (trifluoromethoxy) benzene (Intermediate 200); 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.12 (br s, 1H), 8.26 (br s, 2H), 8.08 (dd, J = 12.9, 2.5 Hz, 1H), 7.66-7.70 (m, 2H), 7.45-7.59 (m, 4H), 7.29-7.34 (m, 1H). LC-MS (method 2) Rt = 1.21 min MS (ESIpos): m/z = 398.2 [M + H].sup.+ 96% yield {4-amino-2-[3-fluoro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5- yl}(phenyl)methanone 153 2-chloro-4- isothiocyanato-1- (trifluoromethoxy) benzene; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.08 (br s, 1H), 8.28 (br s, 2H), 8.16 (d, J = 2.3 Hz, 1H), 7.65-7.72 (m, 2H), 7.45-7.59 (m, 5H). LC-MS (method 2) Rt = 1.22 min MS (ESIpos): m/z = 414.2 [M + H].sup.+ 91% yield {4-amino-2-[3-chloro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5- yl}(phenyl)methanone 154 2,2-difluoro-5- isothiocyanato-1,3- benzodioxole; 2-bromo-1-(4- methoxyphenyl) ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.92 (br s, 1H), 8.17 (br s, 2H), 7.95 (d,J = 2.0 Hz, 1H), 7.65-7.70 (m, 2H), 7.40 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 8.7, 2.2 Hz, 1H), 6.99-7.05 (m, 2H), 3.82 (s, 3H). LC-MS (method 2) Rt = 1.21 min MS (ESIpos): m/z = 406.2 [M + H].sup.+ 89% yield {4-amino-2-[(2,2-difluoro- 1,3-benzodioxol-5- yl)amino]-1,3-thiazol-5- yl}(4- methoxyphenyl)methanone 155 0 2,2-difluoro-5- isothiocyanate-1,3- benzodioxole; 2-bromo-1-(4- chlorophenyltethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.00 (br d, J = 1.3 Hz, 1H), 8.28 (br s, 2H), 7.94 (d, J = 2.0 Hz, 1H), 7.66-7.73 (m, 2H), 7.51-7.58 (m, 2H), 7.40 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 8.9, 2.3 Hz, 1H). LC-MS (method 2) Rt = 1.25 min MS (ESIpos): m/z = 410.2 [M + H].sup.+ 93% yield {4-amino-2-[(2,2-difluoro- 1,3-benzodioxol-5- yl)amino]-1,3-thlazol-5- yl}(4- chlorophenyl)methanone 156 2,2-difluoro-5- isothiocyanate-1,3- benzodioxole; 2-bromo-1-[4- (difluoromethoxy) phenyl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.98 (br s, 1H), 8.24 (br s, 2H), 7.93 (d, J = 1.5 Hz, 1H), 7.71-7.78 (m, 2H), 7.40 (d, J = 8.6 Hz, 1H), 7.35 (t, J = 73.8 Hz, 1H), 7.21-7.29 (m, 3H). LC-MS (method 2) Rt = 1.23 min MS (ESIpos): m/z = 442.2 [M + H].sup.+ 61% yield {4-amino-2-[(2,2-difluoro- 1,3-benzodioxol-5- yl)amino]-1,3-thiazol-5- yl}[4- (difluoromethoxy)phenyl] methanone 157 2,2-difluoro-5- isothiocyanate-1,3- benzodioxole; 2-bromo-1-(pyridin- 4-yl)ethanone hydrobromide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.06 (s, 1H), 8.69-8.74 (m, 2H), 8.38 (br s, 2H), 7.94 (d, J = 1.8 Hz, 1H), 7.56-7.60 (m, 2H), 7.41 (d, J = 8.9 Hz, 1H), 7.25 (dd, J = 8.7, 2.2 Hz, 1H). LC-MS (method 2) Rt = 0.85 min MS (ESIpos): m/z = 377.2 [M + H].sup.+ 13% yield {4-amino-2-[(2,2-difluoro- 1,3-benzodioxol-5- yl)amino]-1,3-thiazol-5- yl}(pyridin-4-yl)methanone 158 2,2-difluoro-5- isothiocyanate-1,3- benzodioxole; 2-bromo-1-[6- (difluoromethoxy) pyridin-3-yl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.05 (br s, 1H), 8.54-8.58 (m, 1H), 8.31 (br s, 2H), 8.17 (dd, J = 8.6, 2.5 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.78 (t, J = 72.5 Hz, 1H), 7.41 (d, J = 8.9 Hz, 1H), 7.25 (dd, J = 8.9, 2.3 Hz, 1H), 7.17- 7.22 (m, 1H). LC-MS (method 2) Rt = 1.15 min MS (ESIpos): m/z = 443.2 [M + H].sup.+ 85% yield {4-amino-2-[(2,2-difluoro- 1,3-benzodioxol-5- yl)amino]-1,3-thiazol-5- yl}[6- (difluoromethoxy)pyridin-3- yl]methanone 159 2-fluoro-4- isothiocyanato-1- (trifluoromethoxy) benzene (Intermediate 200); 2-bromo-1-(4- methoxyphenyl) ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.10 (br s, 1H), 8.20 (br s, 2H), 8.08 (dd, J = 12.9, 2.5 Hz, 1H), 7.66-7.72 (m, 2H), 7.55 (td, J = 8.9, 1.0 Hz, 1H), 7.30-7.35 (m, 1H), 7.00-7.05 (m, 2H), 3.82 (s, 3H). LC-MS (method 2) Rt = 1.24 min MS (ESIpos): m/z = 428.2 [M + H].sup.+ 90% yield {4-amino-2-[3-fluoro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5-yl}(4- methoxyphenyl)methanone 160 2-fluoro-4- isothiocyanato-1- (trifluoromethoxy) benzene (Intermediate 200); 2-bromo-1-(4- chlorophenyl)ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.10 (br s, 1H), 8.20 (br s, 2H), 8.08 (dd, J = 12.9, 2.5 Hz, 1H), 7.66-7.72 (m, 2H), 7.55 (td, J = 9.0, 1.0 Hz, 1H), 7.30-7.35 (m, 1H), 7.00-7.06 (m, 2H), 3.82 (s, 3H). LC-MS (method 2) Rt = 1.23 min MS (ESIpos): m/z = 432.2 [M + H].sup.+ 91% yield {4-amino-2-[3-fluoro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5-yl}(4- chlorophenyl)methanone 161 2-fluoro-4- isothiocyanato-1- (trifluoromethoxy) benzene (Intermediate 200); 2-bromo-1-[4- (difluoromethoxy) phenyl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.15 (br s, 1H), 8.28 (br s, 2H), 8.07 (dd, J = 12.9, 2.5 Hz, 1H), 7.73-7.80 (m, 2H), 7.51-7.62 (m, 1H), 7.36 (t, J = 73.8 Hz, 1H), 7.30-7.34 (m, 1H), 7.25-7.30 (m, 2H). LC-MS (method 2) Rt = 1.24 min MS (ESIpos): m/z = 464.2 [M + H].sup.+ 86% yield {4-amino-2-[3-fluoro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5-yl}[4- (difluoromethoxy)phenyl] methanone 162 2-fluoro-4- isothiocyanato-1- (trifluoromethoxy) benzene (Intermediate 200); 2-bromo-1-(pyridin- 4-yl)ethanone hydrobromide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.23 (s, 1H), 8.70-8.75 (m, 2H), 8.42 (br s, 2H), 8.08 (dd, J = 12.9, 2.5 Hz, 1H), 7.53-7.62 (m, 3H), 7.30-7.35 (m, 1H). LC-MS (method 2) Rt = 0.89 min MS (ESIpos): m/z = 399.2 [M + H].sup.+ 21% yield {4-amino-2-[3-fluoro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5-yl}(pyridln-4- yl)methanone 163 2-fluoro-4- isothiocyanato-1- (trifluoromethoxy) benzene (Intermediate 200); 2-bromo-1-[6- (difluoromethoxy) pyridin-3-yl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.22 (br s, 1H), 8.55-8.61 (m, 1H), 8.34 (br s, 2H), 8.19 (dd, J = 8.5, 2.4 Hz, 1H), 8.07 (dd, J = 12.9, 2.5 Hz, 1H), 7.78 (t, J = 72.5 Hz, 1H), 7.56 (td, J = 8.9, 1.0 Hz, 1H), 7.30-7.36 (m, 1H), 7.18-7.22 (m, 1H). LC-MS (method 2) Rt = 1.15 min MS (ESIpos): m/z = 465.2 [M + H].sup.+ 84% yield {4-amino-2-[3-fluoro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5-yl}[6- (difluoromethoxy)pyridin-3- yl]methanone 164 2-chloro-4- isothiocyanato-1- (trifluoromethoxy) benzene; 2-bromo-1-(4- methoxyphenyl) ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.06 (br s, 1H), 8.05-8.37 (m, 3H), 7.66-7.72 (m, 2H), 7.50- 7.58 (m, 2H), 7.00-7.05 (m, 2H), 3.82 (s, 3H). LC-MS (method 2) Rt = 1.22 min MS (ESIpos): m/z = 444.2 [M + H].sup.+ 79% yield {4-amino-2-[3-chloro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5-yl}(4- methoxyphenyl)methanone 165 00 2-chloro-4- isothiocyanato-1- (trifluoromethoxy) benzene; 2-bromo-1-(4- chlorophenyl)ethanone 1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.87-7.99 (m, 1H), 7.64- 7.71 (m, 2H), 7.48-7.54 (m, 2H), 7.43 (s, 1H), 7.37 (br d, J = 0.8 Hz, 1H). LC-MS (method 2) Rt = 1.3 min MS (ESIpos): m/z = 448.2 [M + H].sup.+ 53% yield {4-amino-2-[3-chloro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5-yl}(4- chlorophenyl)methanone 166 01 2-chloro-4- isothiocyanato-1- (trifluoromethoxy) benzene; 2-bromo-1-[4- (difluoromethoxy) phenyl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.11 (br s, 1H), 8.29 (br s, 2H), 8.15 (d, J = 2.5 Hz, 1H), 7.73-7.79 (m, 2H), 7.50-7.58 (m, 2H), 7.36 (t, J = 73.2 Hz, 1H), 7.25-7.30 (m, 2H). LC-MS (method 2) Rt = 1.24 min MS (ESIpos): m/z = 480.2 [M + H].sup.+ 71% yield {4-amino-2-[3-chloro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5-yl}[4- (difluoromethoxy)phenyl] methanone 167 02 2-chloro-4- isothiocyanato-1- (trifluoromethoxy) benzene; 2-bromo-1-(pyridin- 4-yl)ethanone hydrobromide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.19 (s, 1H), 8.70-8.75 (m, 2H), 8.43 (br s, 2H), 8.17 (d, J = 2.3 Hz, 1H), 7.51-7.61 (m, 4H). LC-MS (method 2) Rt = 0.93 min MS (ESIpos): m/z = 415.2 [M + H].sup.+ 47% yield {4-amino-2-[3-chloro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5-yl}(pyridin-4- yl)methanone 168 03 2-chloro-4- isothiocyanato-1- (trifluoromethoxy) benzene; 2-bromo-1-[6- (difluoromethoxy) pyridin-3-yl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.20 (br s, 1H), 8.54-8.59 (m, 1H), 8.21-8.52 (m, 2H), 8.18 (dd, J = 8.4, 2.5 Hz, 1H), 8.11 (br s, 1H), 7.78 (t, J = 72.5 Hz, 1H), 7.46-7.58 (m, 2H), 7.17-7.21 (m, 1H). LC-MS (method 2) Rt = 1.19 min MS (ESIpos): m/z = 481.2 [M + H].sup.+ 34% yield {4-amino-2-[3-chloro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5-yl}[6- (difluoromethoxy)pyridin-3- yl]methanone 169 04 5-isothiocyanato-2- methoxypyridine; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.69 (br s, 1H), 8.40 (d, J = 2.5 Hz, 1H), 7.96-8.38 (m, 2H), 7.93 (dd, J = 8.9, 2.8 Hz, 1H), 7.62-7.67 (m, 2H), 7.43-7.52 (m, 3H), 6.84-6.88 (m, 1H), 3.83 (s, 3H). LC-MS (method 2) Rt = 0.91 min MS (ESIpos): m/z = 327.2 [M + H].sup.+ 87% yield {4-amino-2-[(6- methoxypyridin-3- yl)amino]-1,3-thiazol-5- yl}(phenyl)methanone 170 05 5-isothiocyanato-2- (trifluoromethoxy) pyridine (Intermediate 201); 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.10 (br s, 1H), 8.67 (d, J = 2.8 Hz, 1H), 8.27 (dd, J = 8.9, 2.8 Hz, 3H), 7.66-7.70 (m, 2H), 7.46-7.53 (m, 3H), 7.34 (d, J = 8.9 Hz, 1H). LC-MS (method 2) Rt = 0.96 min MS (ESIpos): m/z = 381.2 [M + H].sup.+ 82% yield (4-amino-2-{[6- (trifluoromethoxy)pyridin-3- yl]amino}-1,3-thiazol-5- yl)(phenyl)methanone 171 06 2-(difluoromethoxy)- 5- isothiocyanatopyridine (Intermediate 202); 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.94 (br s, 1H), 8.56 (d, J = 2.8 Hz, 1H), 8.16 (dd, J = 8.9, 2.8 Hz, 3H), 7.67 (dd, J = 7.6, 1.8 Hz, 2H), 7.65 (t, J = 73.0 Hz, 1H), 7.45- 7.53 (m, 3H), 7.14 (d, J = 8.9 Hz, 1H). LC-MS (method 2) Rt = 0.93 min MS (ESIpos): m/z = 363.2 [M + H].sup.+ 90% yield (4-amino-2-{[6- (difluoromethoxy)pyridin-3- yl]amino}-1,3-thiazol-5- yl)(phenyl)methanone 172 07 5-isothiocyanato-2- (trifluoromethyl) pyridine; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.26-11.46 (m, 1H), 8.93 (d, J = 2.5 Hz, 1H), 8.40 (dd, J = 8.5, 2.2 Hz, 1H), 8.25 (br s, 2H), 7.89 (d, J = 8.6 Hz, 1H), 7.67- 7.72 (m, 2H), 7.46-7.56 (m, 3H). LC-MS (method 2) Rt = 0.88 min MS (ESIpos): m/z = 365.2 [M + H].sup.+ 69% yield (4-amino-2-{[6- (trifluoromethyl)pyridin-3- yl]amino}-1,3-thiazol-5- yl)(phenyl)methanone 173 08 2-(difluoromethyl)-5- isothiocyanatopyridine (Intermediate 203); 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.21 (br s, 1H), 8.88 (d, J = 2.3 Hz, 1H), 8.15-8.37 (m, 3H), 7.66-7.72 (m, 3H), 7.46-7.55 (m, 3H), 6.92 (t, J = 55.3 Hz, 1H). LC-MS (method 2) Rt = 0.79 min MS (ESIpos): m/z = 347.2 [M + H].sup.+ 66% yield (4-amino-2-{[6- (difluoromethyl)pyridin-3- yl]amino}-1,3-thiazol-5- yl)(phenyl)methanone 174 09 2-chloro-5- isothiocyanatopyridine; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.09 (br s, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.12-8.37 (m, 3H), 7.65-7.71 (m, 2H), 7.45-7.55 (m, 4H). LC-MS (method 2) Rt = 0.79 min MS (ESIpos): m/z = 331.2 [M + H].sup.+ 60% yield {4-amino-2-[(6- chloropyridin-3-yl)amino]- 1,3-thiazol-5- yl}(phenyl)methanone 175 0 2-fluoro-5- isothiocyanatopyridine; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.99 (br s, 1H), 8.52 (dd, J = 2.5, 1.3 Hz, 1H), 7.96-8.46 (m, 3H), 7.65-7.70 (m, 2H), 7.44- 7.54 (m, 3H), 7.22 (dd, J = 8.9, 3.0 Hz, 1H). LC-MS (method 2) Rt = 0.79 min MS (ESIpos): m/z = 315.2 [M + H].sup.+ yield 70% {4-amino-2-[(6- fluoropyridin-3-yl)amino]- 1,3-thiazol-5- yl}(phenyl)methanone 176 5-isothiocyanato-2- methylpyridine; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.83 (br s, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.03-8.52 (m, 2H), 8.00 (dd, J = 8.4, 2.5 Hz, 1H), 7.63-7.70 (m, 2H), 7.44-7.53 (m, 3H), 7.25 (d, J = 8.4 Hz, 1H), 2.43 (s, 3H). LC-MS (method 2) Rt = 0.81 min MS (ESIpos): m/z = 311.2 [M + H].sup.+ {4-amino-2-[(6- 88% yield methylpyridin-3-yl)amino]- 1,3-thiazol-5- yl}(phenyl)methanone 177 1-fluoro-4- isothiocyanato-2- (trifluoromethoxy) benzene (Intermediate 204); 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.01 (br s, 1H), 8.09-8.42 (m, 2H), 7.99 (dd, J = 7.1, 1.3 Hz, 1H), 7.66-7.70 (m, 2H), 7.56-7.61 (m, 1H), 7.45-7.55 (m, 4H). LC-MS (method 2) Rt = 1.21 min MS (ESIpos): m/z = 398.2 [M + H].sup.+ 94% yield {4-amino-2-[4-fluoro-3- (trifluoromethoxy)anilino]- 1,3-thiazol-5- yl}(phenyl)methanone 178 1-chloro-4- isothiocyanato-2- (trifluoromethoxy) benzene; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.12 (br s, 1H), 8.25 (br s, 2H), 8.01 (d, J = 0.8 Hz, 1H), 7.60-7.71 (m, 4H), 7.45-7.55 (m, 3H). LC-MS (method 2) Rt = 1.28 min MS (ESIpos): m/z = 414.2 [M + H].sup.+ 90% yield {4-amino-2-[4-chloro-3- (trifluoromethoxy)anilino]- 1,3-thiazol-5- yl}phenyl)methanone 179 2-(difluoromethoxy)- 1-fluoro-4- isothiocyanatobenzene (Intermediate 205); 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.91 (br s, 1H), 8.06-8.43 (m, 2H), 7.74 (dd, J = 6.7, 2.2 Hz, 1H), 7.64-7.70 (m, 2H), 7.45-7.53 (m, 4H), 7.37-7.42 (m, 1H), 7.25 (t, J = 73.0 Hz, 1H). LC-MS (method 2) Rt = 1.1 min MS (ESIpos): m/z = 380.2 [M + H].sup.+ 95% yield {4-amino-2-[3- (difluoromethoxy)-4- fluoroanilino]-1,3-thiazol-5- yl}(phenyl)methanone 180 1-chloro-2- (difluoromethoxy)-4- isothiocyanatobenzene; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.03 (br s, 1H), 8.23 (br s, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.65-7.70 (m, 2H), 7.46-7.58 (m, 5H), 7.27 (t, J = 73.0 Hz, 1H). LC-MS (method 2) Rt = 1.12 min MS (ESIpos): m/z = 396.2 [M + H].sup.+ 98% yield {4-amino-2-[4-chloro-3- (difluoromethoxy)anilino]- 1,3-thiazol-5- yl}(phenyl)methanone 181 2-fluoro-1- isothiocyanato-4- (trifluoromethoxy) benzene (Intermediate 206); 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.69 (br s, 1H), 8.25 (br t, J = 9.0 Hz, 3H), 7.63-7.69 (m, 2H), 7.43-7.56 (m, 4H), 7.28 (dd, J = 9.1, 1.0 Hz, 1H). LC-MS (method 2) Rt = 1.02 min MS (ESIpos): m/z = 398.2 [M + H].sup.+ 100% yield {4-amino-2-[2-fluoro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5- yl}(phenyl)methanone 182 2-chloro-1- isothiocyanato-4- (trifluoromethoxy) benzene; 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 9.25-9.70 (m, 1H), 8.46 (s, 1H), 7.55-7.68 (m, 3H), 7.32-7.46 (m, 4H), 7.16-7.25 (m, 1H). LC-MS (method 2) Rt = 1.05 min MS (ESIpos): m/z = 414.2 [M + H].sup.+ 45% yield {4-amino-2-[2-chloro-4- (trifluoromethoxy)anilino]- 1,3-thiazol-5- yl}(phenyl)methanone 183 4-(difluoromethoxy)- 2-fluoro-1- isothiocyanatobenzene (Intermediate 207); 2-bromo-1- phenylethanone 1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.25-10.79 (m, 1H), 7.90- 8.47 (m, 3H), 7.61-7.66 (m, 2H), 7.40-7.50 (m, 4H), 7.24-7.29 (m, 2H), 7.02-7.09 (m, 1H). LC-MS (method 2) Rt = 0.98 min MS (ESIpos): m/z = 380.2 [M + H].sup.+ 100% yield {4-amino-2-[4- (difluoromethoxy)-2- fluoroanilino]-1,3-thiazol-5- yl}(phenyl)methanone 184 2-chloro-4- (difluoromethoxy)-1- isothiocyanatobenzene (Intermediate 208); 2-bromo-1- phenylethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.43 (br s, 1H), 7.88-8.41 (m, 2H), 7.84 (d, J = 8.6 Hz, 1H), 7.62 (dd, J = 7.6, 1.8 Hz, 2H), 7.41- 7.48 (m, 4H), 7.30 (t, J = 73.8 Hz, 1H), 7.21 (dd, J = 8.7, 2.7 Hz, 1H). LC-MS (method 2) Rt = 1.02 min MS (ESIpos): m/z = 396.2 [M + H].sup.+ 99% yield {4-amino-2-[2-chloro-4- (difluoromethoxy)anilino]- 1,3-thiazol-5- yl}(phenyl)methanone 185 0 1-(difluoromethyl)-4- isothiocyanatobenzene; 2-bromo-1-(4- methoxyphenyl) ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.97 (br s, 1H), 8.17 (br s, 2H), 7.77 (d, J = 8.6 Hz, 2H), 7.66-7.71 (m, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.00-7.05 (m, 2H), 6.98 (t, J = 56.0 Hz, 1H), 3.82 (s, 3H). LC-MS (method 2) Rt = 1.07 min MS (ESIpos): m/z = 376.1 [M + H].sup.+ 88% yield {4-amino-2-[4- (difluoromethyl)anilino]- 1,3-thiazol-5-yl}(4- methoxyphenyl)methanone 186 1-(difluoromethyl)-4- isothiocyanatobenzene; 2-bromo-1-(4- chlorophenyl)ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.06 (br s, 1H), 8.28 (br s, 2H), 7.75 (brd, J = 8.4 Hz, 2H), 7.68-7.72 (m, 2H), 7.52-7.58 (m, 4H), 6.98 (t, J = 56.0 Hz, 1H). LC-MS (method 2) Rt = 1.11 min MS (ESIpos): m/z = 380.1 [M + H].sup.+ 94% yield {4-amino-2-[4- (difluoromethyl)anilino]- 1,3-thiazol-5-yl}(4- chlorophenyl)methanone 187 1-(difluoromethyl)-4- isothiocyanatobenzene; 2-bromo-1-[4- (difluoromethoxy) phenyl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.03 (br s, 1H), 8.24 (br s, 2H), 7.73-7.78 (m, 4H), 7.56 (d, J = 8.6 Hz, 2H), 7.35 (t, J = 73.8 Hz, 1H), 7.24-7.29 (m, 2H), 6.99 (t, J = 56.0 Hz, 1H). LC-MS (method 2) Rt = 1.09 min MS (ESIpos): m/z = 412.1 [M + H].sup.+ 91% yield {4-amino-2-[4- (difluoromethyl)anilino]- 1,3-thiazol-5-y)[4- (difluoromethoxy)phenyl] methanone 188 1-(difluoromethyl)-4- isothiocyanatobenzene; 2-bromo-1-(pyridin- 4-yl)ethanone hydrobromide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.83-11.29 (m, 1H), 8.67- 8.76 (m, 2H), 8.39 (br s, 2H), 7.77 (d, J = 8.6 Hz, 2H), 7.53-7.63 (m, 4H), 6.99 (t J = 55.8 Hz, 1H). LC-MS (method 2) Rt = 0.72 min MS (ESIpos): m/z = 347.1 [M + H].sup.+ 39% yield {4-amino-2-[4- (difluoromethyl)anilino]- 1,3-thiazol-5-yl}(pyridin-4- yl)methanone 189 1-(difluoromethyl)-4- isothiocyanatobenzene; 2-bromo-1-[6- (difluoromethoxy) pyridin-3-yl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.10 (br s, 1H), 8.56-8.60 (m, 1H), 8.32 (br s, 2H), 8.18 (dd, J = 8.4, 2.5 Hz, 1H), 7.78 (t, J = 72.5 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.18-7.22 (m, 1H), 6.99 (t, J = 55.8 Hz, 1H). LC-MS (method 2) Rt = 1.04 min MS (ESIpos): m/z = 413 [M + H].sup.+ 89% yield {4-amino-2-[4- (difluoromethyl)anilino]- 1,3-thiazol-5-yl}[6- (difluoromethoxy)pyridin-3- yl]methanone 190 5-isothiocyanato-2- (trifluoromethoxy) pyridine (Intermediate 201); 2-bromo-1-(4- methoxyphenyl) ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.07 (br s, 1H), 8.67 (d, J = 2.8 Hz, 1H), 8.27 (dd, J = 8.9, 2.8 Hz, 1H), 8.17 (br s, 2H), 7.65- 7.71 (m, 2H), 7.34 (d, J = 8.9 Hz, 1H), 7.00-7.05 (m, 2H), 3.82 (s, 3H). LC-MS (method 2) Rt = 0.95 min MS (ESIpos): m/z = 411.2 [M + H].sup.+ 63% yield (4-amino-2-{[6- (trifluoromethoxy)pyridin-3- yl]amino}-1,3-thiazol-5- yl)(4- methoxyphenyl)methanone 191 5-isothiocyanato-2- (trifluoromethoxy) pyridine (Intermediate 201); 2-bromo-1-(4- chlorophenyl)ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.18 (br s, 1H), 8.64 (d, J = 2.5 Hz, 1H), 8.25 (br dd, J = 8.9, 3.0 Hz, 3H), 7.67-7.73 (m, 2H), 7.53-7.58 (m, 2H), 7.33 (d, J = 8.9 Hz, 1H). LC-MS (method 2) Rt = 0.98 min MS (ESIpos): m/z = 415.2 [M + H].sup.+ 68% yield (4-amino-2-{[6- (trifluoromethoxy)pyridin-3- yl]amino}-1,3-thiazol-5- yl)(4- chlorophenyl)methanone 192 5-isothiocyanato-2- (trifluoromethoxy) pyridine (Intermediate 201); 2-bromo-1-[4- (difluoromethoxy) phenyl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.13 (br s, 1H), 8.67 (d, J = 2.8 Hz, 1H), 8.27 (dd, J = 8.9, 2.8 Hz, 3H), 7.72-7.79 (m, 2H), 7.16-7.55 (m, 4H). LC-MS (method 2) Rt = 0.97 min MS (ESIpos): m/z = 447.4 [M + H].sup.+ 90% yield (4-amino-2-{[6- (trifluoromethoxy)pyridin-3- yl]amino}-1,3-thiazol-5- yl)[4- (difluoromethoxy)phenyl] methanone 193 5-isothiocyanato-2- (trifluoromethoxy) pyridine (Intermediate 201); 2-bromo-1-[6- (difluoromethoxy) pyridin-3-yl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.23 (br s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 8.55-8.59 (m, 1H), 8.21-8.48 (m, 3H), 8.18 (dd, J = 8.6, 2.5 Hz, 1H), 7.78 (t, J = 72.9 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.17-7.22 (m, 1H). LC-MS (method 2) Rt = 0.85 min MS (ESIpos): m/z = 448.2 [M + H].sup.+ 70% yield (4-amino-2-{[6- (trifluoromethoxy)pyridin-3- yl]amino}-1,3-thiazol-5- yl)[6- (difluoromethoxy)pyridin-3- yl]methanone 194 2-(difiuoromethoxy)- 5- isothiocyanatopyridine (Intermediate 202); 2-bromo-1-(4- methoxyphenyl) ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 10.91 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.17 (dd, J = 8.9, 2.8 Hz, 3H), 7.65-7.70 (m, 2H), 7.65 (t, J = 73.0 Hz, 1H), 7.13 (d, J = 8.9 Hz, 1H), 6.99-7.05 (m, 2H), 3.82 (s, 3H). LC-MS (method 2) Rt = 0.94 min MS (ESIpos): m/z = 393.2 [M + H].sup.+ 86% yield (4-amino-2-{[6- (difluoromethoxy)pyridin-3- yl]amino}-1,3-thiazol-5- yl)(4- methoxyphenyl)methanone 195 0 2-(difluoromethoxy)- 5- isothiocyanatopyridine (Intermediate 202); 2-bromo-1-(4- chlorophenyl)ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 11.00 (br s, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.14 (dd, J = 8.9, 2.8 Hz, 3H), 7.66-7.71 (m, 2H), 7.65 (t, J = 73.3 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.9 Hz, 1H). LC-MS (method 2) Rt = 0.94 min MS (ESIpos): m/z = 397.1 [M + H].sup.+ 82% yield (4-amino-2-{[6- (difluoromethoxy)pyridin-3- yl]amino}-1,3-thiazol-5- yl)(4- chlorophenyl)methanone 196 2-(difluoromethoxy)- 5- isothiocyanatopyridine (Intermediate 202); 2-bromo-1-[4- (difluoromethoxy) phenyl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.56-10.12 (m, 1H), 7.70- 8.09 (m, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.57 (t J = 73.8 Hz, 1H), 7.27 (t, J = 74.1 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.9 Hz, 1H). LC-MS (method 2) Rt = 1.04 min MS (ESIpos): m/z = 429.1 [M + H].sup.+ 87% yield (4-amino-2-{[6- (difluoromethoxy)pyridin-3- yl]amino}-1,3-thiazol-5- yl)[4- (difluoromethoxy)phenyl] methanone 197 2-(difluoromethoxy)- 5- isothiocyanatopyridine (Intermediate 202); 2-bromo-1-[6- (difluoromethoxy) pyridin-3-yl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1H NMR (400 MHz, DMSO-d6, 22? C.): Shift = 11.04 (br s, 1H), 8.53-8.59 (m, 2H), 8.31 (br s, 2H), 8.14-8.19 (m, 2H), 7.78 (t, J = 72.5 Hz, 1H), 7.65 (t, J = 73.0 Hz, 1H), 7.20 (dd, J = 8.6, 0.8 Hz, 1H), 7.14 (d, J = 8.9 Hz, 1H). LC-MS (method 2) Rt = 0.92 min MS (ESIpos): m/z = 430.4 [M + H].sup.+ 86% yield (4-amino-2-{[6- (difluoromethoxy)pyridin-3- yl]amino}-1,3-thiazol-5- yl)[6- (difluoromethoxy)pyridin-3- yl]methanone

(134) Intermediate 198

2-[4-(2-bromoacetyl)phenoxy]ethyl acetate

(135) ##STR00333##

(136) 2-(4-acetylphenoxy)ethyl acetate (940 mg, 4.23 mmol) in THF (12.5 mL) at 0? C. was treated with phenyl trimethyl ammonium tribromide (1.59 g, 4.23 mmol). The reaction mixture was stirred at rt overnight, diluted with water and extracted three times with dichloromethane. The combined organic phases were washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The crude product was purified by Biotage (method X) to give 237 mg (0.79 mmol, 18% yield) of the title compound.

(137) LC-MS (method 1): Rt=1.05 min; MS(ESIpos) m/z=300.0 [M+H].sup.+

(138) Intermediate 199

2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone

(139) ##STR00334##

(140) 3-(difluoromethoxy)acetophenone (1 g, 5.37 mmol) in THF (15 mL) at 0? C. was treated with phenyl trimethyl ammonium tribromide (2.02 g, 5.37 mmol). The reaction mixture was stirred at rt overnight, diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The crude product (quant.) was used without further purification.

(141) LC-MS (method 1): Rt=1.14 min; MS(ESIpos) m/z=264.9 [M+H].sup.+

(142) Intermediate 200

2-Fluoro-4-isothiocyanato-1-(trifluoromethoxy)benzene

(143) ##STR00335##

(144) 3-fluoro-4-(trifluoromethoxy)aniline (560 mg, 2.81 mmol) was suspended in dichloromethane (12 mL) followed by the addition of triethylamine (1.76 mL, 12.65 mmol). The mixture was cooled to 0? C. and carbonothioyl dichloride (356 mg, 3.09 mmol) diluted in dichloromethane (1.5 mL) was added slowly. After removal of the ice bath the batch was stirred at room temperature for one hour. Water (12 mL) and dichloromethane (7.5 mL) were added, the organic layer was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The crude material was purified via Biotage (hexanes/ethyl acetate) to yield 350 mg (1.36 mmol, 48%) of the title compound.

(145) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm=7.79 (dd, J=11.0, 2.4 Hz, 1H), 7.65-7.71 (m, 1H), 7.43 (ddd, J=8.9, 2.5, 1.5 Hz, 1H).

(146) The following Intermediates were prepared from the starting materials stated in Table 5, below, using the procedure as for 2-fluoro-4-isothiocyanato-1-(trifluoromethoxy)benzene/Intermediate 200.

(147) TABLE-US-00005 TABLE 5 Intermediates 201-208 Inter- mediate Chemical structure number Compound name Starting materials Analytics/yield 201 6- (trifluoromethoxy) pyridin-3-amine dihydrochloride; carbonothioyl dichloride .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.52 (d, J = 2.8 Hz, 1H), 8.13 (dd, J = 8.7, 2.7 Hz, 1H), 7.39-7.43 (m, 1H). 79% yield 5-isothiocyanato-2- (trifluoromethoxy)pyridine 202 6- (difluoromethoxy) pyridin-3-amine; carbonothioyl dichloride .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.43 (d, J = 2.8 Hz, 1H), 8.05 (dd, J = 8.7, 2.7 Hz, 1H), 7.69 (t, J = 72.5 Hz, 1H), 7.20 (d, J = 8.9 Hz, 1H). 86% yield 2-(difluoromethoxy)-5- isothiocyanato-pyridine 203 6- (difluoromethyl) pyridin-3-amine dihydrochloride; carbonothioyl dichloride .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1H NMR (400 MHz, DMSO-d6, 22? C.): Shift = 8.78 (d, J = 2.0 Hz, 1H), 8.06 (dd, J = 8.4, 2.3 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.00 (t, J = 54.8 Hz, 1H). 77% yield 2-(difluoromethyl)-5- isothiocyanato-pyridine 204 4-fluoro-3- (trifluoromethoxy) aniline; carbonothioyl dichloride .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.83-7.88 (m, 1H), 7.59- 7.65 (m, 2H). 53% yield 1-fluoro-4-isothiocyanato- 2-(trifluoromethoxy)- benzene 205 0 3-(difluoromethoxy)- 4-fluoroaniline hydrochloride; carbonothioyl dichloride .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.60 (dd, J = 7.0, 2.4 Hz, 1H), 7.51 (dd, J = 10.4, 8.9 Hz, 1H), 7.39-7.44 (m, 1H), 7.30 (t, J = 72.8 Hz, 1H). 73% yield 2-(difluoromethoxy)-1- fluoro-4-isothiocyanato- benzene 206 2-fluoro-4- (trifluoromethoxy) aniline; carbonothioyl dichloride .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.70 (dd, J = 10.0, 2.4 Hz, 1H), 7.64 (t, J = 8.7 Hz, 1H), 7.33 (ddt, J = 8.9, 2.4, 1.3 Hz, 1H). 35% yield 2-fluoro-1-isothiocyanato- 4-(trifluoromethoxy)- benzene 207 4-(difluoromethoxy)- 2-fluoroaniline; carbonothioyl dichloride .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.58 (t, J = 8.9 Hz, 1H), 7.43 (dd, J = 11.0, 2.7 Hz, 1H), 7.34 (t, J = 73.3 Hz, 1H), 7.07- 7.13 (m. 1H). 70% yield 4-(difluoromethoxy)-2- fluoro-1-isothiocyanato- benzene 208 2-chloro-4- (difluoromethoxy) aniline; carbonothioyl dichloride .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.64 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.34 (t, J = 73.3 Hz, 1H), 7.25 (dd, J = 8.9, 2.8 Hz, 1H). 48% yield 2-chloro-4- (difluoromethoxy)-1- isothiocyanato-benzene

(148) Intermediate 209

[4-amino-2-(4-fluoroanilino)thiazol-5-yl]-[4-(2-hydroxyethoxy)phenyl]methanone

(149) ##STR00344##

(150) The title compound (36 mg, 0.09 mmol, 11% yield) was isolated as a byproduct in the formation of 2-(4-{[4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl]carbonyl}phenoxy)ethyl acetate (Intermediate 112).

(151) LC-MS (method 2): Rt=0.90 min; MS(ESIpos) m/z=374.3 [M+H].sup.+

(152) Intermediate 210

Ethyl 4-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]benzoate

(153) ##STR00345##

(154) 1-fluoro-4-isothiocyanatobenzene (5.65 g, 36.9 mmol) was dissolved in acetonitrile (200 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (5.61 g, 36.9 mmol) and cyanamide (1.86 g, 44.3 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (2.8 g, 18.5 mmol) and ethyl 4-(bromoacetyl)benzoate (10 g, 36.9 mmol) dissolved in acetonitrile (80 mL) were added. The reaction mixture was stirred at rt for 2.5 h and treated with water. The precipitate was filtered off, washed with water and dried in vacuo to give 14.2 g (quant.) of the title compound.

(155) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm=1.34 (t, J=7.1 Hz, 3H), 4.34 (d, J=7.1 Hz, 3H), 7.22 (m, 2H), 7.61 (m, 1H), 7.78 (d, J=8.62 Hz, 2H), 8.04 (d, J=8.62 Hz, 2H), 8.32 (m, 2H), 10.87 (br s, 1H).

(156) LC-MS (method 2): Rt=1.10 min; MS(ESIpos) m/z=386.3 [M+H].sup.+

(157) Intermediate 211

rac-4-[(4-amino-2-{[(2RS)-1-amino-1-oxopropan-2-yl](4-fluorophenyl)amino}-1,3-thiazol-5-yl)carbonyl]benzoic acid

(158) ##STR00346##

(159) rac-Ethyl 4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]benzoate (15.47 g, 33 mmol, Example 257) was suspended in THF (150 mL) and treated with 1M aqueous sodium hydroxide (43 mL, 43 mmol). The reaction mixture was stirred overnight followed by the addition of 1M aqueous hydrochloric acid up to pH 3. The solution was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness to give 11.63 g (25 mmol, 87% yield) of the title compound.

(160) LC-MS (method 2): Rt=0.53 min; MS(ESIpos) m/z=429.4 [M+H].sup.+

(161) Intermediate 212

Ethyl 4-[4-amino-2-(4-chloro-3-fluoro-anilino)thiazole-5-carbonyl]benzoate

(162) ##STR00347##

(163) 1-chloro-2-fluoro-4-isothiocyanatobenzene (692 mg, 3.7 mmol) was dissolved in acetonitrile (20 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (561.5 mg, 3.68 mmol) and cyanamide (186 mg, 4.43 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (280.75 mg, 1.84 mmol) and ethyl 4-(bromoacetyl)benzoate (1 g, 3.7 mmol) dissolved in acetonitrile (14 mL) were added. The reaction mixture was stirred 2 h at rt. The suspension was treated with water and the precipitate was isolated by filtration, washed with water and some ethyl acetate and dried in vacuo to give 1.24 g (2.52 mmol, 68%, purity 85%) of the title compound.

(164) LC-MS (method 2): Rt=1.12 min; MS(ESIpos) m/z=420.2 [M+H].sup.+

(165) Intermediate 213

rac-4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-chloro-3-fluoro-anilino)thiazole-5-carbonyl]benzoic acid

(166) ##STR00348##

(167) rac-Ethyl 4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-chloro-3-fluoro-anilino)thiazole-5-carbonyl]benzoate (830 mg, 1.7 mmol, Example 258) was suspended in THF (10 mL) and treated with 2M aqueous sodium hydroxide (8.5 mL, 17 mmol). The reaction mixture was stirred at room temperature overnight followed by the addition of 2M aqueous hydrochloric acid up to pH 3. The precipitate was filtered off, washed with water and dried in vacuo to yield 680 mg (1.47 mmol, 88%) of the title compound.

(168) LC-MS (method 1): Rt=1.07 min; MS(ESIpos) m/z=463.1 [M+H].sup.+

(169) Intermediate 214

Ethyl 2-[4-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]phenoxy]-2-methyl-propanoate

(170) ##STR00349##

(171) 1-fluoro-4-isothiocyanatobenzene (349 mg, 2.28 mmol) was dissolved in acetonitrile (8 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (346 mg, 2.28 mmol) and cyanamide (115 mg, 2.7 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (173 mg, 1.14 mmol) and ethyl 2-[4-(2-bromoacetyl)phenoxy]-2-methyl-propanoate (750 mg, 2.28 mmol) dissolved in acetonitrile (4 mL) were added. The reaction mixture was stirred overnight at rt. The suspension was treated with water and the precipitate was isolated by filtration, washed with water and dried in vacuo to give 1.01 g (2.28 mmol, 70%) of the title compound.

(172) .sup.1H NMR (400 MHz, DMSO-d6) ? ppm=1.15 (t, J=7.1 Hz, 3H), 1.57 (s, 6H), 4.17 (q, J=7.1 Hz, 2H), 6.80 (m, 2H), 7.15 (m, 2H), 7.50 (m, 2H), 7.59 (m, 2H), 8.12 (m, 2H), 10.51 (m, 1H).

(173) LC-MS (method 2): Rt=1.24 min; MS(ESIpos) m/z=444.3 [M+H].sup.+

(174) Intermediate 215

rac-2-[4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]-2-methyl-propanoic acid

(175) ##STR00350##

(176) Rac-Ethyl 2-[4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]-2-methyl-propanoate (925 mg, 1.79 mmol, Example 259) was suspended in THF (10 mL) and treated with 1M aqueous sodium hydroxide (2.7 mL, 2.7 mmol). The reaction mixture was stirred at room temperature overnight followed by the addition of 1M aqueous hydrochloric acid up to pH 3. The reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness to yield 861 mg (1.6 mmol, 91%) of the title compound.

(177) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm=1.16 (d, J=7.35 Hz, 3H), 1.52 (s, 6H), 5.06 (m, 1H), 6.76 (m, 2H), 7.24 (s, 1H), 7.33 (t, J=8.74 Hz, 2H), 7.45 (m, 2H), 7.57 (s, 1H), 7.64 (m, 2H), 8.10 (m, 2H), 13.15 (m, 1H).

(178) LC-MS (method 2): Rt=0.63 min; MS(ESIpos) m/z=487.4 [M+H].sup.+

Intermediate 216

[4-amino-2-(4-fluoroanilino)thiazol-5-yl]-(6-amino-3-pyridyl)methanone

(179) ##STR00351##

(180) 1-fluoro-4-isothiocyanatobenzene (250 mg, 1.63 mmol) was dissolved in acetonitrile (8 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (248.5 mg, 1.63 mmol) and cyanamide (82 mg, 1.96 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (124.2 mg, 0.82 mmol) and 1-(8-amino-3-pyridyl)-2-bromo-ethanone (351 mg, 1.63 mmol) dissolved in acetonitrile (7 mL) were added. The reaction mixture was stirred 2.5 h at rt. The suspension was treated with water and the precipitate was isolated by filtration, washed with water and dried in vacuo to give 350 mg (1.05 mmol, 64%) of the title compound.

(181) .sup.1H NMR (400 MHz, DMSO-de) ? ppm=4.65 (s, 2H), 6.96 (d, J=9.63 Hz, 1H), 7.03 (d, J=9.38 Hz, 2H), 8.24 (m, 3H), 8.62 (d, J=2.28 Hz, 2H), 8.82 (d, J=2.28 Hz, 1H).

(182) LC-MS (method 2): Rt=0.82 min; MS(ESIpos) m/z=330.2 [M+H].sup.+

(183) Intermediate 217

Benzyl N-[5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-2-pyridyl]carbamate

(184) ##STR00352##

(185) [4-amino-2-(4-fluoroanilino)thiazol-5-yl]-(6-amino-3-pyridyl)methanone (205 mg, 0.62 mmol, Intermediate 216) was suspended in THF (5 mL) and treated with benzyl carbonochloridate (106 mg, 0.62 mmol) and triethylamine (94 mg, 0.93 mmol). The reaction mixture was stirred overnight at rt followed by the addition of further benzyl carbonochloridate (106 mg, 0.62 mmol), triethylamine (94 mg, 0.93 mmol) and DMAP (1 mg). After 4.5 h water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The residue was purified via Biotage chromatography (method Y) to yield 25 mg (0.05 mmol, 9%) of the title compound.

(186) LC-MS (method 2): Rt=1.11 min; MS(ESIpos) m/z=464.3 [M+H].sup.+

(187) Intermediate 218

[4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](6-bromopyridin-3-yl)methanone

(188) ##STR00353##

(189) 1-fluoro-4-isothiocyanatobenzene (1.29 g, 8.43 mmol) was dissolved in acetonitrile (65 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (1.28 g, 8.43 mmol) and cyanamide (0.43 g, 10.1 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (0.64 g, 4.2 mmol) and 2-bromo-1-(6-bromo-3-pyridyl)ethanone (2.35 g, 8.43 mmol) dissolved in acetonitrile (15 mL) were added. The reaction mixture was stirred at rt overnight and treated with water. The precipitate was filtered off, washed with water and dried in vacuo to give 2.52 g (6.4 mmol, 76%) of the title compound.

(190) LC-MS (method 2): Rt=0.95 min; MS(ESIpos) m/z=395.1 [M+H].sup.+

EXPERIMENTAL SECTIONPREPARATION OF EXAMPLE COMPOUNDS

Example 1

rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-4-methoxy-2-methyl-anilino)propanamide

(191) ##STR00354##

(192) [4-amino-2-(4-methoxy-2-methyl-anilino)thiazol-5-yl]-phenyl-methanone (100 mg, 0.295 mmol; Intermediate 4) were dissolved in N,N-dimethylformamide (3 mL) followed by the addition of potassium carbonate (407 mg, 2.95 mmol) and rac-2-bromopropanamide (224 mg, 1.47 mmol). The reaction mixture was stirred at 90? C. for 2 h. The reaction mixture was filtrated and purified by RP-HPLC (method D, basic) to give 57 mg (47% yield) of the title compound.

(193) .sup.1H-NMR: (400 MHz, DMSO-d6): ? ppm=1.03 (d, J=7.35 Hz, 3H), 2.13 (s, 3H), 3.75-3.78 (m, 3H), 4.93-5.13 (m, 1H), 6.85-6.93 (m, 2H), 7.17-7.24 (m, 1H), 7.34-7.42 (m, 3H), 7.42-7.50 (m, 2H), 7.54 (br s, 1H), 7.64 (d, J=8.62 Hz, 1H), 7.73-8.60 (m, 2H).

(194) LC-MS (method 2) Rt=1.08 min; MS (ESIpos): m/z=411.5 [M+H].sup.+

(195) The following examples were prepared from the starting materials stated in Table 6, below, using the procedure as for Example 1.

(196) The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (methods X, Y or Z depending on polarity) after precipitation, extraction or filtration of the reaction mixture if necessary.

(197) Enantiomers were separated from their racemate by chiral HPLC using the column and solvent conditions stated.

