Pyridine and Pyrazine Derivative for the Treatment of CF

Abstract

The present invention provides pyridine and pyrazine derivatives which restore or enhance the function of mutant and/or wild type CFTR to treat cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (IBS, IBD, opioid induced). Pharmaceutical compositions comprising such derivatives are also encompassed.

Claims

1-15. (canceled)

16. A method for the treatment of chronic bronchitis in a subject in need thereof, comprising administering an effective amount of at least one compound of Formula I ##STR00118## or a pharmaceutically acceptable salt thereof, wherein: A is N or CR.sup.4a; R.sup.1 is H; C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.2-C.sub.8 alkenyl; C.sub.2-C.sub.8 alkynyl; C.sub.3-C.sub.10 cycloalkyl; C.sub.5-C.sub.10 cycloalkenyl; —C.sub.1-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; halogen; SO.sub.2NR′R.sup.9; SO.sub.2R.sup.10; S—C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; S—C.sub.6-C.sub.14 aryl; CN; NR.sup.11R.sup.12; C(O)NR.sup.13R.sup.14; NR.sup.13SO.sub.2R.sup.15; NR.sup.13C(O)R.sup.15, CO.sub.2R.sup.15, —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; R.sup.2 is C.sub.1-C.sub.4 haloalkyl; R.sup.3 and R.sup.4a are each independently H or C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; R.sup.4 is H, or C.sub.1-C.sub.8 alkyl optionally substituted with one or more halogen atoms; R.sup.5 is —(CH.sub.2).sub.m—NR.sup.17R.sup.18, —(CH.sub.2).sub.m—OR′; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; —(C.sub.0-C.sub.4 alkyl)-CO.sub.2R.sup.15; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.4 aryl or −3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl and —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; R.sup.6 is C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.3-C.sub.10 cycloalkyl; —C.sub.0-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl and —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; or R.sup.6 is H, and R.sup.5 is —(CH.sub.2).sub.m—NR.sup.17R.sup.18, —(CH.sub.2).sub.m—OR′, C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or —(C.sub.0-C.sub.4 alkyl)-CO.sub.2R.sup.15, wherein —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl and —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group groups are each optionally substituted by one or more Z substituents; or R.sup.4 and R.sup.6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or R.sup.4 and R.sup.5 together form an oxo group (C═O) and R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or R.sup.5 and R.sup.6 together with the carbon atoms to which they are bound form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; or R.sup.4 and R.sup.5 and R.sup.6 together with the carbon atoms to which they are bound form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; R′ is H, or C.sub.1-C.sub.8 alkyl optionally substituted with one or more halogen atoms; m is 0, 1, 2 or 3; R.sup.8, R.sup.11, R.sup.13 and R.sup.17 are each independently H, C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms, C.sub.3-C.sub.10 cycloalkyl or —(C.sub.1-C.sub.4 alkyl)-C.sub.3-C.sub.8 cycloalkyl; R.sup.9, R.sup.10, R.sup.12, R.sup.14, R.sup.15, and R.sup.18 are each independently H; C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.2-C.sub.8 alkenyl; C.sub.2-C.sub.8 alkynyl; C.sub.3-C.sub.10 cycloalkyl; C.sub.5-C.sub.10 cycloalkenyl; —C.sub.1-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or R.sup.8 and R.sup.9, R.sup.11 and R.sup.12, R.sup.13 and R.sup.14, and R.sup.17 and R.sup.18 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents; Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C.sub.1-C.sub.6 alkyl optionally substituted by one or more OH groups or NH.sub.2 groups, C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms, C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy, (SO.sub.2)NR.sup.19R.sup.21, (SO.sub.2)R.sup.21, C(O)NR.sup.19R.sup.21, NR.sup.19R.sup.21, C(O)OR.sup.19, C(O)R.sup.19, SR.sup.19, OR.sup.19, oxo, CN, NO.sub.2, halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; R.sup.