(198) TABLE-US-00006 TABLE 6 Examples 2-80 Example Chemical structure Starting number Compound name materials Analytics/purification/yield 2 Intermediate 5 rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.14 (d, J = 7.35 Hz, 3 H), 2.93 (s, 6 H), 5.06 (br d, J = 6.08 Hz, 1 H), 6.70 (d, J = 9.38 Hz, 2 H), 7.15-7.20 (m, 1 H), 7.28 (d, J = 8.87 Hz, 2 H), 7.34- 7.41 (m, 3 H), 7.43-7.50 (m, 3 H), 7.74-8.53 (m, 2 H). LC-MS (method 2) Rt = 1.11 min; MS (ESIpos): m/z = 410.6 [M + H].sup.+ RP-HPLC (method D, basic) 51% yield rac-2-[N-(4-amino-5-benzoyl- thiazol-2-yl)-4- (dimethylamino)anilino]propanamide 3 Intermediate 6 rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J =7.35 Hz, 3 H), 1.27 (d, J =6.08 Hz, 6 H), 4.62 (spt, J =6.04 Hz, 1 H), 5.01- 5.11 (m, 1 H), 6.96 (d, J = 9.12 Hz, 2 H), 7.21 (s, 1 H), 7.35- 7.49 (m, 7 H), 7.52 (s, 1 H), 7.75- 8.51 (m, 2 H). LC-MS (method 1) Rt = 1.18 min; MS (ESIpos): m/z = 425.7 [M + H].sup.+ RP-HPLC (method D, basic) 42% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-4-isopropoxy- anilino)propanamide 4 Intermediate 7; rac-2- bromo- propanamide .sup.1H-NMR (500 MHz, DMSO-d6): ? ppm = 1.32 (d, J = 6.99 Hz, 3 H), 4.95 (q, J = 6.57 Hz, 1 H), 7.04-7.11 (m, 1 H), 7.33 (brs, 2 H), 7.39-7.48 (m, 4 H), 7.56 (dd, J = 7.79, 1.75 Hz, 2 H), 7.96 (br s, 2 H) LC-MS (method 2) Rt = 1.08 min; MS (ESIpos): m/z = 421.5 [M + H].sup.+ RP-HPLC (method D, basic) preparative flash chromatography (method X, 40-100%) 33% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-2,4,6-trifluoro- anilino)propanamide 5 Intermediate 8; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.03-1.15 (m, 3 H), 4.98-5.13 (m, 1 H), 7.21-7.34 (m, 1 H), 7.34-7.55 (m, 6 H), 7.57-7.87 (m, 2 H), 7.90-8.49 (m, 3 H). LC-MS (method 2) Rt = 1.11 min; MS (ESIpos): m/z = 463.2 [M + H].sup.+ RP-HPLC (method D, basic) 83% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-2-bromo-4-fluoro- anilino)propanamide 6 rac-2-(N-[4-amino-5-(6- Intermediate 9; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 2.45 (s, 3 H), 5.00-5.11 (m, 1 H), 7.24-7.28 (m, 2 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.59 (s, 1 H), 7.62-7.67 (m, 2 H), 7.74 (dd, J = 8.11, 2.28 Hz, 1 H), 7.97- 8.46 (m, 2 H), 8.54 (d, J = 2.03 Hz, 1 H). LC-MS (method 2) Rt = 0.93 min; MS (ESIpos): m/z = 400.4 [M + H].sup.+ RP-HPLC (method C, basic) 59% yield methylpyridine-3- carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide 7 0 rac-2-(N-[4-amino-5-(pyridine-4- Intermediate 10; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 5.06 (br d, J = 7.10 Hz, 1 H), 7.26 (s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.38-7.42 (m, 2 H), 7.59 (s, 1 H), 7.61-7.67 (m, 2 H), 8.10-8.50 (m, 2 H), 8.59-8.64 (m, 2 H). LC-MS (method 2) Rt = 0.85 min; MS (ESIpos): m/z = 386.3 [M + H].sup.+ RP-HPLC (method C, acidic) 17% yield carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide 8 Intermediate 11; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.14 (d, J = 7.35 Hz, 3 H), 4.89-5.13 (m, 1 H), 7.15- 7.34 (m, 7 H), 7.40 (tdd, J = 7.73, 7.73, 5.58, 1.77 Hz, 1 H), 7.53- 7.66 (m, 3 H), 8.09 (brs, 2 H). LC-MS (method 1) Rt = 1.05 min; MS (ESIpos): m/z = 403.4 [M + H].sup.+ RP-HPLC (method D, basic) 71% yield rac-2-(N-[4-amino-5-(2- fluorobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 9 Intermediate 12; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.05 (q, J = 7.69 Hz, 1 H), 7.31 (s, 1 H), 7.36-7.43 (m, 3 H), 7.48-7.52 (m, 2 H), 7.64 (s, 1 H), 7.81 (d, J = 8.62 Hz, 2 H), 8.16 (brs, 2 H), 7.99 (d, J = 8.36 Hz, 2 H). LC-MS (method 1) Rt = 0.99 min; MS (ESIpos): m/z = 392.3 [M + H].sup.+ RP-HPLC (method C, basic) 8% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-4-cyano- anilino)propanamide 10 Intermediate 13; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.01-5.14 (m, 1 H), 7.27 (s, 1 H), 7.34 (t, J = 8.87 Hz, 2 H), 7.59 (s, 1 H), 7.62-7.67 (m, 2 H), 7.77 (s, 2 H), 7.89-7.91 (m, 1 H), 8.08-8.64 (m, 2 H). LC-MS (method 2) Rt = 1.30 min; MS (ESIpos): m/z = 487.2 [M + H].sup.+ RP-HPLC (method D, basic) 22% yield rac-2-(N-[4-amino-5-[4-chloro-3- (trifluoromethyl)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide 11 Intermediate 14; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.09 (d, J = 7.35 Hz, 3 H), 4.98-5.21 (m, 1 H), 7.26- 7.34 (m, 1 H), 7.36-7.55 (m, 6 H), 7.59-7.76 (m, 2 H), 7.89- 8.45 (m, 2 H), 8.03 (dd, J = 8.87, 5.83 Hz, 1 H). LC-MS (method 2) Rt = 1.13 min; MS (ESIpos): m/z = 419.4 [M + H].sup.+ RP-HPLC (method D, basic) 48% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-2-chloro-4-fluoro- anilino)propanamide 12 Intermediate 15; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.01-5.10 (m, 1 H), 7.24- 7.28 (m, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.57-7.66 (m, 4 H), 7.78 (dt, J = 7.79, 1.30 Hz, 1 H), 7.86-7.89 (m, 2 H), 8.25 (br s, 2 H). LC-MS (method 2) Rt = 1.02 min; MS (ESIpos): m/z = 410.3 [M + H].sup.+ RP-HPLC (method C, basic) rac-2-(N-[4-amino-5-(3- 31% yield cyanobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 13 Intermediate 16; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 2.77 (s, 6 H), 4.99-5.09 (m, 1 H), 7.18 (d, J = 8.62 Hz, 1 H), 7.22-7.27 (m, 1 H), 7.35-7.46 (m, 4 H), 7.47-7.52 (m, 2 H), 7.57 (s, 1 H), 7.63 (d, J = 2.28 Hz, 1 H), 8.16 (brs, 2 H). LC-MS (method 2) Rt = 0.91 min; MS (ESIpos): m/z = 444.5 [M + H].sup.+ RP-HPLC (method C, basic) rac-2-[N-(4-amino-5-benzoyl- 51% yield thiazol-2-yl)-3-chloro-4- (dimethylamino)anilino] propanamide 14 Intermediate 17; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 3.85 (s, 3 H), 5.01-5.11 (m, 1 H), 6.83 (dd, J = 8.62, 0.51 Hz, 1 H), 7.24-7.28 (m, 1 H), 7.34 (t, J = 8.87 Hz, 2 H), 7.59 (s, 1 H), 7.62-7.68 (m, 2 H), 7.82 (dd, J = 8.62, 2.53 Hz, 1 H), 8.17 (br s, 2 H), 8.33 (d, J = 2.03 Hz, 1 H). LC-MS (method 2) Rt = 1.02 min; MS (ESIpos): m/z = 416.4 [M + H].sup.+ RP-HPLC (method C, basic) 43% yield rac-2-(N-[4-amino-5-(6- methoxypyridine-3- carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide 15 Intermediate 18; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 2.75 (d, J = 4.56 Hz, 3 H), 4.99-5.12 (m, 1 H), 7.25 (s, 1 H), 7.32 (t, J = 8.87 Hz, 2 H), 7.53 (d, J = 8.36 Hz, 2 H), 7.58 (brs, 1 H), 7.60-7.66 (m, 2 H), 7.78 (d, J = 8.36 Hz, 2 H), 8.17 (brs, 2 H), 8.46 (q, J = 4.48 Hz, 1 H). LC-MS (method 2) Rt = 0.85 min; MS (ESIpos): m/z = 442.5 [M + H].sup.+ RP-HPLC (method C, basic) 10% yield rac-4-[4-amino-2-(N-[2-amino-1- methyl-2-oxo-ethyl]-4-fluoro- anilino)thiazole-5-carbonyl]-N- methyl-benzamide 16 Intermediate 19; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 4.98-5.17 (m, 1 H), 7.22- 7.29 (m, 3 H), 7.29-7.36 (m, 3 H), 7.39-7.48 (m, 1 H), 7.58 (s, 1 H), 7.64 (dd, J = 8.62, 5.07 Hz, 2 H), 7.97-8.59 (m, 2 H). LC-MS (method 1) Rt = 1.10 min; MS (ESIpos): m/z = 403.3 [M + H]+ RP-HPLC (method D, basic) 68% yield rac-2-(N-[4-amino-5-(3- fluorobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 17 0 Intermediate 20; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 3.89 (s, 3 H), 4.96-5.10 (m, 1 H), 7.22 (d, J = 8.87 Hz, 1 H), 7.25 (s, 1 H), 7.35-7.43 (m, 3 H), 7.46-7.54 (m, 3 H), 7.59 (s, 1 H), 7.71 (d, J = 2.53 Hz, 1 H), 7.87-8.37 (m, 2 H). LC-MS (method 2) Rt = 1.10 min; MS (ESIpos): m/z = 431.3 [M + H].sup.+ RP-HPLC (method D, basic) rac-2-(N-(4-amino-5-benzoyl- 60% yield thiazol-2-yl)-3-chloro-4-methoxy- anilino)propanamide 18 Intermediate 21; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.14 (d, J = 7.35 Hz, 3 H), 3.78 (s, 3 H), 5.01-5.10 (m, 1 H), 7.01 (d, J = 9.13 Hz, 2 H), 7.17-7.24 (m, 3 H), 7.46 (d, J = 8.62 Hz, 2 H), 7.51-7.58 (m, 3 H), 8.09 (brs, 2 H). LC-MS (method 1) Rt = 1.08 min; MS (ESIpos): m/z = 415.6 [M + H].sup.+ RP-HPLC (method C, acidic) 36% yield rac-2-(N-[4-amino-5-(4- fluorobenzoyl)thiazol-2-yl]-4- methoxy-anilino)propanamide 19 Intermediate 22; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 3.23 (s, 3 H), 4.96-5.15 (m, 1 H), 7.26 (s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.59 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.70 (d, J = 8.36 Hz, 2 H), 7.93 (d, J = 8.62 Hz, 2 H), 8.04-8.56 (m, 2 H). LC-MS (method 1) Rt = 0.91 min; MS (ESIpos): m/z = 463.4 [M + H].sup.+ RP-HPLC (method C, basic) 31% yield rac-2-(N-[4-amino-5-(4- methylsulfonylbenzoyl)thiazol-2- yl]-4-fluoro-anilino)propanamide 20 Intermediate 23; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.00-5.13 (m, 1 H), 7.10 (s, 1 H), 7.26 (s, 1 H), 7.34 (t, J = 8.74 Hz, 2 H), 7.56-7.73 (m, 7 H), 7.78 (t, J = 1.27 Hz, 1 H), 7.88-8.62 (m, 2 H), 8.30 (s, 1 H). LC-MS (method 1) Rt = 0.70 min; MS (ESIpos): m/z = 451.5 [M + H].sup.+ RP-HPLC (method C, basic) 68% yield rac-2-(N-[4-amino-5-(4-imidazol- 1-ylbenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide 21 Intermediate 24; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 5.01-5.11 (m, 1 H), 7.25 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.45 (dd, J = 7.86, 1.27 Hz, 1 H), 7.55 (dd, J = 9.89, 1.27 Hz, 1 H), 7.58-7.66 (m, 3 H), 7.93 (dd, J = 7.86, 6.59 Hz, 1 H), 8.11- 8.52 (m, 2 H). LC-MS (method 1) Rt = 1.08 min; MS (ESIpos): m/z = 428.3 [M + H].sup.+ RP-HPLC (method C, basic) 5% yield rac-2-(N-[4-amino-5-(4-cyano-3- fluoro-benzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 21.1 and (R)-2-(N-[4-amino-5-(4-cyano-3- 21.2 fluoro-benzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-(4-cyano-3- fluoro-benzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 21.1 Example 21 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 5.01-5.11 (m, 1 H), 7.25 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.45 (dd, J = 7.86, 1.27 Hz, 1 H), 7.55 (dd, J = 9,89, 1.27 Hz, 1 H), 7.58-7.66 (m, 3 H), 7.93 (dd, J = 7.86, 6.59 Hz, 1 H), 8.11- 8.52 (m, 2 H). LC-MS (method 1) Rt = 1.07 min; MS (ESIpos): m/z = 428.3 [M + H].sup.+ RP-HPLC (method C, basic) 8% yield 2-(N-[4-amino-5-(4-cyano-3- fluoro-benzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 21.1 HPLC separation of rac-2-(N-[4-amino-5-(4-cyano-3-fluoro-benzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (Example 21, 106 mg. 0.25 mmol) on a chiral column followed by another preparative HPLC gave 9.2 mg (8% yield) of 2-(N-[4-amino-5-(4-cyano-3-fluoro- benzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 80% A + 20% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 5.46 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 21.2 Example 21 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 5.01-5.11 (m, 1 H), 7.25 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.45 (dd, J = 7.86, 1.27 Hz, 1 H), 7.55 (dd, J = 9.89, 1.27 Hz, 1 H), 7.58-7.66 (m, 3 H), 7.93 (dd, J = 7.86, 6.59 Hz, 1 H), 8.11- 8.52 (m, 2 H). LC-MS (method 1) Rt = 1.07 min; MS (ESIpos): m/z = 428.3 [M + H].sup.+ RP-HPLC (method C, basic) 7% yield 2-(N-[4-amino-5-(4-cyano-3- fluoro-benzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 21.2 HPLC separation of rac-2-(N-[4-amino-5-(4-cyano-3-fluoro-benzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (Example 21, 106 mg. 0.25 mmol) on a chiral column followed by another preparative HPLC gave 7 mg (6% yield) of 2-(N-[4-amino-5-(4-cyano-3-fluoro-benzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 80% A + 20% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 7.71 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 22 Intermediate 25; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.01-5.11 (m, 1 H), 7.27 (s, 1 H), 7.34 (t, J = 8.87 Hz, 2 H), 7.45 (dd, J = 8.11, 1.27 Hz, 1 H), 7.56 (dd, J = 9.76, 1.14 Hz, 1 H), 7.59 (s, 1 H), 7.64 (dd, J = 8.74, 4.94 Hz, 2 H), 7.92-7.97 (m, 1 H), 8.18-8.50 (m, 2 H). LC-MS (method 1) Rt = 1.07 min; MS (ESIpos): m/z = 428.3 [M + H].sup.+ RP-HPLC (method D, basic) 40% yield rac-2-(N-[4-amino-5-(4-cyano-2- fluoro-benzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 23 Intermediate 26; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.14 (d, J = 7.60 Hz, 3 H), 3.75 (s, 3 H), 4.98-5.09 (m, 1 H), 6.76 (d, J = 20.28 Hz, 1 H), 6.78 (br d, J = 23.32 Hz, 1 H), 7.22-7.27 (m, 2 H), 7.31 (t, J = 8.87 Hz, 2 H), 7.57 (s, 1 H), 7.59-7.64 (m, 2 H), 8.03 (br s, 2 H). LC-MS (method 2) Rt = 1.06 min; MS (ESIpos): m/z = 433.4 [M + H].sup.+ RP-HPLC (method D, basic) 47% yield rac-2-(N-[4-amino-5-(2-fluoro-4- methoxy-benzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 24 Intermediate 27; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.17 (d, J = 7.35 Hz, 3 H), 5.05 (q, J = 7.18 Hz, 1 H), 7.28 (s, 1 H), 7.36-7.42 (m, 3 H), 7.45-7.52 (m, 4 H), 7.61 (s, 1 H), 7.69-7.75 (m, 2 H), 8.16 (brs, 2 H). LC-MS (method 2) Rt = 1.20 min; MS (ESIpos): m/z = 451.5 [M + H].sup.+ RP-HPLC (method D, basic) 49% yield rac-2-[N-(4-amino-5-benzoyl- thiazol-2-yl)-4- (trifluoromethoxy)anilino] propanamide 25 0 rac-2-(N-[4-amino-5-(3,4- Intermediate 28; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.02-5.10 (m, 1 H), 7.26 (s, 1 H), 7.34 (t, J = 8.62 Hz, 3 H), 7.41-7.49 (m, 1 H), 7.52 (ddd, J = 11 .15, 7.98, 2.15 Hz, 1 H), 7.58 (s, 1 H), 7.62-7.66 (m, 2 H), 7.98-8.50 (m, 2 H). LC-MS (method 2) Rt = 1.14 min; MS (ESIpos): m/z = 419.3 [M + H].sup.+ RP-HPLC (method D, basic) 30% yield difluorobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 26 rac-2-(N-[4-amino-5-(3,4- Intermediate 29; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.00-5.11 (m, 1 H), 7.26 (s, 1 H), 7.34 (t, J = 8.74 Hz, 2 H), 7.44 (dd, J = 8.36, 2.03 Hz, 1 H), 7.57-7.61 (m, 1 H), 7.62-7.66 (m, 2 H), 7.67 (d, J = 11.66 Hz, 1 H), 7.67 (d, J = 1.27 Hz, 1 H), 8.03-8.48 (m, 2 H). LC-MS (method 2) Rt = 1.24 min; MS (ESIpos): m/z = 453.1 [M + H].sup.+ RP-HPLC (method D, basic) dichlorobenzoyl)thiazol-2-yl]-4- 38% yield fluoro-anilino)propanamide 27 Intermediate 30; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15-1.19 (m, 3 H), 5.02-5.09 (m, 1 H), 7.22 (t, J = 8.87 Hz, 2 H), 7.28 (s, 1 H), 7.50 (d, J = 8.11 Hz, 2 H), 7.56 (dd, J = 8.62, 5.58 Hz, 2 H), 7.61 (s, 1 H), 7.73 (d, J = 9.13 Hz, 2 H), 7.90-8.49 (m, 2 H). LC-MS (method 2) Rt = 1.23 min; MS (ESIpos): m/z = 469.3 [M + H].sup.+ 59% yield rac-2-[N-[4-amino-5-(4- fluorobenzoyl)thiazol-2-yl]-4- (trifluoromethoxy)anilino] propanamide 27.1 and (R)-2-[N-[4-amino-5-(4- 27.2 fluorobenzoyl)thiazol-2-yl]-4- (trifluoromethoxy)anilino] propanamide and (S)-2-[N-[4-amino-5-(4- fluorobenzoyl)thiazol-2-yl]-4- (trifiuoromethoxy)anilino] propanamide 27.1 Example 27 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.17 (d, J = 7.35 Hz, 3 H), 5.05 (q, J = 7.27 Hz, 1 H), 7.22 (t, J = 9.00 Hz, 2 H), 7.28 (s, 1 H), 7.48-7.53 (m, 2 H), 7.53- 7.59 (m, 2 H), 7.61 (s, 1 H), 7.70- 7.75 (m, 2 H), 7.95-8.42 (m, 2 H). LC-MS (method 1) Rt = 1.23 min; MS (ESIpos): m/z = 469.3 [M + H].sup.+ 39% yield 2-[N-[4-amino-5-(4- fluorobenzoyl)thiazol-2-yl]-4- (trifluoromethoxy)anilino] propanamide (enantiomer 1) Chiral HPLC Example 27.1 HPLC separation of rac-2-[N-[4-amino-5-(4-fluorobenzoyl)thiazol-2-yl]-4- (trifluoromethoxy)anilino]propanamide (1130 mg, 2.4 mmol; Example 27) on a chiral column gave 448 mg (39% yield) of 2-[N-[4-amino-5-(4-fluorobenzoyl)thiazol-2-yl]-4- (trifluoromethoxy)anilino]propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5u, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 80% A + 20% B; flow: 60 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.99 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 27.2 Example 27 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.17 (d, J = 7.60 Hz, 3 H), 5.05 (br d, J =7.10 Hz, 1 H), 7.19-7.25 (m, 2 H), 7.28 (s, 1 H), 7.47-7.53 (m, 2 H), 7.53- 7.59 (m, 2 H), 7.59-7.63 (m, 1 H), 7.70-7.76 (m, 2 H), 7.96- 8.40 (m, 2 H). LC-MS (method 1) Rt = 1.23 min; MS (ESIpos): m/z = 469.2 [M + H].sup.+ 37% yield 2-[N-(4-amino-5-(4- fluorobenzoyl)thiazol-2-yl]-4- (trifluoromethoxy)anilino] propanamide (enantiomer 2) Chiral HPLC Example 27.2 HPLC separation of rac-2-[N-[4-amino-5-(4-fluorobenzoyl)thiazol-2-yl]-4- (trifluoromethoxy)anilino]propanamide (1130 mg, 2.4 mmol; Example 27) on a chiral column gave 430 mg (37% yield) of 2-[N-[4-amino-5-(4-fluorobenzoyl)thiazol-2-yl]-4- (trifluoromethoxy)anilino]propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 80% A + 20% B; flow: 60 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.81 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100x4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 28 Intermediate 31; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.06 (q, J = 7.52 Hz, 1 H), 7.30 (s, 1 H), 7.36-7.44 (m, 3 H), 7.47-7.52 (m, 2 H), 7.63 (s, 1 H), 7.80-7.91 (m, 4 H), 8.18 (br s, 2 H). LC-MS (method 1) Rt = 1.18 min; MS (ESIpos): m/z = 435.3 [M + H].sup.+ RP-HPLC (method D, basic) 29% yield rac-2-[N-(4-amino-5-benzoyl- thiazol-2-yl)-4- (trifluoromethyl)anilino] propanamide 29 rac-2-(N-[4-amino-5-[6- Intermediate 32; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 5.02-5.13 (m, 1 H), 7.25 (s, 1 H), 7.30-7.38 (m, 2 H), 7.60 (s, 1 H), 7.64 (dd, J = 8.87. 5.07 Hz, 2 H), 7.94 (d, J = 7.86 Hz, 1 H), 8.12 (dd, J = 8.11, 1.77 Hz, 1 H), 8.23-8.46 (m, 2 H), 8.84 (br d, J =1.80 Hz, 1 H). LC-MS (method 1) Rt = 1.13 min; MS (ESIpos): m/z = 454.5 [M + H].sup.+ RP-HPLC (method C, basic) 42% yield (trifluoromethyl)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide 29.1 and (R)-2-(N-[4-amino-5-(6- 29.2 (trifluoromethyl)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-[6- (trifluoromethyl)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide 29.1 2-(N-[4-amino-5-[6- Example 29 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.00-5.16 (m, 1 H), 7.27 (s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.58-7.69 (m, 3 H), 7.93 (d, J = 8.11 Hz, 1 H), 8.11 (br d, J = 1.77 Hz, 1 H), 8.17-8.50 (m, 2 H), 8.84 (d, J = 1.27 Hz, 1 H). LC-MS (method 1) Rt = 1.13 min; MS (ESIpos): m/z = 454.5 [M + H].sup.+ [?].sub.D.sup.20 = +53.2? (c = 1.00, dimethylsulfoxide) 13% yield (trifluoromethyl)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 29.1 HPLC separation of rac-2-(N-[4-amino-5-[6-(trifluoromethyl)pyridine-3-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide (394 mg, 1.0 mmol; Example 29) on a chiral column gave 163 mg (33% yield) of 2-(N-[4-amino-5-[6-(trifluoromethyl)pyridine-3-carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.24 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 29.2 2-(N-[4-amino-5-[6- Example 29 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.17 (d, J = 7.35 Hz, 3 H), 5.01-5.17 (m, 1 H), 7.28 (s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.54-7.72 (m, 3 H), 7.93 (d, J = 8.11 Hz, 1 H), 8.12 (dd, J = 8.11, 1.77 Hz, 1 H), 8.21- 8.54 (m, 2 H), 8.84 (d, J = 1.27 Hz, 1 H). LC-MS (method 1) Rt = 1.12 min; MS (ESIpos): m/z = 454.5 [M + H].sup.+ [?].sub.D.sup.20 = ?44.3? (c = 1.00, dimethylsulfoxide) 13% yield (trifluoromethyl)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 29.2 HPLC separation of rac-2-(N-[4-amino-5-[6-(trifluoromethyl)pyridine-3-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide (394 mg, 1.0 mmol; Example 29) on a chiral column gave 164 mg (33% yield) of 2-(N-[4-amino-5-[6-(trifluoromethyl)pyridine-3-carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.26 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 30 Intermediate 33; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.11-1.22 (m, 3 H), 4.92-5.22 (m, 1 H), 7.28-7.36 (m, 1 H), 7.39-7.54 (m, 6 H), 7.59-7.76 (m, 2 H), 7.79-7.93 (m, 1 H), 7.97-8.32 (m, 2 H). LC-MS (method 1) Rt = 1.16 min; MS (ESIpos): m/z = 417.2 [M + H].sup.+ RP-HPLC (method D, basic) 37% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-4-chloro-2-fluoro- anilino)propanamide 31 0 rac-2-(N-[4-amino-5-(indane-5- Intermediate 34; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 1.98 (quin, J = 7.41 Hz, 2 H), 2.82 (td, J =7.29, 4.18 Hz, 4 H), 5.04 (brq, J = 6.67 Hz, 1 H), 7.18- 7.23 (m, 2 H), 7.24 (s, 1 H), 7.29-7.35 (m, 3 H), 7.56-7.59 (m, 1 H), 7.60-7.65 (m, 2 H), 7.80-8.40 (m, 2 H). LC-MS (method 2) Rt = 1.23 min; MS (ESIpos): m/z = 425.6 [M + H].sup.+ RP-HPLC (method D, basic) carbonyl)thiazol-2-yl]-4-fluoro- 24% yield anilino)propanamide 32 Intermediate 35; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J =7.35 Hz, 3 H), 5.02 (q, J = 7.69 Hz, 1 H), 7.29 (s, 1 H), 7.36-7.44 (m, 3 H), 7.47-7.53 (m, 3 H), 7.54- 7.60 (m, 1 H), 7.61-7.65 (m, 1 H), 7.77 (ddd, J = 11.47, 7.54, 2.28 Hz, 1 H), 8.15 (br s, 2 H). LC-MS (method 1) Rt = 1.11 min; MS (ESIpos): m/z = 403.3 [M + H].sup.+ RP-HPLC (method C, basic) 48% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-3,4-difluoro- anilino)propanamide 33 Intermediate 36; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 4.90-5.24 (m, 1 H), 7.23- 7.29 (m, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.59 (s, 1 H), 7.60- 7.66 (m, 4 H), 7.86 (d, J = 8.36 Hz, 2 H), 8.05-8.57 (m, 2 H). LC-MS (method 2) Rt = 1.02 min; MS (ESIpos): m/z = 410.3 [M + H].sup.+ RP-HPLC (method C, basic) 78% yield rac-2-(N-[4-amino-5-(4- cyanobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 33.1 and (R)-2-(N-[4-amino-5-(4- 33.2 cyanobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-(4- cyanobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 33.1 Example 33 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.02-5.11 (m, 1 H), 7.24- 7.28 (m, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.58 (s, 1 H), 7.61- 7.66 (m, 4 H), 7.86 (d, J = 8.62 Hz, 2 H), 8.05-8.50 (m, 2 H). LC-MS (method 2) Rt = 1.02 min; MS (ESIpos): m/z = 410.3 [M + H].sup.+ [?].sub.D.sup.20 = +93.9? (c = 1.00, dimethylsulfoxide) 31% yield 2-(N-[4-amino-5-(4- cyanobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 33.1 HPLC separation of rac-2-(N-[4-amino-5-(4-cyanobenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (96 mg, 0.23 mmol; Example 33) on a chiral column gave 30 mg (30% yield) of 2-(N-[4-amino-5-(4-cyanobenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 150 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.26 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 33.2 Example 33 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 5.01-5.12 (m, 1 H), 7.26 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.58 (s, 1 H), 7.63 (d, J = 8.36 Hz, 4 H), 7.86 (d, J = 8.36 Hz, 2 H), 8.05-8.53 (m, 2 H). LC-MS (method 2) Rt = 1.02 min; MS (ESIpos): m/z = 410.3 [M + H].sup.+ [?].sub.D.sup.20 = ?89.9? (c = 1.00, dimethylsulfoxide) 30% yield 2-(N-[4-amino-5-(4- cyanobenzoyl) thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 33.2 HPLC separation of rac-2-(N-[4-amino-5-(4-cyanobenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (96 mg, 0.23 mmol; Example 33) on a chiral column gave 32 mg (31% yield) of 2-(N-[4-amino-5-(4-cyanobenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 150 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.05 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 34 Intermediate 37; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.05 (q, J = 7.18 Hz, 1 H), 7.26 (s, 1 H), 7.35-7.42 (m, 3 H), 7.47-7.50 (m, 2 H), 7.54- 7.63 (m, 5 H), 8.16 (brs, 2 H). LC-MS (method 2) Rt = 1.15 min; MS (ESIpos): m/z = 402.2 [M + H].sup.+ RP-HPLC (method D, basic) 9% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-4-chloro- anilino)propanamide 35 rac-2-(N-(4-amino-5-benzoyl- Intermediate 38; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 5.01 (q, J = 7.18 Hz, 1 H), 7.31 (s, 1 H), 7.37-7.45 (m, 3 H), 7.49-7.54 (m, 2 H), 7.62 (dd, J = 8.90, 2.53 Hz, 1 H), 7.64 (s, 1 H), 7.79 (d, J = 8.36 Hz, 1 H), 7.95 (d, J = 2.28 Hz, 1 H), 8.24 (br s, 2 H). LC-MS (method 1) Rt = 1.23 min; MS (ESIneg): m/z = 433.4 [M ? H].sup.+ RP-HPLC (method D, basic) 27% yield thiazol-2-yl)-3,4-dichloro- anilino)propanamide 36 Intermediate 39; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 5.02 (q, J = 7.35 Hz, 1 H), 7.30 (s, 1 H), 7.38-7.45 (m, 3 H), 7.49-7.53 (m, 3 H), 7.63 (s, 1 H), 7.72-7.77 (m, 2 H), 8.15 (br s, 2 H). LC-MS (method 1) Rt = 1.17 min; MS (ESIpos): m/z = 419.3 [M + H].sup.+ RP-HPLC (method D, basic) 39% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-4-chloro-3-fluoro- anilino)propanamide 37 Intermediate 40; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 5.02-5.11 (m, 1 H), 7.25 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.43-7.52 (m, 4 H), 7.58 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.98-8.43 (m, 2 H). LC-MS (method 2) Rt = 1.18 min; MS (ESIpos): m/z = 419.2 [M + H].sup.+ 55% yield rac-2-(N-[4-amino-5-(4- fluorobenzoyl)thiazol-2-yl]-4- chloro-anillno)propanamide 37.1 and (R)-2-(N-[4-amino-5-(4- 37.2 fluorobenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide and (S)-2-(N-[4-amino-5-(4- fluorobenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide 37.1 Example 37 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.13-1.19 (m, 3 H), 5.01-5.11 (m, 1 H), 7.25 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.43- 7.53 (m, 4 H), 7.58 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.88-8.52 (m, 2 H). LC-MS (method 1) Rt = 1.19 min; MS (ESIpos): m/z = 419.2 [M + H].sup.+ 31% yield 2-(N-[4-amino-5-(4- fluorobenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 37.1 HPLC separation of rac-2-(N-[4-amino-5-(4-fluorobenzoyl)thiazol-2-yl]-4-chloro- anilino)propanamide (170 mg, 0.41 mmol, Example 37) on a chiral column gave 54 mg (31% yield) of 2-(N-[4-amino-5-(4-fluorobenzoyl)thiazol-2-yl]-4-chloro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.66 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 37.2 00 Example 37 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.01-5.11 (m, 1 H), 7.23- 7.27 (m, 1 H), 7.33 (t J = 8.87 Hz, 2 H), 7.43-7.53 (m, 4 H), 7.58 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.92-8.37 (m, 2 H). LC-MS (method 1) Rt = 1.19 min; MS (ESIpos): m/z = 419.2 [M + H].sup.+ 32% yield 2-(N-[4-amino-5-(4- fluorobenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 37.2 HPLC separation of rac-2-(N-[4-amino-5-(4-fluorobenzoyl)thiazol-2-yl]-4-chloro- anilino)propanamide (170 mg, 0.41 mmol, Example 37) on a chiral column gave 57 mg (32% yield) 2-(N-[4-amino-5-(4-fluorobenzoyl)thiazol-2-yl]-4-chloro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.20 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 38 01 Intermediate 41; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 5.01-5.12 (m, 1 H), 7.25 (s, 1 H), 7.29-7.37 (m, 2 H), 7.43- 7.53 (m, 4 H), 7.58 (s, 1 H), 7.63 (dd, J = 8.87, 5.07 Hz; 2 H), 7.92- 8.44 (m, 2 H). LC-MS (method 1) Rt = 1.19 min; MS (ESIpos): m/z = 419.2 [M + H].sup.+ RP-HPLC (method C, basic) 42% yield rac-2-(N-[4-amino-5-(4- chlorobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 38.1 and (R)-2-(N-[4-amino-5-(4- 38.2 chlorobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-(4- chlorobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 38.1 02 Example 38 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 4.98-5.16 (m, 1 H), 7.25 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.43-7.52 (m, 4 H), 7.58 (s, 1 H), 7.63 (dd, J = 8.87, 5.07 Hz, 2 H), 7.92-8.50 (m, 2 H). LC-MS (method 1) Rt = 1.19 min; MS (ESIpos): m/z = 419.2 [M + H].sup.+ RP-HPLC (method D, basic) 16% yield 2-(N-[4-amino-5-(4- chlorobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 38.1 HPLC separation of rac-2-(N-[4-amino-5-(4-chlorobenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (115 mg, 0.27 mmol; Example 38) on a chiral column, followed by an additional RP-HPLC gave 19 mg (16% yield) of 2-(N-[4-amino-5-(4-chlorobenzoyl)thiazol-2-yl]- 4-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.23 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: exane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B; flow: 1.4 mL/mi n; temperature: 25? C.; UV: 254 nm 38.2 03 Example 38 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.02-5.10 (m, 1 H), 7.25 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.43-7.52 (m, 4H), 7.57-7.60 (m, 1 H), 7.63 (dd, J = 8.87, 5.07 Hz, 2 H), 7.95-8.47 (m, 2 H). LC-MS (method 1) Rt = 1.19 min; MS (ESIpos): m/z = 419.2 [M + H].sup.+ RP-HPLC (method D, basic) 38% yield 2-(N-[4-amino-5-(4- chlorobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 38.2 HPLC separation of rac-2-(N-[4-amino-5-(4-chlorobenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (115 mg, 0.27 mmol; Example 38) on a chiral column, followed by an additional RP-HPLC gave 20 mg (17% yield) of 2-(N-[4-amino-5-(4-chlorobenzoyl)thiazol-2-yl]- 4-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.79 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: exane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B, flow: 1.4 mL/mi n; temperature: 25? C.; UV: 254 nm 39 04 Intermediate 42; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.07 (t, J = 7.10 Hz, 3 H), 1.15 (d, J = 7.35 Hz, 3 H), 1.53 (s, 6 H), 4.12 (q, J = 7.01 Hz, 2 H), 5.02-5.09 (m, 1 H), 6.72-6.76 (m, 2 H), 7.24 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.44 (d, J = 8.87 Hz, 2 H), 7.58 (s, 1 H), 7.63 (dd, J = 9.00, 5.20 Hz, 2 H), 7.88 (brs, 2 H). LC-MS (method 1) Rt = 1.21 min; MS (ESIpos): m/z = 515.4 [M + H].sup.+ RP-HPLC (method D, basic) 50% yield rac-ethyl 2-[4-[4-amino-2-(N-[2- amino-1-methyl-2-oxo-ethyl]-4- fluoro-anilino)thiazole-5- carbonyl]phenoxy]-2-methyl- propanoate 40 05 Intermediate 43; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.06 (br d, J = 6.84 Hz, 1 H), 7.26 (s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.38 (d, J = 7.86 Hz, 2 H), 7.58 (s, 1 H), 7.60-7.67 (m, 4 H), 7.95-8.56 (m, 2 H). LC-MS (method 1) Rt = 1.25 min; MS (ESIpos): m/z = 469.5 [M + H].sup.+ RP-HPLC (method D, basic) 83% yield rac-2-(N-[4-amino-5-[4- (trifluoromethoxy)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide 40.1 and (R)-2-(N-[4-amino-5-[4- 40.2 (trifluoromethoxy)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-[4- (trifluoromethoxy)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide 40.1 06 Example 40 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.02-5.11 (m, 1 H), 7.26 (s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.38 (d, J = 8.11 Hz, 2 H), 7.58 (s, 1 H), 7.60-7.67 (m, 4 H), 7.95-8.46 (m, 2 H). LC-MS (method 2) Rt = 1.24 min; MS (ESIpos): m/z = 469.4 [M + H]+ 20% yield 2-(N-[4-amino-5-[4- (trifluoromethoxy)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 40.1 HPLC separation of rac-2-(N-[4-amino-5-[4-(trifluoromethoxy)benzoyl]thiazol-2-yl]-4-fluoro- anilino)propanamide (69 mg, 0.15 mmol; Example 40) on a chiral column gave 20 mg (20% yield) of 2-(N-[4-amino-5-[4-(trifluoromethoxy)benzoyl]thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5? 250 ? 30mm; eluent A: CO.sub.2; eluent B: ethanol + 0.2 vol % aqueous ammonia (32%); isocratic: 15% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 2.73 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IC 5? 100 ? 4.6 mm; eluent A: CO.sub.2; eluent B: ethanol + 0.2 vol % aqueous ammonia (32%); isocratic: 15% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 40.2 07 Example 40 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.02-5.11 (m, 1 H), 7.26 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.38 (d, J = 8.11 Hz, 2 H), 7.58 (s, 1 H), 7.60-7.67 (m, 4 H), 7.95-8.48 (m, 2 H). LC-MS (method 2) Rt = 1.25 min; MS (ESIpos): m/z = 469.3 [M + H]+ 21% yield 2-(N-[4-amino-5-[4- (trifluoromethoxy)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 40.2 HPLC separation of rac-2-(N-[4-amino-5-[4-(trifluoromethoxy)benzoyl]thiazol-2-yl]-4-fluoro- anilino)propanamide (69 mg, 0.15 mmol; Example 40) on a chiral column gave 20 mg (21% yield) of 2-(N-[4-amino-5-[4-(trifluoromethoxy)benzoyl]thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5? 250 ? 30mm; eluent A: CO.sub.2; eluent B: 1thanol + 0.2 vol % aqueous ammonia (32%); isocratic: 15% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 3.48 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IC 5? 100 ? 4.6mm; eluent A: CO.sub.2; eluent B: ethanol + 0.2 vol % aqueous ammonia (32%); isocratic: 15% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 41 08 Intermediate 44; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.06 (q, J = 7.27 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.44-7.53 (m, 4 H), 7.55-7.63 (m, 5 H), 7.96-8.44 (m, 2 H). LC-MS (method 2) Rt = 1.27 min; MS (ESIpos): m/z = 435.2 [M + H].sup.+ 47% yield rac-2-(N-[4-amino-5-(4- chlorobenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide 41.1 and (R)-2-(N-(4-amino-5-(4- 41.2 chlorobenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide and (S)-2-(N-[4-amino-5-(4- chlorobenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide 41.1 09 Example 41 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.14-1.19 (m, 3 H), 5.06 (q, J =7.10 Hz, 1 H), 7.27 (s, 1 H), 7.44-7.53 (m, 4 H), 7.55-7.64 (m, 5 H), 7.99-8.41 (m, 2 H). LC-MS (method 1) Rt = 1.27 min; MS (ESIpos): m/z = 435.2 [M + H].sup.+ [?].sub.D.sup.20 = +83.8? (c = 1.00, dimethylsulfoxide) 25% yield 2-(N-[4-amino-5-(4- chlorobenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 41.1 HPLC separation of rac-2-(N-[4-amino-5-(4-chlorobenzoyl)thiazol-2-yl]-4-chloro- anilino)propanamide (144 mg, 0.33 mmol; Example 41) on a chiral column gave 36 mg (25% yield) of 2-(N-[4-amino-5-(4-chlorobenzoyl)thiazol-2-yl]-4-chloro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 150 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.84 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 41.2 0 Example 41 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.06 (q, J = 7.10 Hz, 1 H), 7.26-7.29 (m, 1 H), 7.44-7.52 (m, 4 H), 7.55-7.63 (m, 5 H), 7.94-8.68 (m, 2 H). LC-MS (method 1) Rt = 1.27 min; MS (ESIpos): m/z = 435.2 [M + H].sup.+ [?].sub.D.sup.20 = ?78.4? (c = 1.00, dimethylsulfoxide) 18% yield 2-(N-[4-amino-5-(4- chlorobenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 41.2 HPLC separation of rac-2-(N-[4-amino-5-(4-chlorobenzoyl)thiazol-2-yl]-4-chloro- anilino)propanamide (144 mg, 0.33 mmol; Example 41) on a chiral column gave 26 mg (18% yield) of 2-(N-[4-amino-5-(4-chlorobenzoyl)thiazol-2-yl]-4-chloro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 150 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.34 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 42 Intermediate 45; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.00-5.13 (m, 1 H), 7.26 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.59 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.72 (dd, J = 37.13, 8.24 Hz, 4 H), 7.98- 8.51 (m, 2 H). LC-MS (method 1) Rt = 1.22 min; MS (ESIpos): m/z = 453.4 [M + H].sup.+ RP-HPLC (method D, basic) 71% yield rac-2-(N-[4-amino-5-[4- (trifluoromethyl)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide 43 Intermediate 46; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.07 (q, J = 7.27 Hz, 1 H), 7.28 (t, J = 72.24 Hz, 1 H), 7.18 (d, J = 9.38 Hz, 2 H), 7.30 (s, 1 H), 7.57 (d, J = 8.87 Hz, 2 H), 7.64 (s, 1 H), 7.86 (dd, J = 27.88, 8.36 Hz, 4 H), 8.18 (br s, 2 H). LC-MS (method 1) Rt = 1.22 min; MS (ESIpos): m/z = 501.4 [M + H].sup.+ RP-HPLC (method D, basic) 54% yield rac-2-[N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl-4- (trifluoromethyl)anilino] propanamide 43.1 and (R)-2-[N-[4-amino-5-[4- 43.2 (difluoromethoxy)benzoyl]thiazol- 2-yl]-4- (trifluoromethyl)anilino] propanamide and (S)-2-[N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl-4- (trifluoromethyl)anilino] propanamide 43.1 Example 43 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.07 (q, J = 7.35 Hz, 1 H), 7.28 (t, J = 74.01 Hz, 1 H), 7.18 (d, J = 8.62 Hz, 2 H), 7.31 (s, 1 H), 7.57 (d, J = 8.87 Hz, 2 H), 7.63 (s, 1 H), 7.86 (dd, J = 27.88, 8.62 Hz, 4 H), 7.99-8.36 (m, 2 H). LC-MS (method 1) Rt = 1.22 min; MS (ESIpos): m/z = 501.4 [M + H].sup.+ 34% yield 2-[N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl)-4- (trifluoromethyl)anilino] propanamide (enantiomer 1) Chiral HPLC Example 43.1 HPLC separation of rac-2-[N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4- (trifluoromethyl)anilino]propanamide (280 mg, 0.56 mmol; Example 43) on a chiral column gave 99 mg (35% yield) of 2-[N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4- (trifluoromethyl)anilino]propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 80% A + 20% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 4.50 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 43.2 Example 43 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.07 (q, J = 7.35 Hz, 1 H), 7.28 (t, J = 73.76 Hz, 1 H), 7.18 (d, J = 8.62 Hz, 2 H), 7.31 (s, 1 H), 7.57 (d, J = 8.87 Hz, 2 H), 7.63 (s, 1 H), 7.86 (dd, J = 27.88, 8.62 Hz, 4 H), 8.18 (br s, 2 H). LC-MS (method 1) Rt = 1.22 min; MS (ESIpos): m/z = 501.3 [M + H].sup.+ 27% yield 2-[N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl-4- (trifluoromethyl)anilino] propanamide (enantiomer 2) Chiral HPLC Example 43.2 HPLC separation of rac-2-[N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4- (trifluoromethyl)anilino]propanamide (280 mg, 0.56 mmol; Example 43) on a chiral column gave 79 mg (27% yield) of 2-[N-[4-amlno-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4- (trifluoromethyl)anilino]propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 80% A + 20% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 5.44 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 44 Intermediate 47; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.06 (q, J = 7.10 Hz, 1 H), 7.28 (t, J = 73.76 Hz, 1 H), 7.17 (d, J = 8.62 Hz, 2 H), 7.25 (br s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.55 (d, J = 8.87 Hz, 2 H), 7.58 (br s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 8.21 (brs, 2 H). LC-MS (method 2) Rt = 1.13 min; MS (ESIpos): m/z = 451.6 [M + H].sup.+ RP-HPLC (method D, basic) 87% yield rac-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide 44.1 and (R)-2-(N-(4-amino-5-[4- 44.2 (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide 44.1 Example 44 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.02-5.10 (m, 1 H), 7.26 (t, J = 74.01 Hz, 1 H), 7.17 (d, J = 9.38 Hz, 2 H), 7.25 (s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.55 (d, J = 8.87 Hz, 2 H), 7.58 (br s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.86-8.45 (m, 2 H). LC-MS (method 2) Rt = 1.12 min; MS (ESIpos): m/z = 451.3 [M + H].sup.+ [?].sub.D.sup.20 = +77.2% (c = 1.00, dimethylsulfoxide) 38% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 44.1 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-fluoro- anilino)propanamide (2552 mg, 5.61 mmol; Example 44) on a chiral column gave 1096 mg (35% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.81 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 44.2 Example 44 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.01-5.12 (m, 1 H), 7.28 (t, J = 73.76 Hz, 1 H), 7.17 (d, J = 8.62 Hz, 2 H), 7.25 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.55 (d, J = 8.87 Hz, 2 H), 7.58 (br s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 8.15 (br s, 2 H). LC-MS (method 2) Rt = 1.12 min; MS (ESIpos): m/z = 451.4 [M + H].sup.+ [?].sub.D.sup.20 = ?79.7? (c = 1.00, dimethylsulfoxide) 38% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 44.2 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-fluoro- anilino)propanamide (2552 mg, 5.61 mmol; Example 44) on a chiral column gave 1139 mg (37% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 4.61 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 45 Intermediate 48; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 1.41 (d, J = 6.59 Hz, 3 H), 4.63 (q, J = 6.59 Hz, 1 H), 5.04- 5.12 (m, 1 H), 6.86 (d, J = 8.87 Hz, 2 H), 7.24 (br d, J = 3.80 Hz, 2 H), 7.42-7.52 (m, 6 H), 7.53- 7.58 (m, 3 H), 8.08 (br s, 2 H). LC-MS (method 2) Rt = 0.85 min; MS (ESIpos): m/z = 454.4 [M + H].sup.+ RP-HPLC (method C, basic) 70% yield 2-(N-[4-amino-5-[4-[2-amino-1- methyl-2-oxo- ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide (mixture of stereoisomers) 45.1, (2R)-(N-[4-amino-5-[4-[2-amino- 45.2, (1 R)-methyl-2-oxo- 45.3 and ethoxy]benzoyl]thiazol-2- 45.4 yl]anilino)propanamide, (2R)-(N-[4-amino-5-[4-[2-amino- (1S)-methyl-2-oxo- ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide, (2S)-(N-[4-amino-5-[4-[2-amino- (1R)-methyl-2-oxo- ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide, and (2S)-(N-[4-amino-5-[4-[2-amino- (1S)-methyl-2-oxo- ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide 45.1 Example 45 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 1.41 (d, J = 6.59 Hz, 3 H), 4.63 (q, J = 6.76 Hz, 1 H), 5.08 (q, J = 7.35 Hz, 1 H), 6.86 (d, J = 8.87 Hz, 2 H), 7.23 (br d, J = 3.30 Hz, 2 H), 7.43-7.52 (m, 6 H), 7.53-7.60 (m, 3 H), 7.75- 8.37 (m, 2 H). LC-MS (method 1) Rt = 0.86 min; MS (ESIpos): m/z = 454.3 [M + H].sup.+ 4% yield 2-(N-[4-amino-5-[4-[2-amino-1- methyl-2-oxo- ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide (stereoisomer 1) Chiral HPLC Example 45.1 HPLC separation of 2-(N-[4-amino-5-[4-[2-amino-1-methyl-2-oxo-ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide (mixture of stereoisomers; 449 mg, 0.99 mmol; Example 45) on a chiral column gave 29 mg (6% yield) of 2-(N-[4-amino-5-[4-[2-amino-1-methyl-2-oxo- ethoxy]benzoyl]thiazol-2-yl]anilino)propanamide, stereoisomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 6.48 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 1.4 ml/min; temperature: 25? C.; UV: 254 nm 45.2 0 Example 45 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 1.41 (d, J = 6.59 Hz, 3 H), 4.63 (q, J = 6.59 Hz, 1 H), 5.08 (q, J = 7.27 Hz, 1 H), 6.86 (d, J = 8.87 Hz, 2 H), 7.23 (br d, J = 4.82 Hz, 2 H), 7.42-7.52 (m, 6 H), 7.55 (br d, J = 1.27 Hz, 3 H), 8.14 (brs, 2 H). LC-MS (method 1) Rt = 0.85 min; MS (ESIpos): m/z = 454.3 [M + H].sup.+ 5% yield 2-(N-[4-amino-5-[4-[2-amino-1- methyl-2-oxo- ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide (stereoisomer 2) Chiral HPLC Example 45.2 HPLC separation of 2-(N-[4-amino-5-[4-[2-amino-1-methyl-2-oxo-ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide (mixture of stereoisomers; 449 mg, 0.99 mmol; Example 45) on a chiral column gave 36 mg (7% yield) of 2-(N-[4-amino-5-[4-[2-amino-1-methyl-2-oxo- ethoxy]benzoyl]thiazol-2-yl]anilino)propanamide, stereoisomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 6.48 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 1.4 ml/min; temperature: 25? C.; UV: 254 nm 45.3 Example 45 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 1.41 (d, J = 6.59 Hz, 3 H), 4.59-4.66 (m, 1 H), 5.08 (q, J = 7.77 Hz, 1 H), 6.86 (d, J = 8.87 Hz, 2 H), 7.23 (br d, J = 4.06 Hz, 2 H), 7.42-7.52 (m, 6 H), 7.53- 7.59 (m, 3 H), 8.05 (br s, 2 H). LC-MS (method 1) Rt = 0.85 min; MS (ESIpos): m/z = 454.3 [M + H].sup.+ 5% yield 2-(N-[4-amino-5-[4-[2-amino-1- methyl-2-oxo- ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide (stereoisomer 3) Chiral HPLC Example 45.3 HPLC separation of 2-(N-[4-amino-5-[4-[2-amino-1-methyl-2-oxo-ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide (mixture of stereoisomers; 449 mg, 0.99 mmol; Example 45) on a chiral column gave 36 mg (8% yield) of 2-(N-[4-amino-5-[4-[2-amino-1-methyl-2-oxo- ethoxy]benzoyl]thiazol-2-yl]anilino)propanamide, stereoisomer 3. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 6.48 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 1.4 ml/min; temperature: 25? C.; UV: 254 nm 45.4 Example 45 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 1.41 (d, J = 6.59 Hz, 3 H), 4.63 (q, J = 6.59 Hz, 1 H), 5.08 (q, J = 6.93 Hz, 1 H), 6.86 (d, J = 8.87 Hz, 2 H), 7.23 (br d, J = 3.04 Hz, 2 H), 7.43-7.52 (m, 6 H), 7.53-7.58 (m, 3 H), 8.04 (br s, 2 H). LC-MS (method 2) Rt = 0.86 min; MS (ESIpos): m/z = 454.3 [M + H].sup.+ 5% yield 2-(N-[4-amino-5-[4-[2-amino-1- methyl-2-oxo- ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide (stereoisomer 4) Chiral HPLC Example 45.4 HPLC-separation of 2-(N-[4-amino-5-[4-[2-amino-1-methyl-2-oxo-ethoxy]benzoyl]thiazol-2- yl]anilino)propanamide (mixture of stereoisomers; 449 mg, 0.99 mmol; Example 45) on a chiral column gave 36 mg (8% yield) of 2-(N-[4-amino-5-[4-[2-amino-1-methyl-2-oxo- ethoxy]benzoyl]thiazol-2-yl]anilino)propanamide, stereoisomer 4. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 6.48 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 1.4 ml/min; temperature: 25? C.; UV: 254 nm 46 Intermediate 49; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.17 (s, 3 H), 4.98- 5.23 (m, 1 H), 7.30 (br t, J = 73.76 Hz, 1 H), 7.19 (br d, J = 8.36 Hz, 2 H), 7.32 (br s, 1 H), 7.48 (br d, J = 8.90 Hz, 1 H), 7.59 (br d, J = 7.35 Hz, 2 H), 7.65 (br s, 1 H), 7.71 (br d, J = 9.12 Hz, 1 H), 7.80-7.91 (m, 1 H), 8.18 (br s, 2 H). LC-MS (method 1) Rt = 1.21 min; MS (ESIpos): m/z = 485.3 [M + H].sup.+ RP-HPLC (method D, basic) 40% yield rac-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro-2-fluoro- anilino)propanamide 46.1 and (R)-2-(N-(4-amino-5-[4- 46.2 (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro-2-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro-2-fluoro- anilino)propanamide 46.1 Example 46 .sup.1H-NMR (400 MHz, DMSO-d6) ? ppm = 1.13-1.22 (m, 3 H), 5.02- 5.22 (m, 1 H), 7.19 (br d, J = 8.36 Hz, 2 H), 7.30 (t, 1 H), 7.32 (brs, 1 H), 7.47-7.50 (m, 1 H), 7.56-7.63 (m, 2 H), 7.63- 7.67 (m, 1 H), 7.68-7.75 (m, 1 H), 7.81-7.94 (m, 1 H), 8.02- 8.36 (m, 2 H). LC-MS (method 1) Rt = 1.21 min; MS (ESIpos): m/z = 485.3 [M + H].sup.+ 35% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro-2-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 46.1 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro-2- fluoro-anilno)propanamide (253 mg, 0.52 mmol; Example 46) on a chiral column gave 90 mg (35% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro-2-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5? 250 ? 30; eluent A: exane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 70% A + 30% B; flow: 40 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.42 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic; 70% A + 30% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 46.2 Example 46 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.12-1.22 (m, 3 H), 4.97-5.23 (m, 1 H), 7.19 (br d, J = 8.36 Hz, 2 H), 7.30 (s, 1 H), 7.32 (brs, 1 H), 7.47-7.51 (m, 1 H), 7.59 (br d, J = 7.60 Hz, 2 H), 7.65 (brs, 1 H), 7.69-7.76 (m, 1 H), 7.82-7.92 (m, 1 H), 7.99-8.31 (m, 2 H). LC-MS (method 1) Rt = 1.21 min; MS (ESIpos): m/z = 485.2 [M + H].sup.+ 52% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro-2-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 46.2 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro-2- fluoro-anilno)propanamide (253 mg, 0.52 mmol; Example 46) on a chiral column gave 135 mg (52% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro-2-fluoro- anilino)prepanamide, enantiomer 2. Preparative chiral HPLC Instrument PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: exane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 70% A + 30% B; flow: 40 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.13 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 70% A + 30% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 47 Intermediate 50; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.06 (br q, J = 7.27 Hz, 1 H), 7.28 (t, J = 73.51 Hz, 1 H), 7.17 (d, J = 8.62 Hz, 2 H), 7.26 (s, 1 H), 7.54-7.64 (m, 7 H), 8.14 (br s, 2 H). LC-MS (method 2) Rt = 1.19 min; MS (ESIpos): m/z = 467.3 [M + H].sup.+ 40% yield rac-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro- anilino)propanamide 47.1 and (R)-2-(N-[4-amino-5-[4- 47.2 (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro- anilino)propanamide and (S)-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro- anilino)propanamide 47.1 Example 47 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.17 (d, J = 7.35 Hz, 3 H), 5.06 (q, J = 7.18 Hz, 1 H), 7.28 (t, J = 73.76 Hz, 1 H), 7.18 (d, J = 8.62 Hz, 2 H), 7.27 (s, 1 H), 7.54-7.64 (m, 7 H), 8.14 (br s, 2 H). LC-MS (method 2) Rt = 1.19 min; MS (ESIpos): m/z = 467.2 [M + H]+ [?].sub.D.sup.20 = +73.5? (c = 1.00, dimethylsulfoxide). RP-HPLC (method D, basic) 11% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 47.1 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro- anilino)propanamide (524 mg, 1.12 mmol; Example 47) on a chiral column gave 147 mg (29% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B; flow: 40 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.99 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 47.2 Example 47 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.17 (d, J = 7.35 Hz, 3 H), 5.06 (q, J = 7.18 Hz, 1 H), 7.28 (t, J = 73.76 Hz, 1 H), 7.18 (d, J = 8.62 Hz, 2 H), 7.27 (s, 1 H), 7.54-7.64 (m, 7 H), 8.14 (br s, 2 H). LC-MS (method 2) Rt = 1.19 min; MS (ESIpos): m/z = 467.2 [M + H]+ [?].sub.D.sup.20 = ?67.1? (c = 1.00, dimethylsulfoxide). RP-HPLC (method D, basic) 13% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 47.2 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro- anilino)propanamide (524 mg, 1.12 mmol; Example 47) on a chiral column gave 178 mg (34% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B; flow: 40 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 4.37 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 48 Intermediate 51; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 5.00-5.07 (m, 1 H), 7.29 (t, J = 73.76 Hz, 1 H), 7.19 (d, J = 8.62 Hz, 2 H), 7.30 (s, 1 H), 7.49-7.54 (m, 1 H), 7.58 (d, J = 8.87 Hz, 2 H), 7.63 (s, 1 H), 7.73-7.79 (m, 2 H), 8.19 (br s, 2 H). LC-MS (method 1) Rt = 1.22 min; MS (ESIpos): m/z = 485.4 [M + H].sup.+ RP-HPLC (method D, basic) 25% yield rac-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro-3-fluoro- anilino)propanamide 48.1 and (R)-2-(N-[4-amino-5-[4- 48.2 (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro-3-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro-3-fluoro- anilino)propanamide 48.1 0 Example 48 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.60 Hz, 3 H), 5.03 (q, J = 7.44 Hz, 1 H), 7.29 (t, J = 73.76 Hz, 1 H), 7.19 (d, J = 8.62 Hz, 2 H), 7.30 (s, 1 H), 7.49-7.54 (m, 1 H), 7.58 (d, J = 8.87 Hz, 2 H), 7.63 (s, 1 H), 7.73-7.78 (m, 2 H), 8.17 (br s, 2 H). LC-MS (method 1) Rt = 1.22 min; MS (ESIpos): m/z = 485.2 [M + H].sup.+ 19% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro-3-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 48.1 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro-3- fluoro-anilno)propanamide (144 mg, 0.3 mmol; Example 48) on a chiral column gave 29 mg (20% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Amylose SA 5?, 250 ? 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 85% A + 15% B; flow: 50 m L/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.54 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 85% A + 15% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 48.2 Example 48 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 5.03 (q, J = 7.10 Hz, 1 H), 7.29 (t, J = 73.76 Hz, 1 H), 7.19 (d, J = 8.87 Hz, 2 H), 7.30 (s, 1 H), 7.51 (dt, J = 8.62, 1.27 Hz, 1 H), 7.58 (d, J = 8.62 Hz, 2 H), 7.63 (s, 1 H), 7.73-7.79 (m, 2 H), 8.18 (br s, 2 H). LC-MS (method 1) Rt = 1.22 min; MS (ESIpos): m/z = 485.3 [M + H].sup.+ 24% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-4-chloro-3-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 48.2 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro-3- fluoro-anilno)propanamide (144 mg, 0.3 mmol; Example 48) on a chiral column gave 36 mg (24% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Amylose SA 5?, 250 ? 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 85% A + 15% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.09 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 85% A + 15% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 49 Intermediate 52; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.03 (q, J = 6.76 Hz, 1 H), 7.28 (t, J = 73.76 Hz, 1 H), 7.18 (d, J = 8.62 Hz, 2 H), 7.30 (s, 1 H), 7.48-7.53 (m, 1 H), 7.58 (d, J = 8.62 Hz, 4 H), 7.78 (ddd, J =11.34, 7.41,2.53 Hz, 1 H), 8.13 (brs, 2 H). LC-MS (method 1) Rt = 1.16 min; MS (ESIpos): m/z = 469.3 [M + H].sup.+ RP-HPLC (method D, basic) 65% yield rac-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl-3,4-difluoro- anilino)propanamide 49.1 and (R)-2-(N-[4-amino-5-(4- 49.2 (difluoromethoxy)benzoyl]thiazol- 2-yl]-3,4-difluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-3,4-difluoro- anilino)propanamide 49.1 Example 49 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.03 (brq, J = 7.18 Hz, 1 H), 7.29 (t, J = 73.51 Hz, 3 H), 7.18 (d, J = 8.36 Hz, 1 H), 7.30 (s, 1 H), 7.48-7.53 (m, 1 H), 7.56- 7.64 (m, 4 H), 7.78 (ddd, J = 11.34, 7.54, 2.41 Hz, 1 H), 8.17 (brs, 2 H). LC-MS (method 1) Rt = 1.16 min; MS (ESIpos): m/z = 469.3 [M + H].sup.+ 39% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-3,4-difluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 49.1 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-3,4-difluoro- anilino)propanamide (381 mg, 0.81 mmol; Example 49) on a chiral column gave 155 mg (39% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-3,4-difluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 80% A + 20% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 4.31 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 49.2 Example 49 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.03 (q, J = 7.35 Hz, 1 H), 7.28 (t, J = 74.01 Hz, 1 H), 7.18 (d, J = 8.62 Hz, 2 H), 7.30 (s, 1 H), 7.48-7.53 (m, 1 H), 7.55- 7.65 (m, 4 H), 7.78 (ddd, J = 11.34, 7.54, 2.41 Hz, 1 H), 8.19 (brs, 2 H). LC-MS (method 1) Rt = 1.16 min; MS (ESIpos): m/z = 469.3 [M + H].sup.+ 34% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl]thiazol- 2-yl]-3,4-difluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 49.2 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-3,4-difluoro- anilino)propanamide (381 mg, 0.81 mmol; Example 49) on a chiral column gave 136 mg (34% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-3,4-difluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 80% A + 20% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 5.54 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 49.2 Example 49.2 was determined to be (R)-2-(N-[4- amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2- yl]-3,4-difluoro-anilino)propanamide, by means of X-ray crystal structure analysis. 50 Intermediate 53; rac-2- bromo- propanamide .sup.1H-NMR (400MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.60 Hz, 3 H), 5.03 (q, J = 7.35 Hz, 1 H), 7.30 (s, 1 H), 7.40-7.44 (m, 2 H), 7.47-7.53 (m, 1 H), 7.55-7.66 (m, 2 H), 7.77 (ddd, J = 11.34, 7.54, 2.41 Hz, 1 H), 8.13-8.49 (m, 2 H), 8.60-8.66 (m, 2 H). LC-MS (method 2) Rt = 0.90 min; MS (ESIpos): m/z = 404.3 [M + H].sup.+ 97% yield rac-2-(N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-3,4- difluoro-anilino)propanamide 50.1 and (R)-2-(N-[4-amino-5-(pyridine-4- 50.2 carbonyl)thiazol-2-yl]-3,4- difluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-3,4- difluoro-anilino)propanamide 50.1 2-(N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-3,4- Example 50 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.03 (br q, J =7.27 Hz, 1 H), 7.30 (s, 1 H), 7.40-7.45 (m, 2 H), 7.47-7.53 (m, 1 H), 7.55- 7.65 (m, 2 H), 7.78 (br ddd, J = 11.34, 7.54, 2.41 Hz, 1 H), 8.17-8.47 (m, 2 H), 8.60-8.66 (m, 2 H). LC-MS (method 2) Rt = 0.87 min; MS (ESIpos): m/z = 404.2 [M + H].sup.+ [?].sub.D.sup.20 = ?79.8? (c = 1.00, dimethylsulfoxide) 21% yield difluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 50.1 HPLC separation of rac-2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-3,4-difluoro- anilino)propanamide (974 mg, 2.35 mmol; Example 50) on a chiral column gave 205 mg (21% yield) of 2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-3,4-difluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 20%A + 80% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.71 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 20% A + 80% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 50.2 2-(N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-3,4- Example 50 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J =7.60 Hz, 3 H), 5.03 (q, J = 6.67 Hz, 1 H), 7.30 (s, 1 H), 7.40-7.44 (m, 2 H), 7.47-7.53 (m, 1 H), 7.55- 7.65 (m, 2 H), 7.77 (ddd, J = 11.34, 7.54, 2.41 Hz, 1 H), 8.14-8.46 (m, 2 H), 8.60-8.66 (m, 2 H). LC-MS (method 2) Rt = 0.87 min; MS (ESIpos): m/z = 404.2 [M + H].sup.+ [?].sub.D.sup.20 = +84.9? (c = 1.00, dimethylsulfoxide) 21% yield difluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 50.2 HPLC separation of rac-2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-3,4-difluoro- anilino)propanamide (974 mg, 2.35 mmol; Example 50) on a chiral column gave 204 mg (21% yield) of 2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-3,4-difluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 20% A + 80% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.06 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 20% A + 80% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 51 Intermediate 54; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.60 Hz, 3 H), 3.76 (s, 3 H), 5.02 (q, J = 7.27 Hz, 1 H), 6.94 (d, J = 8.87 Hz, 2 H), 7.29 (s, 1 H), 7.50 (d, J = 8.62 Hz, 3 H), 7.56-7.65 (m, 2 H), 7.78 (ddd, J =11.41, 7.48, 2.41 Hz, 1 H), 7.89-8.45 (m, 2 H) LC-MS (method 2) Rt = 1.09 min; MS (ESIpos): m/z = 433.2 [M + H].sup.+ 85% yield rac-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]- 3,4-difluoro-anilino)propanamide 51.1 and (R)-2-(N-[4-amino-5-(4- 51.2 methoxybenzoyl)thiazol-2-yl]- 3,4-difluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]- 3,4-difluoro-anilino)propanamide 51.1 0 Example 51 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 3.76 (s, 3 H), 5.03 (q, J = 7.18 Hz, 1 H), 6.94 (d, J = 8.87 Hz, 2 H), 7.29 (s, 1 H), 7.48-7.53 (m, 3 H), 7.55-7.64 (m, 2 H), 7.78 (ddd, J =11.47, 7.41, 2.41 Hz, 1 H), 7.87-8.36 (m, 2 H). LC-MS (method 1) Rt = 1.10 min; MS (ESIpos): m/z = 433.5 [M + H].sup.+ 33% yield 2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]- 3,4-difluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 51.1 HPLC separation of rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-3,4-difluoro- anilino)propanamide (88 mg, 0.20 mmol; Example 51) on a chiral column gave 19 mg (21% yield) of 2 -(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-3,4-difluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 100 nL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt =1.57 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/mi n; temperature: 25? C.; UV: 254 nm 51.2 Example 51 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 3.76 (s, 3 H), 5.03 (q, J =7.10 Hz, 1 H), 6.94 (d, J = 8.87 Hz, 2 H), 7.29 (s, 1 H), 7.48-7.53 (m, 3 H), 7.56-7.65 (m, 2 H), 7.75- 7.82 (m, 1 H), 7.89-8.38 (m, 2 H). LC-MS (method 1) Rt = 1.10 min; MS (ESIpos): m/z = 433.5 [M + H].sup.+ 36% yield 2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]- 3,4-difluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 51.2 HPLC separation of rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-3,4-difluoro- anilino)propanamide (88 mg, 0.20 mmol; Example 51) on a chiral column gave 22 mg (24% yield) of 2 (N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-3,4-difluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 100 nL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.84 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 52 rac-2-(N-[4-amino-5-(6- methoxypyridine-3- Intermediate 55; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 3.86 (s, 3 H), 5.03 (q, J = 7.69 Hz, 1 H), 6.84 (dd, J = 8.62, 0.76 Hz, 1 H), 7.30 (s, 1 H), 7.49- 7.54 (m, 1 H), 7.56-7.65 (m, 2 H), 7.79 (ddd, J =11.41, 7.35, 2.53 Hz, 1 H), 7.84 (dd, J = 8.62, 2.28 Hz, 1 H), 8.16 (br s, 2 H), 8.36 (dd, J = 2.41, 0.63 Hz, 1 H). LC-MS (method 1) Rt = 1.07 min; MS (ESIpos): m/z = 434.3 [M + H].sup.+ RP-HPLC (method C, basic) 48% yield carbonyl)thiazol-2-yl]-3,4- difluoro-anilino)propanamide 52.1 and (R)-2-(N-[4-amino-5-(6- 52.2 methoxypyridine-3- carbonyl)thiazol-2-yl]-3,4- difluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-(6- methoxypyridine-3- carbonyl)thiazol-2-yl]-3,4- difluoro-anilino)propanamide 52.1 2-(N-[4-amino-5-(6- Example 52 .sup.1H-NMR (400 MHz, DMSOd6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 3.86 (s, 3 H), 5.03 (q, J = 6.84 Hz, 1 H), 6.84 (dd, J = 8.49, 0.63 Hz, 1 H), 7.30 (s, 1 H), 7.49- 7.54 (m, 1 H), 7.56-7.65 (m, 2 H), 7.79 (ddd, J =11.34, 7.54, 2.41 Hz, 1 H), 7.84 (dd, J = 8.62, 2.28 Hz, 1 H), 7.97-8.32 (m, 2 H), 8.35-8.37 (m, 1 H). LC-MS (method 1) Rt = 1.07 min; MS (ESIpos): m/z = 434.3 [M + H].sup.+ 31% yield methoxypyridine-3- carbonyl)thiazol-2-yl]-3,4- difluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 52.1 HPLC separation of rac-2-(N-[4-amjno-5-(6-methoxypyridine-3-carbonyl)thiazol-2-yl]-3,4- difluoro-anilino)propanamide (31 mg, 0.07 mmol; Example 52) on a chiral column gave 9 mg (27% yield) of 2-(N-[4-amino-5-(6-methoxypyridine-3-carbonyl)thiazol-2-yl]-3,4-difluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Amylose SA 5?, 250 ? 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile + 0.1 vol % diethylamine; isocratic: 50% A + 50% B; flow: 40 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.25 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25?C.; UV: 254 nm 52.2 2-(N-[4-amino-5-(6- Example 52 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 3.86 (s, 3 H), 5.03 (q, J = 6.93 Hz, 1 H), 6.82-6.86 (m, 1 H), 7.30 (s, 1 H), 7.49-7.54 (m, 1 H), 7.56-7.64 (m, 2 H), 7.79 (ddd, J = 1 1.28, 7.48, 2.28 Hz, 1 H), 7.84 (dd, J = 8.62, 2.53 Hz, 1 H), 7.96-8.31 (m, 2 H), 8.36 (d, J = 2.03 Hz, 1 H). LC-MS (method 1) Rt = 1.07 min; MS (ESIpos): m/z = 434.3 [M + H].sup.+ 31% yield methoxypyridine-3- carbonyl)thiazol-2-yl]-3,4- difluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 52.2 HPLC separation of rac-2-(N-[4-amjno-5-(6-methoxypyridine-3-carbonyl)thiazol-2-yl]-3,4- difluoro-anilino)propanamide (31 mg, 0.07 mmol; Example 52) on a chiral column gave 7 mg (20% yield) of 2-(N-[4-amino-5-(6-methoxypyridine-3-carbonyl)thiazol-2-yl]-3.sub.i4-difluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Amylose SA 5?, 250 ? 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile + 0.1 vol % diethylamine; isocratic: 50% A + 50% B; flow: 40 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.74 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 53 rac-2-(N-[4-amino-5-[6- (trifluoromethyl)pyridine-3- Intermediate 56; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.60 Hz, 3 H), 4.99-5.09 (m, 1 H), 7.31 (s, 1 H), 7.47-7.54 (m, 1 H), 7.55- 7.67 (m, 2 H), 7.78 (ddd, J = 11 .22, 7.54, 2.53 Hz, 1 H), 7.95 (d, J = 7.60 Hz, 1 H), 8.15 (dd, J = 7.98, 1.90 Hz, 1 H), 8.24- 8.49 (m, 2 H), 8.86 (d, J = 1.77 Hz, 1 H). LC-MS (method 1) Rt = 1.16 min; MS (ESIpos): m/z = 472.3 [M + H].sup.+ RP-HPLC (method C, basic) 55% yield carbonyl]thiazol-2-yl]-3,4- difluoro-anilino)propanamide 53.1 and (R)-2-(N-[4-amino-5-[6- 53.2 (trifluoromethyl)pyridine-3- carbonyl]thiazol-2-yl]-3,4- difluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-[6- (trifluoromethyl)pyridine-3- carbonyl]thiazol-2-yl]-3,4- difluoro-anilino)propanamide 53.1 Example 53 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.60 Hz, 3 H), 5.04 (br q, J = 6.84 Hz, 1 H), 7.31 (s, 1 H), 7.48-7.53 (m, 1 H), 7.55-7.66 (m, 2 H), 7.78 (ddd, J = 11.28, 7.48, 2.28 Hz, 1 H), 7.95 (dd, J = 8.24, 0.63 Hz, 1 H), 8.15 (dd, J = 7.98, 1.90 Hz, 1 H), 8.23-8.51 (m, 2 H), 8.86 (d, J =1.77 Hz, 1 H). LC-MS (method 1) Rt = 1.13 min; MS (ESIpos): m/z = 472.2 [M + H].sup.+ 30 % yield 2-(N-[4-amino-5-[6- (trifluoromethyl)pyridine-3- carbonyl]thiazol-2-yl]-3,4- difluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 53.1 HPLC separation of rac-2-(N-[4-amino-5-[6-(trifluoromethyl)pyridine-3-carbonyl]thiazol-2-yl]- 3,4-difluoro-anilino)propanamide (164 mg, 0.35 mmol; Example 53) on a chiral column gave 51 mg (30% yield) of 2-(N-[4-amino-5-[6-(trifluoromethyl)pyridine-3-carbonyl]thiazol-2-yl]-3,4- difluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Amylose SA 5?, 250 ? 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 50 m L/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.05 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 53.2 Example 53 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 5.04 (br q, J = 7.10 Hz, 1 H), 7.31 (s, 1 H), 7.46-7.53 (m, 1 H), 7.55-7.66 (m, 2 H), 7.78 (ddd, J =1 1.34, 7.54, 2.41 Hz, 1 H), 7.95 (dd, J = 8.24, 0.63 Hz, 1 H), 8.15 (dd, J = 7.98, 1.90 Hz, 1 H), 8.23-8.56 (m, 2 H), 8.86 (d, J = 1.77 Hz, 1 H). LC-MS (method 1) Rt = 1.13 min; MS (ESIpos): m/z = 472.2 [M + H].sup.+ 27% yield 2-(N-[4-amino-5-[6- (trifluoromethyl)pyridine-3- carbonyl]thiazol-2-yl]-3,4- difluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 53.2 HPLC separation of rac-2-(N-[4-amino-5-[6-(trifluoromethyl)pyridine-3-carbonyl]thiazol-2-yl]- 3,4-difluoro-anilino)propanamide (164 mg, 0.35 mmol; Example 53) on a chiral column gave 47 mg (27% yield) of 2-(N-[4-amino-5-[6-(trifluoromethyl)pyridine-3-carbonyl]thiazol-2-yl]-3,4- difluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Amylose SA 5?, 250 ? 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 50 m L/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.36 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 54 Intermediate 78; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 2.28 (s, 3 H), 5.11 (q, J = 7.10 Hz, 1 H), 7.15-7.25 (m, 3 H), 7.33-7.39 (m, 3 H), 7.61-7.71 (m, 5 H). LC-MS (method 1) Rt = 1.20 min; MS (ESIpos): m/z = 449.1 [M + H].sup.+ RP-HPLC (method D, basic) 52% yield rac-2-(N-[5-[4- (difluoromethoxy)benzoyi]-4- methyl-thiazol-2-yl]-4-fluoro- anilino)propanamide 55 Intermediate 79; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 2.27 (s, 3 H), 5.09 (q, J = 7.27 Hz, 1 H), 7.16-7.38 (m, 4 H), 7.51-7.56 (m, 1 H), 7.58-7.69 (m, 4 H), 7.82 (ddd, J = 11.34, 7.54, 2.41 Hz, 1 H). LC-MS (method 1) Rt = 1.23 min; MS (ESIpos): m/z = 466.3 [M + H].sup.+ RP-HPLC (method D, basic) 7% yield rac-2-(N-[5-[4- (difluoromethoxy)benzoyl]-4- methyl-thiazol-2-yl]-3,4-difluoro- anilino)propanamide 55.1 and (R)-2-(N-[5-4- 55.2 (difluoromethoxy)benzoyl]-4- methyl-thiazol-2-yl]-3,4-difluoro- anilino)propanamide and (S)-2- (N-[5-[4- (difluoromethoxy)benzoyl]-4- methyl-thiazol-2-yl]-3,4-difluoro- anilino)propanamide 55.1 0 Example 55 .sup.1H NMR (400 MHz, DMSO-d6) ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 2.27 (s, 3 H), 5.08-5.10 (m, 1 H), 7.20-7.24 (m, 3 H), 7.35 (t, J = 72 Hz, 1 H), 7.52-7.54 (m, 1 H), 7.60-7.66 (m, 4 H), 7.81- 7.83 (m, 1 H) LC-MS (method 1) Rt = 1.23 min MS (ESIpos): m/z = 468.5 [M + H].sup.+ 35% yield 2-(N-[5-[4- (difluoromethoxy)benzoyl]-4- methyl-thiazoi-2-yl]-3,4-difluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 55.1 HPLC separation of rac-2-(N-[5-[4-(difluoromethoxy)benzoyl]-4-methyl-thiazol-2-yl]-3,4- difluoro-anilino)propanamide (59 mg, 0.13 mmol, Example 55) on a chiral column gave 21 mg (35% yield) of 2-(N-[5-[4-(difluoromethoxy)benzoyl]-4-methyl-thiazol-2-yl]-3,4-difluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-2; Column: Chiralpak AS 5?, 250 ? 20; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 80% A + 20% B; flow: 20 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 5.43 min Instrument: Thermo Fisher UltiMate 3000; Column: Chiralpak AS 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic; 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 55.2 Example 55 .sup.1H NMR (400 MHz, DMSO-d6) ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 2.27 (s, 3 H), 5.08-5.10 (m, 1 H), 7.20-7.24 (m, 3 H), 7.35 (t, J = 72 Hz, 1 H), 7.52-7.54 (m, 1 H), 7.60-7.66 (m, 4 H), 7.81- 7.83 (m, 1 H) LC-MS (method 1) Rt = 1.23 min MS (ESIpos): m/z = 468.5 [M + H].sup.+ 17% yield 2-(N-[5-[4- (difluoromethoxy)benzoyl]-4- methyl-thiazol-2-yl]-3,4-difluoro- anilino)propanamidepropanamide (enantiomer 2) Chiral HPLC Example 55.2 HPLC separation of rac-2-(N-[5-[4-(difluoromethoxy)benzoyl]-4-methyl-thiazol-2-yl]-3,4- difluoro-anilino)propanamide (59 mg, 0.13 mmol, Example 55) on a chiral column gave 10 mg (17% yield) of 2-(N-[5-[4-(difluoromethoxy)benzoyl]-4-methyl-thiazol-2-yl]-3,4-difluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-2; Column: Chiralpak AS 5?, 250 ? 20; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 80% A + 20% B; flow: 20 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 9.88 min Instrument: Thermo Fisher UltiMate 3000; Column: Chiralpak AS 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 56 Intermediate 57; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 5.03 (q, J = 7.35 Hz, 1 H), 7.31 (s, 1 H), 7.43 (br d, J = 4.31 Hz, 2 H), 7.49-7.53 (m, 1 H), 7.64 (s, 1 H), 7.71-7.78 (m, 2 H), 8.13-8.48 (m, 2 H), 8.63 (br s, 2 H). LC-MS (method 2) Rt = 0.96 min; MS (ESIpos): m/z = 420.3 [M + H].sup.+ RP-HPLC (method C, basic) 33% yield rac-2-(N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-4-chloro-3- fluoro-anilino)propanamide 56.1 and (R)-2-(N-[4-amino-5-(pyridine-4- 56.2 carbonyl)thiazol-2-yl]-4-chloro-3- fluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-4-chloro-3- fluoro-anilino)propanamide 56.1 Example 56 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.60 Hz, 3 H), 4.98-5.08 (m, 1 H), 7.31 (s, 1 H), 7.41-7.45 (m, 2 H), 7.48- 7.53 (m, 1 H), 7.64 (s, 1 H), 7.72- 7.77 (m, 2 H), 8.07-8.45 (m, 2 H), 8.62-8.65 (m, 2 H). LC-MS (method 2) Rt = 0.94 min; MS (ESIpos): m/z = 420.2 [M + H].sup.+ 19% yield 2-(N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-4-chloro-3- fluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 56.1 HPLC separation of rac-2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide (133 mg, 0.32 mmol; Example 56) on a chiral column gave 26 mg (20% yield) of 2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 60% A + 40% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.10 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 56.2 Example 56 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J =7.60 Hz, 3 H), 5.03 (q, J = 7.35 Hz, 1 H), 7.31 (s, 1 H), 7.40-7.46 (m, 2 H), 7.49-7.53 (m, 1 H), 7.64 (s, 1 H), 7.72-7.79 (m, 2 H), 8.12- 8.47 (m, 2 H), 8.61-8.66 (m, 2 H) LC-MS (method 2) Rt = 0.94 min; MS (ESIpos): m/z = 420.2 [M + H].sup.+ 20% yield 2-(N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-4-chloro-3- fluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 56.2 HPLC separation of rac-2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide (133 mg, 0.32 mmol; Example 56) on a chiral column gave 27 mg (20% yield) of 2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 60% A + 40% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.34 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 57 Intermediate 58; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.06 (q, J = 7.27 Hz, 1 H), 7.27 (s, 1 H), 7.41 (d, J = 6.08 Hz, 2 H), 7.59 (d, J = 10.90 Hz, 5 H), 8.08-8.48 (m, 2 H), 8.62 (d, J = 6.08 Hz, 2 H). LC-MS (method 2) Rt = 0.91 min; MS (ESIpos): m/z = 402.2 [M + H].sup.+ 50% yield rac-2-(N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-4-chloro- anilino)propanamide 57.1 and (R)-2-(N-[4-amino-5-(pyridine-4- 57.2 carbonyl)thiazol-2-yl]-4-chloro- anilino)propanamide and (S)-2- (N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-4-chloro- anilino)propanamide 57.1 Example 57 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.17 (d, J = 7.35 Hz, 3 H), 5.06 (m, 1 H), 7.28 (s, 1 H), 7.41 (m, 2 H), 7.59 (m, 5 H), 8.28 (m, 2 H), 8.62 (m, 2 H) LC-MS (method 1) Rt = 0.85 min MS (ESIpos): m/z = 402.4 [M + H].sup.+ [?].sub.D.sup.20 = ?67? c = 8.2 mg/mL in DMSO 38% yield 2-(N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-4-chloro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 57.1 HPLC separation of rac-2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-4-chloro- anilino)propanamide (590 mg, 1.47 mmol, Example 57) on a chiral column gave 234 mg (38% yield) of 2 (N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-4-chloro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IG 5? 250 ? 30mm; eluent A: CO.sub.2; eluent B: 6 thanol + 0.2 vol % aqueous ammonia (32%); isocratic: 30% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 4.76 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IG 5? 100 ? 4.6 mm; eluent A: CO.sub.2; eluent B: ethanol + 0.2 vol % aqueous ammonia (32%); isocratic: 30% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 57.2 Example 57 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.17 (d, J =7.35 Hz, 3 H), 5.06 (m, 1 H), 7.28 (s, 1 H), 7.41 (m, 2 H), 7.59 (m, 5 H), 8.28 (m, 2 H), 8.62 (m, 2 H) LC-MS (method 1) Rt = 0.85 min MS (ESIpos): m/z = 402.4 [M + H].sup.+ [?].sub.D.sup.20 = 76? c = 9.6 mg/mL in DMSO 36% yield 2-(N-[4-amino-5-(pyridine-4- carbonyl)thiazol-2-yl]-4-chloro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 57.2 HPLC separation of rac-2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-4-chloro- anilino)propanamide (590 mg, 1.47 mmol, Example 57) on a chiral column gave 225 mg (36% yield) of 2 (N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-4-chloro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IG 5? 250 ? 30mm; eluent A: CO.sub.2; eluent B: 6 thanol + 0.2 vol % aqueous ammonia (32%); isocratic: 30% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 2.59 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IG 5? 100 ? 4.6 mm; eluent A: CO.sub.2; eluent B: ethanol + 0.2 vol % aqueous ammonia (32%); isocratic: 30% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 58 Intermediate 59; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J =7.35 Hz, 3 H), 3.76 (s, 3 H), 5.05 (q, J = 7.18 Hz, 1 H), 6.93 (d, J = 8.87 Hz, 2 H), 7.26 (s, 1 H), 7.49 (d, J = 8.87 Hz, 2 H), 7.55-7.64 (m, 5 H), 7.82-8.39 (m, 2 H). LC-MS (method 2) Rt = 1.13 min; MS (ESIpos): m/z = 431.2 [M + H].sup.+ 77% yield rac-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- chloro-anillno)propanamide 58.1 and (R)-2-(N-[4-amino-5-(4- 58.2 methoxybenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide and (S)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide 58.1 Example 58 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J =7.35 Hz, 3 H), 3.76 (s, 3 H), 5.06 (m, 1 H), 6.93 (m, 2 H), 7.25 (m, 1 H), 7.49 (m, 2 H), 7.60 (m, 5 H), 8.04 (m, 2 H) LC-MS (method 1) Rt = 1.14 min MS (ESIpos): m/z = 431.4 [M + H].sup.+ [?].sub.D.sup.20 = ?80? c = 11.1 mg/mL in DMSO 36% yield 2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 58.1 HPLC separation of rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-chloro- anilino)propanamide (2.83 g, 6.57 mmol, Example 58) on a chiral column gave 1.03 g (36% yield) of 2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-chloro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: Labomatic HD3000, Knauer Pump 100, Labcol Vario 4000 Plus, Knauer DAD 2600; Column: Cellulose SB 5? 250x50mm Nr. 034; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol + 0.1 Vol-% diethylamine (99%); isocratic: 60% A + 40% B; flow 100.0 mL/min, UV @ 254 nm Analytical chiral HPLC: Rt = 4.15 min Instrument: Agilent HPLC 1260; Column: Cellulose SB 3? 100x4,6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol + 0.1 Vol-% diethylamine (99%); isocratic: 60% A + 40% B; flow 1.0 mL/min; temperature: 25? C.; DAD 254 nm 58.2 0 Example 58 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 3.76 (s, 3 H), 5.06 (m, 1 H), 6.93 (m, 2 H), 7.25 (m, 1 H), 7.49 (m, 2 H), 7.60 (m, 5 H), 8.04 (m, 2 H) LC-MS (method 1) Rt = 1.14 min MS (ESIpos): m/z = 431.4 [M + H].sup.+ [?].sub.D.sup.20 = 79? c = 11.1 mg/mL in DMSO 41% yield 2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- chloro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 58.2 HPLC separation of rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-chloro- anilino)propanamide (2.83 g, 6.57 mmol, Example 58) on a chiral column gave 1.18 g (41% yield) of 2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-chloro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: Labomatic HD3000, Knauer Pump 100, Labcol Vario 4000 Plus, Knauer DAD 2600; Column: Cellulose SB 5? 250x50mm Nr. 034; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol + 0.1 Vol-% diethylamine (99%); isocratic: 60% A + 40% B; flow 100.0 mL/min, UV @ 254 nm Analytical chiral HPLC: Rt = 3.40 min Instrument: Agilent HPLC 1260; Column: Cellulose SB 3? 100x4,6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol + 0.1 Vol-% diethylamine (99%); isocratic: 60% A + 40% B; flow 1.0 mL/min; temperature: 25? C.; DAD 254 nm 59 Intermediate 60; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.20 (d, J = 7.35 Hz, 3 H), 3.77 (s, 3 H), 5.03 (q, J = 7.35 Hz, 1 H), 6.94 (d, J = 8.87 Hz, 2 H), 7.30 (s, 1 H), 7.49-7.53 (m, 3 H), 7.63 (s, 1 H), 7.73-7.79 (m, 2 H), 7.88-8.31 (m, 2 H). LC-MS (method 2) Rt = 1.17 min; MS (ESIpos): m/z = 449.3 [M + H].sup.+ 83% yield rac-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide 59.1 and (R)-2-(N-[4-amino-5-(4- 59.2 methoxybenzoyl)thiazol-2-yl]-4- chloro-3-fluoro- aniiino)propanamide and (S)-2- (N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide 59.1 Example 59 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3 H), 3.76 (s, 3 H), 5.03 (q, J = 7.35 Hz, 1 H), 6.94 (m, 2 H), 7.30 (s, 1 H), 7.52 (m, 3 H), 7.63 (s, 1 H), 7.75 (m, 2 H), 8.10 (m, 2 H) LC-MS (method 1) Rt = 1.16 min MS (ESIpos): m/z = 449.4 [M + H].sup.+ [?].sub.D.sup.20 = ?82? c = 8.2 mg/mL in DMSO 29% yield 2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 59.1 HPLC separation of rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide (442 mg, 0.98 mmol, Example 59) on a chiral column gave 132 mg (29% yield) of 2 -(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Amylose SA 5?, 250 ? 30; eluent A: nethyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 70% A + 30% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.49 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: nethyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 70%A + 30% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 59.1 Example 59.1 was determined to be (R)-2-(N-[4- amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- chloro-3-fluoro-anilino)propanamide, by means of X-ray crystal structure analysis. 59.2 Example 59 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3 H), 3.76 (s, 3 H), 5.03 (q, J = 7.35 Hz, 1 H), 6.94 (m, 2 H), 7.30 (s, 1 H), 7.52 (m, 3 H), 7.63 (s, 1 H), 7.75 (m, 2 H), 8.10 (m, 2 H) LC-MS (method 1) Rt = 1.16 min MS (ESIpos): m/z = 449.4 [M + H].sup.+ [?].sub.D.sup.20 = 87? c = 7.6 mg/mL in DMSO 15% yield 2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 59.2 HPLC separation of rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide (442 mg, 0.98 mmol, Example 59) on a chiral column gave 68 mg (15% yield) of 2 -(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Amylose SA 5?, 250 ? 30; eluent A: nethyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 70% A + 30% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.03 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: nethyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 70% A + 30% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 60 Intermediate 83; rac-2- bromo- propanamide .sup.1H-NMR (600 MHz, DMSO-d6): ? ppm = 1.16 (d, J =7.25 Hz, 3 H), 5.09 (q, J =7.25 Hz, 1 H), 7.24 (s, 1 H), 7.35-7.40 (m, 3 H), 7.42-7.50 (m, 5 H), 7.54- 7.57 (m, 3 H), 7.74-8.52 (m, 2 H). LC-MS (method 2) Rt= 1.02 min; MS (ESIpos): m/z = 367.1 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 46% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)anilino)propanamide 61 Intermediate 84; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.00-5.10 (m, 1 H), 7.25 (s, 1 H), 7.32 (t, J = 8.87 Hz, 2 H), 7.35-7.42 (m, 3 H), 7.45-7.52 (m, 2 H), 7.58 (s, 1 H), 7.63 (dd, J = 9.00, 5.20 Hz, 2 H), 7.80- 8.46 (m, 2 H). LC-MS (method 2) Rt = 1.07 min; MS (ESIpos): m/z = 385.3 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 87% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-4-fluoro- anilino)propanamide 61.1 and (R)-2-(N-(4-amino-5-benzoyl- 61.2 thiazol-2-yl)-4-fluoro- aniiino)propanamide and (S)-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-4-fluoro- anilino)propanamide 61.1 Example 61 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 7.60 Hz, 3 H), 5.02-5.09 (m, 1 H), 7.25 (s, 1 H), 7.32 (t, J =8.87 Hz, 2 H), 7.36-7.42 (m, 3 H), 7.46-7.50 (m, 2 H), 7.58 (s, 1 H), 7.63 (dd, J = 8.74, 5.20 Hz, 2 H), 7.80- 8.50 (m, 2 H). LC-MS (method 1) Rt = 1.07 min; MS (ESIpos): m/z = 385.5 [M + H].sup.+ 24% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-4-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 61.1 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide (414 mg, 1.08 mmol; Example 61) on a chiral column gave 139 mg (33% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IA 5? 250 ? 30mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 25% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 280 nm Analytical chiral HPLC: Rt = 2.10 min Instrument: Agilent: 1260, Aurora SFC-Modul;column Chiralpak IA 5? 100 ? 4.6mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4% diethylamine (99%); isocratic: 25% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 280 nm 61.2 Example 61 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 7.60 Hz, 3 H), 5.02-5.09 (m, 1 H), 7.25 (s, 1 H), 7.32 (t, J = 8.87 Hz, 2 H), 7.36-7.42 (m, 3 H), 7.46-7.50 (m, 2 H), 7.58 (s, 1 H), 7.63 (dd, J = 8.74, 5.20 Hz, 2 H), 7.80- 8.50 (m, 2 H). LC-MS (method 1) Rt = 1.07 min; MS (ESIpos): m/z = 385.5 [M + H].sup.+ 26% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-4-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 61.2 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide (414 mg, 1.08 mmol; Example 61) on a chiral column gave 103 mg (24% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IA 5? 250 ? 30mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 25% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 280 nm Analytical chiral HPLC: Rt = 3.08 min Instrument: Agilent: 1260, Aurora SFC-Modul; column: Chiralpak IA 5? 100 ? 4.6mm; eluent A: CO.sub.2; eluent B: 2-Propanol + 0.4% diethylamine (99%); isocratic; 25%B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 280 nm 61.2 Example 61.2 was determined to be (R)-2-(N- (4-amino-5-benzoyl-thiazol-2-yl)-4-fluoro- anilino)propanamide, by means of X-ray crystal structure analysis. 62 0 Intermediate 85; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 3.75 (s, 3 H), 5.06 (q, J = 6.76 Hz, 1 H), 6.93 (d, J = 8.87 Hz, 2 H), 7.22-7.27 (m, 1 H), 7.34 (t, J = 8.87 Hz, 2 H), 7.48 (d, J = 8.87 Hz, 2 H), 7.57 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.79- 8.38 (m, 2 H). LC-MS (method 2) Rt = 1.06 min; MS (ESIpos): m/z = 415.5 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 49% yield rac-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 62.1 and (R)-2-(N-[4-amino-5-(4- 62.2 methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 62.1 Example 62 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 3.75 (s, 3 H), 5.06 (q, J = 6.76 Hz, 1 H), 6.93 (d, J = 8.87 Hz, 2 H), 7.22-7.27 (m, 1 H), 7.34 (t, J = 8.87 Hz, 2 H), 7.48 (d, J = 8.87 Hz, 2 H), 7.57 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.79- 8.38 (m, 2 H). [?].sub.D.sup.20 = ?142.9? (c = 1.00, chloroform) 45% yield 2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 62.1 HPLC separation of rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (350 mg, 0.80 mmol; Example 62) on a chiral column gave 135 mg (45% yield) of 2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IA 5? 250 ? 30mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 30% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 1.72 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IA 5? 100 ? 4.6mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 30% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 62.2 Example 62 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 3.75 (s, 3 H), 5.06 (q, J = 6.76 Hz, 1 H), 6.93 (d, J = 8.87 Hz, 2 H), 7.22-7.27 (m, 1 H), 7.34 (t, J = 8.87 Hz, 2 H), 7.48 (d, J = 8.87 Hz, 2 H), 7.57 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.79- 8.38 (m, 2 H). [?].sub.D.sup.20 = +114.5? (c = 1.00, chloroform) 49% yield 2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 62.2 HPLC separation of rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (350 mg, 0.80 mmol; Example 62) on a chiral column gave 15 mg (49% yield) of 2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IA 5? 250 ? 30mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 30% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 2.61 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IA 5? 100 ? 4.6mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 30% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 62.2 Example 62.2 was determined to be (R)-2-(N-[4- amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide, by means of X-ray crystal structure analysis. 63 Intermediate 86; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J =7.60 Hz, 3 H), 2.29 (s, 3 H), 5.05 (q, J = 6.67 Hz, 1 H), 7.18 (d, J = 8.11 Hz, 2 H), 7.24 (s, 1 H), 7.32 (t, J = 8.87 Hz, 2 H), 7.38 (d, J = 8.11 Hz, 2 H), 7.57 (s, 1 H), 7.63 (dd, J = 8.62, 5.07 Hz, 2 H), 8.10 (br s, 2 H). LC-MS (method 2) Rt = 1.15 min; MS (ESIpos): m/z = 399.3 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 18% yield rac-2-(N-[4-amino-5-(4- methylbenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 63.1 and (R)-2-(N-[4-amino-5-(4- 63.2 methylbenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-(4- methylbenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 63.1 Example 63 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J =7.60 Hz, 3 H), 2.29 (s, 3 H), 5.05 (q, J = 6.67 Hz, 1 H), 7.18 (d, J = 8.11 Hz, 2 H), 7.24 (s, 1 H), 7.32 (t, J = 8.87 Hz, 2 H), 7.38 (d, J = 8.11 Hz, 2 H), 7.57 (s, 1 H), 7.63 (dd, J = 8.62, 5.07 Hz, 2 H), 8.10 (br s, 2 H). [?].sub.D.sup.20 = ?159.9? (c = 1.00, chloroform) 13% yield 2-(N-[4-amino-5-(4- methylbenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 63.1 HPLC separation of rac-2-(N-[4-amino-5-(4-methylbenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (1.5 g, 3.58 mmol; Example 63) on a chiral column gave 660 mg (45% yield) of 2-(N-[4-amino-5-(4-methylbenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamlde, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.46 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 63.2 Example 63 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 2.29 (s, 3 H), 5.05 (q, J = 6.67 Hz, 1 H), 7.18 (d, J = 8.11 Hz, 2 H), 7.24 (s, 1 H), 7.32 (t, J = 8.87 Hz, 2 H), 7.38 (d, J = 8.11 Hz, 2 H), 7.57 (s, 1 H), 7.63 (dd, J = 8.62, 5.07 Hz, 2 H), 8.10 (br s, 2 H). [?].sub.D.sup.20 = +147.0? (c = 1.00, chloroform) 13% yield 2-(N-[4-amino-5-(4- methylbenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 63.2 HPLC separation of rac-2-(N-[4-amino-5-(4-methylbenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (1.5 g, 3.58 mmol; Example 63) on a chiral column gave 680 mg (44% yield) of 2-(N-[4-amino-5-(4-methylbenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamlde, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol + 0.1 vol % diethylamine; isocratic: 60%A + 40% B; flow: 140 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.69 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 64 Intermediate 87; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.06 (br q, J = 6.84 Hz, 1 H), 7.22 (t, J = 8.87 Hz, 2 H), 7.25 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.55 (dd, J = 8.74, 5.45 Hz, 2 H), 7.58 (br s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.86- 8.56 (m, 2 H). LC-MS (method 2) Rt = 1.09 min; MS (ESIpos): m/z = 403.3 [M +H].sup.+ preparative flash chromatography (method Z, 0-3%) 7% yield rac-2-(N-[4-amino-5-(4- fluorobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 65 Intermediate 88; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, CHLOROFORM-d): ? ppm = 1.27 (d, J = 7.10 Hz, 3 H), 5.23 (q, J = 7.18 Hz, 1 H), 5.39-5.48 (m, 1 H), 6.58-6.70 (m, 1 H), 6.94-7.02 (m, 2 H), 7.33-7.43 (m, 4 H), 7.58-7.64 (m, 2 H) (NH2 missing). LC-MS (method 2) Rt = 1.08 min; MS (ESIpos): m/z = 403.3 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 29% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-2,4-difluoro- anilino)propanamide 66 Intermediate 89; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 6.84 Hz, 3 H), 3.78 (s, 3 H), 5.06 (q, J = 6.59 Hz, 1 H), 7.00 (d, J = 9.12 Hz, 2 H), 7.21 (s, 1 H), 7.35-7.42 (m, 3 H), 7.43-7.49 (m, 4 H), 7.52 (s, 1 H), 7.65-8.49 (m, 2 H). LC-MS (method 2) Rt = 1.03 min; MS (ESIpos): m/z = 397.4 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 19% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-4-methoxy- anilino)propanamide 67 0 Intermediate 83; rac-2- bromo- butanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 0.84 (t, J = 7.35 Hz, 3 H), 1.47-1.60 (m, 1 H), 1.69- 1.81 (m, 1 H), 4.87-4.95 (m, 1 H), 7.30 (s, 1 H), 7.34-7.51 (m, 8 H), 7.54-7.58 (m, 3 H), 7.78- 8.48 (m, 2 H). LC-MS (method 2) Rt = 1.09 min; MS (ESIpos): m/z = 381.3 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 43% yield rac-2-[(4-amino-5-benzoyl-1,3- thiazol-2- yl)(phenyl)amino]butanamide 68 Intermediate 84; rac-2- bromo- butanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 0.84 (t, J = 7.35 Hz, 3 H), 1.46-1.58 (m, 1 H), 1.68- 1.79 (m, 1 H), 4.85-4.92 (m, 1 H), 7.32 (s, 3 H), 7.37-7.42 (m, 3 H), 7.47-7.50 (m, 2 H), 7.59 (s, 1 H), 7.64 (dd, J = 9.12, 5.07 Hz, 2 H), 7.83-8.36 (m, 2 H). LC-MS (method 2) Rt = 1.12 min; MS (ESIpos): m/z = 399.3 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 29% yield rac-2-[(4-amino-5-benzoyl-1,3- thiazol-2-yl)(4- fluorophenyl)amino]butanamide 69 Intermediate 90; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 1.41 (d, J = 6.59 Hz, 3 H), 4.64 (q, J = 6.59 Hz, 1 H), 5.05 (q, J = 6.76 Hz, 1 H), 6.87 (d, J = 8.87 Hz, 2 H), 7.25 (br s, 2 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.46 (d, J = 8.62 Hz, 2 H), 7.50 (s, 1 H), 7.57 (s, 1 H), 7.64 (dd, J = 9.00, 5.20 Hz, 2 H), 7.78-8.35 (m, 2 H). LC-MS (method 2) Rt = 0.87 min; MS (ESIpos): m/z = 472.2 [M + H].sup.+ preparative flash chromatography (method Z, 0-8%) 28% yield 2-(N-[4-amino-5-[4-(2-amino-1- methyl-2-oxo- ethoxy) benzoyl]thiazol-2-yl]-4- fluoro-anilino)propanamide (mixture of stereoisomers) 70 Intermediate 85; rac-2- bromo- butanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 0.84 (t, J =7.22 Hz, 3 H), 1.46-1.58 (m, 1 H), 1.67- 1.78 (m, 1 H), 3.76 (s, 3 H), 4.85- 4.93 (m, 1 H), 6.93 (d, J = 8.87 Hz, 2 H), 7.33 (t J = 8.74 Hz, 2 H), 7.32 (br s, 1 H), 7.49 (d, J = 8.87 Hz, 2 H), 7.59 (s, 1 H), 7.65 (dd, J = 9.00, 4.94 Hz, 2 H), 8.11 (brs, 2 H). LC-MS (method 2) Rt = 1.12 min; MS (ESIpos): m/z = 429.3 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 28% yield rac-2-{[4-amino-5-(4- methoxybenzoyl)-1,3-thiazol-2- yl](4- fluorophenyl)amino}butanamide 71 Intermediate 84; 2- bromo- acetamide .sup.1H-NMR (500 MHz, DMSO-d6): ? ppm = 4.44 (s, 2 H), 7.23 (s, 1 H), 7.32 (t, J = 8.67 Hz, 2 H), 7.38- 7.43 (m, 3 H), 7.50-7.53 (m, 2 H), 7.56 (s, 1 H), 7.61 (dd, J = 8.83, 5.04 Hz, 2 H), 7.94- 8.44 (m, 2 H). LC-MS (method 2) Rt = 1.00 min; MS (ESIpos): m/z = 371.4 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 8% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-4-fluoro-anilino)acetamide 72 Intermediate 86; 2- bromo- acetamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 2.30 (s, 3 H), 4.44 (s, 2 H), 7.18-7.24 (m, 3 H), 7.32 (t, J = 8.87 Hz, 2 H), 7.42 (d, J = 8.11 Hz, 2 H), 7.55 (s, 1 H), 7.61 (dd, J = 9.13, 5.07 Hz, 2 H), 7.79- 8.41 (m, 2 H). LC-MS (method 2) Rt = 1.07 min; MS (ESIpos): m/z = 385.5 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 6% yield 2-(N-[4-amino-5-(4- methylbenzoyl)thiazol-2-yl]-4- fluoro-anilino)acetamide 73 Intermediate 91; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 2.33 (s, 3 H), 5.07 (q, J = 7.01 Hz, 1 H), 7.21 (s, 1 H), 7.27 (d, J = 8.11 Hz, 2 H), 7.35-7.43 (m, 5 H), 7.44-7.48 (m, 2 H), 7.52 (s, 1 H), 8.10 (brs, 2 H). LC-MS (method 2) Rt = 1.10 min; MS (ESIpos): m/z = 381.5 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 35% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-4-methyl- anilino)propanamide 73.1 and (R)-2-(N-(4-amino-5-benzoyl- 73.2 thiazol-2-yl)-4-methyl- anilino)propanamide and (S)-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-4-methyl- anilino)propanamide 73.1 Example 73 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 2.33 (s, 3 H), 5.07 (q, J = 7.01 Hz, 1 H), 7.21 (s, 1 H), 7.27 (d, J = 8.11 Hz, 2 H), 7.35-7.43 (m, 5 H), 7.44-7.48 (m, 2 H), 7.52 (s, 1 H), 8.10 (br s, 2 H). [?].sub.D.sup.20 = ?173.6? (c = 1.00, chloroform) 35% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-4-methyl- anilino)propanamide (enantiomer 1) Chiral HPLC Example 73.1 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-4-methyl-anilino)propanamide (440 mg, 1.10 mmol; Example 73) on a chiral column gave 160 mg (36% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-4-methyl-anilino)propanamide.sub.i enantiomer 1. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IA 5? 250 ? 30mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 25% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 280 nm Analytical chiral HPLC: Rt = 2.88 min Instrument: Agilent: 1260, Aurora SFC-module; column: Chiralpak IA 5? 100 ? 4.6mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine, isocratic: 25% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 280 nm 73.2 Example 73 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 2.33 (s, 3 H), 5.07 (q, J = 7.01 Hz, 1 H), 7.21 (s, 1 H), 7.27 (d, J = 8.1 1 Hz, 2 H), 7.35-7.43 (m, 5 H), 7.44-7.48 (m, 2 H), 7.52 (s, 1 H), 8.10 (br s, 2 H). [?].sub.D.sup.20 = +161.4% (c = 1.00, chloroform) 8% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-4-methyl- anilino)propanamide (enantiomer 2) Chiral HPLC Example 73.2 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-4-methyl-anilino)propanamide (440 mg, 1.10 mmol; Example 73) on a chiral column gave 100 mg (23% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-4-methyl-anilino)propanamide.sub.i enantiomer 2. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IA 5? 250 ? 30 mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 25% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 280 nm Analytical chiral HPLC: Rt = 4.57 min Instrument: Agilent: 1260, Aurora SFC-module; column: Chiralpak IA 5? 100 ? 4.6 mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine, isocratic: 25% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 280 nm 74 Intermediate 92; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.05 (q, J = 7.18 Hz, 1 H), 7.28 (s, 1 H), 7.32 (td, J = 8.30, 2.15 Hz, 1 H), 7.37-7.46 (m, 4 H), 7.47-7.56 (m, 4 H), 7.60 (s, 1 H), 7.85-8.35 (m, 2 H). LC-MS (method 2) Rt = 1.06 min; MS (ESIpos): m/z = 385.5 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 15% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-3-fluoro- anilino)propanamide 74.1 and (R)-2-(N-(4-amino-5-benzoyl- 74.2 thiazol-2-yl)-3-fluoro- anilino)propanamide and (S)-2-(N-(4-amino-5-benzoyi- thiazol-2-yl)-3-fluoro- anilino)propanamide 74.1 0 Example 74 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.05 (q, J = 7.18 Hz, 1 H), 7.28 (s, 1 H), 7.32 (td, J = 8.30, 2.15 Hz, 1 H), 7.37-7.46 (m, 4 H), 7.47-7.56 (m, 4 H), 7.60 (s, 1 H), 7.85-8.35 (m, 2 H). [?].sub.D.sup.20 = ?143.6? (c = 1.00, chloroform) 4% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-3-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 74.1 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-3-fluoro-anilino)propanamide (260 mg, 0.64 mmol; Example 74) on a chiral column gave 65 mg (25% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-3-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument PrepCon Labomatic HPLC; Column: YMC Cellulose SC 10?, 250 x 50; eluent A: hexane; eluent B: 2-propanol; isocratic: 70% A + 30% B; flow: 150 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 5.46 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: hexane; eluent B: 2-propanol; isocratic: 70% A + 30% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 74.2 Example 74 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.05 (q, J = 7.18 Hz, 1 H), 7.28 (s, 1 H), 7.32 (td, J = 8.30, 2.15 Hz, 1 H), 7.37-7.46 (m, 4 H), 7.47-7.56 (m, 4 H), 7.60 (s, 1 H), 7.85-8.35 (m, 2 H). [?].sub.D.sup.20 = +151.0? (c = 1.00, chloroform) 4% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-3-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 74.2 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-3-fluoro-anilino)propanamide (260 mg, 0.64 mmol; Example 74) on a chiral column gave 65 mg (25% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-3-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: hexane; eluent B: 2-propanol; isocratic: 70% A + 30% B; flow: 150 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 6.76 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: hexane; eluent B: 2-propanol; isocratic: 70% A + 30% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 75 Intermediate 93; rac-2- bromo- propanamide .sup.1H-NMR (500 MHz, DMSO-d6): ? ppm = 1.22 (d, J = 7.31 Hz, 3 H), 5.04 (q, J = 7.10 Hz, 1 H), 6.87-7.30 (m, 2 H), 7.32 (td, J = 7.63, 1.27 Hz, 1 H), 7.34- 7.43 (m, 4 H), 7.49-7.55 (m, 3 H), 7.77 (td, J = 7.95, 1.59 Hz, 1 H), 7.92 (br s, 2 H). LC-MS (method 2) Rt = 1.04 min; MS (ESIpos): m/z = 385.4 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 52% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-2-fluoro- anilino)propanamide 75.1 and (R)-2-(N-(4-amino-5-benzoyl- 75.2 thiazol-2-yl)-2-fluoro- anilino)propanamide and (S)-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-2-fluoro- anilino)propanamide 75.1 Example 75 .sup.1H-NMR (500 MHz, DMSO-d6): ? ppm = 1.22 (d, J = 7.31 Hz, 3 H), 5.04 (q, J = 7.10 Hz, 1 H), 6.87-7.30 (m, 2 H), 7.32 (td, J = 7.63, 1.27 Hz, 1 H), 7.34- 7.43 (m, 4 H), 7.49-7.55 (m, 3 H), 7.77 (td, J = 7.95, 1.59 Hz, 1 H), 7.92 (brs, 2 H). [?].sub.D.sup.20 = ?116.9? (c = 1.00, chloroform) 13% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-2-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 75.1 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-2-fluoro-anilino)propanamide (560 mg, 1.38 mmol; Example 75) on a chiral column gave 135 mg (24% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-2-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 70% A + 30% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.50 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 70% A + 30% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 75.2 Example 75 .sup.1H-NMR (500 MHz, DMSO-d6): ? ppm = 1.22 (d, J = 7.31 Hz, 3 H), 5.04 (q, J = 7.10 Hz, 1 H), 6.87-7.30 (m, 2 H), 7.32 (td, J = 7.63, 1.27 Hz, 1 H), 7.34- 7.43 (m, 4 H), 7.49-7.55 (m, 3 H), 7.77 (td, J = 7.95, 1.59 Hz, 1 H), 7.92 (br s, 2 H). [?].sub.D.sup.20 = +109.3? (c = 1.00, chloroform) 15% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-2-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 75.2 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-2-fluoro-anilino)propanamide (560 mg, 1.38 mmol; Example 75) on a chiral column gave 165 mg (31% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-2-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 70% A + 30% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 4.39 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 70% A + 30% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 76 Intermediate 72; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 2.31 (s, 3 H), 5.05 (q, J = 7.18 Hz, 1 H), 7.22 (s, 1 H), 7.23- 7.27 (m, 1 H), 7.33-7.41 (m, 6 H), 7.45-7.50 (m, 2 H), 7.53 (s, 1 H), 7.70-8.47 (m, 2 H). LC-MS (method 2) Rt = 1.10 min; MS (ESIpos): m/z = 381.5 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 71% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-3-methyl- anilino)propanamide 76.1 and (R)-2-(N-(4-amino-5-benzoyl- 76.2 thiazol-2-yl)-3-methyl- anilino)propanamide and (S)-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-3-methyl- anilino)propanamide 76.1 Example 76 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 2.31 (s, 3 H), 5.05 (q, J = 7.18 Hz, 1 H), 7.22 (s, 1 H), 7.23- 7.27 (m, 1 H), 7.33-7.41 (m, 6 H), 7.45-7.50 (m, 2 H), 7.53 (s, 1 H), 7.70-8.47 (m, 2 H). [?].sub.D.sup.20 = +177.3? (c = 1.00, chloroform) 31% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-3-methyl- anilino)propanamide (enantiomer 1) Chiral HPLC Example 76.1 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-3-methyl-anilino)propanamide (1170 mg, 3.00 mmol; Example 76) on a chiral column gave 525 mg (44% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-3-methyl-anilino)propanamide.sub.l enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 150 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 6.56 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 76.2 Example 76 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 2.31 (s, 3 H), 5.05 (q, J = 7.18 Hz, 1 H), 7.22 (s, 1 H), 7.23- 7.27 (m. 1 H), 7.33-7.41 (m, 6 H), 7.45-7.50 (m, 2 H), 7.53 (s, 1 H), 7.70-8.47 (m, 2 H). [?].sub.D.sup.20 = +177.3% (c = 1.00, chloroform) 34% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-3-methyl- anilino)propanamide (enantiomer 2) Chiral HPLC Example 76.2 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-3-methyl-anilino)propanamide (1170 mg, 3.00 mmol; Example 76) on a chiral column gave 525 mg (45% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-3-methyl-anilino)propanamide.sub.l enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 150 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 8.91 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 77 Intermediate 73; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 0.97-1.08 (m, 3 H), 2.17 (s, 3 H), 4.97-5.12 (m, 1 H), 7.24 (br s, 1 H), 7.33-7.40 (m, 6 H), 7.46 (br d, J = 5.32 Hz, 2 H), 7.57 (br s, 1 H), 7.71-7.77 (m, 1 H), 7.85-8.48 (m, 2 H). LC-MS (method 2) Rt = 1.08 min; MS (ESIpos): m/z = 381.4 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 56% yield rac-2-(N-(4-amino-5-benzoyl- thiazol-2-yl)-2-methyl- anilino)propanamide 77.2 thiazol-2-yl)-2-methyl- aniiino)propanamide and (S)-2-(N-(4-amino-5-benzoyi- thiazol-2-yl)-2-methyl- anilino)propanamide 77.1 Example 77 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 0.97-1.08 (m, 3 H), 2.17 (s, 3 H), 4.97-5.12 (m, 1 H), 7.24 (br s, 1 H), 7.33-7.40 (m, 6 H), 7.46 (br d, J = 5.32 Hz, 2 H), 7.57 (br s, 1 H), 7.71-7.77 (m, 1 H), 7.85-8.48 (m, 2 H). [?].sub.D.sup.20= +166.1? (c = 1.00, chloroform) 23% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-2-methyl- anilino)propanamide (enantiomer 1) Chiral HPLC Example 77.1 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-2-methyl-anilino)propanamide (1010 mg, 2.52 mmol; Example 77) on a chiral column gave 420 mg (42% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-2-methyl-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: Chiralpak IG 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 85% A + 15% B; flow: 60 m L/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 7.09 min Instrument: Waters Alliance 2695; Column: Chiralpak IG 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 85% A + 15% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 77.2 00 Example 77 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 0.97-1.08 (m, 3 H), 2.17 (s, 3 H), 4.97-5.12 (m, 1 H), 7.24 (br s, 1 H), 7.33-7.40 (m, 6 H), 7.46 (br d, J = 5.32 Hz, 2 H), 7.57 (brs, 1 H), 7.71-7.77 (m, 1 H), 7.85-8.48 (m, 2 H). [?].sub.D.sup.20 = ?152.0? (c = 1.00, chloroform) 23% yield 2-(N-(4-amino-5-benzoyl-thiazol- 2-yl)-2-methyl- anilino)propanamide (enantiomer 1) Chiral HPLC Example 77.2 HPLC separation of rac-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-2-methyl-anilino)propanamide (1010 mg, 2.52 mmol; Example 77) on a chiral column gave 420 mg (42% yield) of 2-(N-(4- amino-5-benzoyl-thiazol-2-yl)-2-methyl-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: Chiralpak IG 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 85% A + 15% B; flow: 60 m L/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 10.30 min Instrument: Waters Alliance 2695; Column: Chiralpak IG 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diet ylamine; eluent B: ethanol; isocratic: 85% A + 15% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 78 01 Intermediate 94; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 3.83 (s, 3 H), 4.99-5.18 (m, 1 H), 7.18 (s, 1 H), 7.37-7.44 (m, 3 H), 7.48 (s, 1 H), 7.49- 7.53 (m, 3 H), 7.80-8.48 (m, 2 H), 7.90 (s, 1 H). LC-MS (method 2) Rt = 0.80 min; MS (ESIpos): m/z = 371.3 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 17% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-(1-methylpyrazol-4- yl)amino]propanamide 78.1 and (R)-2-[(4-amino-5-benzoyl- 78.2 thiazol-2-yl)-(1-methylpyrazol-4- yl)amino]propanamide and (S)-2-[(4-amino-5-benzoyl- thiazol-2-yl)-(1-methylpyrazol-4- yl)amino]propanamide 78.1 02 Example 78 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 3.83 (s, 3 H), 4.99-5.18 (m, 1 H), 7.18 (s, 1 H), 7.37-7.44 (m, 3H), 7.48 (s, 1 H),7.49- 7.53 (m, 3 H), 7.80-8.48 (m, 2 H), 7.90 (s, 1 H). [?].sub.D.sup.20 = ?82.8? (c = 1.00, chloroform) 6% yield 2-[(4-amino-5-benzoyl-thiazol-2- yl)-(1-methylpyrazol-4- yl)amino]propanamide (enantiomer 1) Chiral HPLC Example 78.1 HPLC separation of rac-2-[(4-amino-5-benzoyl-thiazol-2-yl)-(1-methylpyrazol-4- yl)amino]propanamide (240 mg, 0.64 mmol; Example 78) on a chiral column gave 89 mg (36% yield) of 2-[(4-amino-5-benzoyl-thiazol-2-yl)-(1-methylpyrazol-4-yl)amino]propanamide, enantiomer 1. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5? 250 ? 30mm; eluent A: CO.sub.2; eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 40% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 1.77 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IC 5? 100 ? 4.6 mm; eluent A: CO2 eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 40% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 78.2 03 Example 78 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 3.83 (s, 3 H), 4.99-5.18 (m, 1 H), 7.18 (s, 1 H), 7.37-7.44 (m, 3 H), 7.48 (s, 1 H), 7.49- 7.53 (m, 3 H), 7.80-8.48 (m, 2 H), 7.90 (s, 1 H). [?].sub.D.sup.20 = +72.6? (c = 1.00, chloroform) 6% yield 2-[(4-amino-5-benzoyl-thiazol-2- yl)-(1-methylpyrazol-4- yl)amino]propanamide (enantiomer 2) Chiral HPLC Example 78.2 HPLC separation of rac-2-[(4-amino-5-benzoyl-thiazol-2-yl)-(1-methylpyrazol-4- yi)amino]propanamide (240 mg, 0.64 mmol; Example 78) on a chiral column gave 80 mg (33% yield) of 2-[(4-amino-5-benzoyl-thiazol-2-yl)-(1-methylpyrazol-4-yl)amino]propanamide, enantiomer 2. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5? 250 ? 30mm; eluent A: CO.sub.2; eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 40% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 2.66 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IC 5? 100 ? 4.6 mm; eluent A: CO.sub.2; eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 40% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 79 04 rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-(3- Intermediate 95; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.17 (d, J =7.35 Hz, 3 H), 5.07 (q, J =7.10 Hz, 1 H), 5.76 (s, 1 H), 7.30 (s, 1 H), 7.35- 7.43 (m, 3 H), 7.47-7.51 (m, 2 H), 7.54 (dd, J = 8.1 1, 4.82 Hz, 1 H), 7.64 (s, 1 H), 7.90-8.44 (m, 2 H), 8.04-8.08 (m, 1 H), 8.63 (dd, J = 4.56, 1.52 Hz, 1 H), 8.74 (d, J = 2.03 Hz, 1 H). LC-MS (method 2) Rt = 0.84 min; MS (ESIpos): m/z = 368.5 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 10% yield pyridyl)amino]propanamide 79.1 and (R)-2-[(4-amino-5-benzoyl- 79.2 thiazol-2-yl)-(3- pyridyl)amino]propanamide and (S)-2-[(4-amino-5-benzoyl- thiazol-2-yl)-(3- pyridyl)amino]propanamide 79.1 05 Example 79 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.17 (d, J = 7.35 Hz, 3 H), 5.07 (q, J = 7.10 Hz, 1 H), 5.76 (s, 1 H), 7.30 (s, 1 H), 7.35- 7.43 (m, 3 H), 7.47-7.51 (m, 2 H), 7.54 (dd, J = 8.11, 4.82 Hz, 1 H), 7.64 (s, 1 H), 7.90-8.44 (m, 2 H), 8.04-8.08 (m, 1 H), 8.63 (dd, J = 4.56, 1.52 Hz, 1 H), 8.74 (d, J = 2.03 Hz, 1 H). [?].sub.D.sup.20 = ?119.3? (c = 1.00, chloroform) 3% yield 2-[(4-amino-5-benzoyl-thiazol-2- yl)-(3- pyridyl)amino]propanamide (enantiomer 1) Chiral HPLC Example 79.1 HPLC separation of rac-2-[(4-amino-5-benzoyl-thiazol-2-yl)-(3-pyridyl)amino]propanamide (200 mg, 0.52 mmol; Example 79) on a chiral column gave 50 mg (25% yield) of 2-[(4-amino-5- benzoyl-thiazol-2-yl)-(3-pyridyl)amino]propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 150 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.15 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 ml/min; temperature: 25? C.; UV: 254 nm 79.2 06 Example 79 .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.17 (d, J = 7.35 Hz, 3 H), 5.07 (q, J = 7.10 Hz, 1 H), 5.76 (s, 1 H), 7.30 (s, 1 H), 7.35- 7.43 (m, 3 H), 7.47-7.51 (m, 2 H), 7.54 (dd, J = 8.11, 4.82 Hz, 1 H), 7.64 (s, 1 H), 7.90-8.44 (m, 2 H), 8.04-8.08 (m, 1 H), 8.63 (dd, J = 4.56, 1.52 Hz, 1 H), 8.74 (d, J = 2.03 Hz, 1 H). [?].sub.D.sup.20 = +138.1% (c = 1.00, chloroform) 3% yield 2-[(4-amino-5-benzoyl-thiazol-2- yl)-(3- pyridyl)amino]propanamide (enantiomer 2) Chiral HPLC Example 79.2 HPLC separation of rac-2-[(4-amino-5-benzoyl-thiazol-2-yl)-(3-pyridyl)amino]propanamide (200 mg, 0.52 mmol; Example 79) on a chiral column gave 50 mg (25% yield) of 2-[(4-amino-5- benzoyl-thiazol-2-yl)-(3-pyridyl)amino]propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 150 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.15 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 ml/min; temperature: 25? C.; UV: 254 nm 80 07 Intermediate 96; rac-2- bromo- propanamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.06 (q, J = 6.25 Hz, 1 H), 7.25 (s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.40-7.46 (m, 2 H), 7.57- 7.67 (m, 5 H), 7.82-8.54 (m, 2 H). LC-MS (method 2) Rt = 1.20 min; MS (ESIpos): m/z = 463.4 [M + H].sup.+ preparative flash chromatography (method Z, 0-3%) 19% yield rac-2-(N-[4-amino-5-(4- bromobenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide

Example 81

rac-ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate

(199) ##STR00508##

(200) Ethyl 2-[4-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]phenoxy]acetate (18.54 g, 44.6 mmol; Intermediate 80) was dissolved in N,N-dimethylformamide (493 mL), followed by the addition of potassium carbonate (30.84 g, 223.1 mmol) and rac-2-bromopropanamide (8.14 g, 53.6 mmol). The reaction mixture was stirred at 90? C. for 1 h. After cooling down the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with saturated aqueous ammonium chloride solution and brine. Afterwards, the organic layer was filtrated by a water repellent filter circle (MN 617 WA) and evaporated to dryness. Water was added to the residue and the resulting suspension was dried by lyophilization to give 6.16 g (27% yield) of rac-ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]-acetate.

(201) .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm=1.16 (d, J=7.86 Hz, 3H), 1.18 (t, J=6.84 Hz, 3H), 4.15 (q, J=7.10 Hz, 2H), 4.80 (s, 2H), 5.06 (q, J=6.25 Hz, 1H), 6.91 (d, J=8.87 Hz, 2H), 7.25 (s, 1H), 7.33 (t, J=8.74 Hz, 2H), 7.47 (d, J=8.87 Hz, 2H), 7.58 (s, 1H), 7.64 (dd, J=8.87, 5.07 Hz, 2H), 8.15 (br s, 2H).

(202) LC-MS (method 2) Rt=1.09 min; MS (ESIpos): m/z=487.5 [M+H].sup.+

Example 81.1 and 81.2

(R)-ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate and (S)-ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate

Example 81.1

ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate (enantiomer 1)

(203) ##STR00509##

(204) HPLC separation of rac-ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate (6.16 g, 12.66 mmol; Example 81) on a chiral column gave 2.50 g (39% yield) of ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate, enantiomer 1.

(205) Preparative Chiral HPLC

(206) Labomatic HD3000, Knauer Pump 100, Labcol Vario 4000 Plus, Knauer DAD 2600; column: Amylose SB 5? 250?50 mm Nr.34; Eluent A: hexane; Eluent B: ethanol; isocratic: 70% A+30% B; flow 150.0 mL/min; UV @ 254 nm

(207) Analytical chiral HPLC: Rt=7.31 min

(208) Instrument: Agilent HPLC 1260; column: Amylose SB 3? 100?4, 6 mm; Eluent A: hexane; Eluent B: ethanol; isocratic: 70% A+30% B; flow 1.4 mL/min; temperature: 25? C.; DAD 254 nm

Example 81.2

ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate (enantiomer 2)

(209) ##STR00510##

(210) HPLC separation of rac-ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate (6.16 g, 12.66 mmol; Example 81) on a chiral column gave 2.60 g (40% yield) of ethyl 2-[4-[4-amino-2-(4-fluoro-N-[2-amino-1-methyl-2-oxo-ethyl]anilino)thiazole-5-carbonyl]phenoxy]acetate, enantiomer 2.

(211) Preparative Chiral HPLC

(212) Labomatic HD3000, Knauer Pump 100, Labcol Vario 4000 Plus, Knauer DAD 2600; column: Amylose SB 5? 250?50 mm Nr.34; Eluent A: hexane; Eluent B: ethanol; isocratic: 70% A+30% B; flow 150.0 mL/min; UV @ 254 nm

(213) Analytical chiral HPLC: Rt=10.17 min

(214) Instrument: Agilent HPLC 1260; column: Amylose SB 3? 100?4, 6 mm; Eluent A: hexane; Eluent B: ethanol; isocratic: 70% A+30% B; flow 1.4 mL/min; temperature: 25? C.; DAD 254 nm

Example 82

rac-2-(N-[4-amino-5-[4-[2-(isopropylamino)-2-oxo-ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

(215) ##STR00511##

(216) Rac-2-[4-[4-amino-2-(N-[2-amino-1-methyl-2-oxo-ethyl]-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]acetic acid (12 mg, 26 ?mol, intermediate 100) and isopropylamine (3 mg, 51 ?mol) were dissolved in dimethylformamide (0.4 mL). N,N-diisopropylethylamine (13 mg, 102 ?mol), 4-dimethylaminopyridine (0.2 mg, 1 ?mol) and HATU (19 mg, 51 ?mol) were added. The reaction mixture was stirred at rt for 2 h.

(217) The reaction mixture was filtrated and purified by RP-HPLC (method C, basic) to give 6 mg (42% yield) of the title compound.

(218) .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm=1.04-1.07 (m, 6H), 1.16 (d, J=7.35 Hz, 3H), 3.86-3.97 (m, 1H), 4.45 (s, 2H), 5.05 (q, J=6.34 Hz, 1H), 6.92 (d, J=8.87 Hz, 2H), 7.24 (s, 1H), 7.33 (t, J=8.87 Hz, 2H), 7.47 (d, J=8.87 Hz, 2H), 7.58 (s, 1H), 7.64 (dd, J=8.87, 5.07 Hz, 2H), 7.88 (br d, J=7.86 Hz, 1H), 8.13 (br s, 2H).

(219) LC-MS (method 2) Rt=1.00 min; MS (ESIpos): m/z=500.6 [M+H].sup.+

(220) The following examples were prepared from the starting materials stated in Table 7, below, using the procedure as for Example 82.

(221) The crude product was purified by method F (individual gradient given, depending on retention time in analytical HPLC) after filtration of the reaction mixture.

(222) TABLE-US-00007 TABLE 7 Examples 83-141 Example Chemical structure Starting Analytics/ number Compound name materials purification/yield 83 Intermediate 100, 1-(3- methylphenyl) methanamine LC-MS (method 3) Rt = 1.12 min; MS (ESIpos): m/z = 562.2 [M + H].sup.+ Method F: Prep_30-60% B 11% yield rac-2-(N-[4-amino-5-[4-[2-(m-tolylmethylamino)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 84 Intermediate 100, 1-(2- methylphenyl) methanamine LC-MS (method 3) Rt = 1.11 min; MS (ESIpos): m/z = 562.1 [M + H].sup.+ Method F: Prep_30-60% B 11% yield rac-2-(N-[4-amino-5-[4-[2-(o-tolylmethylamino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 85 Intermediate 100, 1-(3- chlorophenyl) methanamine LC-MS(method 3) Rt = 1.13 min; MS (ESIpos): m/z = 582.1 [M + H].sup.+ Method F: Prep_35-65% B 10% yield rac-2-(N-(4-amino-5-[4-[2-1(3-chlorophenyl)methylamino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 86 Intermediate 100, 1- methylpiperazine LC-MS (method 3) Rt = 0.88 min; MS (ESIpos): m/z = 541.1 [M + H].sup.+ Method F: Prep_20-50% B 12% yield rac-2-(N-[4-amino-5-[4-[2-(4-methylpiperazin-1-yl)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 87 Intermediate 100, m-toluidine LC-MS (method 3) Rt = 1.15 min; MS (ESIpos): m/z = 548.1 [M + H].sup.+ Method F: Prep_40-70% B 12% yield rac-2-(N-[4-amino-5-[4-[2-(3-methylanilino)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 88 Intermediate 100, morpholine LC-MS (method 3) Rt = 0.90 min; MS (ESIpos): m/z = 528.1 [M + H].sup.+ Method F: Prep_20-50% B 13% yield rac-2-(N-[4-amino-5-[4-(2-morpholino-2-oxo-ethoxy) benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 89 Intermediate 100, 2-(piperidin-1- yl)ethanamine LC-MS (method 3) Rt = 1.07 min; MS (ESIpos): m/z = 569.2 [M + H].sup.+ Method F: Prep_30-60% B 5% yield rac-2-(N-[4-amino-5-[4-[2-oxo-2-[2-(1-piperidyl)ethylamino]ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 90 Intermediate 100, 4- benzylpiperidine LC-MS (method 3) Rt = 1.26 min; MS (ESIpos): m/z = 616.2 [M + H].sup.+ Method F: Prep_45-75% B 5% yield rac-2-(N-[4-amino-5-[4-[2-(4-benzyl-1-piperidyl)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 91 0 Intermediate 100, 2- methoxyethanamine LC-MS (method 3) Rt = 0.90 min; MS (ESIpos): m/z = 516.1 [M + H].sup.+ Method F: Prep_20-50% B 5% yield rac-2-(N-(4-amino-5-[4-[2-(2-methoxyethylamino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 92 Intermediate 100, 4- aminobenzonitrile LC-MS (method 3) Rt = 1.06 min; MS (ESIpos): m/z = 559.1 [M + H].sup.+ Method F: Prep_30-60% B 9% yield rac-2-(N-[4-amino-5-[4-[2-(4-cyanoanilino)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 93 Intermediate 100, N-methylprop-2- yn-1-amine LC-MS (method 3) Rt = 0.96 min; MS (ESIpos): m/z = 510.1 [M + H].sup.+ Method F: Prep_25-55% B 9% yield rac-2-(N-[4-amino-5-[4-[2-[methyl(prop-2-ynyl)amino]-2- oxo-ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 94 Intermediate 100, 1-(2- methoxyphenyl) methanamine LC-MS (method 3) Rt = 1.08 min; MS (ESIpos): m/z = 578.1 [M + H].sup.+ Method F: Prep_30-60% B 13% yield rac-2-(N-[4-amino-5-[4-[2-[(2-methoxyphenyl)methylamino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 95 Intermediate 100, 1-(3- methoxyphenyl) methanamine LC-MS (method 3) Rt = 1.06 min; MS (ESIpos): m/z = 578.1 [M + H].sup.+ Method F: Prep_30-60% B 10% yield rac-2-(N-(4-amino-5-[4-[2-[(3-methoxyphenyl)methylamino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 96 Intermediate 100, 1-(2- fluorophenyl) methanamine LC-MS (method 3) Rt = 1.07 min; MS (ESIpos): m/z = 566.1 [M + H].sup.+ Method F: Prep_30-60% B 10% yield rac-2-(N-[4-amino-5-[4-[2-[(2-fluorophenyl)methylamino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 97 Intermediate 100, 1-(4- fluorophenyl) methanamine LC-MS (method 3) Rt = 1.07 min; MS (ESIpos): m/z = 566.1 [M + H].sup.+ Method F: Prep_30-60% B 13% yield rac-2-(N-[4-amino-5-[4-[2-[(4-fluorophenyl)methylamino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 98 Intermediate 100, 1-(1H- benzimidazol-2- yl)methanamine LC-MS (method 3) Rt = 0.93 min; MS (ESIpos): m/z = 588.1 [M + H].sup.+ Method F: Prep_25-55% B 7% yield rac-2-(N-[4-amino-5-[4-[2-(1H-benzimidazol-2- ylmethylamino)-2-oxo-ethoxy]benzoyl]thiazol-2-yl]- 4-fluoro-anilino)propanamide 99 Intermediate 100, 2,2,2- trifluoroethanamine LC-MS (method 3) Rt = 1.00 min; MS (ESIpos): m/z = 540.0 [M + H].sup.+ Method F: Prep_25-55% B 21% yield rac-2-(N-[4-amino-5-[4-[2-oxo-2-(2,2,2-trifluoroethylamino) ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 100 Intermediate 100, N-methylpyridin- 2-amine LC-MS (method 3) Rt = 0.99 min; MS (ESIpos): m/z = 549.1 [M + H].sup.+ Method F: Prep_25-55% B 9% yield rac-2-(N-[4-amino-5-[4-[2-[methyl(2-pyridyl)amino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 101 0 Intermediate 100, N,1- dimethylpiperidin- 4-amine LC-MS (method 3) Rt = 0.94 min; MS (ESIpos): m/z = 569.1 [M + H].sup.+ Method F: Prep_25-55% B 23% yield rac-2-(N-[4-amino-5-[4-[2-[methyl-(1-methyl-4-piperidyl)amino]- 2-oxo-ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 102 Intermediate 100, O-methylhydroxy- lamine LC-MS (method 3) Rt = 0.90 min; MS (ESIpos): m/z = 488.1 [M + H].sup.+ Method F: Prep_20-50% B 22% yield rac-2-(N-[4-amino-5-[4-[2-(methoxyamino)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 103 Intermediate 100, 5-methyl-1,2- oxazoi-3-amine LC-MS (method 3) Rt = 0.99 min; MS (ESIpos): m/z = 539.1 [M + H].sup.+ Method F: Prep_25-55% B 7% yield rac-2-(N-[4-amino-5-[4-[2-[(5-methylisoxazol-3-yl)amino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 104 Intermediate 100, ethanamine LC-MS (method 3) Rt = 0.92 min; MS (ESIpos): m/z = 486.0 [M + H].sup.+ Method F: Prep_25-55% B 33% yield rac-2-(N-[4-amino-5-[4-[2-(ethylamino)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 105 Intermediate 100, p-toluidine LC-MS (method 3) Rt = 1.15 min; MS (ESIpos): m/z = 548.1 [M + H].sup.+ Method F: Prep_40-70% B 37% yield rac-2-(N-[4-amino-5-[4-[2-(4-methylanilino)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 106 Intermediate 100, cyclohexanamine LC-MS (method 3) Rt = 1.12 min; MS (ESIpos): m/z = 540.1 [M + H].sup.+ Method F: Prep_35-65% B 11% yield rac-2-(N-(4-amino-5-[4-[2-(cyclohexylamino)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 107 Intermediate 100, 3- aminobenzamide LC-MS (method 3) Rt = 0.89 min; MS (ESIpos): m/z = 577.1 [M + H].sup.+ Method F: Prep_20-50% B 20% yield rac-3-[[2-[4-[4-amino-2-(N-[2-amino-1-methyl-2-oxo-ethyl]-4-fluoro- anilino)thiazole-5-carbonyl]phenoxy]acetyl]amino]benzamide 108 Intermediate 100, quinolin-6-amine LC-MS (method 3) Rt = 1.01 min; MS (ESIpos): m/z = 585.1 [M + H].sup.+ Method F: Prep_25-55% B 30% yield rac-2-(N-(4-amino-5-[4-[2-oxo-2-(6-quinolylamino)ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 109 Intermediate 100, 4- aminobenzamide LC-MS (method 3) Rt = 1.01 min; MS (ESIpos): m/z = 577.1 [M + H].sup.+ Method F: Prep_20-50% B 7% yield rac-4-[[2-[4-[4-amino-2-(N-[2-amino-1-methyl-2-oxo- ethyl]-4-fluoro-anilino)thiazole-5- carbonyl]phenoxy]acetyl]amino]benzamide 110 Intermediate 100, L-prolinamide LC-MS (method 3) Rt = 0.82 min; MS (ESIpos): m/z = 555.1 [M + H].sup.+ Method F: Prep_15-45% B 15% yield (2S)-1-[2-[4-[4-amino-2-(N-[2-amino-(1RS)-methyl-2- oxo-ethyl]-4-fluoro-anilino)thiazole-5- carbonyl]phenoxy]acetyl]pyrrolidine-2-carboxamide (mixture of two diastereomers) 111 0 Intermediate 100, N- methylethanamine LC-MS (method 3) Rt = 0.96 min; MS (ESIpos): m/z = 500.1 [M + H].sup.+ Method F: Prep_25-55% B 23% yield rac-2-(N-[4-amino-5-[4-[2-[ethyl(methyl)amino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 112 Intermediate 100, 3-methyl-1,2- oxazol-5-amine LC-MS (method 3) Rt = 0.80 min; MS (ESIpos): m/z = 539.1 [M + H].sup.+ Method F: Prep_10-40% B 4% yield rac-2-(N-(4-amino-5-[4-[2-[(3-methylisoxazol-5-yl)amino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 113 Intermediate 100, N,N,N- trimethylpropane- 1,3-diamine LC-MS (method 3) Rt = 1.02 min; MS (ESIpos): m/z = 557.2 [M + H].sup.+ Method F: Prep_25-55% B 12% yield rac-2-(N-(4-amino-5-[4-[2-[3-(dimethylamino)propyl-methyl-amino]- 2-oxo-ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 114 Intermediate 100, 1-(piperazin-1- yl)ethanone LC-MS (method 3) Rt = 0.84 min; MS (ESIpos): m/z = 569.1 [M + H].sup.+ Method F: Prep_15-45% B 14% yield rac-2-(N-[5-[4-[2-(4-acetylpiperazin-1-yl)-2-oxo-ethoxy]benzoyl]- 4-amino-thiazol-2-yl]-4-fluoro-anilino)propanamide 115 Intermediate 100, 1-(pyridin-3-yl) methanamine LC-MS (method 3) Rt = 0.90 min; MS (ESIpos): m/z = 549.1 [M + H].sup.+ Method F: Prep_20-50% B 4% yield rac-2-(N-[4-amino-5-[4-[2-oxo-2-(3-pyridylmethylamino)ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 116 Intermediate 100, rac-3- aminopropane- 1,2-diol LC-MS (method 3) Rt = 0.77 min; MS (ESIpos): m/z = 532.0 [M + H].sup.+ Method F: Prep_10-40% B 12% yield 2-(N-[4-amino-5-(4-[2-(2,3-dihydroxypropylamino)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (mixture of stereoisomers) 117 Intermediate 100, 4-methoxyaniline LC-MS (method 3) Rt = 1.07 min; MS (ESIpos): m/z = 564.1 [M + H].sup.+ Method F: Prep_30-60% B 21% yield rac-2-(N-[4-amino-5-[4-[2-(4-methoxyanilino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 118 Intermediate 100, N-methyl-1- phenylmethanamine LC-MS (method 3) Rt = 1.10 min; MS (ESIpos): m/z = 562.1 [M + H].sup.+ Method F: Prep_30-60% B 14% yield rac-2-(N-[4-amino-5-[4-[2-[benzyl(methyl)amino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 119 Intermediate 100, 4-chloroaniline LC-MS (method 3) Rt = 1.18 min; MS (ESIpos): m/z = 568.1 [M + H].sup.+ Method F: Prep_40-70% B 22% yield rac-2-(N-[4-amino-5-[4-[2-(4-chloroanilino)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 120 Intermediate 100, 1-(2- chlorophenyl) methanamine LC-MS (method 3) Rt = 1.13 min; MS (ESIpos): m/z = 582.1 [M + H].sup.+ Method F: Prep_35-65% B 12% yield rac-2-(N-[4-amino-5-[4-[2-[(2-chlorophenyl)methylamino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 121 0 Intermediate 100, 1-(4- chlorophenyl) methanamine LC-MS (method 3) Rt = 1.13 min; MS (ESIpos): m/z = 582.1 [M + H].sup.+ Method F: Prep_35-65% B 15% yield rac-2-(N-(4-amino-5-[4-[2-[(4-chlorophenyl)methylamino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 122 Intermediate 100, 4-fluoroaniline LC-MS (method 3) Rt = 1.10 min; MS (ESIpos): m/z = 552.1 [M + H].sup.+ Method F: Prep_30-60% B 24% yield rac-2-(N-[4-amino-5-[4-[2-(4-fluoroanilino)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 123 Intermediate 100, azepane LC-MS (method 3) Rt = 1.08 min; MS (ESIpos): m/z = 540.1 [M + H].sup.+ Method F: Prep_30-60% B 6% yield rac-2-(N-[4-amino-5-[4-[2-(azepan-1-yl)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino) propanamide 124 Intermediate 100, 1-(4- methoxyphenyl) methanamine LC-MS (method 3) Rt = 1.05 min; MS (ESIpos): m/z = 578.1 [M + H].sup.+ Method F: Prep_30-60% B 8% yield rac-2-(N-[4-amino-5-[4-[2-[(4-methoxyphenyl)methylamino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 125 Intermediate 100, rac-1- phenylethanamine LC-MS (method 3) Rt = 1.10 min; MS (ESIpos): m/z = 562.1 [M + H].sup.+ Method F: Prep_30-60% B 9% yield 2-(N-[4-amino-5-[4-[2-oxo-2-(1-phenylethylamino)ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (mixture of stereoisomers) 126 Intermediate 100, 1-(4- methylphenyl) methanamine LC-MS (method 3) Rt = 1.12 min; MS (ESIpos): m/z = 562.1 [M + H].sup.+ Method F: Prep_35-65% B 13% yield rac-2-(N-[4-amino-5-[4-[2-oxo-2-(p-tolylmethylamino)ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 127 Intermediate 100, N-methyl-2- phenylethanamine LC-MS (method 3) Rt = 1.11 min; MS (ESIpos): m/z = 576.1 [M + H].sup.+ Method F: Prep_30-60% B 23% yield rac-2-(N-[4-amino-5-[4-[2-[methyl(2-phenylethyl)amino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 128 Intermediate 100, rac-3- methylpiperidine LC-MS (method 3) Rt = 1.11 min; MS (ESIpos): m/z = 540.1 [M + H].sup.+ Method F: Prep_30-60% B 4% yield 2-(N-[4-amino-5-[4-[2-(3-methyl-1-piperidyl)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (mixture of stereoisomers) 129 Intermediate 100, 4- methylpiperidine LC-MS (method 3) Rt = 1.11 min; MS (ESIpos): m/z = 540.1 [M + H].sup.+ Method F: Prep_30-60% B 5% yield rac-2-(N-[4-amino-5-(4-[2-(4-methyl-1-piperidyl)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 130 Intermediate 100, N-(4- aminophenyl) acetamide LC-MS (method 3) Rt = 0.92 min; MS (ESIpos): m/z = 591.1 [M + H].sup.+ Method F: Prep_25-55% B 25% yield rac-2-(N-[5-[4-[2-(4-acetamidoanilino)-2-oxo-ethoxy]benzoyl]-4- amino-thiazol-2-yl]-4-fluoro-anilino)propanamide 131 0 Intermediate 100, 1H-pyrazolo[3,4- d]pyrimidin-4- amine LC-MS (method 3) Rt = 0.80 min; MS (ESIpos): m/z = 576.1 [M + H].sup.+ Method F: Prep_10-40% B 7% yield rac-2-(N-[4-amino-5-[4-[2-oxo-2-(1H-pyrazolo[3,4-d]pyrimidin-4- ylamino)ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 132 Intermediate 100, cyclopentanamine LC-MS (method 3) Rt = 1.06 min; MS (ESIpos): m/z = 526.1 [M + H].sup.+ Method F: Prep_30-60% B 8% yield rac-2-(N-[4-amino-5-[4-[2-(cyclopentylamino)-2-oxo-ethoxy] benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 133 Intermediate 100, 1,2,3,4- tetrahydroiso- quinoline LC-MS (method 3) Rt = 1.13 min; MS (ESIpos): m/z = 574.1 [M + H].sup.+ Method F: Prep_35-65% B 8% yield rac-2-(N-[4-amino-5-[4-[2-(3,4-dihydro-1H-isoquinolin- 2-yl)-2-oxo-ethoxy]benzoyl]thiazol-2-yl]-4-fluoro- anilino)propanamide 134 Intermediate 100, isoindoline LC-MS (method 3) Rt = 1.09 min; MS (ESIpos): m/z = 560.1 [M + H].sup.+ Method F: Prep_30-60% B 6% yield rac-2-(N-[4-amino-5-[4-(2-isoindolin-2-yl-2-oxo- ethoxy)benzoyl]thiazol-2-yl]-4-fluoro- anilino)propanamide 135 Intermediate 100, 1-(2-furyl)-N- methylmethanamine LC-MS (method 3) Rt = 1.04 min; MS (ESIpos): m/z = 552.1 [M + H].sup.+ Method F: Prep_30-60% B 12% yield rac-2-(N-[4-amino-5-[4-[2-[2-furylmethyl(methyl)amino]-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 136 Intermediate 100, N,N- dimethylpiperidin- 4-amine LC-MS (method 3) Rt = 0.97 min; MS (ESIpos): m/z = 569.2 [M + H].sup.+ Method F: Prep_25-55% B 13% yield rac-2-(N-[4-amino-5-[4-[2-[4-(dimethylamino)-1-piperidyl]- 2-oxo-ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 137 Intermediate 100, N-methyl-1- (pyridin-3- yl)methanamine LC-MS (method 3) Rt = 0.92 min; MS (ESIpos): m/z = 563.1 [M + H].sup.+ Method F: Prep_25-55% B 24% yield rac-2-(N-[4-amino-5-[4-[2-[methyl(3-pyridylmethyl)amino]-2- oxo-ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 138 Intermediate 100, N,2- dimethylaniline LC-MS (method 3) Rt = 1.13 min; MS (ESIpos): m/z = 562.1 [M + H].sup.+ Method F: Prep_35-65% B 13% yield rac-2-(N-[4-amino-5-[4-[2-(N,2-dimethylanilino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 139 intermediate 100, N,4- dimethylaniline LC-MS (method 3) Rt = 1.16 min; MS (ESIpos): m/z = 562.1 [M + H].sup.+ Method F: Prep_40-70% B 26% yield rac-2-(N-[4-amino-5-[4-[2-(N,4-dimethylanilino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 140 Intermediate 100, N,3- dimethylaniline LC-MS (method 3) Rt = 1.15 min; MS (ESIpos): m/z = 562.1 [M + H].sup.+ Method F: Prep_40-70% B 31% yield rac-2-(N-[4-amino-5-[4-[2-(N,3-dimethylanilino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 141 0 Intermediate 100, 2,2- dimethylpropan- 1-amine LC-MS (method 3) Rt = 1.08 min; MS (ESIpos): m/z = 528.1 [M + H].sup.+ Method F: Prep_30-60% B 4% yield rac-2-(N-[4-amino-5-[4-[2-(2,2-dimethylpropylamino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

Example 142

2-(N-[5-[4-[2-(1-adamantylamino)-2-oxo-ethoxy]benzoyl]-4-amino-thiazol-2-yl]-4-fluoro-anilino)propanamide (single stereoisomer)

(223) ##STR00571##

(224) 2-[4-[4-amino-2-(N-[2-amino-1-methyl-2-oxo-ethyl]-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]acetic acid (enantiomer 2) (30 mg, 65 ?mol; Intermediate 100.2) and adamantan-1-amine (20 mg, 131 ?mol) were dissolved in dimethylformamide (0.5 mL). N,N-diisopropylethylamine (25 mg, 196 ?mol), 4-dimethylaminopyridine (0.4 mg, 3 ?mol) and HATU (50 mg, 131 ?mol) were added. The reaction mixture was stirred overnight at rt.

(225) The reaction mixture was filtrated and purified by RP-HPLC (method E, basic) to give 12 mg (29% yield) of the title compound.

(226) .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm=1.16 (d, J=7.60 Hz, 3H), 1.59-1.63 (m, 6H), 1.92 (d, J=2.53 Hz, 6H), 2.00 (br d, J=1.77 Hz, 3H), 4.41 (s, 2H), 5.00-5.13 (m, 1H), 6.89 (d, J=8.87 Hz, 2H), 7.24 (s, 1H), 7.30-7.36 (m, 3H), 7.46 (d, J=8.87 Hz, 2H), 7.57 (s, 1H), 7.64 (dd, J=9.00, 5.20 Hz, 2H), 8.11 (br s, 2H).

(227) LC-MS (method 2) Rt=1.32 min; MS (ESIpos): m/z=592.5 [M+H].sup.+

(228) The following examples were prepared from the starting materials stated in Table 8, below, using the procedure as for Example 142.

(229) TABLE-US-00008 TABLE 8 Examples 143-155 Example Chemical structure Starting number Compound name materials Analytics/purification/yield 143 Intermediate 100.2; 1- adamantyl- methanamine .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 1.31 (d, J = 2.03 Hz, 6 H), 1.44- 1.48 (m, 3 H), 1.55-1.61 (m, 3 H), 1.80 (br s, 3 H), 2.78 (d, J = 6.59 Hz, 2 H), 4.54 (s, 2 H), 5.02-5.11 (m, 1 H), 6.94 (d, J = 8.87 Hz, 2 H), 7.25 (s, 1 H), 7.32 (t, J = 8.74 Hz, 2 H), 7.48 (d, J = 8.62 Hz, 2 H), 7.57 (s, 1 H), 7.63 (dd, J = 8.87, 4.82 Hz, 2 H), 7.82 (t, J = 6.21 Hz, 1 H), 8.19 (br s, 2 H). LC-MS (method 1) Rt = 1.29 min; MS (ESIpos): m/z = 606.5 [M + H].sup.+ 2-(N-[5-[4-[2-(1- RP-HPLC (method E, basic) adamantylmethylamino)-2- 41% yield oxo-ethoxy]benzoyl]-4- amino-thiazol-2-yl]-4-fluoro- anilino)propanamide(single stereoisomer) 144 Intermediate 100.2; 2-(1- adamantyl) ethanamine .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.13-1.17 (m, 3 H), 1.17- 1.24 (m, 2 H), 1.44 (d, J = 2.03 Hz, 6 H), 1.55-1.61 (m, 3 H), 1.62- 1.68 (m, 3 H), 1.87-1.91 (m, 3 H), 3.07-3.15 (m, 2 H), 4.45 (s, 2 H), 5.01-5.10 (m, 1 H), 6.92 (d, J = 8.87 Hz, 2 H), 7.24 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.47 (d, J = 8.87 Hz, 2 H), 7.57 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 8.30 (br s, 2 H), 7.97 (t, J = 5.83 Hz, 1 H). LC-MS (method 1) Rt = 1.40 min; MS (ESIpos): m/z = 620.6 [M + H].sup.+ RP-HPLC (method E, basic) 2-(N-[5-[4-[2-2-(1- adamantyl)ethylamino]-2- oxo-ethoxy]benzoyl]-4- amino-thiazol-2-yl]-4-fluoro- anilino)propanamide(single stereoisomer) 145 Intermediate 100.2; 4-chloroaniline .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 4.73 (s, 2 H), 5.00-5.11 (m, 1 H), 6.98 (d, J = 8.87 Hz, 2 H), 7.24 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.38 (d, J = 8.87 Hz, 2 H), 7.49 (d, J = 8.87 Hz, 2 H), 7.57 (s, 1 H), 7.61-7.67 (m, 4 H), 8.08 (br s, 2 H), 10.24 (s, 1 H). LC-MS (method 1) Rt = 1.20 min; MS (ESIpos): m/z = 568.4 [M + H].sup.+ RP-HPLC (method D, basic) 59% yield 2-(N-[4-amino-5-[4-[2-(4- chloroanilino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]- 4-fluoro- anilino)propanamide(single stereoisomer) 146 Intermediate 100.2; 4- amino- benzamide .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 4.76 (s, 2 H), 5.01-5.09 (m, 1 H), 6.99 (d, J = 8.87 Hz, 2 H), 7.24 (s, 1 H), 7.26 (br s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.49 (d, J = 8.62 Hz, 2 H), 7.58 (s, 1 H), 7.64 (dd, J = 9.00, 5.20 Hz, 2 H), 7.68 (d, J = 8.87 Hz, 2 H), 7.84 (d, J = 8.87 Hz, 2 H), 7.87-7.90 (m, 1 H), 8.10 (br s, 2 H), 10.31 (s, 1 H). LC-MS (method 1) Rt = 0.88 min; MS (ESIpos): m/z = 577.4 [M + H].sup.+ RP-HPLC (method C, basic) 48% yield 4-[[2-[4-[4-amino-2-(4- fluoro-N-[2-amino-1-methyl- 2-oxo-ethyl]anilino)thiazole- 5- carbonyl]phenoxy]acetyl] amino]benzamide(single stereoisomer) 147 Intermediate 100.2; rac-3- aminopropane- 1,2-diol .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 2.99-3.08 (m, 1 H), 3.24-3.30 (m, 4 H), 3.48-3.56 (m, 2 H), 4.49-4.53 (m, 2 H), 4.55-4.60 (m, 1 H), 4.75-4.85 (m, 1 H), 5.05 (br d, J = 7.10 Hz, 1 H), 6.92- 6.96 (m, 2 H), 7.24 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.48 (d, J = 8.62 Hz, 2 H), 7.58 (s, 1 H), 7.61-7.67 (m, 2 H), 7.93-7.99 (m, 1 H). LC-MS (method 1) Rt = 0.78 min; MS (ESIpos): m/z = 532.4 [M + H].sup.+ RP-HPLC (method B, basic) 54% yield 2-(N-[4-amino-5-[4-[2- ((2RS),3- dihydroxypropylamino)-2- oxo-ethoxy]benzoyl]thiazol- 2-yl]-4-fluoro- anilino)propanamide (mixture of two diastereomers) 148 Intermediate 100.2; 2-(piperidin-1- yl)ethanamine (salt with hydrogen chloride) .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 1.28-1.46 (m, 7 H), 2.22-2.30 (m, 6 H), 3.16-3.24 (m, 2 H), 4.42-4.56 (m, 2 H), 4.96-5.19 (m, 1 H), 6.90-6.95 (m, 2 H), 7.23-7.26 (m, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.45-7.50 (m, 2 H), 7.56-7.59 (m, 1 H), 7.61- 7.66 (m, 2 H), 7.87 (t, J = 5.32 Hz, 1 H). LC-MS (method 1) Rt = 0.77 min; MS (ESIpos): m/z = 569.5 [M + H].sup.+ RP-HPLC (method C, basic) 54% yield 2-(N-[4-amino-5-[4-[2-oxo- 2-[2-(1- piperidyl)ethylamino]ethoxy] benzoyl]thiazol-2-yl]-4- fluoro-anilino)propanamide (single stereoisomer) 149 Intermediate 100.2; ammonia in dioxane .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 4.44 (s, 2 H), 5.05 (q, J = 6.84 Hz, 1 H), 6.92 (d, J = 8.87 Hz, 2 H), 7.24 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.38 (br s, 1 H), 7.47 (d, J = 8.87 Hz, 2 H), 7.52 (br s, 1 H), 7.58 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 8.07 (br s, 2 H). LC-MS (method 1) Rt = 0.82 min; MS (ESIpos): m/z = 458.3 [M + H].sup.+ RP-HPLC (method B, basic) 60% yield 2-(N-[4-amino-5-[4-(2- amino-2-oxo- ethoxy)benzoyl]thiazol-2-yl]- 4-fluoro- anilino)propanamide(single stereoisomer) 150 (R)-2-(N-[4-amino-5-[4-[2- and (methylamino)-2-oxo- 151 ethoxy]benzoyl]thiazol-2-yl]- 4-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-[4-[2- (methylamino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]- 4-fluoro- anilino)propanamide 150 Intermediate 100.1; methanamine in tetrahydrofurane 2.0M .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 2.63 (d, J = 4.82 Hz, 3 H), 4.47 (s, 2 H), 5.05 (q, J = 6.00 Hz, 1 H), 6.93 (d, J = 8.87 Hz, 2 H), 7.24 (s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.48 (d, J = 8.62 Hz, 2 H), 7.58 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 8.15 (br s, 2 H), 8.00-8.04 (m, 1 H). LC-MS (method 1) Rt = 0.88 min; MS (ESIpos): m/z = 472.3 [M + H].sup.+ RP-HPLC (method C, basic) 64% yield 2-(N-[4-amino-5-[4-[2- (methylamino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]- 4-fluoro- anilino)propanamide (enantiomer 1) 151 0 Intermediate 100.2; methanamine in tetrahydrofurane 2.0M .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 2.63 (d, J = 4.82 Hz, 3 H), 4.47 (s, 2 H), 5.05 (q, J = 7.35 Hz, 1 H), 6.93 (d, J = 8.87 Hz, 2 H), 7.25 (s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.48 (d, J = 8.62 Hz, 2 H), 7.58 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 8.07 (br s, 2 H), 7.99-8.05 (m, 1 H). LC-MS (method 1) Rt = 0.88 min; MS (ESIpos): m/z = 472.3 [M + H].sup.+ RP-HPLC (method C, basic) 29% yield 2-(N-[4-amino-5-[4-[2- (methylamino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]- 4-fluoro- anilino)propanamide (enantiomer 2) 152 (R)-2-(N-[4-amino-5-[4-[2- and (isopropylamino)-2-oxo- 153 ethoxy]benzoyl]thiazol-2-yl]- 4-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-[4-[2- (isopropylamino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]- 4-fluoro- anilino)propanamide 152 Intermediate 100.1; propan-2-amine .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.04-1.08 (m, 6 H), 1.16 (d, J = 7.35 Hz, 3 H), 3.86-3.96 (m, 1 H), 4.45 (s, 2 H), 5.05 (br q, J = 7.10 Hz, 1 H), 6.92 (d, J = 8.87 Hz, 2 H), 7.24 (s, 1 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.47 (d, J = 8.87 Hz, 2 H), 7.57 (s, 1 H), 7.64 (dd, J = 9.00, 5.20 Hz, 2 H), 8.08 (br s, 2 H), 7.87 (brd, J = 8.11 Hz, 1 H). LC-MS (method 1) Rt = 1.00 min; MS (ESIpos): m/z = 500.4 [M + H].sup.+ RP-HPLC (method C, basic) 75% yield 2-(N-[4-amino-5-[4-[2- (isopropylamino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]- 4-fluoro- anilino)propanamide (enantiomer 1) 153 Intermediate 100.2; propan-2-amine .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.06 (d, J = 6.59 Hz, 6 H), 1.16 (d, J = 7.35 Hz, 3 H), 3.87- 3.96 (m, 1 H), 4.45 (s, 2 H), 5.05 (q, J = 7.86 Hz, 1 H), 6.92 (d, J = 8.87 Hz, 2 H), 7.24 (s, 1 H), 7.33 (t, J = 8. 87 Hz, 2 H), 7.47 (d, J = 8.87 Hz, 2 H), 7.57 (s, 1 H), 7.64 (dd, J = 9.00, 5.20 Hz, 2 H), 8.06 (br s, 2 H), 7.87 (br d, J = 7.86 Hz, 1 H). LC-MS (method 1) Rt = 1.00 min; MS (ESIpos): m/z = 500.4 [M + H].sup.+ RP-HPLC (method C, basic) 72% yield 2-(N-[4-amino-5-[4-[2- (isopropylamino)-2-oxo- ethoxy]benzoyl]thiazol-2-yl]- 4-fluoro- anilino)propanamide (enantiomer 2) 154 Intermediate 82; propan-2-amine .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ? ppm = 0.94 (d, J = 6.59 Hz, 6 H), 1.16 (d, J = 7.35 Hz, 3 H), 1.43 (s, 6 H), 3.83-3.96 (m, 1 H), 4.99- 5.11 (m, 1 H), 6.79 (d, J = 8.62 Hz, 2 H), 7.24 (s, 1 H), 7.32 (t, J = 8.87 Hz, 2 H), 7.42 (d, J = 8.62 Hz, 2 H), 7.57 (s, 1 H), 7.63 (dd, J = 8.74, 5.20 Hz, 2 H), 7.75 (d, J = 8.11 Hz, 1 H), 7.80-8.50 (m, 2 H). LC-MS (method 1) Rt = 1.10 min; MS (ESIpos): m/z = 528.4 [M + H].sup.+ RP-HPLC (method D, basic) 23% yield rac-2-[4-[4-amino-2-(N-(2- amino-1-methyl-2-oxo- ethyl)-4-fluoro- anilino)thiazole-5- carbonyl]phenoxy]-N- isopropyl-2-methyl- propanamide 155 Intermediate 82; ammonia .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 1.43 (s, 6 H), 4.99-5.11 (m, 1 H), 6.82 (d, J = 8.87 Hz, 2 H), 7.25 (br d, J = 7.86 Hz, 2 H), 7.33 (t, J = 8.87 Hz, 2 H), 7.44 (d, J = 8.62 Hz, 2 H), 7.50-7.52 (m, 1 H), 7.57-7.59 (m, 1 H), 7.64 (dd, J = 8.74, 5.20 Hz, 2 H), 7.82-8.34 (m, 2 H). LC-MS (method 1) Rt = 0.93 min; MS (ESIpos): m/z = 486.3 [M + H].sup.+ RP-HPLC (method C, basic) 42% yield rac-2-[4-[4-amino-2-(N-(2- amino-1-methyl-2-oxo- ethyl)-4-fluoro- anilino)thiazole-5- carbonyl]phenoxy]-2- methyl-propanamide

Example 156

rac-2-(N-(5-benzoyl-4-methyl-thiazol-2-yl)-4-fluoro-anilino)propanamide

(230) ##STR00585##

(231) [2-(4-fluoroanilino)-4-methyl-thiazol-5-yl]-phenyl-methanone (40 mg, 0.13 mmol; Intermediate 81) was dissolved in N,N-dimethylformamide (1.4 mL), followed by the addition of potassium carbonate (177 mg, 1.28 mmol) and rac-2-bromopropanamide (97 mg, 0.64 mmol). The reaction mixture was stirred at 90? C. for 1 h. The reaction mixture was filtrated and purified by RP-HPLC (method D, basic) to give 24 mg (48% yield) of the title compound.

(232) .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm=1.16 (d, J=7.35 Hz, 3H), 2.24-2.27 (m, 3H), 5.11 (q, J=7.35 Hz, 1H), 7.20 (s, 1H), 7.36 (t, J=8.87 Hz, 2H), 7.43-7.48 (m, 2H), 7.51-7.57 (m, 3H), 7.62 (s, 1H), 7.67 (dd, J=9.13, 5.07 Hz, 2H).

(233) LC-MS (method 2) Rt=1.16 min; MS (ESIpos): m/z=384.4 [M+H].sup.+

Example 157

rac-2-(N-[4-amino-5-(4-hydroxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

(234) ##STR00586##

(235) Rac-2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (100 mg, 204 ?mol, Example 158) was dissolved in ethanol (2.5 mL). Under nitrogen atmosphere was added palladium on carbon (325 mg, 10% purity, 306 ?mol; CAS-RN 7440-05-3) and then the nitrogen atmosphere was evacuated and was replaced with hydrogen. The mixture was stirred for 3.5 h at rt under hydrogen atmosphere. Further palladium on carbon (100 ?mol) was added and the mixture was stirred for a further 3 h at rt under hydrogen atmosphere. The reaction mixture was filtered over celite, washed with ethanol and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (method B, basic) to give 27 mg (31% yield) of the title compound.

(236) LC-MS (method 2) Rt=0.69 min; MS (ESIpos): m/z=401.2 [M+H].sup.+

(237) .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm=1.16 (d, J=7.35 Hz, 3H), 2.08 (s, 1H), 5.01-5.09 (m, 1H), 6.70-6.75 (m, 2H), 7.24 (s, 1H), 7.33 (t, J=8.87 Hz, 2H), 7.37-7.41 (m, 2H), 7.57 (s, 1H), 7.64 (dd, J=9.00, 4.94 Hz, 2H), 7.76-8.21 (m, 2H), 9.90 (br s, 1H)

Example 158

rac-2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

(238) ##STR00587##

(239) [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl][4-(benzyloxy)phenyl]methanone (610 mg, 1.45 mmol, Intermediate 77) was suspended in DMF (10 mL), rac-2-bromopropanamide (265 mg, 1.75 mmol) and potassium carbonate (301 mg, 2.18 mmol) were added. The reaction mixture was stirred for 3.5 h at rt. Further rac-2-bromopropanamide (265 mg, 1.75 mmol) and potassium carbonate (301 mg, 2.18 mmol) were added and the mixture was stirred overnight at rt. The mixture was treated with water and stirred for 30 min. The resulting precipitate was isolated by filtration, washed with water and dried to give 641 mg (98% purity, 88% yield) of the title compound.

(240) .sup.1H-NMR (400 MHz, DMSO-d6): ? ppm=1.16 (d, J=7.35 Hz, 3H), 5.02-5.09 (m, 1H), 5.11 (s, 2H), 7.00 (d, J=8.87 Hz, 2H), 7.25 (s, 1H), 7.31-7.45 (m, 7H), 7.46-7.50 (m, 2H), 7.57 (s, 1H), 7.64 (dd, J=8.87, 5.07 Hz, 2H), 7.78-8.38 (m, 2H).

(241) LC-MS (method 2) Rt=1.25 min; MS (ESIpos): m/z=491.3 [M+H].sup.+

(242) The following examples were prepared from the starting materials stated in Table 9, below, using the procedure as for Example 1.

(243) The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (methods X, Y or Z depending on polarity) after precipitation, extraction or filtration of the reaction mixture if necessary.

(244) Enantiomers were separated from their racemate by chiral HPLC using the column and solvent conditions stated.

(245) TABLE-US-00009 TABLE 9 Example 159-256 Example Chemical structure number Compound name Starting materials Analytics/purification/yield 159 Intermediate 101; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.04-5.08 (m, 1 H), 6.94 (t, J = 60 Hz, 1 H), 7.29-7.33 (m, 3 H), 7.60-7.65 (m, 3 H), 7.72 (d, J = 8.11 Hz, 1 H), 8.04 (dd, J = 7.98, 2.15 Hz, 1 H), 8.30 8.34 (m, 2 H), 8.76 (d, J = 1.52 Hz, 1 H). RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.00 min MS (ESIpos): m/z = 436.4 [M + H].sup.+ 48% yield rac-2-(N-[4-amino-5-[6- (difluoromethyl)pyridine-3- carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide 160 Intermediate 102; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.00-5.04 (m, 1 H), 7.31 (s, 1 H), 7.40-7.44 (m, 2 H), 7.55- 7.58 (m, 1 H), 7.63-7.67 (m, 2 H), 7.91 (dd, J = 6.84, 2.28 Hz, 1 H), 8.27-8.31 (m, 2 H), 8.60- 8.64 (m, 2 H). Isolated via precipitation LC-MS (method 2) Rt = 0.94 min MS (ESIpos): m/z = 420.3 [M + H].sup.+ 60% yield rac-2-(N-[4-amino-5- (pyridine-4- carbonyl)thiazol-2-yl]-3- chloro-4-fluoro- anilino)propanamide 160.1 (R)-2-(N-[4-amino-5- and (pyridine-4- 160.2 carbonyl)thiazol-2-yl]-3- chloro-4-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5- (pyridine-4- carbonyl)thiazol-2-yl]-3- chloro-4-fluoro- anilino)propanamide 160.1 0 Example 160 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.35 Hz, 4 H), 5.00-5.05 (m, 1 H), 7.31 (s, 1 H), 7.42 (d, J = 6.08 Hz, 2 H), 7.57 (m, 1 H), 7.62-7.67 (m, 2 H), 7.92 (dd, J = 6.84, 2.53 Hz, 1 H), 8.25-8.29 (m, 2 H), 8.63 (d, J = 5.83 Hz, 2 H). LC-MS (method 1) Rt = 0.86 min; MS (ESIpos): m/z = 420.3 [M + H].sup.+ 34% yield 2-(N-[4-amino-5-(pyridine- 4-carbonyl)thiazol-2-yl]-3- chloro-4-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 160.1 HPLC separation of rac-2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-3-chloro-4-fluoro- anilino)propanamide(560 mg, 1.33 mmol, Example 160) on a chiral column gave 190 mg (34% yield) of 2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-3-chloro-4-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC PrepCon Labomatic HPLC; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 120 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.23 min Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 160.2 Example 160 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.35 Hz, 4 H), 5.00-5.04 (m, 1 H), 7.31 (s, 1 H), 7.42 (d, J = 6.08 Hz, 2 H), 7.55- 7.59 (m, 1 H), 7.63-7.67 (m, 2 H), 7.92 (dd, J = 6.84, 2.53 Hz, 1 H), 8.24-8.30 (m, 2 H), 8.63 (d, J = 5.83 Hz, 2 H). LC-MS (method 1) Rt = 0.86 min; MS (ESIpos): m/z = 420.3 [M + H].sup.+ 33% yield 2-(N-[4-amino-5-(pyridine- 4-carbonyl)thiazol-2-yl]-3- chloro-4-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 160.2 HPLC separation of rac-2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-3-chloro-4-fluoro- anilino)propanamide(560 mg, 1.33 mmol, Example 160) on a chiral column gave 185 mg (33% yield) of 2-(N-[4-amino-5-(pyridine-4-carbonyl)thiazol-2-yl]-3-chloro-4-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC PrepCon Labomatic HPLC; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 120 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.67 min Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 161 Intermediate 103; rac-2- bromopropanamide .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.57 Hz, 3 H), 3.76 (s, 3 H), 5.00-5.04 (m, 1 H), 6.94 (d, J = 8.83 Hz, 2 H), 7.29 (s, 1 H), 7.50 (d, J = 8.83 Hz, 2 H), 7.57-7.59 (m, 1 H), 7.63 (s, 1 H), 7.64-7.68 (m, 1 H), 7.92 (m, 1 H), 8.12-8.17 (m, 2 H). LC-MS (method 2) Rt = 1.17 min Isolated via precipitation MS (ESIpos): m/z = 449.3 [M + H].sup.+ 70% yield rac-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-3-chloro-4-fluoro- anilino)propanamide 161.1 (R)-2-(N-[4-amino-5-(4- and methoxybenzoyl)thiazol-2- 161.2 yl]-3-chloro-4-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-3-chloro-4-fluoro- anilino)propanamide 161.1 Example 161 .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.57 Hz, 3 H), 3.76 (s, 3 H), 5.00-5.04 (m, 1 H), 6.94 (d, J = 8.83 Hz, 2 H), 7.29 (s, 1 H), 7.50 (d, J = 8.83 Hz, 2 H), 7.55-7.59 (m, 1 H), 7.63 (s, 1 H), 7.64-7.66 (m, 1 H), 7.90- 7.94 (m, 1 H), 8.14 (m, 2 H). LC-MS (method 1) Rt = 1.13 min MS (ESIpos): m/z = 449.4 [M + H].sup.+ [?].sub.D.sup.20 = 85? C. = 10.3 mg/mL in DMSO 31% yield 2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-3-chloro-4-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 161.1 HPLC separation of rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-3-chloro-4-fluoro- anilino)propanamide (1300 mg, 2.9 mmol, Example 161) on a chiral column followed by trituration in MTBE gave 401 mg (31% yield) of 2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2- yl]-3-chloro-4-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B; flow: 40 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.11 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% B + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 161.2 Example 161 .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.57 Hz, 3 H), 3.76 (s, 3 H), 5.00-5.04 (m, 1 H), 6.94 (d, J = 8.83 Hz, 2 H), 7.29 (s, 1 H), 7.50 (d, J = 8.83 Hz, 2 H), 7.58 (m, 1 H), 7.63 (s, 1 H), 7.66 (m, 1 H), 7.90-7.94 (m, 1 H), 8.10-8.16 (m, 2 H). LC-MS (method 1) Rt = 1.13 min; MS (ESIpos): m/z = 449.4 [M + H].sup.+ [?].sub.D.sup.20 = ?89? C. = 10.1 mg/mL in DMSO 29% yield 2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-3-chloro-4-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 161.2 HPLC separation of rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-3-chloro-4-fluoro- anilino)propanamide(1300 mg, 2.9 mmol, Example 161) on a chiral column followed by trituration in MTBE gave 375 mg (29% yield) of 2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2- yl]-3-chloro-4-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC; Column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% A + 40% B; flow: 40 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 5.48 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: 2-propanol; isocratic: 60% B + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 162 Intermediate 104; rac-2- bromopropanamide .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ? ppm = 1.13-1.20 (m, 3 H), 5.00- 5.12 (m, 1 H), 7.10 (d, J = 8.62 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.34 (t, J = 8.87 Hz, 2 H), 7.52- 7.68 (m, 3 H), 7.97-8.03 (m, 1 H), 8.06-8.35 (m, 1 H), 8.35- 8.42 (m, 1 H). LC-MS (method 2) Rt = 1.10 min Isolated via precipitation MS (ESIpos): m/z = 452.2 [M + H].sup.+ 61% yield rac-2-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide 162.1 (R)-2-(N-[4-amino-5-(6- and (difluoromethoxy)pyridine- 162.2 3-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide 162.1 Example 162 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.06 (m, 1 H), 7.11 (d, J = 8.62 Hz, 1 H), 7.26 (s, 1 H), 7.34 (m, 2 H), 7.59 (s, 1 H), 7.65 (br d, J = 3.80 Hz, 2 H), 7.71 (t, J = 72 Hz, 1 H), 8.00 (dd, J = 8.49, 2.41 Hz, 1 H), 8.19 (m, 1 H), 8.38 (d, J = 2.03 Hz, 1 H), 8.38 (m, 1 H). LC-MS (method 2) Rt = 1.13 min; MS (ESIpos): m/z = 452.3 [M + H].sup.+ [?].sub.D.sup.20 = ?71? C. = 8 mg/mL in DMSO 37% yield 2-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 162.1 HPLC separation of rac-2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide(105 mg, 0.23 mmol, Example 162) on a chiral column gave 39 mg (37% yield) of 2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 70% A + 30% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.07 min Instrument: Waters Alliance 2695; column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 70% A + 30% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 162.2 Example 162 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.02-5.08 (m, 1 H), 7.11 (d, J = 8.62 Hz, 1 H), 7.26 (s, 1 H), 7.34 (m, 2 H), 7.59 (s, 1 H), 7.65 (br d, J = 3.80 Hz, 2 H), 7.71 (t, J = 72 Hz, 1 H), 8.00 (dd, J = 8.49, 2.41 Hz, 1 H), 8.17-8.21 (m, 1 H), 8.38 (d, J = 2.03 Hz, 1 H), 8.38 (m, 1 H). LC-MS (method 2) Rt = 1.13 min; MS (ESIpos): m/z = 452.3 [M + H].sup.+ [?].sub.D.sup.20 = 74? C. = 8.7 mg/mL in DMSO 39% yield 2-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 162.2 HPLC separation of rac-2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide(105 mg, 0.23 mmol, Example 162) on a chiral column gave 41 mg (39% yield) of 2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; column: YMC Cellulose SB 5?, 250 ? 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 70% A + 30% B; flow: 50 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.40 min Instrument: Waters Alliance 2695; column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 70% A + 30% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 163 Intermediate 105; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.19 (d, J = 8 Hz, 3 H), 5.03 (q, J = 6.84 Hz, 1 H), 7.09-7.12 (m, 1 H), 7.30 (s, 1 H), 7.58 (m, 3 H), 7.71 (t, J = 72 Hz, 1 H), 7.79 (m, 1 H), 8.02 (dd, J = 8.49, 2.41 Hz, 1 H), 8.19-8.23 (m, 2 H), 8.41 (d, J = 2.03 Hz, 1 H). LC-MS (method 2) Rt = 1.15 min Biotage (method X) MS (ESIpos): m/z = 470.3 [M + H].sup.+ 56% yield rac-2-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]- 3,4-difluoro- anilino)propanamide 163.1 (R)-(N-[4-amino-5-[6- and (difluoromethoxy)pyridine- 163.2 3-carbonyl]thiazol-2-yl]- 3,4-difluoro- anilino)propanamide and (S)-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]- 3,4-difluoro- anilino)propanamide 163.1 Example 163 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.02-5.06 (m, 1 H), 7.11 (d, J = 8.62 Hz, 1 H), 7.26 (s, 1 H), 7.34 (m, 2 H), 7.59 (s, 1 H), 7.65 (br d, J = 3.80 Hz, 2 H), 7.71 (t, J = 72 Hz, 1 H), 8.00 (dd, J = 8.49, 2.41 Hz, 1 H), 8.17-8.22 (m, 1 H), 8.38 (d, J = 2.03 Hz, 1 H), 8.35- 8.37 (m, 1 H). LC-MS (method 2) Rt = 1.15 min 41% yield 2-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]- 3,4-difluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 163.1 HPLC separation of rac-2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]- 3,4-difluoro-anilino)propanamide(120 mg, 0.26 mmol, Example 163) on a chiral column gave 49 mg (41% yield) of 2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]-3,4- difluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-2; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 100 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 2.42 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 280 nm 163.2 00 Example 163 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 5.02-5.06 (m, 1 H), 7.12 (d, J = 8.62 Hz, 1 H), 7.30 (s, 1 H), 7.48-7.52 (m, 1 H), 7.58-7.62 (m, 2 H), 7.72 (t, J = 72 Hz, 1 H), 7.77-7.82 (m, 1 H), 8.02 (dd, J = 8.49, 2.41 Hz, 1 H), 8.20-8.25 (m, 2 H), 8.41 (d, J = 2.53 Hz, 1 H). LC-MS (method 2) Rt = 1.15 min 56% yield 2-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]- 3,4-difluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 163.2 HPLC separation of rac-2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]- 3,4-difluoro-anilino)propanamide(120 mg, 0.26 mmol, Example 163) on a chiral column gave 68 mg (56% yield) of 2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]-3,4- difluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-2; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 100 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 3.72 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 280 nm 164 01 Intermediate 106, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 8.11 Hz, 3 H), 5.01-5.05 (m, 1 H), 7.12 (d, J = 8.62 Hz, 1 H), 7.32 (s, 1 H), 7.53 (m, 1 H), 7.64 (s, 1 H), 7.71 (t, J = 72 Hz, 1 H), 7.72-7.76 (m, 2 H), 8.03 (dd, J = 8.62, 2.53 Hz, 1 H), 8.20-8.25 (m, 2 H), 8.41 (d, J = 2.28 Hz, 1 H). Biotage (method X) LC-MS (method 2) Rt = 1.21 min MS (ESIpos): m/z = 486.3 [M + H].sup.+ 53% yield rac-2-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide 164.1 (R)-2-(N-[4-amino-5-[6- and (difluoromethoxy)pyridine- 164.2 3-carbonyl]thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide 164.1 02 Example 164 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.01-5.05 (m, 1 H), 7.12 (m, 1 H), 7.32 (s, 1 H), 7.53 (m, 1 H), 7.64 (s, 1 H), 7.71 (t, J = 72 Hz, 1 H), 7.72-7.77 (m, 2 H), 8.03 (dd, J = 8.62, 2.53 Hz, 1 H), 8.21-8.26 (m, 2 H), 8.39-8.42 (m, 1 H). 45% yield 2-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 164.1 HPLC separation of rac-2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]-4- chloro-3-fluoro-anilino)propanamide(113 mg, 0.23 mmol, Example 164) on a chiral column gave 51 mg (45% yield) of 2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]-4- chloro-3-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-2; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 100 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 2.6 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 280 nm 164.2 03 Example 164 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.01-5.05 (m, 1 H), 7.10-7.14 (m, 1 H), 7.32 (s, 1 H), 7.50- 7.56 (m, 1 H), 7.64 (s, 1 H), 7.71 (t, J = 72 Hz, 1 H), 7.70-7.78 (m, 2 H), 8.03 (dd, J = 8.62, 2.53 Hz, 1 H), 8.20-8.25 (m, 2 H), 8.40- 8.43 (m, 1 H). 45% yield 2-(N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 164.2 HPLC separation of rac-2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]-4- chloro-3-fluoro-anilino)propanamide(113 mg, 0.23 mmol, Example 164) on a chiral column gave 51 mg (45% yield) of 2-(N-[4-amino-5-[6-(difluoromethoxy)pyridine-3-carbonyl]thiazol-2-yl]-4- chloro-3-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-2; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 100 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 3.87 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 95% A + 5% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 280 nm 165 04 Intermediate 107, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.00-5.04 (m, 1 H), 5.12 (s, 2 H), 7.00-7.05 (m, 2 H), 7.24- 7.64 (m, 11 H), 7.77-7.81 (m, 1 H), 8.03-8.07 (m, 2 H). Biotage (method X) LC-MS (method 2) Rt = 1.32 min MS (ESIpos): m/z = 509.4 [M + H].sup.+ 57% yield rac-2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-3,4-difluoro- anilino)propanamide 165.1 (R)-2-(N-[4-amino-5-(4- and benzyloxybenzoyl)thiazol- 165.2 2-yl-3,4-difluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-3,4-difluoro- anilino)propanamide 165.1 05 Example 165 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.19 (d, J = 7.35 Hz, 4 H), 5.00-5.04 (m, 1 H), 5.12 (s, 2 H), 7.00-7.05 (m, 2 H), 7.28 (s, 1 H), 7.36-7.44 (m, 5 H), 7.47- 7.52 (m, 3 H), 7.59-7.63 (m, 2 H), 7.78 (ddd, J = 11.34, 7.54, 2.41 Hz, 1 H), 8.02-8.06 (m, 2 H) 46% yield 2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-3,4-difluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 165.1 HPLC separation of rac-2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-3,4-difluoro- anilino)propanamide(340 mg, 0.67 mmol, Example 165) on a chiral column gave 155 mg (46% yield) of 2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-3,4-difluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Amylose SA 5?, 250 ? 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 50 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 1.73 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 280 nm 165.2 06 Example 165 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.19 (d, J = 7.35 Hz, 4 H), 5.00-5.04 (m, 1 H), 5.12 (s, 2 H), 7.02 (m, 2 H), 7.28 (s, 1 H), 7.35-7.45 (m, 5 H), 7.47-7.52 (m, 3 H), 7.58-7.62 (m, 2 H), 7.78 (ddd, J = 11.34, 7.54, 2.41 Hz, 1 H), 8.02-8.05 (m, 2 H) 46% yield 2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-3,4-difluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 165.2 HPLC separation of rac-2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-3,4-difluoro- anilino)propanamide(340 mg, 0.67 mmol, Example 165) on a chiral column gave 156 mg (46% yield) of 2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-3,4-difluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Amylose SA 5?, 250 ? 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 50 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 2.32 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 280 nm 166 07 Intermediate 108, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.00-5.04 (m, 1 H), 5.12 (s, 2 H), 7.00-7.05 (m, 2 H), 7.30- 7.42 (m, 6 H), 7.47-7.52 (m, 3 H), 7.63 (s, 1 H), 7.73-7.77 (m, 2 H), 8.09-8.13 (m, 2 H) Biotage (method X) LC-MS (method 2) Rt = 1.36 min MS (ESIpos): m/z = 525.3 [M + H].sup.+ 57% yield rac-2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-4-chloro-3-fluoro- anilino)propanamide 166.1 (R)-2-(N-[4-amino-5-(4- and benzyloxybenzoyl)thiazol- 166.2 2-yl]-4-chloro-3-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-4-chloro-3-fluoro- anilino)propanamide 166.1 08 Example 166 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.01-5.04 (m, 1 H), 5.12 (s, 2 H), 7.00-7.05 (m, 2 H), 7.35- 7.45 (m, 9 H), 7.63 (s, 1 H), 7.73- 7.77 (m, 2 H), 8.08-8.13 (m, 2 H) 39% yield 2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-4-chloro-3-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 166.1 HPLC separation of rac-2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide(790 mg, 1.5 mmol, Example 166) on a chiral column gave 313 mg (39% yield) of 2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 100 mL/min; temperature: 25? C.; UV: 325 nm Analytical chiral HPLC: Rt = 2.94 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 325 nm 166.2 09 Example 166 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.01-5.05 (m, 1 H), 5.12 (s, 2 H), 7.00-7.05 (m, 2 H), 7.35- 7.45 (m, 9 H), 7.63 (s, 1 H), 7.73- 7.77 (m, 2 H), 8.08-8.13 (m, 2 H) 35% yield 2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-4-chloro-3-fluoro- anilino)propanamide (enantiomer 2) HPLC separation of rac-2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide(790 mg, 1.5 mmol, Example 166) on a chiral column gave 276 mg (35% yield) of 2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 100 mL/min; temperature: 25? C.; UV: 325 nm Analytical chiral HPLC: Rt = 3.51 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 325 nm 167 0 Intermediate 109, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.60 Hz, 3 H), 5.01 (br d, J = 7.35 Hz, 1 H), 5.15 (s, 2 H), 7.28 (s, 1 H), 7.40 (m, 6 H), 7.48 (m, 5H), 7.57 (m, 1 H), 7.61 (s, 1 H), 7.77 (ddd, J = 11.41, 7.48, 2.41 Hz, 1 H), 7.95 (m, 2 H) Biotage (method X) LC-MS (method 2) Rt = 1.22 min MS (ESIpos): m/z = 552.4 [M + H].sup.+ 64% yield rac-benzyl N-[4-[4-amino- 2-(N-(2-amino-1-methyl-2- oxo-ethyl)-3,4-difluoro- anilino)thiazole-5- carbonyl]phenyl]carbamate 167.1 (R)-benzyl N-[4-[4-amino- and 2-(N-(2-amino-1-methyl-2- 167.2 oxo-ethyl)-3,4-difluoro- anilino)thiazole-5- carbonyl]phenyl]carbamate and (S)-benzyl N-[4-[4- amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-3,4- difluoro-anilino)thiazole-5- carbonyl]phenyl]carbamate 167.1 Example 167 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.01 (q, J = 7.35 Hz, 1 H), 5.15 (s, 2 H), 5.76 (s, 1 H), 7.28 (s, 1 H), 7.35-7.42 (m, 5 H), 7.46-7.52 (m, 5 H), 7.57 (m, 1 H), 7.61 (s, 1 H), 7.78 (m, 1 H), 8.18 (m, 2 H), 10.00 (s, 1 H) 32% yield Benzyl N-[4-[4-amino-2- (N-(2-amino-1-methyl-2- oxo-ethyl)-3,4-difluoro- anilino)thiazole-5- carbonyl]phenyl]carbamate (enantiomer 1) Chiral HPLC Example 167.1 HPLC separation of rac-benzyl N-[4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro- anilino)thiazole-5-carbonyl]phenyl]carbamate(385 mg, 0.7 mmol, Example 167) on a chiral column followed by trituration in MTBE gave 123 mg (32% yield) of benzyl N-[4-[4-amino-2-(N- (2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]phenyl]carbamate, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 100 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 2.87 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 325 nm 167.2 Example 167 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.01 (q, J = 7.35 Hz, 1 H), 5.15 (s, 2 H), 5.76 (s, 1 H), 7.28 (s, 1 H), 7.40 (m, 5 H), 7.48 (m, 5 H), 7.57 (m, 1 H), 7.61 (s, 1 H), 7.78 (m, 1 H), 8.18 (m, 2 H), 10.00 (s, 1 H) 34% yield Benzyl N-[4-[4-amino-2- (N-(2-amino-1-methyl-2- oxo-ethyl)-3,4-difluoro- anilino)thiazole-5- carbonyl]phenyl]carbamate (enantiomer 2) Chiral HPLC Example 167.2 HPLC separation of rac-benzyl N-[4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro- anilino)thiazole-5-carbonyl]phenyl]carbamate(385 mg, 0.7 mmol, Example 167) on a chiral column followed by trituration in MTBE gave 129 mg (34% yield) of benzyl N-[4-[4-amino-2-(N- (2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]phenyl]carbamate, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 100 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 3.90 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 325 nm 168 Intermediate 112, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.60 Hz, 3 H), 2.01 (s, 3 H), 4.18 (dd, J = 5.32, 3.55 Hz, 2 H), 4.30 (dd, J = 5.45, 3.42 Hz, 2 H), 5.06 (m, 1 H), 6.94 (m, 2 H), 7.23 (s, 1 H), 7.33 (t, J = 8.74 Hz, 2 H), 7.47 (d, J = 8.87 Hz, 2 H), 7.58 (s, 1 H), 7.63 (m, 2 H), 8.06 (m, 2 H) RP-HPLC (method C basic) LC-MS (method 1) Rt = 1.04 min MS (ESIpos): m/z = 487.6 [M + H].sup.+ 54% yield rac-2-[4-[4-amino-2-(N-(2- amino-1-methyl-2-oxo- ethyl)-4-fluoro- anilino)thiazole-5- carbonyl]phenoxy]ethyl acetate 169 Intermediate 132, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.05 (q, J = 7.35 Hz, 1 H), 5.15 (s, 2 H), 7.25 (s, 1 H), 7.40 (m, 11 H), 7.58 (s, 1 H), 7.64 (m, 2 H), 8.12 (m, 2 H), 9.99 (m, 1 H) Biotage (method X) LC-MS (method 1) Rt = 1.19 min MS (ESIpos): m/z = 534.4 [M + H].sup.+ 65% yield rac-benzyl N-[4-[4-amino- 2-(N-(2-amino-1-methyl-2- oxo-ethyl)-4-fluoro- anilino)thiazole-5- carbonyl]phenyl]carbamate 169.1 (R)-benzyl N-[4-[4-amino- and 2-(N-(2-amino-1-methyl-2- 169.2 oxo-ethyl)-4-fluoro- anilino)thiazole-5- carbonyl]phenyl]carbamate and (S)-benzyl N-[4-[4- amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-4- fluoro-anilino)thiazole-5- carbonyl]phenyl]carbamate 169.1 Example 169 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.05 (q, J = 7.35 Hz, 1 H), 5.15 (s, 2 H), 7.25 (s, 1 H), 7.40 (m, 11 H), 7.58 (s, 1 H), 7.64 (m, 2 H), 8.12 (m, 2 H), 9.99 (m, 1 H) LC-MS (method 1) Rt = 1.19 min MS (ESIpos): m/z = 534.4 [M + H].sup.+ 14% yield Benzyl N-[4-[4-amino-2- (N-(2-amino-1-methyl-2- oxo-ethyl)-4-fluoro- anilino)thiazole-5- carbonyl]phenyl]carbamate (enantiomer 1) Chiral HPLC Example 169.1 HPLC separation of rac-benzyl N-[4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro- anilino)thiazole-5-carbonyl]phenyl]carbamate(422 mg, 0.76 mmol, Example 169) on a chiral column followed by trituration in MTBE gave 88 mg (14% yield) of benzyl N-[4-[4-amino-2-(N-(2- amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]phenyl]carbamate, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 80 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 1.39 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 280 nm 169.2 Example 169 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.05 (q, J = 7.35 Hz, 1 H), 5.15 (s, 2 H), 7.25 (s, 1 H), 7.40 (m, 11 H), 7.58 (s, 1 H), 7.64 (m, 2 H), 8.12 (m, 2 H), 9.99 (m, 1 H) LC-MS (method 1) Rt = 1.19 min MS (ESIpos): m/z = 534.4 [M + H].sup.+ 16% yield Benzyl N-[4-[4-amino-2- (N-(2-amino-1-methyl-2- oxo-ethyl)-4-fluoro- anilino)thiazole-5- carbonyl]phenyl]carbamate (enantiomer 2) Chiral HPLC Example 169.2 HPLC separation of rac-benzyl N-[4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro- anilino)thiazole-5-carbonyl]phenyl]carbamate(422 mg, 0.76 mmol, Example 169) on a chiral column followed by trituration in MTBE gave 106 mg (14% yield) of benzyl N-[4-[4-amino-2-(N- (2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]phenyl]carbamate, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 80 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 1.80 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 280 nm 170 Intermediate 110, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.05 (m, 1 H), 5.11 (s, 2 H), 7.00 (m, 2 H), 7.25 (s, 1 H), 7.37 (m, 7 H), 7.48 (m, 2 H), 7.57 (s, 1 H), 7.64 (m, 2 H), 8.11 (m, 2H) RP-HPLC (method B basic) LC-MS (method 2) Rt = 1.25 min MS (ESIpos): m/z = 491.3 [M + H].sup.+ 88% yield rac-2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-4-fluoro- anilino)propanamide 170.1 (R)-2-(N-[4-amino-5-(4- and benzyloxybenzoyl)thiazol- 170.2 2-yl]-4-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-4-fluoro- anilino)propanamide 170.1 Example 170 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.02-5.06 (m, 1 H), 5.11 (s, 2 H), 7.00 (m, 2 H), 7.25 (s, 1 H), 7.30-7.40 (m, 7 H), 7.46-7.50 (m, 2 H), 7.57 (s, 1 H), 7.62- 7.66 (m, 2 H), 8.08-8.12 (m, 2H) LC-MS (method 2) Rt = 1.25 min MS (ESIpos): m/z = 491.3 [M + H].sup.+ 35% yield 2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-4-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 170.1 HPLC separation of rac-2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide(150 mg, 0.3 mmol, Example 170) on a chiral column gave 53 mg (35% yield) of 2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IB 5? 250 ? 30 mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 35% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 3.08 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IB 5? 100 ? 4.6 mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 35% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 170.2 Example 170 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.04-5.07 (m, 1 H), 5.11 (s, 2 H), 6.97-7.02 (m, 2 H), 7.25 (s, 1 H), 7.30-7.40 (m, 7 H), 7.46- 7.50 (m, 2 H), 7.57 (s, 1 H), 7.62- 7.66 (m, 2 H), 8.09-8.11 (m, 2H) LC-MS (method 2) Rt = 1.25 min MS (ESIpos): m/z = 491.3 [M + H].sup.+ 34% yield 2-(N-[4-amino-5-(4- benzyloxybenzoyl)thiazol- 2-yl]-4-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 170.2 HPLC separation of rac-2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide(150 mg, 0.3 mmol, Example 170) on a chiral column gave 51 mg (34% yield) of 2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IB 5? 250 ? 30 mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 35% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 4.42 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IB 5? 100 ? 4.6 mm; eluent A: CO.sub.2; eluent B: 2-propanol + 0.4 vol % diethylamine; isocratic: 35% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 171 0 Intermediate 111, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.07 (q, J = 7.35 Hz, 1 H), 7.29 (m, 5 H), 7.58 (m, 1 H), 7.63 (m, 2 H), 7.76 (m, 2 H), 8.21 (m, 2 H) Biotage (method X) LC-MS (method 2) Rt = 1.21 min MS (ESIpos): m/z = 511.0 [M + H].sup.+ 39% yield rac-2-(N-[4-amino-5-(4- iodobenzoyl)thiazol-2-yl] 4-fluoro- anilino)propanamide 172 Intermediate 113, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3 H), 3.87 (s, 3 H), 5.03 (q, J = 7.35 Hz, 1 H), 6.85 (dd, J = 8.62, 0.76 Hz, 1 H), 7.31 (s, 1 H), 7.52 (m, 1 H), 7.64 (s, 1 H), 7.76 (m, 2 H), 7.84 (dd, J = 8.49, 2.41 Hz, 1 H), 8.14 (m, 2 H), 8.37 (m, 1 H) Biotage (method Y) LC-MS (method 2) Rt = 1.14 min MS (ESIpos): m/z = 450.3 [M + H].sup.+ 38% yield rac-2-(N-[4-amino-5-(6- methoxypyridine-3- carbonyl)thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide 172.1 (R)-2-(N-[4-amino-5-(6- and methoxypyridine-3- 172.2 carbonyl)thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-(6- methoxypyridine-3- carbonyl)thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide 172.1 Example 172 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3 H), 3.87 (s, 3 H), 5.03 (q, J = 7.35 Hz, 1 H), 6.85 (dd, J = 8.62, 0.76 Hz, 1 H), 7.31 (s, 1 H), 7.52 (m, 1 H), 7.64 (s, 1 H), 7.76 (m, 2 H), 7.84 (dd, J = 8.49, 2.41 Hz, 1 H), 8.14 (m, 2 H), 8.37 (m, 1 H) LC-MS (method 2) Rt = 1.14 min MS (ESIpos): m/z = 450.3 [M + H].sup.+ 24% yield 2-(N-[4-amino-5-(6- methoxypyridine-3- carbonyl)thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 172.1 HPLC separation of rac-2-(N-[4-amino-5-(6-methoxypyridine-3-carbonyl)thiazol-2-yl]-4-chloro-3- fluoro-anilino)propanamide(312 mg, 0.69 mmol, Example 172) on a chiral column gave 78 mg (24% yield) of 2-(N-[4-amino-5-(6-methoxypyridine-3-carbonyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IG 5? 250 ? 30 mm; eluent A: CO.sub.2; eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 30% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 2.61 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IG 5? 100 ? 4.6 mm; eluent A: CO.sub.2; eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 30% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 172.2 Example 172 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3 H), 3.87 (s, 3 H), 5.03 (q, J = 7.35 Hz, 1 H), 6.85 (dd, J = 8.62, 0.76 Hz, 1 H), 7.31 (s, 1 H), 7.52 (m, 1 H), 7.64 (s, 1 H), 7.76 (m, 2 H), 7.84 (dd, J = 8.49, 2.41 Hz, 1 H), 8.14 (m, 2 H), 8.37 (m, 1 H) LC-MS (method 2) Rt = 1.14 min MS (ESIpos): m/z = 450.3 [M + H].sup.+ 23% yield 2-(N-[4-amino-5-(6- methoxypyridine-3- carbonyl)thiazol-2-yl]-4- chloro-3-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 172.2 HPLC separation of rac-2-(N-[4-amino-5-(6-methoxypyridine-3-carbonyl)thiazol-2-yl]-4-chloro-3- fluoro-anilino)propanamide(312 mg, 0.69 mmol, Example 172) on a chiral column gave 73 mg (23% yield) of 2-(N-[4-amino-5-(6-methoxypyridine-3-carbonyl)thiazol-2-yl]-4-chloro-3-fluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IG 5? 250 ? 30 mm; eluent A: CO.sub.2; eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 30% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar UV: 254 nm Analytical chiral HPLC: Rt = 3.40 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IG 5? 100 ? 4.6 mm; eluent A: CO.sub.2; eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 30% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 173 Intermediate 114, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.07 (m, 1 H), 6.94 (m, 2 H), 7.06 (m, 2 H), 7.20 (m, 1 H), 7.25 (s, 1 H), 7.33 (dd, J = 8.87 Hz, 2 H), 7.41 (m, 2 H), 7.53 (m, 2 H), 7.58 (s, 1 H), 7.64 (m, 2 H), 8.14 (m, 2 H) Biotage (method X) LC-MS (method 2) Rt = 1.26 min MS (ESIpos): m/z = 477.2 [M + H].sup.+ 56% yield rac-2-(N-[4-amino-5-(4- phenoxybenzoyl)thiazol-2- yl]-4-fluoro- anilino)propanamide 174 Intermediate 115, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 3.73 (s, 3H), 5.06 (q, J = 7.35 Hz, 1 H), 7.01 (d, J = 9.13 Hz, 2 H), 7.16 (m, 2 H), 7.21 (s, 1 H), 7.27 (t, J = 72 Hz, 1 H), 7.46 (m, 2 H), 7.54 (m, 3 H), 8.15 (m, 2 H) Biotage (method X) LC-MS (method 2) Rt = 1.08 min MS (ESIpos): m/z = 463.2 [M + H].sup.+ 77% yield rac-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-4-methoxy- anilino)propanamide 174.1 (R)-2-(N-[4-amino-5-[4- and (difluoromethoxy)benzoyl] 174.2 thiazol-2-yl]-4-methoxy- anilino)propanamide and (S)-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-4-methoxy- anilino)propanamide 174.1 Example 174 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 3.73 (s, 3H), 5.06 (q, J = 7.35 Hz, 1 H), 7.01 (d, J = 9.13 Hz, 2 H), 7.16 (m, 2 H), 7.21 (s, 1 H), 7.27 (t, J = 72 Hz, 1 H), 7.46 (m, 2 H), 7.54 (m, 3 H), 8.15 (m, 2 H) LC-MS (method 2) Rt = 1.08 min MS (ESIpos): m/z = 463.2 [M + H].sup.+ 31% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-4-methoxy- anilino)propanamide (enantiomer 1) Chiral HPLC Example 174.1 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-methoxy- anilino)propanamide(316 mg, 0.66 mmol, Example 174 on a chiral column gave 121 mg (31% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-methoxy- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: methanol; isocratic: 50% A + 50% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.28 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 174.2 Example 174 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 3.73 (s, 3H), 5.06 (q, J = 7.35 Hz, 1 H), 7.01 (d, J = 9.13 Hz, 2 H), 7.16 (m, 2 H), 7.21 (s, 1 H), 7.27 (t, J = 72 Hz, 1 H), 7.46 (m, 2 H), 7.54 (m, 3 H), 8.15 (m, 2 H) LC-MS (method 2) Rt = 1.08 min MS (ESIpos): m/z = 463.2 [M + H].sup.+ 31% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-4-methoxy- anilino)propanamide (enantiomer 2) Chiral HPLC Example 174.2 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-methoxy- anilino)propanamide(316 mg, 0.66 mmol, Example 174 on a chiral column gave 121 mg (31% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-methoxy- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: methanol; isocratic: 50% A + 50% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.62 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 175 Intermediate 116, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 5.07 (q, J = 7.35 Hz, 1 H), 7.26 (br s, 1 H), 7.33 (m, 3 H), 7.59 (br s, 1 H), 7.63 (m, 3 H), 7.71 (m, 2 H), 8.23 (m, 3 H), 8.38 (m, 1 H) Biotage (method X) LC-MS (method 2) Rt = 1.05 min MS (ESIpos): m/z = 430.1 [M + H].sup.+ 66% yield rac-2-(N-[4-amino-5-(4- nitrobenzoyl)thiazol-2-yl]- 4-fluoro- anilino)propanamide 176 Intermediate 117, rac-2- bromopropanamide .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.57 Hz, 3 H), 2.29 (s, 3 H), 3.80 (s, 3 H), 5.11 (q, J = 7.35 Hz, 1 H), 6.99 (d, J = 8.83 Hz, 2 H), 7.20 (s, 1 H), 7.36 (dd, J = 8.83 Hz, 2 H), 7.58 (m, 2 H), 7.61 (s, 1 H), 7.68 (m, 2 H) LC-MS (method 2) Rt = 1.16 min MS (ESIpos): m/z = 414.5 [M + H].sup.+ 79% yield rac-2-(4-fluoro-N-[5-(4- methoxybenzoyl)-4- methyl-thiazol-2- yl]anilino)propanamide 176.1 (R)-2-(4-fluoro-N-[5-(4- and methoxybenzoyl)-4- 176.2 methyl-thiazol-2- yl]anilino)propanamide and (S)-2-(4-fluoro-N-[5- (4-methoxybenzoy)-4- methyl-thiazol-2- yl]anilino)propanamide 176.1 0 Example 176 .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.57 Hz, 3 H), 2.29 (s, 3 H), 3.80 (s, 3 H), 5.11 (q, J = 7.35 Hz, 1 H), 6.99 (d, J = 8.83 Hz, 2 H), 7.20 (s, 1 H), 7.36 (dd, J = 8.83 Hz, 2 H), 7.58 (m, 2 H), 7.61 (s, 1 H), 7.68 (m, 2 H) LC-MS (method 2) Rt = 1.16 min MS (ESIpos): m/z = 414.5 [M + H].sup.+ 49% yield 2-(4-fluoro-N-[5-(4- methoxybenzoyl)-4- methyl-thiazol-2- yl]anilino)propanamide (enantiomer 1) Chiral HPLC Example 176.1 HPLC separation of rac-2-(4-fluoro-N-[5-(4-methoxybenzoyl)-4-methyl-thiazol-2- yl]anilino)propanamide(80 mg, 0.19 mmol, Example 176 on a chiral column gave 39 mg (49% yield) of 2-(4-fluoro-N-[5-(4-methoxybenzoyl)-4-methyl-thiazol-2-yl]anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 4.20 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 176.2 Example 176 .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.57 Hz, 3 H), 2.29 (s, 3 H), 3.80 (s, 3 H), 5.11 (q, J = 7.35 Hz, 1 H), 6.99 (d, J = 8.83 Hz, 2 H), 7.20 (s, 1 H), 7.36 (dd, J = 8.83 Hz, 2 H), 7.58 (m, 2 H), 7.61 (s, 1 H), 7.68 (m, 2 H) LC-MS (method 2) Rt = 1.16 min MS (ESIpos): m/z = 414.5 [M + H].sup.+ 49% yield 2-(4-fluoro-N-[5-(4- methoxybenzoyl)-4- methyl-thiazol-2- yl]anilino)propanamide (enantiomer 2) Chiral HPLC Example 176.2 HPLC separation of rac-2-(4-fluoro-N-[5-(4-methoxybenzoyl)-4-methyl-thiazol-2- yl]anilino)propanamide(80 mg, 0.19 mmol, Example 176 on a chiral column gave 31 mg (39% yield) of 2-(4-fluoro-N-[5-(4-methoxybenzoyl)-4-methyl-thiazol-2-yl]anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 4.84 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 177 Intermediate 118, rac-2- bromopropanamide .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 0.75-0.80 (m, 4 H), 1.16 (d, J = 7.31 Hz, 3 H), 1.77 (m, 1 H), 5.05 (m, 1 H), 7.24 (br s, 1 H), 7.32 (dd, J = 8.74 Hz, 2 H), 7.45 (d, J = 8.58 Hz, 2 H), 7.57 (m, 3 H), 7.64 (dd, J = 8.74, 4.93 Hz, 2 H), 8.11 (m, 2 H), 10.34 (s, 1 H) RP-HPLC (method C basic) LC-MS (method 1) Rt = 0.99 min MS (ESIpos): m/z = 468.5 [M + H].sup.+ 57% yield rac-4-[4-[4-amino-2-(N-(2- amino-1-methyl-2-oxo- ethyl)-4-fluoro- anilino)thiazole-5- carbonyl]phenyl] cyclopropanecarboxamide 178 Intermediate 119, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 3.16 (m, 4 H), 3.70 (m, 4 H), 5.06 (q, J = 7.35 Hz, 1 H), 6.90 (d, J = 8.87 Hz, 2 H), 7.24 (br s, 1 H), 7.34 (dd, J = 8.74 Hz, 2 H), 7.43 (m, J = 8.87 Hz, 2 H), 7.57 (br s, 1 H), 7.65 (m, 2H), 7.97 (m, 2 H) LC-MS (method 2) Rt = 1.01 min MS (ESIpos): m/z = 470.3 [M + H].sup.+ 48% yield rac-2-(N-[4-amino-5-(4- morpholinobenzoyl)thiazol- 2-yl]-4-fluoro- anilino)propanamide 179 Intermediate 120, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.14 (d, J = 7.35 Hz, 3 H), 5.04 (q, J = 7.35 Hz, 1 H), 5.32 (m, 2 H), 6.27 (dd, J = 2.03 Hz, 1 H), 7.15 (d, J = 8.36 Hz, 2 H), 7.23 (s, 1 H), 7.31 (m, 2 H), 7.43 (m, 2 H), 7.45 (m, 1 H), 7.60 (m, 3 H), 7.82 (dd, J = 2.28, 0.76 Hz, 1 H), 8.18 (m, 2 H) RP-HPLC (method C basic) LC-MS (method 1) Rt = 1.0 min MS (ESIpos): m/z = 465.6 [M + H].sup.+ 66% yield rac-2-(N-[4-amino-5-[4- (pyrazol-1- ylmethyl)benzoyl]thiazol-2- yl]-4-fluoro- anilino)propanamide 180 Intermediate 121, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 2.92 (s, 6 H), 5.05 (q, J = 7.35 Hz, 1 H), 6.65 (m, 2 H), 7.23 (s, 1 H), 7.34 (dd, J = 8.87 Hz, 2 H), 7.43 (m, 2 H), 7.57 (br d, J = 0.76 Hz, 1 H), 7.65 (m, 2H), 7.96 (m, 2 H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 428.5 [M + H].sup.+ 63% yield rac-2-(N-[4-amino-5-[4- (dimethylamino)benzoyl] thiazol-2-yl]-4-fluoro- anilino)propanamide 181 Intermediate 122, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (br d, J = 7.35 Hz, 3 H), 1.93 (m, 4H), 3.23 (m, 4 H), 5.06 (m, 1 H), 6.47 (br d, J = 8.62 Hz, 2 H), 7.24 (m, 1 H), 7.34 (s, 2 H), 7.42 (brd, J = 8.36 Hz, 2 H), 7.57 (br s, 1 H), 7.65 (m, 2 H), 7.97 (m, 2 H) LC-MS (method 2) Rt = 1.21 min MS (ESIpos): m/z = 454.3 [M + H].sup.+ 82% yield rac-2-(N-[4-amino-5-(4- pyrrolidin-1- ylbenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 182 Intermediate 123, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 5.03-5.06 (m, 1 H), 5.08-5.12 (m, 2 H), 7.09-7.14 (m, 4 H), 7.22 (s, 1 H), 7.28 (s, 1 H), 7.35- 7.45-7.62 (m, 10 H), 8.10-8.15 (m, 2 H) Biotage (method X) LC-MS (method 2) Rt = 1.29 min MS (ESIpos): m/z = 539.4 [M + H].sup.+ 73% yield rac-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-4-benzyloxy- anilino)propanamide 182.1 (R)-2-(N-[4-amino-5-[4- and (difluoromethoxy)benzoyl] 182.2 thiazol-2-yl]-4-benzyloxy- anilino)propanamide and (S)-2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-4-benzyloxy- anilino)propanamide 182.1 Example 182 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 5.05 (m, 1 H), 5.11 (m, 2 H), 7.13 (m, 4 H), 7.22 (s, 1 H), 7.28 (s, 1 H), 7.35-7.55 (m, 10 H), 8.13 (m, 2 H) LC-MS (method 2) Rt = 1.29 min MS (ESIpos): m/z = 539.4 [M + H].sup.+ 44% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-4-benzyloxy- anilino)propanamide (enantiomer 1) Chiral HPLC Example 182.1 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-benzyloxy- anilino)propanamide(813 mg, 1.51 mmol, Example 182) on a chiral column gave 360 mg (44% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-benzyloxy- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.76 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 182.2 Example 182 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 5.03-5.06 (m, 1 H), 5.09-5.12 (m, 2 H), 7.09-7.14 (m, 4 H), 7.22 (s, 1 H), 7.28 (s, 1 H), 7.35- 7.55 (m, 10 H), 8.10-8.15 (m, 2 H) LC-MS (method 2) Rt = 1.29 min MS (ESIpos): m/z = 539.4 [M + H].sup.+ 45% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-4-benzyloxy- anilino)propanamide (enantiomer 2) Chiral HPLC Example 182.2 HPLC separation of rac-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-benzyloxy- anilino)propanamide(813 mg, 1.51 mmol, Example 182) on a chiral column gave 365 mg (45% yield) of 2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-4-benzyloxy- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Cellulose SB 10?, 250 ? 50; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.49 min Instrument: Waters Alliance 2695; Column: YMC Cellulose SB 3?, 100 ? 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 183 0 Intermediate 124, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 5.03-5.06 (m, 1 H), 7.20-7.28 (m, 4 H), 7.33 (d, J = 8.87 Hz, 3 H), 7.42 (d, J = 8.11 Hz, 1 H), 7.59- 7.63 (m, 3 H), 8.17-8.21 (m, 2 H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 451.5 [M + H].sup.+ 41% yield rac-2-(N-[4-amino-5-[3- (difluoromethoxy)benzoyl] thiazol-2-yl]-4-fluoro- anilino)propanamide 184 Intermediate 125, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 4.97-5.09 (m, 1 H), 7.30 (s, 1 H), 7.40-7.48 (m, 1 H), 7.48- 7.53 (m, 1 H), 7.55-7.61 (m, 1 H), 7.63 (s, 1 H), 7.74-7.81 (m, 1 H), 7.85-7.90 (m, 1 H), 8.07- 8.41 (m, 2 H), 8.61 (dd, J = 4.82, 1.52 Hz, 1 H), 8.69 (dd, J = 2.28, 0.76 Hz, 1 H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 0.92 min rac-2-(N-[4-amino-5- MS (ESIpos): m/z = 404.3 [M + H].sup.+ (pyridine-3- 54% yield carbonyl)thiazol-2-yl]-3,4- difluoro- anilino)propanamide 184.1 (R)-2-(N-[4-amino-5- and (pyridine-3- 184.2 carbonyl)thiazol-2-yl]-3,4- difluoro- anilino)propanamide and (S)-2-(N-[4-amino-5- (pyridine-3- carbonyl)thiazol-2-yl]-3,4- difluoro- anilino)propanamide 184.1 Example 184 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 4.97-5.09 (m, 1 H), 7.30 (s, 1 H), 7.40-7.48 (m, 1 H), 7.48- 7.53 (m, 1 H), 7.55-7.61 (m, 1 H), 7.63 (s, 1 H), 7.74-7.81 (m, 1 H), 7.85-7.90 (m, 1 H), 8.07- 8.41 (m, 2 H), 8.61 (dd, J = 4.82, 1.52 Hz, 1 H), 8.69 (dd, J = 2.28, 0.76 Hz, 1 H) LC-MS (method 2) Rt = 0.92 min MS (ESIpos): m/z = 404.3 [M + H].sup.+ 2-(N-[4-amino-5-(pyridine- 39% yield 3-carbonyl)thiazol-2-yl]- 3,4-difluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 184.1 HPLC separation of rac-2-(N-[4-amino-5-(pyridine-3-carbonyl)thiazol-2-yl]-3,4-difluoro- anilino)propanamide(115 mg, 0.29 mmol, Example 184) on a chiral column gave 45 mg (39% yield) of 2-(N-[4-amino-5-(pyridine-3-carbonyl)thiazol-2-yl]-3,4-difluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 100 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 2.11 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 184.2 Example 184 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.19 (d, J = 7.35 Hz, 3 H), 4.97-5.09 (m, 1 H), 7.30 (s, 1 H), 7.40-7.48 (m, 1 H), 7.48- 7.53 (m, 1 H), 7.55-7.61 (m, 1 H), 7.63 (s, 1 H), 7.74-7.81 (m, 1 H), 7.85-7.90 (m, 1 H), 8.07- 8.41 (m, 2 H), 8.61 (dd, J = 4.82, 1.52 Hz, 1 H), 8.69 (dd, J = 2.28, 0.76 Hz, 1 H) LC-MS (method 2) Rt = 0.92 min MS (ESIpos): m/z = 404.3 [M + H].sup.+ 2-(N-[4-amino-5-(pyridine- 43% yield 3-carbonyl)thiazol-2-yl]- 3,4-difluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 184.2 HPLC separation of rac-2-(N-[4-amino-5-(pyridine-3-carbonyl)thiazol-2-yl]-3,4-difluoro- anilino)propanamide(115 mg, 0.29 mmol, Example 184) on a chiral column gave 50 mg (43% yield) of 2-(N-[4-amino-5-(pyridine-3-carbonyl)thiazol-2-yl]-3,4-difluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 100 mL/min; temperature: 25? C.; UV: 280 nm Analytical chiral HPLC: Rt = 2.83 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 185 Intermediate 126, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 2.03 (s, 3 H), 5.05 (q, J = 7.35 Hz, 1 H), 7.24 (s, 1 H), 7.32 (dd, J = 8.87 Hz, 2 H), 7.44 (d, J = 8.87 Hz, 2 H), 7.55 (d, J = 8.62 Hz, 2 H), 7.58 (br s, 1 H), 7.61-7.66 (m, 2 H), 7.81-8.39 (m, 2 H), 10.11 (br s, 1 H) RP-HPLC (method C basic) LC-MS (method 1) Rt = 0.87 min MS (ESIpos): m/z = 442.4 [M + H].sup.+ 54% yield rac-2-(N-[5-(4- acetamidobenzoyl)-4- amino-thiazol-2-yl]-4- fluoro-anilino)propanamide 186 Intermediate 127, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.60 Hz, 3 H), 5.00-5.13 (m, 1 H), 7.27 (s, 1 H), 7.34 (dd, J = 8.87 Hz, 2 H), 7.41 (dd, J = 5.07, 1.27 Hz, 1 H), 7.49 (s, 1 H), 7.59 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 8.20- 8.42 (m, 2 H), 8.45 (d, J = 5.07 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.03 min MS (ESIpos): m/z = 420.3 [M + H].sup.+ 25% yield rac-2-(N-[4-amino-5-(2- chloropyridine-4- carbonyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 187 Intermediate 128, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.60 Hz, 3 H), 2.45 (s, 3 H), 5.06 (br s, 1 H), 7.10-7.23 (m, 1 H), 7.23-7.28 (m, 2 H), 7.33 (dd, J = 8.74 Hz, 2 H), 7.59 (br s, 1 H), 7.63 (dd, J = 8.87, 5.07 Hz, 2 H), 8.05-8.42 (m, 2 H), 8.46 (d, J = 5.07 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.90 min MS (ESIpos): m/z = 400.5 [M + H].sup.+ 66% yield rac-2-(N-[4-amino-5-(2- methylpyridine-4- carbonyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 187.1 (R)-2-(N-[4-amino-5-(2- and methylpyridine-4- 187.2 carbonyl)thiazol-2-yl]-4- fluoro-anilino)propanamide and (S)-2-(N-[4-amino-5- (2-methylpyridine-4- carbonyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 187.1 Example 187 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.60 Hz, 3 H), 2.45 (s, 3 H), 5.06 (br s, 1 H), 7.10-7.23 (m, 1 H), 7.23-7.28 (m, 2 H), 7.33 (dd, J = 8.74 Hz, 2 H), 7.59 (br s, 1 H), 7.63 (dd, J = 8.87, 5.07 Hz, 2 H), 8.05-8.42 (m, 2 H), 8.46 (d, J = 5.07 Hz, 1 H) 32% yield 2-(N-[4-amino-5-(2- methyipyridine-4- carbonyl)thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 187.1 HPLC separation of rac-2-(N-[4-amino-5-(2-methylpyridine-4-carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide(333 mg, 0.83 mmol, Example 187) on a chiral column gave 105 mg (32% yield) of 2-(N-[4-amino-5-(2-methylpyridine-4-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IG 5? 250 ? 30 mm; eluent A: CO.sub.2; eluent B: ethanol + 0.2 vol % aqueous ammonia (32%); isocratic: 15% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 2.81 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IG 5? 100 ? 4.6 mm; eluent A: CO.sub.2; eluent B: ethanol + 0.2 vol % aqueous ammonia (32%); isocratic: 25% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 187.2 Example 187 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.60 Hz, 3 H), 2.45 (s, 3 H), 5.06 (br s, 1 H), 7.10-7.23 (m, 1 H), 7.23-7.28 (m, 2 H), 7.33 (dd, J = 8.74 Hz, 2 H), 7.59 (br s, 1 H), 7.63 (dd, J = 8.87, 5.07 Hz, 2 H), 8.05-8.42 (m, 2 H), 8.46 (d, J = 5.07 Hz, 1 H) 23% yield 2-(N-[4-amino-5-(2- methylpyridine-4- carbonyl)thiazol-2-yl]-4- fluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 187.2 HPLC separation of rac-2-(N-[4-amino-5-(2-methylpyridine-4-carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide(333 mg, 0.83 mmol, Example 187) on a chiral column gave 78 mg (23% yield) of 2-(N-[4-amino-5-(2-methylpyridine-4-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IG 5? 250 ? 30 mm; eluent A: CO.sub.2; eluent B: ethanol + 0.2 vol % aqueous ammonia (32%); isocratic: 15% B; flow: 100 mL/min; temperature: 40? C.; BPR: 150 bar; UV: 254 nm Analytical chiral HPLC: Rt = 3.56 min Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IG 5? 100 ? 4.6 mm; eluent A: CO.sub.2; eluent B: ethanol + 0.2 vol % aqueous ammonia (32%); isocratic: 25% B; flow: 4 mL/min; temperature: 37.5? C.; BPR: 100 bar; UV: 254 nm 188 Intermediate 129, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3 H), 4.99-5.13 (m, 1 H), 6.97 (t, J = 52 Hz, 1 H), 7.27 (s, 1 H), 7.33 (t J = 8.87 Hz, 2 H), 7.56-7.61 (m, 2 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.67 (s, 1 H), 8.20-8.57 (m, 2 H), 8.73 (d, J = 4.56 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.00 min MS (ESIpos): m/z = 436.3 [M + H].sup.+ 13% yield rac-2-(N-[4-amino-5-[2- (difluoromethyl)pyridine-4- carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide 189 0 Intermediate 130, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.22 (d, J = 7.35 Hz, 3 H), 5.05 (q, J = 7.35 Hz, 1 H), 5.74 (s, 1 H), 7.32 (s, 1 H), 7.37-7.44 (m, 2 H), 7.48-7.55 (m, 2 H), 7.56-7.65 (m, 3 H), 8.06-8.42 (m, 2 H), 8.68-8.73 (m, 2 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.80 min MS (ESIpos): m/z = 368.2 [M + H].sup.+ 17% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-(4- pyridyl)amino]propanamide 190 Intermediate 131, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.15 (d, J = 7.35 Hz, 3 H), 3.83 (s, 3H), 5.00-5.11 (m, 1 H), 6.76 (s, 1 H), 6.99 (dd, J = 5.20, 1.39 Hz, 1 H), 7.26 (s, 1 H), 7.30- 7.37 (m, 2 H), 7.59 (s, 1 H), 7.63 (dd, J = 8.87, 5.07 Hz, 2 H), 8.17-8.20 (m, 1 H), 8.21-8.48 (m, 2 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.98 min MS (ESIpos): m/z = 416.2 [M + H].sup.+ 29% yield rac-2-(N-[4-amino-5-(2- methoxypyridine-4- carbonyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 191 Intermediate 133; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.12 (br s, 2H), 7.57 (s, 1H), 7.46-7.53 (m, 3H), 7.34-7.44 (m, 4H), 7.21-7.28 (m, 2H), 4.98- 5.10 (m, 1H), 3.87 (s, 3H), 1.16 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.06 min MS (ESIpos): m/z = 415.3 [M + H].sup.+ 78% yield rac-2-(N-(4-amino-5- benzoyl-thiazol-2-yl)-3- fluoro-4-methoxy- anilino)propanamide 192 Intermediate 134; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1H NMR (400 MHz, DMSO-d6, 22? C.): Shift = 7.95- 8.40 (m, 3H), 7.86 (dd, J = 10.4, 1.8 Hz, 1H), 7.64-7.72 (m, 2H), 7.50-7.55 (m, 2H), 7.38-7.48 (m, 3H), 7.36 (s, 1H), 5.01 (q, J = 7.4 Hz, 1H), 1.22 (d, J = 7.4 Hz, 3H) LC-MS (method 2) Rt = 1.04 min MS (ESIpos): m/z = 410.3 [M + H].sup.+ 18% yield rac-2-(N-(4-amino-5- benzoyl-thiazol-2-yl)-4- cyano-3-fluoro- anilino)propanamide 193 Intermediate 135; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.17 (br s, 2H), 7.66-7.72 (m, 2H), 7.59 (s, 1H), 7.51-7.57 (m, 2H), 7.46-7.51 (m, 2H), 7.36- 7.44 (m, 3H), 7.26 (s, 1H), 5.05 (q, J = 7.3 Hz, 1H), 1.16 (d, J = 7.6 Hz, 3H). LC-MS (method 2) Rt = 1.19 min MS (ESIpos): m/z = 445.3 [M + H].sup.+ 47% yield rac-2-(N-(4-amino-5- benzoyl-thiazol-2-yl)-4- bromo- anilino)propanamide 194 Intermediate 136; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.13 (br s, 2H), 7.90 (d, J = 2.5 Hz, 1H), 7.60-7.68 (m, 2H), 7.45-7.52 (m, 3H), 7.39-7.44 (m, 3H), 7.39 (t, J = 73.0 Hz, 1H), 7.29 (s, 1H), 5.02 (q, J = 7.1 Hz, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.18 min MS (ESIpos): m/z = 467.4 [M + H].sup.+ 68% yield rac-2-[N-(4-amino-5- benzoyl-thiazol-2-yl)-3- chloro-4- (difluoromethoxy)anilino] propanamide 195 Intermediate 137; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.11 (br s, 2H), 7.52 (s, 1H), 7.41-7.49 (m, 4H), 7.34-7.41 (m, 3H), 7.20 (s, 1H), 6.98 (d, J = 9.1 Hz, 2H), 5.00-5.12 (m, 1H), 4.03 (q, J = 6.8 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H), 1.14 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.15 min MS (ESIpos): m/z = 411.5 [M + H].sup.+ 61% yield rac-2-(N-(4-amino-5- benzoyl-thiazol-2-yl)-4- ethoxy- anilino)propanamide 196 Intermediate 138; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.08 (br s, 2H), 7.54 (s, 1H), 7.46-7.51 (m, 2H), 7.36-7.44 (m, 3H), 7.22 (s, 1H), 7.14 (d, J = 1.8 Hz, 1H), 7.01-7.07 (m, 1H), 6.96-7.00 (m, 1H), 6.10 (s, 2H), 4.97-5.09 (m, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.03 min MS (ESIpos): m/z = 411.4 [M + H].sup.+ 67% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-(1,3- benzodioxol-5- yl)amino]propanamide 197 Intermediate 139; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.13 (br s, 2H), 7.71 (d, J = 2.0 Hz, 1H), 7.61 (s, 1H), 7.45- 7.56 (m, 4H), 7.35-7.44 (m, 3H), 7.28 (s, 1H), 5.03 (br d, J = 6.8 Hz, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.2 min MS (ESIpos): m/z = 447.3 [M + H].sup.+ 51% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-(2,2-difluoro- 1,3-benzodioxol-5- yl)amino]propanamide 198 Intermediate 140; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.14 (br s, 2H), 7.69-7.76 (m, 1H), 7.62 (s, 1H), 7.46-7.52 (m, 4H), 7.36-7.46 (m, 3H), 7.34 (t, J = 73.0 Hz, 1H), 7.29 (s, 1H), 5.03 (q, J = 7.1 Hz, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.12 min MS (ESIpos): m/z = 451.3 [M + H].sup.+ 49% yield rac-2-[N-(4-amino-5- benzoyl-thiazol-2-yl)-4- (difluoromethoxy)-3-fluoro- anilinojpropanamide 199 0 Intermediate 141; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.12 (br s, 2H), 7.53 (s, 1H), 7.44-7.51 (m, 6H), 7.32-7.43 (m, 6H), 7.21 (s, 1H), 7.09 (d, J = 9.1 Hz, 2H), 4.99-5.15 (m, 3H), 1.15 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.28 min MS (ESIpos): m/z = 473.4 [M + H].sup.+ 57% yield rac-2-(N-(4-amino-5- benzoyl-thiazol-2-yl)-4- benzyloxy- anilino)propanamide 200 Intermediate 142; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.93-8.45 (m, 2H), 7.91 (d, J = 2.3 Hz, 1H), 7.63-7.67 (m, 1H), 7.62 (s, 1H), 7.47-7.53 (m, 3H), 7.40 (t, J = 73.0 Hz, 1H), 7.29 (s, 1H), 6.92-6.96 (m, 2H), 4.98-5.07 (m, 1H), 3.76 (s, 3H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.17 min MS (ESIpos): m/z = 497.3 [M + H].sup.+ 63% yield rac-2-[N-[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-3-chloro-4- (difluoromethoxy)anilino] propanamide 201 Intermediate 143; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.93-8.54 (m, 2H), 7.91 (d, J = 2.5 Hz, 1H), 7.61-7.68 (m, 2H), 7.55-7.61 (m, 2H), 7.08-7.53 (m, 6H), 4.98-5.08 (m, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.21 min MS (ESIpos): m/z = 533.3 [M + H].sup.+ 58% yield rac-2-[N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-3-chloro-4- (difluoromethoxy)anilino] propanamide 202 Intermediate 144; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.92-8.51 (m, 2H), 7.90 (d, J = 2.5 Hz, 1H), 7.60-7.68 (m, 2H), 7.50-7.55 (m, 2H), 7.45-7.50 (m, 3H), 7.39 (t, J = 73.0 Hz, 1H), 7.30 (s, 1H), 4.98-5.08 (m, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.28 min MS (ESIpos): m/z = 501.3 [M + H].sup.+ 56% yield rac-2-[N-[4-amino-5-(4- chlorobenzoyl)thiazol-2- yl]-3-chloro-4- (difluoromethoxy)anilino] propanamide 203 Intermediate 145; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.61-8.66 (m, 2H), 8.06- 8.54 (m, 2H), 7.90 (d, J = 2.5 Hz, 1H), 7.61-7.67 (m, 2H), 7.48 (d, J = 8.6 Hz, 1H), 7.40-7.45 (m, 2H), 7.39 (t, J = 72.7 Hz, 1H), 7.31 (s, 1H), 4.98-5.07 (m, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 0.98 min MS (ESIpos): m/z = 468.3 [M + H].sup.+ 47% yield rac-2-[N-[4-amino-5- (pyridine-4- carbonyl)thiazol-2-yl]-3- chloro-4- (difluoromethoxy)anilino] propanamide 204 Intermediate 146; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.41 (d, J = 1.8 Hz, 1H), 8.05-8.38 (m, 2H), 8.02 (dd, J = 8.6, 2.5 Hz, 1H), 7.91 (d, J = 2.5 Hz, 1H), 7.72 (t, J = 72.5 Hz, 1H), 7.61-7.68 (m, 2H), 7.47-7.52 (m, 1H), 7.40 (t, J = 72.8 Hz, 1H), 7.31 (s, 1H), 7.10-7.15 (m, 1H), 4.98-5.08 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.21 min MS (ESIpos): m/z = 534.3 [M + H].sup.+ 42% yield rac-2-[N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-3- chloro-4- (difluoromethoxy)anilino] propanamide 205 Intermediate 147; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.77-8.42 (m, 2H), 7.74 (dd, J = 11.4, 1.3 Hz, 1H), 7.62 (s, 1H), 7.47-7.53 (m, 4H), 7.35 (t, J = 73.0 Hz, 1H), 6.91-6.97 (m, 2H), 4.99-5.08 (m, 1H), 3.76 (s, 3H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 481.3 [M + H].sup.+ 57% yield rac-2-[N-[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-4-(difluoromethoxy)-3- fluoro-anilino]propanamide 206 Intermediate 148; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.80-8.55 (m, 2H), 7.73 (dd, J = 11.3, 1.4 Hz, 1H), 7.62 (s, 1H), 7.46-7.55 (m, 6H), 7.35 (t, J = 72.8 Hz, 1H), 7.30 (s, 1H), 4.99- 5.08 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.24 min MS (ESIpos): m/z = 485.3 [M + H].sup.+ 53% yield rac-2-[N-[4-amino-5-(4- chlorobenzoyl)thiazol-2- yl]-4-(difluoromethoxy)-3- fluoro-anilino]propanamide 207 Intermediate 149; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.78-8.47 (m, 2H), 7.73 (dd, J = 11.2, 1.3 Hz, 1H), 7.62 (s, 1H), 7.55-7.60 (m, 2H), 7.34-7.54 (m, 3H), 7.09-7.32 (m, 4H), 4.98- 5.08 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.18 min MS (ESIpos): m/z = 517.3 [M + H].sup.+ 50% yield rac-2-[N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-4- (difluoromethoxy)-3-fluoro- anilino]propanamide 208 Intermediate 150; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.61-8.65 (m, 2H), 8.30 (br s, 2H), 7.73 (dd, J = 11.0, 1.4 Hz, 1H), 7.63 (s, 1H), 7.48-7.52 (m, 2H), 7.39-7.45 (m, 2H), 7.35 (t, J = 73.0 Hz, 1H), 7.31 (s, 1H), 4.98- 5.08 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 0.94 min MS (ESIpos): m/z = 452.3 [M + H].sup.+ 48% yield rac-2-[N-[4-amino-5- (pyridine-4- carbonyl)thiazol-2-yl]-4- (difluoromethoxy)-3-fluoro- anilino]propanamide 209 0 Intermediate 151; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.41 (d, J = 2.0 Hz, 1H), 8.02 (dd, J = 8.5, 2.4 Hz, 3H), 7.74 (dd, J = 11.4, 1.3 Hz, 1H), 7.72 (t, J = 72.5 Hz, 1H), 7.63 (s, 1H), 7.49-7.53 (m, 2H), 7.36 (t, J = 73.0 Hz, 1H), 7.31 (s, 1H), 7.10- 7.15 (m, 1H), 4.99-5.09 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.18 min MS (ESIpos): m/z = 518.3 [M + H].sup.+ 51% yield rac-2-[N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-4- (difluoromethoxy)-3-fluoro- anilino]propanamide 210 Intermediate 152; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.41 (d, J = 2.0 Hz, 1H), 8.02 (dd, J = 8.5, 2.4 Hz, 3H), 7.74 (dd, J = 11.4, 1.3 Hz, 1H), 7.72 (t, J = 72.5 Hz, 1H), 7.63 (s, 1H), 7.49-7.53 (m, 2H), 7.36 (t, J = 73.0 Hz, 1H), 7.31 (s, 1H), 7.10- 7.15 (m, 1H), 4.99-5.09 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.18 min MS (ESIpos): m/z = 518.3 [M + H].sup.+ 51% yield rac-2-[N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-4- (difluoromethoxy)-3-fluoro- anilino]propanamide 211 Intermediate 153; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.01 (dd, J = 1.9, 0.9 Hz, 3H), 7.74 (d, J = 1.8 Hz, 2H), 7.66 (s, 1H), 7.49-7.55 (m, 2H), 7.37- 7.47 (m, 3H), 7.32 (s, 1H), 4.95- 5.05 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.29 min MS (ESIpos): m/z = 485.3 [M + H].sup.+ 48% yield rac-2-[N-(4-amino-5- benzoyl-thiazol-2-yl)-3- chloro-4- (trifluoromethoxy)anilino] propanamide 212 Intermediate 154; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.80-8.36 (m, 2H), 7.72 (d, J = 1.8 Hz, 1H), 7.61 (s, 1H), 7.46-7.57 (m, 4H), 7.28 (s, 1H), 6.90-6.97 (m, 2H), 5.03 (br d, J = 7.6 Hz, 1H), 3.76 (s, 3H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.19 min MS (ESIpos): m/z = 476.3 [M + H].sup.+ 67% yield rac-2-[[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-(2,2-difluoro-1,3- benzodioxol-5- yl)amino]propanamide 213 Intermediate 155; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.19 (br s, 2H), 7.71 (d, J = 2.0 Hz, 1H), 7.61 (s, 1H), 7.44- 7.56 (m, 6H), 7.29 (s, 1H), 4.98- 5.09 (m, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.31 min MS (ESIpos): m/z = 481.2 [M + H].sup.+ 59% yield rac-2-[[4-amino-5-(4- chlorobenzoyl)thiazol-2- yl]-(2,2-difluoro-1 ,3- benzodioxol-5- yl)amino]propanamide 214 Intermediate 156; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.80-8.54 (m, 2H), 7.72 (d, J = 1.8 Hz, 1H), 7.61 (s, 1H), 7.53-7.60 (m, 3H), 7.47-7.52 (m, 1H), 7.30 (br s, 1H), 7.28 (t, J = 73.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 5.04 (br d, J = 6.3 Hz, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.23 min MS (ESIpos): m/z = 513.3 [M + H].sup.+ 37% yield rac-2-[[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-(2,2-difluoro- 1,3-benzodioxol-5- yl)amino]propanamide 215 Intermediate 157; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.60-8.65 (m, 2H), 8.07- 8.53 (m, 2H), 7.71 (d, J = 2.0 Hz, 1H), 7.63 (s, 1H), 7.52-7.58 (m, 1H), 7.46-7.51 (m, 1H), 7.39-7.45 (m, 2H), 7.30 (s, 1H), 4.95-5.13 (m, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 0.99 min MS (ESIpos): m/z = 448.3 [M + H].sup.+ 64% yield rac-2-[[4-amino-5- (pyridine-4- carbonyl)thiazol-2-yl]-(2,2- difluoro-1,3-benzodioxol-5- yl)amino]propanamide 216 Intermediate 158; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.41 (d, J = 2.3 Hz, 3H), 8.02 (dd, J = 8.5, 2.4 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.71 (t, J = 72.5 Hz, 1H), 7.62 (s, 1H), 7.54- 7.58 (m, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.30 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.96-5.12 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.23 min MS (ESIpos): m/z = 514.3 [M + H].sup.+ 59% yield rac-2-[[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]- (2,2-difluoro-1,3- benzodioxol-5- yl)amino]propanamide 217 Intermediate 159; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.88-8.42 (m, 2H), 7.85 (dd, J = 11.2, 2.5 Hz, 1H), 7.75 (td, J = 8.7, 1.0 Hz, 1H), 7.64 (s, 1H), 7.58-7.63 (m, 1H), 7.48-7.55 (m, 2H), 7.32 (s, 1H), 6.91-6.97 (m, 2H), 5.01 (q J = 7.4 Hz, 1H), 3.77 (s, 3H), 1.20 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.23 min MS (ESIpos): m/z = 499.3 [M + H].sup.+ 55% yield rac-2-[N-[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-3-fluoro-4- (trifluoromethoxy)anilino] propanamide 218 Intermediate 160; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.90-8.49 (m, 2H), 7.85 (dd, J = 11.2, 2.3 Hz, 1H), 7.75 (td, J = 8.7, 1.0 Hz, 1H), 7.65 (s, 1H), 7.58-7.62 (m, 1H), 7.51-7.56 (m, 2H), 7.45-7.50 (m, 2H), 7.32 (s, 1H), 4.97-5.06 (m, 1H), 1.20 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.34 min MS (ESIpos): m/z = 503.3 [M + H].sup.+ 46% yield rac-2-[N-[4-amino-5-(4- chlorobenzoyl)thiazol-2- yl]-3-fluoro-4- (trifluoromethoxy)anilino] propanamide 219 0 Intermediate 161; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.89-8.50 (m, 2H), 7.85 (dd, J = 11.2, 2.3 Hz, 1H), 7.70- 7.80 (m, 1H), 7.65 (s, 1H), 7.57- 7.63 (m, 3H), 7.32 (s, 1H), 7.29 (t, J = 73.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 5.02 (q, J = 7.4 Hz, 1H), 1.20 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.26 min MS (ESIpos): m/z = 525.3 [M + H].sup.+ 40% yield rac-2-[N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-3-fluoro-4- (trifluoromethoxy)anilino] propanamide 220 Intermediate 162; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.61-8.66 (m, 2H), 8.05- 8.54 (m, 2H), 7.85 (dd, J = 11.2, 2.3 Hz, 1H), 7.71-7.78 (m, 1H), 7.66 (s, 1H), 7.60 (dd, J = 8.7, 1.4 Hz, 1H), 7.41-7.46 (m, 2H), 7.33 (s, 1H), 4.97-5.06 (m, 1H), 1.20 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.04 min MS (ESIpos): m/z = 470.3 [M + H].sup.+ 40% yield rac-2-[N-[4-amino-5- (pyridine-4- carbonyl)thiazol-2-yl]-3- fluoro-4- (trifluoromethoxy)anilino] propanamide 221 Intermediate 163; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.42 (d, J = 2.0 Hz, 1H), 8.23 (br s, 2H), 8.03 (dd, J = 8.5, 2.4 Hz, 1H), 7.86 (dd, J = 11.2, 2.3 Hz, 1H), 7.73-7.79 (m, 1H), 7.72 (t, J = 72.5 Hz, 1H), 7.66 (s, 1H), 7.58-7.64 (m, 1H), 7.34 (s, 1H), 7.13 (dd, J = 8.6, 0.8 Hz, 1H), 4.97-5.06 (m, 1H), 1.20 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.29 min MS (ESIpos): m/z = 536.3 [M + H].sup.+ 51% yield rac-2-[N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-3- fluoro-4- (trifluoromethoxy)anilino] propanamide 222 Intermediate 164; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.78-8.36 (m, 2H), 7.74 (s, 2H), 7.66 (s, 1H), 7.49-7.55 (m, 2H), 7.32 (s, 1H), 6.91-6.98 (m, 2H), 5.00 (q, J = 7.0 Hz, 1H), 3.77 (s, 3H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.29 min MS (ESIpos): m/z = 515.3 [M + H].sup.+ 46% yield rac-2-[N-[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-3-chloro-4- (trifluoromethoxy)anilino] propanamide 223 Intermediate 165; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.03-8.45 (m, 2H), 8.01 (t, J = 1.4 Hz, 1H), 7.74 (s, 2H), 7.66 (s, 1H), 7.51-7.57 (m, 2H), 7.45- 7.50 (m, 2H), 7.33 (s, 1H), 4.96- 5.05 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.4 min MS (ESIpos): m/z = 519.2 [M + H].sup.+ 40% yield rac-2-[N-[4-amino-5-(4- chlorobenzoyl)thiazol-2- yl]-3-chloro-4- (trifluoromethoxy)anilino] propanamide 224 Intermediate 166; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.04-8.37 (m, 2H), 8.01 (t, J = 1.3 Hz, 1H), 7.74 (s, 2H), 7.66 (s, 1H), 7.57-7.62 (m, 2H), 7.33 (s, 1H), 7.29 (t, J = 73.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 5.00 (q, J = 7.0 Hz, 1H), 1.19 (d, J = 7.6 Hz, 3H). LC-MS (method 2) Rt = 1.32 min MS (ESIpos): m/z = 551.3 [M + H].sup.+ 42% yield rac-2-[N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-3-chloro-4- (trifluoromethoxy)anilino] propanamide 225 Intermediate 167; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.62-8.66 (m, 2H), 8.03- 8.60 (m, 2H), 8.01 (t, J = 1.4 Hz, 1H), 7.74 (s, 2H), 7.67 (s, 1H), 7.41-7.46 (m, 2H), 7.34 (s, 1H), 4.95-5.04 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.09 min MS (ESIpos): m/z = 486.2 [M + H].sup.+ 42% yield rac-2-[N-[4-amino-5- (pyridine-4- carbonyl)thiazol-2-yl]-3- chloro-4- (trifluoromethoxy)anilino] propanamide 226 Intermediate 168; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.42 (d, J = 1.8 Hz, 1H), 8.07-8.40 (m, 2H), 8.01-8.06 (m, 2H), 7.75 (s, 2H), 7.72 (t, J = 72.2 Hz, 1H), 7.67 (s, 1H), 7.34 (s, 1H), 7.13 (d, J = 9.1 Hz, 1H), 4.96-5.05 (m, 1H), 1.20 (d, J = 7.6 Hz, 3H). LC-MS (method 2) Rt = 1.33 min MS (ESIpos): m/z = 552.2 [M + H].sup.+ 34% yield rac-2-[N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-3- chloro-4- (trifluoromethoxy)anilino] propanamide 227 Intermediate 169; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.32 (d, J = 2.5 Hz, 1H), 7.93 (dd, J = 8.9, 2.8 Hz, 3H), 7.61 (s, 1H), 7.47-7.52 (m, 2H), 7.35-7.44 (m, 3H), 7.26 (s, 1H), 6.93 (d, J = 8.9 Hz, 1H), 4.98- 5.16 (m, 1H), 3.87 (s, 3H), 1.17 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.01 min MS (ESIpos): m/z = 398.3 [M + H].sup.+ 75% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-(6-methoxy-3- pyridyl)amino]propanamide 228 Intermediate 170; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.56 (d, J = 2.5 Hz, 1H), 8.30 (dd, J = 8.7, 2.7 Hz, 1H), 8.15 (br s, 2H), 7.68 (s, 1H), 7.52 (dd, J = 7.6, 1.5 Hz, 2H), 7.37- 7.48 (m, 4H), 7.33 (s, 1H), 4.97- 5.07 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.16 min MS (ESIpos): m/z = 452.3 [M + H].sup.+ 50% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-[6- (trifluoromethoxy)-3- pyridyl]amino]propanamide 229 0 Intermediate 171; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.46 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 8.7, 2.7 Hz, 3H), 7.74 (t, J = 72.2 Hz, 1H), 7.66 (s, 1H), 7.47-7.53 (m, 2H), 7.36-7.46 (m, 3H), 7.31 (s, 1H), 7.23 (d, J = 8.6 Hz, 1H), 5.04 (br d, J = 5.6 Hz, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.1 min MS (ESIpos): m/z = 434.3 [M + H].sup.+ 68% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-[6- (difluoromethoxy)-3- pyridyl]amino]propanamide 230 Intermediate 172; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.95 (s, 1H), 8.35-8.40 (m, 1H), 8.09 (brd, J = 8.4 Hz, 3H), 7.72 (s, 1H), 7.50-7.56 (m, 2H), 7.34-7.47 (m, 4H), 4.97-5.04 (m, 1H), 1.21 (brd, J = 7.1 Hz, 3H). LC-MS (method 2) Rt = 1.1 min MS (ESIpos): m/z = 436.3 [M + H].sup.+ 20% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-[6- (trifluoromethyl)-3- pyridyl]amino]propanamide 231 Intermediate 173; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.86 (d, J = 2.3 Hz, 1H), 7.89-8.50 (m, 3H), 7.86 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.49-7.54 (m, 2H), 7.37-7.46 (m, 3H), 7.34 (s, 1H), 7.03 (t, J = 54.7 Hz, 1H), 5.03 (q, J = 7.4 Hz, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.0 min MS (ESIpos): m/z = 418.3 [M + H].sup.+ 39% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-[6- (difluoromethyl)-3- pyridyl]amino]propanamide 232 Intermediate 174; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.61 (d, J = 2.8 Hz, 1H), 8.14 (dd, J = 8.4, 2.8 Hz, 3H), 7.69 (d, J = 8.6 Hz, 2H), 7.48- 7.55 (m, 2H), 7.37-7.46 (m, 3H), 7.33 (br s, 1H), 4.96-5.07 (m, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.03 min MS (ESIpos): m/z = 402.2 [M + H].sup.+ 49% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-(6-chloro-3- pyridyl)amino]propanamide 233 Intermediate 175; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.46 (d, J = 2.3 Hz, 1H), 7.72-8.42 (m, 3H), 7.67 (s, 1H), 7.48-7.54 (m, 2H), 7.33-7.47 (m, 4H), 7.32 (s, 1H), 4.97-5.10 (m, 1H), 1.19 (d, J = 7.6 Hz, 3H). LC-MS (method 2) Rt = 0.97 min MS (ESIpos): m/z = 386.3 [M + H].sup.+ 65% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-(6-fluoro-3- pyridyl)amino]propanamide 234 Intermediate 176; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.58 (d, J = 2.3 Hz, 1H), 7.90 (dd, J = 8.1,2.5 Hz, 3H), 7.62 (s, 1H), 7.46-7.52 (m, 2H), 7.35-7.44 (m, 4H), 7.27 (s, 1H), 5.01-5.12 (m, 1H), 1.16 (d, J = 7.6 Hz, 3H). LC-MS (method 2) Rt = 0.91 min MS (ESIpos): m/z = 382.3 [M + H].sup.+ 69% yield rac-2-[(4-amino-5-benzoyl- thiazol-2-yl)-(6-methyl-3- pyridyl)amino]propanamide 235 Intermediate 177; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.78-8.47 (m, 3H), 7.73 (td, J = 4.3, 2.5 Hz, 1H), 7.62- 7.70 (m, 2H), 7.47-7.54 (m, 2H), 7.35-7.46 (m, 3H), 7.30 (s, 1H), 5.02 (brd, J = 6.8 Hz, 1H), 1.17 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.26 min MS (ESIpos): m/z = 469.3 [M + H].sup.+ 52% yield rac-2-[N-(4-amino-5- benzoyl-thiazol-2-yl)-4- fluoro-3- (trifluoromethoxy)anilino] propanamide 236 Intermediate 178; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.97 (dd, J = 2.0, 1.3 Hz, 3H), 7.85 (d, J = 8.6 Hz, 1H), 7.65-7.73 (m, 2H), 7.48-7.55 (m, 2H), 7.36-7.47 (m, 3H), 7.32 (s, 1H), 5.03 (q, J = 7.4 Hz, 1 H), 1.18 (d, J = 7.6 Hz, 3H). LC-MS (method 2) Rt = 1.33 min MS (ESIpos): m/z = 485.2 [M + H].sup.+ 44% yield rac-2-[N-(4-amino-5- benzoyl-thiazol-2-yl)-4- chloro-3- (trifluoromethoxy)anilino] propanamide 237 Intermediate 179; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.77-8.54 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.62 (s, 1H), 7.48-7.58 (m, 4H), 7.36-7.44 (m, 3H), 7.27 (s, 1H), 7.26 (t, J = 72.8 Hz, 1H), 4.97-5.08 (m, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.15 min MS (ESIpos): m/z = 451.3 [M + H].sup.+ 66% yield rac-2-[N-(4-amino-5- benzoyl-thiazol-2-yl)-3- (difluoromethoxy)-4-fluoro- anilino]propanamide 238 Intermediate 180; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.78-8.54 (m, 2H), 7.69- 7.77 (m, 2H), 7.63 (s, 1H), 7.48- 7.55 (m, 3H), 7.36-7.45 (m, 3H), 7.09-7.33 (m, 2H), 5.02 (q, J = 7.4 Hz, 1H), 1.19 (d, J = 7.6 Hz, 3H). LC-MS (method 2) Rt = 1.22 min MS (ESIpos): m/z = 467.3 [M + H].sup.+ 51% yield rac-2-[N-(4-amino-5- benzoyl-thiazol-2-yl)-4- chloro-3- (difluoromethoxy)anilino] propanamide 239 00 Intermediate 181; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.03-8.39 (m, 2H), 7.93- 8.03 (m, 1H), 7.61-7.72 (m, 2H), 7.52 (brd, J = 4.3 Hz, 2H), 7.42 (br d, J = 7.1 Hz, 4H), 7.34 (br s, 1H), 4.65-5.38 (m, 1H), 1.09-1.27 (m, 3H). LC-MS (method 2) Rt = 1.19 min MS (ESIpos): m/z = 469.2 [M + H].sup.+ 50% yield rac-2-[N-(4-amino-5- benzoyl-thiazol-2-yl)-2- fluoro-4- (trifluoromethoxy)anilino] propanamide 240 01 Intermediate 182; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.88-8.43 (m, 3H), 7.64- 7.87 (m, 2H), 7.60 (br d, J = 8.4 Hz, 1H), 7.27-7.56 (m, 6H), 4.93- 5.30 (m, 1H), 1.09 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.24 min MS (ESIpos): m/z = 485.1 [M + H].sup.+ 41% yield rac-2-[N-(4-amino-5- benzoyl-thiazol-2-yl)-2- chloro-4- (trifluoromethoxy)anilino] propanamide 241 02 Intermediate 183; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.94-8.49 (m, 2H), 7.88 (br s, 1H), 7.63 (br s, 1H), 7.50 (br s, 2H), 7.39-7.45 (m, 3H), 7.38 (t, J = 73.3 Hz, 1H), 7.35 (brd, J = 2.0 Hz, 1H), 7.31 (br s, 1H), 7.18 (br d, J = 8.9 Hz, 1H), 4.82-5.40 (m, 1H), 1.15 (brd, J = 1.3 Hz, 3H). LC-MS (method 2) Rt = 1.09 min MS (ESIpos): m/z = 451.2 [M + H].sup.+ 38% yield rac-2-[N-(4-amino-5- benzoyl-thiazol-2-yl)-4- (difluoromethoxy)-2-fluoro- anilino]propanamide 242 03 Intermediate 184; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.01 (d, J = 8.9 Hz, 3H), 7.60-7.72 (m, 1H), 7.20-7.59 (m, 9H), 4.97-5.21 (m, 1H), 1.09 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 467.1 [M + H].sup.+ 44% yield rac-2-[N-(4-amino-5- benzoyl-thiazol-2-yl)-2- chloro-4- (difluoromethoxy)anilino] propanamide 243 04 Intermediate 185; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.77-8.41 (m, 2H), 7.67- 7.76 (m, 4H), 7.60 (s, 1H), 7.45- 7.52 (m, 2H), 7.27 (s, 1H), 7.10 (t, J = 55.8 Hz, 1H), 6.90-6.95 (m, 2H), 5.08 (q, J = 7.3 Hz, 1H), 3.75 (s, 3H), 1.17 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.05 min MS (ESIpos): m/z = 447.2 [M + H].sup.+ 54% yield rac-2-[N-[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-4- (difluoromethyl)anilino] propanamide 244 05 Intermediate 186; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.81-8.54 (m, 2H), 7.67- 7.75 (m, 4H), 7.60 (s, 1H), 7.48- 7.53 (m, 2H), 7.43-7.48 (m, 2H), 7.28 (s, 1H), 7.09 (t, J = 55.5 Hz, 1H), 5.08 (q, J = 7.3 Hz, 1H), 1.17 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.15 min MS (ESIpos): m/z = 451.1 [M + H].sup.+ 48% yield rac-2-[N-[4-amino-5-(4- chlorobenzoyl)thiazol-2- yl]-4- (difiuoromethyl)anilino] propanamide 245 06 Intermediate 187; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 7.76-8.57 (m, 2H), 7.67- 7.76 (m, 4H), 7.61 (s, 1H), 7.52- 7.59 (m, 2H), 7.14-7.20 (m, 2H), 6.93-7.48 (m, 3H), 5.08 (q, J = 7.5 Hz, 1H), 1.17 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.09 min MS (ESIpos): m/z = 483.2 [M + H].sup.+ 45% yield rac-2-[N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-4- (difluoromethyl)anilino] propanamide 246 07 Intermediate 188; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.59-8.64 (m, 2H), 8.06- 8.55 (m, 2H), 7.67-7.76 (m, 4H), 7.62 (s, 1H), 7.37-7.43 (m, 2H), 7.29 (s, 1H), 7.09 (t, J = 55.8 Hz, 1H), 5.02-5.13 (m, 1H), 1.17 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 0.85 min MS (ESIpos): m/z = 418.2 [M + H].sup.+ 49% yield rac-2-[N-[4-amino-5- (pyridine-4- carbonyl)thiazol-2-yl]-4- (difluoromethyl)anilino] propanamide 247 08 Intermediate 189; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.03-8.53 (m, 3H), 8.00 (dd, J = 8.5, 2.4 Hz, 1H), 7.50- 7.91 (m, 6H), 7.29 (s, 1H), 6.94- 7.26 (m, 2H), 5.08 (q, J = 7.1 Hz, 1H), 1.18 (d, J = 7.6 Hz, 3H). LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 484.5 [M + H].sup.+ 53% yield rac-2-[N-[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-4- (difluoromethyl)anilino] propanamide 248 09 Intermediate 190; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.57 (d, J = 2.5 Hz, 1H), 8.31 (dd, J = 8.6, 2.5 Hz, 1H), 7.90-8.28 (m, 2H), 7.65-7.71 (m, 1H), 7.50-7.55 (m, 2H), 7.46 (d, J = 8.6 Hz, 1H), 7.33 (s, 1H), 6.92- 6.97 (m, 2H), 5.03 (q, J = 6.8 Hz, 1H), 3.77 (s, 3H), 1.20 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.14 min MS (ESIpos): m/z = 482.4 [M + H].sup.+ 47% yield rac-2-[[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-[6-(trifluoromethoxy)-3- pyridyl]amino]propanamide 249 0 Intermediate 191; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.56 (d, J = 2.5 Hz, 1H), 8.30 (dd, J = 8.7, 2.7 Hz, 3H), 7.69 (s, 1H), 7.51-7.57 (m, 2H), 7.43-7.50 (m, 3H), 7.34 (s, 1H), 5.03 (brd, J = 7.1 Hz, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.24 min MS (ESIpos): m/z = 486.3 [M + H].sup.+ 23% yield rac-2-[[4-amino-5-(4- chlorobenzoyl)thiazol-2- yl]-[6-(trifluoromethoxy)-3- pyridyl]amino]propanamide 250 Intermediate 192; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.57 (d, J = 2.5 Hz, 1H), 8.30 (dd, J = 8.7, 2.7 Hz, 1H), 8.11 (br s, 2H), 7.68 (s, 1H), 7.57- 7.62 (m, 2H), 7.45 (d, J = 9.1 Hz, 1H), 7.34 (s, 1H), 7.29 (t, J = 73.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 5.03 (brd, J = 6.6 Hz, 1H), 1.20 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.19 min MS (ESIpos): m/z = 518.3 [M + H].sup.+ 31% yield rac-2-[[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-[6- (trifluoromethoxy)-3- pyridyl]amino]propanamide 251 Intermediate 293; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.57 (d, J = 2.5 Hz, 1H), 8.43 (d, J = 2.3 Hz, 1H), 8.31 (dd, J = 8.7, 2.7 Hz, 3H), 8.04 (dd, J = 8.5, 2.4 Hz, 1H), 7.72 (t, J = 72.5 Hz, 1H), 7.70 (s, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.35 (s, 1H), 7.13 (d, J = 9.1 Hz, 1H), 5.03 (brd, J = 6.8 Hz, 1H), 1.20 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.21 min MS (ESIpos): m/z = 519.4 [M + H].sup.+ 26% yield rac-2-[[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-[6- (trifluoromethoxy)-3- pyridyl]amino]propanamide 252 Intermediate 194; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.47 (d, J = 2.5 Hz, 1H), 8.19 (dd, J = 8.6, 2.8 Hz, 3H), 7.75 (t, J = 72.2 Hz, 1H), 7.65 (s, 1H), 7.48-7.53 (m, 2H), 7.30 (s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 6.92-6.96 (m, 2H), 5.05 (br d, J = 5.8 Hz, 1H), 3.76 (s, 3H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.09 min MS (ESIpos): m/z = 464.3 [M + H].sup.+ 65% yield rac-2-[[4-amino-5-(4- methoxybenzoyl)thiazol-2- yl]-[6-(difluoromethoxy)-3- pyridyl]amino]propanamide 253 Intermediate 195; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.46 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 8.7, 2.7 Hz, 3H), 7.74 (t, J = 72.5 Hz, 1H), 7.66 (s, 1H), 7.50-7.55 (m, 2H), 7.44-7.49 (m, 2H), 7.31 (s, 1H), 7.22-7.27 (m, 1H), 5.05 (br s, 1H), 1.18 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.19 min MS (ESIpos): m/z = 468.3 [M + H].sup.+ 51% yield rac-2-[[4-amino-5-(4- chlorobenzoyl)thiazol-2- yl]-[6-(difluoromethoxy)-3- pyridyl]amino]propanamide 254 Intermediate 196; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.47 (d, J = 2.5 Hz, 1H), 8.19 (dd, J = 8.7, 2.7 Hz, 3H), 7.75 (t, J = 72.5 Hz, 1H), 7.66 (s, 1H), 7.56-7.61 (m, 2H), 7.31 (s, 1H), 7.29 (t, J = 73.8 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 5.05 (br s, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.14 min MS (ESIpos): m/z = 500.4 [M + H].sup.+ 44% yield rac-2-[[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-[6- (difluoromethoxy)-3- pyridyl]amino]propanamide 255 Intermediate 197; rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 8.47 (d, J = 2.5 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.19 (dd, J = 8.6, 2.5 Hz, 3H), 8.03 (dd, J = 8.6, 2.5 Hz, 1H), 7.75 (t, J = 72.5 Hz, 1H), 7.72 (t, J = 72.3 Hz, 1H), 7.67 (s, 1H), 7.32 (s, 1H), 7.25 (d, J = 9.1 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 5.06 (br s, 1H), 1.19 (d, J = 7.4 Hz, 3H). LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 501.5 [M + H].sup.+ 56% yield rac-2-[[4-amino-5-[6- (difluoromethoxy)pyridine- 3-carbonyl]thiazol-2-yl]-[6- (difluoromethoxy)-3- pyridyl]amino]propanamide 256 Intermediate 217, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.17 (d, J = 7.35 Hz, 3 H), 5.05 (m, J = 6.34 Hz, 1 H), 5.18 (s, 2 H), 7.26 (s, 1 H), 7.29-7.44 (m, 7 H), 7.59 (s, 1 H), 7.64 (dd, J = 8.87, 5.07 Hz, 2 H), 7.80-7.85 (m, 1 H), 7.85-7.91 (m, 1 H), 7.94-8.36 (m, 2 H), 8.40 (d, J = 1.77 Hz, 1 H), 10.49 (s, 1 H) RP-HPLC (method C) LC-MS (method 2) Rt = 1.16 min MS (ESIpos): m/z = 535.4 [M + H].sup.+ 7% yield rac-benzyl N-[5-[4-amino- 2-(N-(2-amino-1-methyl-2- oxo-ethyl)-4-fluoro- anilino)thiazole-5- carbonyl]-2- pyridyl]carbamate

Example 257

rac-Ethyl 4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]benzoate

(246) ##STR00718##

(247) Ethyl 4-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]benzoate (14.2 g, 36.9 mmol, Intermediate 210) was suspended in DMF (300 mL) and treated with rac-2-bromo propionamide (7.9 g, 52 mmol) and potassium carbonate (9 g, 65 mmol). The reaction mixture was stirred at rt overnight and then treated with water. After 30 min the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness to give 15.47 g (33 mmol, 89% yield) of the title compound.

(248) LC-MS (method 2): Rt=1.17 min; MS(ESIpos) m/z=457.3 [M+H].sup.+

Example 258

rac-Ethyl 4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-chloro-3-fluoro-anilino)thiazole-5-carbonyl]benzoate

(249) ##STR00719##

(250) Ethyl 4-[4-amino-2-(4-chloro-3-fluoro-anilino)thiazole-5-carbonyl]benzoate (1.24 g, 2.52 mmol, Intermediate 212) was suspended in DMF (18 mL) and treated with rac-2-bromo propionamide (765.5 mg, 5.04 mmol) and potassium carbonate (522 mg, 3.78 mmol). The reaction mixture was stirred for 3 h and then treated with water. After 30 min the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The crude product was purified by Biotage (method X) to give 1.02 g (82% yield) of the title compound.

(251) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm=1.19 (m, J=8.0 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H), 4.30 (q, J=7.10 Hz, 2H), 5.02 (m, 1H), 7.31 (s, 1H), 7.51 (dt, J=8.49, 1.20 Hz, 1H), 7.62 (m, 3H), 7.74 (m, 2H), 7.97 (m, 2H), 8.28 (m, 2H).

(252) LC-MS (method 2): Rt=1.20 min; MS(ESIpos) m/z=491.2 [M+H].sup.+

Example 259

rac-Ethyl 2-[4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]phenoxy]-2-methyl-propanoate

(253) ##STR00720##

(254) rac-Ethyl 2-[4-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]phenoxy]-2-methyl-propanoate (1.01 g, 2.28 mmol, Intermediate 214) was suspended in DMF (20 mL) and treated with rac-2-bromo propionamide (519 mg, 3.4 mmol) and potassium carbonate (1.57 g, 11.4 mmol). The reaction mixture was stirred overnight at rt and then treated with water. After 30 min the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The crude product was purified by Biotage (method X) to give 926 mg (1.79 mmol, 78% yield) of the title compound.

(255) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm=1.07 (t, J=7.1 Hz, 3H), 1.16 (d, J=7.35 Hz, 3H), 1.53 (s, 6H), 4.13 (q, J=7.1 Hz, 2H), 5.06 (m, 1H), 6.74 (m, 2H), 7.24 (s, 1H), 7.33 (t, J=8.74 Hz, 2H), 7.44 (m, 2H), 7.57 (s, 1H), 7.63 (m, 2H), 8.13 (m, 2H).

(256) LC-MS (method 2): Rt=1.22 min; MS(ESIpos) m/z=515.5 [M+H].sup.+

Example 260

rac-4-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-cyclohexyl-benzamide

(257) ##STR00721##

(258) 4-[(4-amino-2-{[(2RS)-1-amino-1-oxopropan-2-yl](4-fluorophenyl)amino}-1,3-thiazol-5-yl)carbonyl]benzoic acid (Intermediate 211, 75 mg, 0.175 mmol) and cyclohexane amine (35 mg, 0.35 mmol) were solved in 1 mL DMF and treated with HATU (133 mg, 0.35 mmol), N,N-diisopropylethylamine (68 mg, 0.53 mmol) and DMAP (1 mg, 9 ?M). The reaction mixture was stirred at rt overnight, filtrated and purified by RP-HPLC (method D) to yield 48 mg (0.09 mmol, 53%) of the title compound.

(259) .sup.1H NMR (400 MHz, DMSO-de) ? ppm=1.06-1.14 (m, 1H), 1.16 (d, J=7.35 Hz, 3H), 1.20-1.36 (m, 4H), 1.55-1.64 (m, 1H), 1.68-1.76 (m, 2H), 1.76-1.83 (m, 2H), 3.66-3.79 (m, 1H), 5.01-5.12 (m, 1H), 7.25 (s, 1H), 7.32 (t, J=8.74 Hz, 2H), 7.52 (d, J=8.36 Hz, 2H), 7.58 (s, 1H), 7.64 (dd, J=8.87, 5.07 Hz, 2H), 7.78 (d, J=8.36 Hz, 2H), 7.98-8.12 (br s, 1H), 8.23 (d, J=7.86 Hz, 1H), 8.20-8.50 (br s, 1H).

(260) LC-MS (method 2): Rt=1.15 min; MS(ESIpos) m/z=510.4 [M+H].sup.+

(261) The following examples were prepared from the starting materials stated in Table 10, below, using the procedure as for Example 260.

(262) The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (methods X, Y or Z depending on polarity) after precipitation, extraction or filtration of the reaction mixture if necessary.

(263) Enantiomers were separated from their racemate by chiral HPLC using the column and solvent conditions stated.

(264) TABLE-US-00010 TABLE 10 Examples 261-273 Example Chemical structure Starting number Compound name materials Analytics/purification/yield 261 Intermediate 211, propan- 2-amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.11-1.19 (m, 9H), 3.99- 4.11 (m, 1H), 5.00-5.13 (m, 1H), 7.25 (s, 1H), 7.32 (t, J = 8.87 Hz, 2H), 7.53 (d, J = 8.62 Hz, 2H), 7.58 (s, 1H), 7.60-7.67 (m, 2H), 7.79 (d, J = 8.36 Hz, 2H), 7.94-8.22 (m, 1H), 8.24 (d, J = 7.86 Hz, 1H), 8.27-8.48 (m, 1H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.00 min MS (ESIpos): m/z = 470.7 [M + H].sup.+ 73% yield rac-4-[4-amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-4-fluoro- anilino)thiazole-5-carbonyl]-N- isopropyl-benzamide 262 Intermediate 211, 1- phenylmethan- amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3H), 4.46 (d, J = 6.08 Hz, 2H), 5.01- 5.11 (m, 1H), 7.21-7.28 (m, 2H), 7.28-7.35 (m, 6H), 7.53- 7.57 (m, 2H), 7.58 (s, 1H), 7.60- 7.66 (m, 2H), 7.83-7.87 (m, 2H), 8.09 (br s, 1H), 8.38 (br s, 1H), 9.07 (t, J = 5.96 Hz, 1H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.10 min MS (ESIpos): m/z = 518.4 [M + H].sup.+ 59% yield rac-4-[4-amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-4-fluoro- anilino)thiazole-5-carbonyl]-N- benzyl-benzamide 263 Intermediate 211, S-1- aminopropan- 2-ol .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.04 (d, J = 6.34 Hz, 3H), 1.13-1.19 (m, 3H), 3.17 (td, J = 5.96, 1.52 Hz, 2H), 3.70-3.81 (m, 1H), 4.73 (d, J = 4.82 Hz, 1H), 5.01-5.13 (m, 1H), 7.26 (s, 1H), 7.32 (t, J = 8.74 Hz, 2H), 7.53 (d, J = 8.36 Hz, 2H), 7.58 (s, 1H), 7.61-7.66 (m, 2H), 7.81 (d, J = 8.62 Hz, 2H), 7.91-8.14 (m, 1H), 8.17-8.38 (m, 1H), 8.43 (t, J = 5.83 Hz, 1H) 4-[4-amino-2-(N-(2-amino-1- RP-HPLC (method C basic) methyl-2-oxo-ethyl)-4-fluoro- LC-MS (method 2) Rt = 0.83 min anilino)thiazole-5-carbonyl]-N- MS (ESIpos): m/z = 486.6 [M + H].sup.+ [(2S)-2-hydroxypropyl]benzamide 73% yield (mixture of stereoisomers) 264 Intermediate 211, 2- methoxy- ethanamine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3H), 3.25 (s, 3H), 3.36-3.46 (m, 4H), 5.00-5.12 (m, 1H), 7.26 (s, 1H), 7.29-7.36 (m, 2H), 7.54 (d, J = 8.36 Hz, 2H), 7.58 (s, 1H), 7.63 (dd, J = 8.87, 5.07 Hz, 2H), 7.80 (d, J = 8.36 Hz, 2H), 7.90- 8.16 (m, 1H), 8.17-8.47 (m, 1H), 8.55 (t, J = 5.20 Hz, 1H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.90 min rac-4-[4-amino-2-(N-(2-amino-1- MS (ESIpos): m/z = 486.6 [M + H].sup.+ methyl-2-oxo-ethyl)-4-fluoro- 68% yield anilino)thiazole-5-carbonyl]-N-(2- methoxyethyl)benzamide 265 Intermediate 211, R-1- aminopropan- 2-ol .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.04 (d, J = 6.08 Hz, 3H), 1.16 (d, J = 7.60 Hz, 3H), 3.17 (td, J = 6.02, 1.65 Hz, 2H), 3.70-3.80 (m, 1H), 4.73 (d, J = 4.82 Hz, 1H), 5.01-5.12 (m, 1H), 7.25 (s, 1H), 7.32 (t, J = 8.74 Hz, 2H), 7.51- 7.57 (m, 2H), 7.58 (s, 1H), 7.60- 7.67 (m, 2H), 7.81 (d, J = 8.36 Hz, 2H), 7.92-8.17 (m, 1H), 8.18- 8.38 (m, 1H), 8.43 (t, J = 5.70 Hz, 1H) 4-[4-amino-2-(N-(2-amino-1- RP-HPLC (method C basic) methyl-2-oxo-ethyl)-4-fluoro- LC-MS (method 2) Rt = 0.83 min anilino)thiazole-5-carbonyl]-N- MS (ESIpos): m/z = 486.6 [M + H].sup.+ [(2R)-2-hydroxypropyl]benzamide 64% yield (mixture of stereoisomers) 266 Intermediate 211, cyclopropan- amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 0.51-0.58 (m, 2H), 0.64- 0.71 (m, 2H), 1.16 (d, J = 7.35 Hz, 3H), 2.82 (m, J = 4.06 Hz, 1H), 5.06 (m, J = 7.10 Hz, 1H), 7.25 (s, 1H), 7.32 (t, J = 8.87 Hz, 2H), 7.52 (d, J = 8.36 Hz, 2H), 7.58 (s, 1H), 7.61-7.67 (m, 2H), 7.73- 7.81 (m, 2H), 7.92-8.17 (m, 1 H), 8.18-8.40 (m, 1H), 8.44 (d, J = 4.31 Hz, 1H) RP-HPLC (method C basic) rac-4-[4-amino-2-(N-(2-amino-1- LC-MS (method 2) Rt = 0.93 min methyl-2-oxo-ethyl)-4-fluoro- MS (ESIpos): m/z = 468.5 [M + H].sup.+ anilino)thiazole-5-carbonyl]-N- 68% yield cyclopropyl-benzamide 267 Intermediate 211, cyclopentan- amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3H), 1.47-1.58 (m, 4H), 1.63-1.73 (m, 2H), 1.81-1.93 (m, 2H), 4.14-4.26 (m, 1H), 5.01-5.13 (m, 1H), 7.25 (s, 1H), 7.32 (t, J = 8.87 Hz, 2H), 7.50-7.55 (m, 2H), 7.58 (s, 1H), 7.61-7.66 (m, 2H), 7.75-7.82 (m, 2H), 7.94- 8.11 (m, 1H), 8.12-8.27 (m, 1H), 8.31 (d, J = 7.35 Hz, 1H) RP-HPLC (method C basic) rac-4-[4-amino-2-(N-(2-amino-1- LC-MS (method 2) Rt = 1.08 min methyl-2-oxo-ethyl)-4-fluoro- MS (ESIpos): m/z = 496.4 [M + H].sup.+ anilino)thiazole-5-carbonyl]-N- 47% yield cyclopentyi-benzamide 268 Intermediate 213, 2- phenoxy- ethanamine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.19 (d, J = 7.35 Hz, 3H), 3.58-3.65 (m, 2H), 4.09 (t, J = 5.83 Hz, 2H), 4.98-5.08 (m, 1H), 6.90-6.97 (m, 3H), 7.23- 7.34 (m, 3H), 7.48-7.53 (m, 1H), 7.55-7.59 (m, 2H), 7.61- 7.66 (m, 1H), 7.71-7.78 (m, 2H), 7.81-7.87 (m, 2H), 7.96- 8.57 (m, 2H), 8.71-8.77 (m, 1H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 1.15 min MS (ESIpos): m/z = 582.2 [M + H].sup.+ 16% yield rac-4-[4-amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-4-chloro-3- fluoro-anilino)thiazole-5-carbonyl]- N-(2-phenoxyethyl)benzamide 269 0 Intermediate 213, 2- (trifluoro- methoxy) ethanamine hydrochloride (1:1) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3H), 3.55 (q, J = 5.35 Hz, 2H), 4.18 (dd, J = 5.35 Hz, 2H), 4.99-5.07 (m, 1H), 7.30 (s, 1H), 7.51 (dt, J = 8.62, 1.14 Hz, 1H), 7.56-7.61 (m, 2H), 7.63 (s, 1H), 7.72-7.78 (m, 2H), 7.79-7.88 (m, 2H), 8.02-8.47 (m, 2H), 8.78 (t, J = 5.58 Hz, 1H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 1.11 min MS (ESIpos): m/z = 574.1 [M + H].sup.+ 32% yield rac-4-[4-amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-4-chloro-3- fluoro-anilino)thiazole-5-carbonyl]- N-[2- (trifluoromethoxy)ethyl]benzamide 270 Intermediate 213, 2- (difluoro- methoxy) ethanamine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3H), 3.48 (q, J = 5.58 Hz, 2H), 3.91- 3.96 (m, 2H), 4.98-5.09 (m, 1H), 6.68 (t, J = 76 Hz, 1H), 7.30 (s, 1H), 7.48-7.53 (m, 1H), 7.56- 7.60 (m, 2H), 7.63 (s, 1H), 7.70- 7.79 (m, 2H), 7.79-7.86 (m, 2H), 7.95-8.51 (m, 2H), 8.66- 8.71 (m, 1H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 1.02 min MS (ESIpos): m/z = 556.1 [M + H].sup.+ 18% yield rac-4-[4-amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-4-chloro-3- fluoro-anilino)thiazole-5-carbonyl]- N-2- (difluoromethoxy)ethyl]benzamide 271 Intermediate 213, 2-tert- butoxyethan- amine hydro- chloride (1:1) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.12 (s, 9H), 1.20 (d, J = 7.35 Hz, 3H), 3.27-3.33 (m, 2H), 3.37-3.43 (m, 2H), 4.98- 5.07 (m, 1H), 7.30 (s, 1H), 7.47- 7.54 (m, 1H), 7.54-7.59 (m, 2H), 7.63 (s, 1H), 7.71-7.78 (m, 2H), 7.79-7.84 (m, 2H), 7.97- 8.45 (m, 2H), 8.52 (t, J = 5.58 Hz, 1H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 1.02 min MS (ESIpos): m/z = 562.2 [M + H].sup.+ 33% yield rac-4-[4-amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-4-chloro-3- fluoro-anilino)thiazole-5-carbonyl]- N-(2-tert-butoxyethyl)benzamide 272 Intermediate 213, 2- methoxyethan- amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.20 (d, J = 7.35 Hz, 3H), 3.25 (s, 3H), 3.37-3.47 (m, 4H), 4.98-5.08 (m, 1H), 7.31 (s, 1H), 7.49-7.54 (m, 1H), 7.54-7.59 (m, 2H), 7.63 (s, 1H), 7.71-7.78 (m, 2H), 7.80-7.85 (m, 2H), 7.97-8.46 (m, 2H), 8.53-8.59 (m, 1H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.95 min MS (ESIpos): m/z = 520.2 [M + H].sup.+ 17% yield rac-4-[4-amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-4-chloro-3- fluoro-anilino)thiazole-5-carbonyl]- N-(2-methoxyethyl)benzamide 273 Intermediate 215, 1-(4- chlorophenyl) methan- amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3H), 1.45 (s, 6H), 4.23 (d, J = 6.08 Hz, 2H), 5.00-5.13 (m, 1H), 6.77- 6.82 (m, 2H), 7.13-7.19 (m, 2H), 7.24 (s, 1H), 7.27-7.36 (m, 4H), 7.38-7.45 (m, 2H), 7.57 (s, 1H), 7.64 (dd, J = 8.87, 5.07 Hz, 2H), 7.80-8.57 (m, 2H), 8.68 (t, J = 6.08 Hz, 1H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.23 min MS (ESIpos): m/z = 610.4 [M + H].sup.+ 77% yield rac-2-[4-[4-amino-2-(N-(2-amino- 1-methyl-2-oxo-ethyl)-4-fluoro- anilino)thiazole-5- carbonyl]phenoxy]-N-[(4- chlorophenyl)methyl]-2-methyl- propanamide

Example 274

rac-2-(N-[4-amino-5-(6-bromopyridine-3-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

(265) ##STR00735##

(266) [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](6-bromopyridin-3-yl)methanone (2.52 g, 6.4 mmol, Intermediate 218) was suspended in DMF (100 mL) and treated with rac-2-bromo propionamide (1.46 g, 9.6 mmol) and potassium carbonate (4.43 g, 32 mmol). The reaction mixture was stirred overnight at rt and then treated with water. After 30 min the precipitate was filtered off, washed with water and dried in vacuo to give 2.2 g (4.4 mmol, 69% yield) of the title compound.

(267) .sup.1H NMR (400 MHz, DMSO-da) ? ppm=1.16 (d, J=7.35 Hz, 3H), 5.05 (m, 1H), 7.27 (m, 1H), 7.34 (t, J=8.87 Hz, 2H), 7.65 (m, 4H), 7.80 (dd, J=8.24, 2.41 Hz, 1H), 8.25 (m, 2H), 8.48 (d, J=2.03 Hz, 1H).

(268) LC-MS (method 2): Rt=1.08 min; MS(ESIpos) m/z=466.1 [M+H].sup.+

Example 275

rac-2-(N-[4-amino-5-[6-[4-(trifluoromethyl)-1-piperidyl]pyridine-3-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

(269) ##STR00736##

(270) 2-(N-[4-amino-5-(6-bromopyridine-3-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (50 mg, 0.11 mmol, Example 274), 4-(trifluoromethyl)piperidine (25 mg, 0.16 mmol), tetrabutylammonium iodide (4 mg, 0.01 mmol) and potassium carbonate (18 mg, 0.13 mmol) were suspended in DMSO and stirred overnight at 50? C. The reaction mixture was filtrated and purified by RP-HPLC (method D) to yield 24 mg (0.04 mmol, 41%) of the title compound.

(271) .sup.1H NMR (400 MHz, DMSO-de) ? ppm=1.17 (d, J=7.35 Hz, 3H), 1.30-1.43 (m, 2H), 1.84 (br d, J=11.15 Hz, 2H), 2.56-2.65 (m, 1H), 2.87 (td, J=12.86, 2.15 Hz, 2H), 4.42-4.51 (m, 2H), 5.00-5.11 (m, 1H), 6.84 (d, J=8.87 Hz, 1H), 7.25 (s, 1H), 7.35 (t, J=8.87 Hz, 2H), 7.58 (s, 1H), 7.61-7.72 (m, 3H), 7.80-8.26 (m, 2H), 8.31 (d, J=2.28 Hz, 1H).

(272) LC-MS (method 2): Rt=1.25 min; MS(ESIpos) m/z=537.5 [M+H].sup.+

(273) The following examples were prepared from the starting materials stated in Table 11, below, using the procedure as for Example 275.

(274) The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (methods X, Y or Z depending on polarity) after precipitation, extraction or filtration of the reaction mixture if necessary.

(275) Enantiomers were separated from their racemate by chiral HPLC using the column and solvent conditions stated.

(276) TABLE-US-00011 TABLE 11 Examples 276-285.2 Example Chemical structure Starting number Compound name materials Analytics/purification/yield 276 Example 274, 4- methylpiper- idine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 0.89 (d, J = 6.08 Hz, 3H), 0.97-1.09 (m, 2H), 1.17 (d, J = 7.35 Hz, 3H), 1.57-1.68 (m, 3H), 2.76-2.87 (m, 2H), 4.32 (br d, J = 13.18 Hz, 2H), 5.01-5.10 (m, 1H), 6.78 (d, J = 8.87 Hz, 1H), 7.25 (s, 1H), 7.35 (t, J = 8.87 Hz, 2H), 7.58 (br s, 1H), 7.62-7.69 (m, 3H), 7.86-8.24 (m, 2H), 8.29 (d, J = 2.28 Hz, 1H) RP-HPLC (method D basic) rac-2-(N-[4-amino-5-[6-(4-methyl- LC-MS (method 2) Rt = 1.28 min 1-piperidyl)pyridine-3- MS (ESIpos): m/z = 438.3 [M + H].sup.+ carbonyl]thiazol-2-yl]-4-fluoro- 56% yield anilino)propanamide 277 Example 274, 4-(oxetan-3- yl)piperidine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 0.94 (br dd, J = 12.29, 3.42 Hz, 2H), 1.16 (d, J = 7.35 Hz, 3H), 1.61 (br d, J = 11.15 Hz, 2H), 1.81-1.94 (m, 1H), 2.63-2.73 (m, 1H), 2.79-2.89 (m, 2H), 4.30-4.40 (m, 4H), 4.59 (dd, J = 7.86, 6.08 Hz, 2H), 5.05 (q, J = 7.10 Hz, 1H), 6.79 (d, J = 8.87 Hz, 1H), 7.25 (s, 1H), 7.34 (t, J = 8.87 Hz, 2H), 7.58 (s, 1H), 7.60-7.70 (m, 3H), 7.80-8.23 rac-2-(N-[4-amino-5-[6-[4-(oxetan- (m, 2H), 8.29 (d, J = 2.53 Hz, 1H) 3-yl)-1-piperidyl]pyridine-3- RP-HPLC (method D basic) carbonyl]thiazol-2-yl]-4-fluoro- LC-MS (method 2) Rt = 1.06 min anilino)propanamide MS (ESIpos): m/z = 525.5 [M + H].sup.+ 60% yield 278 Example 274, N- methylmethan- amine .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 1.17 (d, J = 7.25 Hz, 3H), 3.03 (s, 6H), 5.01-5.09 (m, 1H), 6.61 (d, J = 8.83 Hz, 1H), 7.25 (s, 1H), 7.35 (t, J = 8.83 Hz, 2H), 7.58 (s, 1H), 7.63-7.70 (m, 3H), 7.82-8.26 (m, 2H), 8.30 (d, J = 2.21 Hz, 1H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 1.04 min MS (ESIpos): m/z = 429.5 [M + H].sup.+ 51% yield rac-2-(N-[4-amino-5-[6- (dimethylamino)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide 279 0 Example 274, 4,4- dimethylpiper- idine hydrochloride (1:1) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 0.95 (s, 6H), 1.17 (d, J = 7.35 Hz, 3H), 1.28-1.34 (m, 4H), 3.52-3.60 (m, 4H), 5.00- 5.12 (m, 1H), 6.78 (d, J = 9.13 Hz, 1H), 7.25 (s, 1H), 7.35 (t, J = 8.87 Hz, 2H), 7.55-7.61 (m, 1H), 7.62-7.69 (m, 3H), 7.80-8.24 (m, 2H), 8.29 (d, J = 2.53 Hz, 1H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 1.37 min MS (ESIpos): m/z = 497.5 [M + H].sup.+ 59% yield rac-2-(N-[4-amino-5-[6-(4,4- dimethyl-1-piperidyl)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide 280 Example 274, 3- azabicyclo [3.2.1]octane hydrochloride (1:1) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.16 (d, J = 7.35 Hz, 3H), 1.37-1.46 (m, 2H), 1.50-1.56 (m, 2H), 1.56-1.67 (m, 2H), 2.26-2.32 (m, 2H), 2.85 (d, J = 10.39 Hz, 2H), 3.93 (br d, J = 10.65 Hz, 2H), 4.99-5.10 (m, 1H), 6.67 (d, J = 8.87 Hz, 1H), 7.25 (s, 1H), 7.34 (t, J = 8.87 Hz, 2H), 7.58 (s, 1H), 7.61-7.69 (m, 3H), 7.75-8.25 (m, 2H), 8.29 (d, J = 2.53 Hz, 1H) rac-2-(N-[4-amino-5-[6-(3- RP-HPLC (method D basic) azabicyclo[3.2.1]octan-3- LC-MS (method 2) Rt = 1.29 min yl)pyridine-3-carbonyl]thiazol-2- MS (ESIpos): m/z = 495.3 [M + H].sup.+ yl]-4-fluoro-anilino)propanamide 60% yield 281 Example 274, 3,5- dimethylpiper- idine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 0.87 (d, J = 6.59 Hz, 6H), 1.17 (d, J = 7.60 Hz, 3H), 1.44- 1.57 (m, 2H), 1.75 (br d, J = 12.42 Hz, 1H), 2.25-2.34 (m, 2H), 4.34 (br d, J = 9.89 Hz, 2H), 5.01- 5.12 (m, 1H), 6.80 (d, J = 8.87 Hz, 1H), 7.25 (s, 1H), 7.35 (t, J = 8.74 Hz, 2H), 7.58 (s, 1H), 7.62-7.70 (m, 3H), 7.81-8.26 (m, 2H), 8.29 (d, J = 2.53 Hz, 1H), 0.78 (q, J = 12 Hz, 1H) RP-HPLC (method D basic) rac-2-(N-[4-amino-5-[6-(3,5- LC-MS (method 2) Rt = 1.37 min dimethyl-1-piperidyl)pyridine-3- MS (ESIpos): m/z = 497.3 [M + H].sup.+ carbonyl]thiazol-2-yl]-4-fluoro- 59% yield anilino)propanamide 282 Example 274, 3- azabicyclo [3.1,0]hexane hydrochloride (1:1) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 0.13 (d, J = 4.31 Hz, 1H), 0.72 (td, J = 7.67, 4.69 Hz, 1H), 1.16 (d, J = 7.35 Hz, 3H), 1.63- 1.69 (m, 2H), 3.34-3.41 (m, 2H), 3.63 (br d, J = 10.39 Hz, 2H), 5.05 (br d, J = 7.35 Hz, 1H), 6.42 (d, J = 8.62 Hz, 1H), 7.25 (s, 1H), 7.34 (t, J = 8 74 Hz, 2H), 7.58 (s, 1H), 7.60-7.70 (m, 3H), 7.83- 8.22 (m, 2H), 8.27 (d, J = 2.28 Hz, 1H) rac-2-(N-[4-amino-5-[6-(3- RP-HPLC (method D basic) azabicyclo[3.1.0]hexan-3- LC-MS (method 2) Rt = 1.12 min yl)pyridine-3-carbonyl]thiazol-2- MS (ESIpos): m/z = 467.3 [M + H].sup.+ yl]-4-fluoro-anilino)propanamide 72% yield 283 Example 274, piperidine .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.17 (d, J = 7.35 Hz, 3H), 1.45-1.55 (m, 4H), 1.56-1.64 (m, 2H), 3.53-3.59 (m, 4H), 5.00-5.10 (m, 1H), 6.78 (d, J = 9.12 Hz, 1H), 7.25 (s, 1H), 7.35 (t, J = 8.74 Hz, 2H), 7.58 (s, 1H), 7.62-7.70 (m, 3H), 7.80- 8.23 (m, 2H), 8.29 (d, J = 2.28 Hz, 1H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 1.22 min rac-2-(N-[4-amino-5-[6-(1- MS (ESIpos): m/z = 469.5 [M + H].sup.+ piperidyl)pyridine-3- 100% yield carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide 284 Example 274, 4,4- difluoropiper- idine hydrochloride (1:1) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 5 ppm = 1.17 (d, J = 7.60 Hz, 3H), 1.90-2.03 (m, 4H), 3.69-3.76 (m, 4H), 5.00-5.11 (m, 1H), 6.93 (d, J = 9.13 Hz, 1H), 7.25 (s, 1H), 7.35 (t, J = 8.74 Hz, 2H), 7.58 (s, 1H), 7.62-7.72 (m, 3H), 7.80-8.26 (m, 2H), 8.31-8.34 (m, 1H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 1.09 min MS (ESIpos): m/z = 466.2 [M + H].sup.+ 26% yield rac-2-(N-[4-amino-5-[6-(4,4- difluoro-1-piperidyl) pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide 285 Example 274, 4- methylpiper- idine-4- carbonitrile hydrochloride (1:1) .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 1.17 (d, J = 7.25 Hz, 3H), 1.35 (s, 3H), 1.49 (td, J = 12.77, 4.10 Hz, 2H), 1.90 (br d, J = 13.87 Hz, 2H), 2.97-3.05 (m, 2H), 4.36 (br d, J = 13.87 Hz, 2H), 5.01- 5.10 (m, 1H), 6.86 (d, J = 8.83 Hz, 1H), 7.25 (s, 1H), 7.35 (t, J = 8.83 Hz, 2H), 7.58 (s, 1H), 7.63-7.70 (m, 3H), 7.78-8.29 (m, 2H), 8.31 (d, J = 2.21 Hz, 1H) RP-HPLC (method D basic) LC-MS (method 2) Rt = 1.04 min rac-2-(N-[4-amino-5-[6-(4-cyano- MS (ESIpos): m/z = 508.8 [M + H].sup.+ 4-methyl-1-piperidy!)pyridine-3- 64% yield carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide 285.1 (R)-2-(N-[4-amino-5-[6-(4-cyano- and 4-methyl-1-piperidyl)pyridine-3- 285.2 carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide and (S)-2-(N- [4-amino-5-[6-(4-cyano-4-methyl- 1-piperidyl)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide 285.1 Example 285 .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 1.17 (d, J = 7.25 Hz, 3H), 1.35 (s, 3H), 1.49 (td, J = 12.77, 4.10 Hz, 2H), 1.90 (br d, J = 13.87 Hz, 2H), 2.97-3.05 (m, 2H), 4.36 (br d, J = 13.87 Hz, 2H), 5.01- 5.10 (m, 1H), 6.86 (d, J = 8.83 Hz, 1H), 7.25 (s, 1H), 7.35 (t, J = 8.83 Hz, 2H), 7.58 (s, 1H), 7.63-7.70 (m, 3H), 7.78-8.29 (m, 2H), 8.31 (d, J = 2.21 Hz, 1H) LC-MS (method 2) Rt = 1.04 min 2-(N-[4-amino-5-[6-(4-cyano-4- MS (ESIpos): m/z = 508.8 [M + H].sup.+ methyl-1-piperidyl)pyridine-3- 39% yield carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide (enantiomer 1) Chiral HPLC Example 285.1 HPLC separation of rac-2-(N-[4-amino-5-[6-(4-cyano-4-methyl-1-piperidyl)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (98 mg, 0.19 mmol, Example 285) on a chiral column gave 38 mg (39% yield) of 2-(N-[4-amino-5-[6-(4-cyano-4-methyl-1-piperidyl)pyridine-3- carbonyl]tiazol-2-yl]-4-fluoro-anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.37 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm 285.2 Example 285 .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? ppm = 1.17 (d, J = 7.25 Hz, 3H), 1.35 (s, 3H), 1.49 (td, J = 12.77, 4.10 Hz, 2H), 1.90 (br d, J = 13.87 Hz, 2H), 2.97-3.05 (m, 2H), 4.36 (br d, J = 13.87 Hz, 2H), 5.01- 5.10 (m, 1H), 6.86 (d, J = 8.83 Hz, 1H), 7.25 (s, 1H), 7.35 (t, J = 8.83 Hz, 2H), 7.58 (s, 1H), 7.63-7.70 (m, 3H), 7.78-8.29 (m, 2H), 8.31 (d, J = 2.21 Hz, 1H) LC-MS (method 2) Rt = 1.04 min MS (ESIpos): m/z = 508.8 [M + H].sup.+ 2-(N-[4-amino-5-[6-(4-cyano-4- 42% yield methyl-1-piperidyl)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro- anilino)propanamide (enantiomer 2) Chiral HPLC Example 285.2 HPLC separation of rac-2-(N-[4-amino-5-[6-(4-cyano-4-methyl-1-piperidyl)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (98 mg, 0.19 mmol, Example 285) on a chiral column gave 41 mg (42% yield) of 2-(N-[4-amino-5-[6-(4-cyano-4-methyl-1-piperidyl)pyridine-3- carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Cellulose SC 10?, 250 ? 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 100 mL/min; temperature: 25? C.; UV: 254 nm Analyticalchiral HPLC: Rt = 3.22 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3?, 100 ? 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 50% A + 50% B; flow: 1.4 mL/min; temperature: 25? C.; UV: 254 nm

Example 286

2-(N-[4-amino-5-(4-hydroxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (single enantiomer)

(277) ##STR00749##

(278) 2-(N-[4-amino-5-(4-benzyloxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (enantiomer 2, example 170.2, 41 mg, 0.084 mmol) was solved in ethanol (1 mL). Under nitrogen, Pd/C (133 mg) was added and the reaction mixture was purged with H.sub.2 and stirred under atmospheric H.sub.2 for 5 h at rt. The mixture was filtrated via Celite and the solvent was evaporated under reduced pressure. The residue was purified by RP-HPLC (method B) to yield 22 mg (0.05 mmol, 61%) of the title compound.

(279) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm=1.16 (d, J=7.35 Hz, 3H), 4.99-5.10 (m, 1H), 6.70-6.75 (m, 2H), 7.24 (s, 1H), 7.30-7.40 (m, 4H), 7.57 (s, 1H), 7.61-7.66 (m, 2H), 7.84-8.32 (m, 2H), 9.90 (br s, 1H).

(280) LC-MS (method 2): Rt=0.68 min; MS(ESIpos) m/z=401.3 [M+H].sup.+

(281) The following examples were prepared from the starting materials stated in Table 12, below, using the procedure as for Example 286.

(282) The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (methods X, Y or Z depending on polarity) after precipitation, extraction or filtration of the reaction mixture if necessary.

(283) Enantiomers were separated from their racemate by chiral HPLC using the column and solvent conditions stated.

(284) TABLE-US-00012 TABLE 12 Examples 287-291 Example Chemical structure number Compound name Starting materials Analytics/purification/yield 287 0 Example 165.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.35 Hz, 3H), 4.96-5.06 (m, 1H), 6.72 (d, J = 8.62 Hz, 2H), 7.28 (s, 1H), 7.37-7.43 (m, 2H), 7.48-7.54 (m, 1H), 7.55-7.64 (m, 2H), 7.72-7.83 (m, 1H), 7.83-8.25 (m, 2H) RP-HPLC (method B basic) LC-MS (method 2) Rt = 0.68 min MS (ESIpos): m/z = 419.3 [M + H].sup.+ 2-(N-[4-amino-5-(4- 49% yield hydroxybenzoyl)thiazol-2- yl]-3,4-difluoro- anilino)propanamide (enantiomer 1) 288 Example 165.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.18 (d, J = 7.35 Hz, 3H), 4.96-5.06 (m, 1H), 6.72 (d, J = 8.62 Hz, 2H), 7.28 (s, 1H), 7.37-7.43 (m, 2H), 7.48-7.54 (m, 1H), 7.55-7.64 (m, 2H), 7.72-7.83 (m, 1H), 7.83-8.25 (m, 2H) RP-HPLC (method B basic) LC-MS (method 2) Rt = 0.68 min MS (ESIpos): m/z = 419.3 [M + H].sup.+ 2-(N-[4-amino-5-(4- 43% yield hydroxybenzoyl)thiazol-2- yl]-3,4-difluoro- anilino)propanamide (enantiomer 2) 289 Example 166.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.19 (d, J = 7.35 Hz, 3H), 4.97-5.06 (m, 1H), 6.72-6.78 (m, 2H), 7.29 (s, 1H), 7.38-7.46 (m, 2H), 7.51 (dt, J = 8.49, 1.20 Hz, 1H), 7.62 (s, 1H), 7.71-7.79 (m, 2H), 7.83-8.26 (m, 2H), 9.93 (s, 1H) Biotage (method X) LC-MS (method 2) Rt = 0.76 min MS (ESIpos): m/z = 435.2 [M + H].sup.+ 2-(N-[4-amino-5-(4- 21% yield hydroxybenzoyl)thiazol-2- yl]-4-chloro-3-fluoro- anilino)propanamide (enantiomer 1) 290 Example 166.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.19 (d, J = 7.35 Hz, 3H), 4.97-5.06 (m, 1H), 6.72-6.78 (m, 2H), 7.29 (s, 1H), 7.38-7.46 (m, 2H), 7.51 (dt, J = 8.49, 1.20 Hz, 1H), 7.62 (s, 1H), 7.71-7.79 (m, 2H), 7.83-8.26 (m, 2H), 9.93 (s, 1H) Biotage (method X) LC-MS (method 2) Rt = 0.76 min MS (ESIpos): m/z = 435.2 [M + H].sup.+ 2-(N-[4-amino-5-(4- 27% yield hydroxybenzoyl)thiazol-2- yl]-4-chloro-3-fluoro- anilino)propanamide (enantiomer 2) 291 Example 182.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm = 1.14 (d, J = 7.35 Hz, 3H), 4.96-5.13 (m, 1H), 6.80 (d, J = 8.87 Hz, 2H), 7.14-7.21 (m, 3H), 7.27 (t, J = 72 Hz, 1H), 7.32 (d, J = 8.62 Hz, 2H), 7.49 (s, 1H), 7.52-7.58 (m, 2H), 7.78-8.55 (m, 2H), 9.85 (s, 1H) RP-HPLC (method B basic) LC-MS (method 2) Rt = 0.68 min MS (ESIpos): m/z = 449.3 [M + H].sup.+ 47% yield 2-(N-[4-amino-5-[4- (difluoromethoxy)benzoyl] thiazol-2-yl]-4-hydroxy- anilino)propanamide (single enantiomer)

Example 292

rac-2-(N-[4-amino-5-[4-(2-hydroxyethoxy)benzoyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

(285) ##STR00755##

(286) [4-amino-2-(4-fluoroanilino)thiazol-5-yl]-[4-(2-hydroxyethoxy)phenyl]methanone (Intermediate 209, 74 mg, 0.2 mmol) was suspended in DMF (4 mL) and treated with rac-2-bromopropamide (30 mg, 0.2 mmol) and potassium carbonate (137 mg, 0.2 mmol). The reaction mixture was stirred at rt for 4 days. The filtrate was purified by RP-HPLC (method C, basic) to give 47 mg (53% yield) of the title compound.

(287) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm=1.15 (d, J=7.35 Hz, 3H) 3.64-3.71 (m, 2H) 3.98 (t, J=4.94 Hz, 2H) 4.87-4.93 (m, 1H) 5.00-5.11 (m, 1H) 6.88-6.95 (m, 2H) 7.23 (s, 1H) 7.30-7.36 (m, 2H) 7.44-7.49 (m, 2H) 7.56-7.60 (m, 1H) 7.61-7.66 (m, 2H) 7.74-8.34 (m, 2H) 9.02-9.07 (m, 1H).

(288) LC-MS (method 1): Rt=0.84 min; MS(ESIpos) m/z=445.6 [M+H].sup.+.

EXPERIMENTAL SECTIONDETERMINATION OF ABSOLUTE STEREOCHEMISTRY BY MEANS OF X-RAY-ANALYSIS

(289) Determination of the Absolute Configuration of Example 49.2

(R)-2-(N-[4-amino-5-[4-(difluoromethoxy)benzoyl]thiazol-2-yl]-3,4-difluoro-anilino)propanamide

(290) The crystallographic data of Example 49.2 as well as a figure depicting the thermal ellipsoids and numbering of the structure, are shown in Table 13 and FIG. 6. Colorless crystals of Example 49.2 were obtained by slow evaporation of an ethanol solution. A single crystal was mounted on a cryoloop using a protective oil. Single-crystal X-ray diffraction data were collected at 100 K on a Rigaku XtaLAB Synergy S system with a kappa goniometer and a HyPix-6000HE hybrid photon detector using Cu X-ray radiation (CuK?, =1.54178 ?). Data were integrated using the program CrysAlisPRO. SHELXM was used for structure solution and SHELXL was used for full-matrix least-squares refinement on F2. In the asymmetric unit two molecules of Example 49.2 and two water molecules are present. The di-fluorinated phenyl rings in both molecules are disordered via a 180? rotation of the ring systems. The occupancies for the alternative positions were refined to 0.25/0.75 in Molecule A and 0.35/0.65 in Molecule B, respectively. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were added in calculated positions and refined riding on their resident atoms. Hydrogens attached to the nitrogen atoms in 49.2 as well as at the water molecules were located in the difference Fourier map and placed manually. The isotropic temperature factors of the hydrogen atoms were refined as 1.2 and 1.5 times the size of the temperature factors of the corresponding heavy atoms, respectively. The absolute stereochemistry (R-configuration) could be assigned unambiguously with a Flack Parameter of 0.008(7). The program XP was used for molecular representations.

(291) TABLE-US-00013 TABLE 13 Crystal data and structure refinement for Example 49.2 Identification code Example 49.2 Empirical formula C40 H36 F8 N8 O8 S2 Formula weight 972.89 Temperature 100(2) K Wavelength 1.54184 ? Crystal system Triclinic Space group P1 Unit cell dimensions a = 7.59740(10) ? a = 78.1410(10)?. b = 9.28630(1) ? b = 89.0340(10)?. c = 15.1835(2) ? g = 83.8330(10)?. Volume 1042.28(2) ?.sup.3 Z 1 Density (calculated) 1.550 Mg/m.sup.3 Absorption coefficient 2.049 mm.sup.?1 F(000) 500 Crystal size 0.050 ? 0.040 ? 0.160 mm.sup.3 Theta range for data collection 2.974 to 68.246?. Index ranges ?9 <= h <= 9, ?11 <= k <= 11, ?18 <= l <= 18 Reflections collected 74868 Independent reflections 7441 (R(int) = 0.0428] Completeness to theta = 67.684? 99.9% Refinement method Full-matrix least-squares on F.sup.2 Data/restraints/parameters 7441/153/651 Goodness-of-fit on F.sup.2 1.044 Final R indices (I > 2sigma(I)] R1 = 0.0425, wR2 = 0.1062 R indices (all data) R1 = 0.0437, wR2 = 0.1072 Absolute structure parameter 0.008(7) Extinction coefficient n/a Largest diff. peak and hole 0.879 and ?0.502 e.?.sup.?3

(292) Determination of the Absolute Configuration of Example 59.1

(R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-chloro-3-fluoro-anilino)propanamide

(293) The crystallographic data of Example 59.1 as well as a figure depicting the thermal ellipsoids and numbering of the structure, are shown in Table 14 and FIG. 7. Colorless crystals of Example 59.1 were obtained by slow evaporation from a toluene solution. A single crystal was mounted on a cryoloop using a protective oil. Single-crystal X-ray diffraction data were collected at 100 K on a Rigaku XtaLAB Synergy S system with a kappa goniometer and a HyPix-6000HE hybrid photon detector using Cu X-ray radiation (CuK?, =1.54178 ?). Data were integrated using the program CrysAlisPRO. SHELXM was used for structure solution and SHELXL was used for full-matrix least-squares refinement on F2. In the asymmetric unit four molecules of Example 59.1 and one disordered toluene molecules are present. The fluorinated phenyl ring systems in three of the four molecules are disordered via a 180? rotation of the ring systems. The occupancies for the alternative positions were refined to 0.30/0.70 in Molecule B, 0.20/0.80 in Molecule C and 0.15/0.85 in Molecule D, respectively. The toluene solvent molecule is disordered over a pseudo 2-fold axis and the occupancies for both alternative positions refined with a ratio of 0.45/0.55. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were added in calculated positions and refined riding on their resident atoms. Hydrogens attached to amine and amide nitrogen atoms were either located in the difference Fourier map and placed manually or were refined using the riding model. The isotropic temperature factors of the hydrogen atoms were refined as 1.2 and 1.5 times the size of the temperature factors of the corresponding heavy atoms, respectively. The absolute stereochemistry (R-configuration) could be assigned unambiguously with a Flack Parameter of 0.015(11). The program XP was used for molecular representations.

(294) TABLE-US-00014 TABLE 14 Crystal data and structure refinement for Example 59.1 Identification code 59.1 Empirical formula C20 H18 N4 O3 F Cl S + 0.25 (C7 H8) Formula weight 448.9 + 23.0 Temperature 100(2) K Wavelength 1.54178 ? Crystal system Triclinic Space group P1 Unit cell dimensions a = 8.9781(2) ? a = 103.099(2)?. b = 13.3867(3) ? b = 92.827(2)?. c = 18.9350(3) ? g = 101.417(2)?. Volume 2162.07(8) ?.sup.3 Z 4 Density (calculated) 1.450 Mg/m.sup.3 Absorption coefficient 2.827 mm.sup.?1 F(000) 978 Crystal size 0.070 ? 0.060 ? 0.005 mm.sup.3 Theta range for data collection 2.407 to 68.401?. Index ranges ?10 <= h <= 10, ?16 <= k <= 16, ?22 <= l <= 22 Reflections collected 76934 Independent reflections 15381 [R(int) = 0.0650] Completeness to theta = 67.679? 100.0% Refinement method Full-matrix least-squares on F.sup.2 Data/restraints/parameters 15381/1400/1272 Goodness-of-fit on F.sup.2 1.003 Final R indices (I > 2sigma(I)] R1 = 0.0496, wR2 = 0.1120 R indices (all data) R1 = 0.0605, wR2 = 0.1185 Absolute structure parameter 0.015(11) Extinction coefficient n/a Largest diff. peak and hole 0.462 and ?0.430 e.?.sup.?3

(295) Determination of the Absolute Configuration of Example 61.2

(R)-2-(N-(4-amino-5-benzoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide

(296) The crystallographic data of Example 61.2 as well as a figure depicting the thermal ellipsoids and numbering of the structure, are shown in Table 15 and FIG. 8. Colorless crystals of Example 61.2 were obtained by slow evaporation from an acetonitrile solution. A single crystal was mounted on a cryoloop using a protective oil. Single-crystal X-ray diffraction data were collected at 100 K on a Rigaku XtaLAB Synergy S system with a kappa goniometer and a HyPix-6000HE hybrid photon detector using Cu X-ray radiation (CuK?, =1.54178 ?). Data were integrated using the program CrysAlisPRO. SHELXM was used for structure solution and SHELXL was used for full-matrix least-squares refinement on F2. In the asymmetric unit eight molecules of Example 61.2 and two water molecules are present. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were added in calculated positions and refined riding on their resident atoms. Hydrogens attached to amine and amide nitrogen atoms were either located in the difference Fourier map and placed manually or were refined using the riding model. The isotropic temperature factors of the hydrogen atoms were refined as 1.2 and 1.5 times the size of the temperature factors of the corresponding heavy atoms, respectively. The absolute stereochemistry (R-configuration) could be assigned unambiguously with a Flack Parameter of 0.027(11). The program XP was used for molecular representations.

(297) TABLE-US-00015 TABLE 15 Crystal data and structure refinement for Example 61.2 Identification code Example 61.2 Empirical formula C19 H20 F N4 O2 S + 0.1875 H2 O Formula weight 390.45 Temperature 100(2) K Wavelength 1.54178 ? Crystal system Tetragonal Space group P4(1) Unit cell dimensions a = 17.135 ? a = 90?. b = 17.135 ? b = 90?. c = 49.3911(2) ? g = 90?. Volume 14502.48(6) ?.sup.3 Z 32 Density (calculated) 1.431 Mg/m.sup.3 Absorption coefficient 1.886 mm.sup.?1 F(000) 6544 Crystal size 0.3 ? 0.2 ? 0.1 mm.sup.3 Theta range for data collection 2.58 to 77.25?. Index ranges ?14 <= h <= 15, 0 <= k <= 21, ?59 <= l <= 61 Reflections collected 178451 Independent reflections 26790 [R(int) = 0.0513] Completeness to theta = 77.25? 91.2% Refinement method Full-matrix least-squares on F.sup.2 Data/restraints/parameters 26790/1889/2043 Goodness-of-fit on F.sup.2 1.315 Final R indices (I > 2sigma(I)] R1 = 0.0508, wR2 = 0.1276 R indices (all data) R1 = 0.0538, wR2 = 0.1292 Absolute structure parameter 0.027(11) Largest diff. peak and hole 0.475 and ?0.425 e.?.sup.?3

(298) Determination of the Absolute Configuration of Example 62.2

(R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

(299) The crystallographic data of Example 62.2 as well as a figure depicting the thermal ellipsoids and numbering of the structure, are shown in Table 16 and FIG. 9. Colorless crystals of Example 62.2 were already present in the purified sample. A single crystal was mounted on a cryoloop using a protective oil. Single-crystal X-ray diffraction data were collected at 100 K on a Rigaku XtaLAB Synergy S system with a kappa goniometer and a HyPix-6000HE hybrid photon detector using Cu X-ray radiation (CuK?, =1.54178 ?). Data were integrated using the program CrysAlisPRO. SHELXM was used for structure solution and SHELXL was used for full-matrix least-squares refinement on F2. In the asymmetric unit two molecules of Example 62.2 are present. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were added in calculated positions and refined riding on their resident atoms. Hydrogens attached to the nitrogen atoms were located in the difference Fourier map and placed manually. The isotropic temperature factors of the hydrogen atoms were refined as 1.2 and 1.5 times the size of the temperature factors of the corresponding heavy atoms, respectively. The absolute stereochemistry (R-configuration) could be assigned unambiguously with a Flack Parameter of 0.004(3). The program XP was used for molecular representations.

(300) TABLE-US-00016 TABLE 16 Crystal data and structure refinement for Example 62.2 Identification code Example 62.2 Empirical formula C40 H38 F2 N8 O6 S2 Formula weight 828.90 Temperature 100(2) K Wavelength 1.54184 ? Crystal system Monoclinic Space group I2 Unit cell dimensions a = 14.128 ? a = 90?. b = 13.01730(10) ? b = 92.60?. c = 21.74910(10) ? g = 90?. Volume 3995.63(4) ?.sup.3 Z 4 Density (calculated) 1.378 Mg/m.sup.3 Absorption coefficient 1.778 mm.sup.?1 F(000) 1728 Crystal size 0.100 ? 0.070 ? 0.020 mm.sup.3 Theta range for data collection 3.656 to 77.353?. Index ranges ?17 <= h <= 17, ?16 <= k <= 15, ?27 <= l <= 27 Reflections collected 75900 Independent reflections 8071 [R(int) = 0.0302] Completeness to theta = 67.684? 100.0% Refinement method Full-matrix least-squares on F.sup.2 Data/restraints/parameters 8071/1/551 Goodness-of-fit on F.sup.2 1.065 Final R indices [I > 2sigma(I)] R1 = 0.0226, wR2 = 0.0591 R indices (all data) R1 = 0.0227, wR2 = 0.0592 Absolute structure parameter ?0.004(3) Extinction coefficient n/a Largest diff. peak and hole 0.151 and ?0.239 e.?.sup.?3

EXPERIMENTAL SECTIONBIOLOGICAL ASSAYS AND BIOLOGICAL DATA

(301) Table 17, below, lists the abbreviations used in this paragraph and in the Assays section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.

(302) TABLE-US-00017 TABLE 17 Abbreviations nL nanoliter ?L microliter mL milliliter nM nanomolar ?M micromolar mM millimolar min minute(s) s second(s) kDa kilodalton MW molecular weight cAMP cyclic adenosine monophosphat ADP adenosine diphosphate ATP adenosine triphosphate FCS fetal calf serum FBS fetal bovine serum PBS phosphate buffered saline RPMI Roswell Park Memorial Institute ACK lysing buffer ammonium-chloride-potassium lysis buffer DMEM Dulbecco's Modified Eagle's Medium HEPES 2-[4-(2-hydroxyethyl)piperazin-1- yl]ethanesulfonic acid MOPS 3-(N-morpholino)propanesulfonic acid Pen/Strep penicillin and streptomycin HBS-P+ buffer containing 0.1M HEPES, 1.5M NaCl and 0.5% v/v Surfactant P20 DTT DL-Dithiothreitol BGG bovine gamma globulin PBMC peripheral blood mononuclear cells APC antigen presenting cells CD cluster of differentiation IgG immunoglobulin G OKT3 CD3 monoclonal antibody FLAG-Tag amino acid sequence DYKDDDDK DNA deoxyribonucleic acid CFSE carboxyfluorescein succinimidyl ester OVA ovalbumin antigen FACS fluorescence-activated cell sorting s.c. subcutaneous i.v. intravenous i.p. intraperitoneal n.d. not determined

(303) Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

(304) Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.

(305) The in vitro activity of the compounds of the present invention can be demonstrated in the following assays:

(306) Human DGK? Kinase Activity Inhibition Assay.

(307) Human diacylglycerol kinase zeta (DGK?) inhibitory activity of compounds of the present invention was quantified employing the human DGK? kinase activity assay as described in the following paragraphs. In essence, the enzyme activity was measured by quantification of the adenosine-di-phosphate (ADP) generated as a co-product of the enzyme reaction via the ADP-Glo? Kinase Assay kit from the company Promega. This detection system works as follows: In a first step the adenosine-tri-phosphate (ATP) not consumed in the kinase reaction is quantitatively converted to cyclic adenosine-mono-phosphate (cAMP) employing an adenylate cyclase (ADP-Glo-reagent), then the adenylate cyclase is stopped and the ADP generated in the kinase reaction is converted to ATP, which subsequently generates in a luciferase-based reaction a glow-luminescence signal (Kinase Detection Reagent).

(308) C-terminally FLAG-tagged, recombinant full-length human DGK? (in house expressed in baculovirus infected insect cells, purified using anti-Flag pulldown and size exclusion chromatography) was used as enzyme. As an alternative, commercially available enzyme by Carnabio can be used. As substrate for the kinase, 1,2-dioleoyl-sn-glycerol, reconstituted in octyl-?-D-glucopyranoside micelles, was used. For the preparation of the micelles, 1 volume of a 16.1 mM solution of 1,2-dioleoyl-sn-glycerol (Avanti, Cat. #O8001-25G) in chloroform was slowly evaporated using a nitrogen stream. Subsequently, 22.55 volumes of a 510 mM solution of octyl-?-D-glucopyranoside (Sigma-Aldrich, Cat. #O8001-10G) in 50 mM MOPS buffer (pH 7.4) were added, and the mixture was sonicated in an ultrasonic bath for 20 s. Then 35 volumes of 50 mM MOPS buffer (pH 7.4) were added to yield a solution of 0.28 mM 1,2 dioleoyl-sn-glycerol and 200 mM octyl-?-D-glucopyranoside, which was aliquoted, flash-frozen in liquid nitrogen, and stored at ?20? C. until use. For each experiment, a fresh aliquot was quickly thawed and diluted 24-fold with aqueous assay buffer (described below) containing 95.7 ?M adenosine triphosphate (Promega) to yield a 1.67-fold concentrated substrate solution.

(309) For the assay 50 nl of a 100-fold concentrated solution of the test compound in dimethyl sulfoxide (DMSO, Sigma) was pipetted into either a white 1536-well or a white low-volume 384-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany). Subsequently, 2 ?l of a solution of human DGK? in aqueous assay buffer [50 mM (3-(N-morpholino)propanesulfonic acid (MOPS, pH 7.4, Sigma-Aldrich), 1 mM dithiothreitol (DTT, Sigma-Aldrich), 100 mM NaCl (Sigma-Aldrich), 10 mM MgCl.sub.2 (Sigma-Aldrich), 0.1% (w/v) bovine gamma globulin (BGG, Sigma-Aldrich), 1 ?M CaCl.sub.2 (Sigma-Aldrich)] were added to the wells, and the mixture was incubated for 15 min at 22? C. to allow pre-binding of the test compounds to the enzyme. The reaction was initiated by the addition of 3 ?L of substrate solution [preparation described above; 11.7 ?M 1,2-dioleoyl-sn-glycerol (=>final conc. in the 5 ?L assay volume is 7 ?M), 8.33 mM octyl-?-D-glucopyranoside (=>final conc. in 5 ?L assay volume is 5 mM), and 91.67 ?M adenosine triphosphate (=>final conc. in 5 ?L assay volume is 55 ?M) in assay buffer] and the resulting mixture was incubated for a reaction time of 20 min at 22? C. The concentration of DGK? was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, a typical concentration is about 0.1 nM. The reaction was stopped by the addition of 2.5 ?L of ADP-Glo-reagent (1 to 1.5 diluted with water) and the resulting mixture was incubated at 22? C. for 1 h to convert the ATP not consumed in the kinase reaction completely to cAMP. Subsequently 2.5 ?l of the kinase detection reagent (1.2 fold more concentrated than recommended by the producer) were added, the resulting mixture was incubated at 22? C. for 1 h and then the luminescence measured with a suitable measurement instrument (e.g. Viewlux? from Perkin-Elmer). The amount of emitted light was taken as a measure for the amount of ADP generated and thereby for the activity of the DGK?.

(310) The data were normalised (enzyme reaction without inhibitor=0% inhibition, all other assay components but no enzyme=100% inhibition). Usually the test compounds were tested on the same microtiterplate in 11 different concentrations in the range of 20 ?M to 0.07 nM (20 ?M, 5.7 ?M, 1.6 ?M, 0.47 ?M, 0.13 ?M, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series prepared separately before the assay on the level of the 100 fold concentrated solutions in DMSO by serial dilutions, exact concentrations may vary depending pipettors used) in duplicate values for each concentration and IC.sub.50 values were calculated using Genedata Screener? software.

(311) TABLE-US-00018 TABLE 18 IC.sub.50 values of examples in in vitro human DGK? kinase activity inhibition assays. Example number IC.sub.50 [nM] 1 946 2 935 3 927 4 833 5 757 6 740 7 705 8 618 9 536 10 425 11 406 12 364 13 357 14 334 15 266 16 283 17 261 18 207 19 200 20 161 21 142 21.1 5510 21.2 51 22 130 23 130 24 115 25 101 26 74.8 27 69.6 27.1 8650 27.2 43.6 28 61 29 58.4 29.1 12500 29.2 46.2 30 57.5 31 43.5 32 38.7 33 42.8 33.1 8610 33.2 22.8 34 34.4 35 25.3 36 22.2 37 19.8 37.1 2000 37.2 9.46 38 19.3 38.1 2000 38.2 7.37 39 19 40 15.4 40.1 792 40.2 7.08 41 13.5 41.1 2930 41.2 7.73 42 11.3 43 11.1 43.1 2730 43.2 5.93 44 8.83 44.1 1390 44.2 6.72 45 338 45.1 201 45.2 8910 45.3 1050 45.4 >20000 46 7.07 46.1 1470 46.2 5.69 47 3.77 47.1 1020 47.2 1.96 48 3.72 48.1 1.76 48.2 120 49 2.76 49.1 1030 49.2 2.1 50 378 50.1 127 50.2 14300 51 16.6 51.1 8.85 51.2 872 52 99.2 52.1 72.7 52.2 11400 53 30.8 53.1 20.3 53.2 1780 54 20.7 55 9.74 55.1 6 55.2 835 56 120 56.1 50.5 56.2 7640 57 155 57.1 137 57.2 14638 58 16.7 58.1 8 58.2 1047 59 10.3 59.1 4 59.2 424 60 403 61 93.2 61.1 5180 61.2 108 62 32.2 62.1 4620 62.2 23.2 63 33.9 63.1 5170 63.2 18.5 64 55.8 65 101 66 363 67 2270 68 457 69 64.1 70 196 71 2310 72 985 73 148 73.1 3720 73.2 82.1 74 190 74.1 17100 74.2 81.4 75 419 75.1 >20000 75.2 214 76 252 76.1 114 76.2 11000 77 533 77.1 234 77.2 10200 78 7220 78.1 >20000 78.2 7550 79 6790 79.1 1660 79.2 2390 80 10.8 81 8.71 81.1 1020 81.2 10.1 82 89.6 83 24.3 84 24.6 85 20.3 86 759 87 8.53 88 667 89 131 90 63.3 91 701 92 16.7 93 187 94 25.7 95 39 96 31.4 97 24.7 98 73.5 99 75.8 100 176 101 329 102 506 103 41.9 104 234 105 6.45 106 33.3 107 77.3 108 19.4 109 51.7 110 366 111 334 112 300 113 703 114 658 115 272 116 581 117 14.9 118 22.4 119 4.54 120 16.7 121 19.9 122 9.07 123 100 124 48.3 125 44 126 28.8 127 73.1 128 72.2 129 97.1 130 46.5 131 180 132 93.3 133 42.5 134 76.8 135 49.5 136 740 137 238 138 61.6 139 56.9 140 37.5 141 389 142 14.5 143 12.7 144 8.79 145 2.66 146 21.6 147 291 148 76.4 149 405 150 372 151 387 152 111 153 107 154 55.6 155 200 156 231 157 190 158 6.71 159 214 160 187 160.1 115 160.2 8448 161 15 161.1 9 161.2 2573 162 22 162.1 12 162.2 6574 163 9 163.1 5 163.2 1091 164 7 164.1 5 164.2 944 165 3 165.1 2 165.2 331 166 3 166.1 2 166.2 129 167 2 167.1 3 167.2 303 168 19 169 3 169.1 3 169.2 859 170 7 170.1 5 170.2 1000 171 11 172 46 172.1 24 172.2 4892 173 25 174 51 174.1 26 174.2 3793 175 20 176 91 176.1 34 176.2 672 177 40 178 48 179 57 180 62 181 65 182 91 182.1 84 182.2 10527 183 222 184 428 184.1 297 184.2 >20000 185 301 186 392 187 1400 187.1 553 187.2 >20000 188 1240 189 6352 190 553 191 356 192 224 193 35 194 66 195 1000 196 128 197 90 198 88 199 396 200 70 201 25 202 69 203 381 204 73 205 54 206 48 207 22 208 672 209 45 210 69 211 183 212 41 213 42 214 16 215 279 216 32 217 41 218 64 219 13 220 219 221 31 222 108 223 235 224 45 225 252 226 87 227 393 228 218 229 193 230 199 231 662 232 112 233 267 234 1640 235 542 236 730 237 749 238 667 239 236 240 1328 241 382 242 2031 243 51 244 30 245 22 246 662 247 40 248 136 249 120 250 36 251 87 252 106 253 59 254 32 255 76 256 9 257 n.d. 258 19 259 19 260 29 261 90 262 6 263 539 264 376 265 459 266 287 267 63 268 3 269 12 270 13 271 18 272 39 273 20 274 107 275 29 276 29 277 494 278 230 279 48 280 43 281 98 282 53 283 36 284 33 285 68 285.1 34 285.2 432 286 31 287 18 288 3442 289 10 290 936 291 178 292 282

(312) TABLE-US-00019 TABLE 19 IC.sub.50 values of intermediates in in vitro human DGK? kinase activity inhibition assays. Intermediate number IC.sub.50 [nM] 41 >20000 43 >20000 62 >20000 63 >20000 64 >20000 65 >20000 66 >20000 67 >20000

(313) Transactivation Assay in Jurkat IL2-Reporter Cell Line

(314) Transactivation assays were carried out in Jurkat cells purchased from Promega (Promega, #CS187001) stably transfected with a firefly luciferase reporter gene construct under the control of the IL2-promoter. Cells were cultured as specified by the manufacturer. Bulk cells were harvested at a culture density of approx. 1E+06 cells/mL, suspended in cryo-storage medium (70% RPMI/20% FCS/10% DMSO), frozen at controlled rate of ?1?/min in 1.8 mL cryo-vials with cell densities of 1E+07 to 1E+08 cells per vial, and stored at ?150? C. or below until further use. Frozen cells were thawed and cultured in medium at a starting density of 3.5E+05 cells/mL for 6 days. On day 6 cells were centrifuged for 5 min at 300?g, medium was decanted and cell concentration was adjusted to 5.0E+06 cells/mL with fresh assay medium (500 mL RPMI (Gibco, #22400)+5 mL L-Glutamin (Sigma, #G7513)+5 mL Penicillin/Streptomycin (Sigma #P0781)+5 mL Non-essential amino acids (Invitrogen, #11140)+5 mL sodium-pyruvate (Gibco #1136088), 5 mL FBS (Biochrom, #S0615)). Cell working stock was split in two parts: neutral control and compounds with EC30 stimulation, high control with EC100 stimulation.

(315) An antibody premix was prepared by diluting anti-CD3 (BD Pharmingen, #555329), anti-CD28 (BD Pharmingen, #555725) and goat anti mouse anti-IgG (ThermoFisher, #31160) antibodies at 1/1/4 ratio in assay medium at 2-fold of final concentration (final concentrations depend on cell batch, typically for neutral control 0.055/0.055/0.22 ?g/mL, for high control 0.5/0.5/2 mg/mL). The premix solutions were added to the cells in 1+1 volume prior use.

(316) Fifty nL of a 100-fold concentrated solution of the test compounds in DMSO were transferred into a white microtiter test plate (384, Greiner Bio-One, Germany). For this, either a Hummingbird liquid handler (Digilab, USA) or an Echo acoustic system (Labcyte, USA) was used. Five ?L of the freshly prepared cell suspension was added to the wells of a test plate and incubated at 37? C. in a 5% CO.sub.2 atmosphere. After completion of the incubation for 4 hours, 3 ?l of Bio-Glo Luciferase assay reagent (Promega, #G7941, prepared as recommended by the supplier) were added to all wells. The test plate was incubated at 20? C. for 10 min before measurement of the luminescence in a microplate reader (typically Pherastar by BMG, Germany, or ViewLux by Perkin-Elmer, USA). Data were normalized (neutral control=0% effect, high control=100% effect). Compounds were tested in duplicates at up to 11 concentrations (typically 20 ?M, 5.7 ?M, 1.6 ?M, 0.47 ?M, 0.13 ?M, 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25 nM and 0.073 nM). Dilution series were made prior to the assay in a 100-fold concentrated form by serial dilution. EC.sub.50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Analyzer, Switzerland).

(317) Polyclonal Activation of Human PBMCs

(318) To test the effect of DGK? inhibitors of the present invention on IL-2 and IFN-? secretion of human Peripheral Blood Mononuclear Cells (PBMCs) a 24 h human PBMC assay was performed as screening assay. For this, a 96 well flat bottom plate was coated with a suboptimal stimulation condition (EC 10-30) of human aCD3 (Invitrogen, clone OKT3) antibody in 50 ?L PBS/well at 4? C. overnight. PBMCs isolated and frozen at liquid N.sub.2 from leucapherese samples was thawed and resuspended in culture medium (X-Vivo-20). 4?10.sup.5 cells/well were plated. Wells were treated with the DGK? inhibitors of the present invention at the respective concentrations (5-fold dilution steps from 10 ?M to 3 nM) and the final DMSO concentration per well is 0.1%. Medium+DMSO (0.1%) was used as baseline value. As positive controls 1000 ng/mL aCD3+aCD28 (1 ?g/mL) and a DGK? reference inhibitor was used. After 24 h the medium was collected and hIL-2 or hIFN-? ELISA were performed. The following parameters were calculated: EC.sub.50 value, concentration at 50% increase; max increase in % and respective concentration and maximum effect normalized to max concentration (10 ?M) of a selected DGK? reference inhibitor.

(319) In Vitro Activation of Mouse OT-I Antigen-Specific T-Cells

(320) To test the effect of DGK? inhibitors of the present invention in murine antigen-specific T-cells, spleens and lymph nodes of OT-I mice were collected and mashed through a 40 ?m cell strainer and incubated for 1 min in 1 mL ACK lysing buffer (Gibco)/spleen. 4?106 cells/mL were incubated in medium containing 0.05 ng/mL SIINFEKL (FIG. 2) in a 50 mL falcon at 37? C. for 30 min. Afterwards cells were centrifuged and 4?106 cells/mL were resuspended in fresh medium (DMEM; 10% FCS, 1% Pen/Strep, 0.1% ?-mercaptoethanol, 1% HEPES). 4?105 cells were plated per well in a 96-well round bottom plate. Wells were treated with DGK? inhibitors of the present invention at the respective concentrations (5-fold dilution steps from 10 ?M to 3 nM) in a final DMSO concentration of 0.1%. Medium+DMSO (0.1%) was used as baseline value. As positive controls cells incubated with the 4? SIINFEKL concentration (0.2 ng/ml) and a DGK? reference inhibitor were used. The plates were centrifuged to reduce the distance between T-cells and APCs before incubation. After 24 h the medium was collected and mIL-2 or mIFN-? ELISAs were performed. The following parameters were calculated: EC.sub.50 value, concentration at 50% increase; max increase in % and respective concentration and maximum effect normalized to max concentration (10 ?M) of a selected DGK? reference inhibitor.

(321) DGK? Surface Plasmon Resonance Interaction Assay

(322) The ability of the compounds described in this invention to bind to DGK? were determined using surface plasmon resonance (SPR). This allows for the quantification of binding in terms of the equilibrium dissociation constant (K.sub.D [M]), as well as association and dissociation rate constants (k.sub.on [1/Ms] and k.sub.off [1/s], respectively). The measurements were performed using Biacore? T200, Biacore? S200 or Biacore? 8K (GE Healthcare).

(323) All buffers described in this section were prepared with 10?HBS-P+ Buffer (GE Healthcare, #BR100671) supplemented with additional buffer components as indicated below, dithiothreitol (DTT from Sigma, #D0632-25G), Adenosine 5-triphosphate (ATP from Sigma, #A26209-10G), MgCl.sub.2 (Sigma, #M1028-100ML), dimethyl sulfoxide (DMSO from Biomol, #54686.500).

(324) For SPR measurements, recombinant and biotinylated human DGK? (obtained from Cama Biosciences, Product number: 12-410-20N) was immobilized via the streptavidin-biotin interaction onto a Series S Sensor Chip SA (GE Healthcare, #BR-1005-31). Briefly, DGK? was diluted to a concentration of 10 ?g/mL in Immobilization Buffer (10 mM HEPES, 150 mM NaCl, 0.05% v/v Surfactant P20.2 mM MgCl.sub.2, 1 mM DTT, pH 7.4) and captured on the SA Chip surface using a flow rate of 10 ?L/min for 500 seconds at a temperature of 10? C. Immobilization levels of approximately 6000 RU were typically achieved. The reference surface consisted of a streptavidin surface without immobilized protein. Compounds were diluted from 10 mM DMSO stock solution into Running Buffer (10 mM HEPES, 150 mM NaCl, 0.05% v/v Surfactant P20, 2 mM MgCl.sub.2, 1 mM DTT, 0.2 mM ATP and 1% v/v DMSO, pH 7.4). For SPR-binding measurements serial dilutions (typically 1:3 dilutions resulting in 8 concentrations up to 2 ?M or 20 ?M) were injected over immobilized protein. Binding affinity and kinetics were measured at 18? C. and at a flow rate of 100 ?L/min.

(325) A variation of the assay with an additional regeneration step was performed by injection of Regeneration Buffer without ATP (10 mM HEPES, 150 mM NaCl, 0.05% v/v Surfactant P20, 1 mM DTT and 1% v/v DMSO, pH 7.4) for 200 s at a flow rate of 30 ?L/min

(326) The double-referenced sensorgrams were fit to a simple reversible Langmuir 1:1 reaction mechanism as implemented in the Biacore? T200, S200 and 8K evaluation software (Biacore T200 Evaluation Software version 2.0, Biacore S200 Evaluation Software version 1.0, Biacore 8K Evaluation Software, GE Healthcare).

(327) Expression of DGK? in Insect Cells Using the Baculovirus System

(328) Expression Constructs:

(329) The cDNA encoding the full length sequence of human DGK? (Uniprot 013574-2) was optimized for expression in eukaryotic cells and synthesized by the GeneArt Technology at Life Technologies.

(330) The DNA sequence encoded the following sequence:

(331) Construct DGK?_hu amino acid M1 to V928

(332) Additionally the expression construct encoded: a Kozak DNA sequence for translation initiation (GCCACC), a translational start codon for methionine followed by amino acid glycine, a Flag (DYKDDDDK) sequence at the N-terminus of DGK?, and at the C-terminus of DGK? two stop codons and moreover 5 and 3 att-DNA sequences for Gateway Cloning.

(333) The DGK? construct was subcloned using the Gateway Technology into the Destination vector pD-INS. The vector pD-INS is a Baculovirus transfer vector (based on vector pVL1393, Pharmingen) which enables the expression of the Flag-DGK? protein. The respective protein was named DGKz_hu_1.

(334) Generation of Recombinant Baculovirus

(335) The DGK? transfer vector was co-transfected in Sf9 cells with Baculovirus DNA (Flashbac Gold DNA, Oxford Expression Technologies) using Fugene HD (Roche). After 5 days the supernatant of the transfected cells containing the recombinant Baculovirus encoding the various DGK proteins was used for further infection of Sf9 cells for virus amplification whereby the virus titer was monitored using qPCR.

(336) DGK? Expression in Sf9 Cells Using Bioreactor

(337) Sf9 cells cultured (Insect-xpress medium, Lonza, 27? C.) in a Wave-bioreactor with a disposable culture bag were infected at a cell density of 10.sup.6 cells/mL with one of the recombinant baculovirus stocks at a multiplicity of infection of 1 and incubated for 72. Subsequently, the cells were harvested by centrifugation (800?g) and the cell pellet frozen at ?80? C.

(338) Purification of the DGKz_hu_1 Protein:

(339) Purification of the DGKz_hu_1 protein was achieved by a two-step chromatography procedure as follows.

(340) The pelleted cells (from 8 L cell culture) were resuspended in Lysis-Buffer (25 mM Tris HCl 8.0; 500 mM NaCl; 250 mM Sucrose, 1 mM DTT; 0.1% Triton X-100; Complete Protease Inhibitor Cocktail-(Roche)) and lysed by a freeze-thaw cycle followed by an incubation on ice for 60 min in the presence of Benzonase (25 U/mL). The lysate was centrifuged at 63.000?g for 30 min at 4? C. The soluble supernatant was than incubated with 40 mL anti-Flag M2 Agarose (Sigma) in a plastic flask rotating for 16 h at 4? C. for binding of the tagged DGK? proteins, subsequently rinsed with 5?50 mL Wash-Buffer (25 mM Tris HCl 8.0; 500 mM NaCl; 250 mM Sucrose; 1 mM DTT) and finally the bound protein was eluted using Elution-Buffer (Wash-Buffer with 250 ?g/mL FLAG-Peptide, incubated 30 min. at 4? C. with 3?25 mL).

(341) The elution fractions from the affinity chromatography were concentrated (using Amicon Ultra 15, Centrifugal Filters, 30 kDa MW cut-off; Millipore #UFC903024) to 25 mL and applied to a size exclusion chromatography column (S200 prep grade 26/60, GE Healthcare) and the resulting monomeric peak fraction was collected, pooled and again concentrated. Wash-buffer with 300 mM NaCl was used for size exclusion chromatography and the final concentrated sample. The final protein sample concentration was 5 to 10 mg/mL and the yield was 5 mg final protein per L cell culture.

(342) The in vivo activity of the compounds of the present invention can be demonstrated in the following assays:

(343) In Vivo Activation of Murine Antigen Specific OT-I T Cells

(344) Oral Administration of compounds enhances antigen-specific T cell activation in vivo.

(345) Direct detection of antigen-specific T cell proliferation in vivo is technically challenging, since it requires the presence of T cells specific for a cognate antigen and also a specific measurement procedure for cell proliferation. Both these requirements are fulfilled in the OT-I transfer model, which utilizes the direct transfer of CD8 T cells transgenic for a T cell receptor recognizing an Ovalbumin-derived peptide as antigen.

(346) Before transfer, the OT-I T cells were labeled with the fluorescent dye CFSE, which was diluted by every cell division and therefore allowed detection of cell proliferation. After transfer of the CFSE-labeled T cells, mice were vaccinated with the Ovalbumin antigen OVA-30 (FIG. 3). Only transferred OT-I cells were able to recognize the OVA-antigen presented by APC and only these transferred T cells then got activated. Flow cytometric analysis of CFSE-levels in the OT-I cells can be combined with measurement of multiple activation markers like CD69, CD25 and PD1. In particular, Wild type C57Bl6 mice received 2?10?6 CFSE-labeled OT-I T cells and were vaccinated one day later by intravenous application of 2.5 ?g OVA-30. Mice were then divided into groups which received vehicle only, DGK? inhibitors of the present invention alone or in combination with other immune modulating agents. Mice were treated for 2 to 20 days and T cell composition (incl. transferred OT-1 cells) of spleen, blood and lymph nodes were analysed by FACS.

(347) In Vivo Syngeneic Tumor Models

(348) Mice were assigned to a study at the age of 6-8 weeks. Animal husbandry, feeding and health conditions were according to animal welfare guidelines. Syngeneic tumor cell lines were cultivated with appropriate medium and split at least 3 times before inoculation. Female mice were inoculated with appropriate amount of tumor cells in medium or a medium/matrigel mixture s.c, i.v., or i.p, depending on the model. After 4-10 days the mice were randomized and therapeutic treatment started when tumors had reached a size of approx. 40-70 mm.sup.2.

(349) Tumor size was measured using calipers determining length (a) and width (b). Tumor volume was calculated according to:
v=(a?b{circumflex over ()}2)/2

(350) Significance of monotherapies and combination treatment was calculated versus control group as determined by 2-Way ANOVA analysis.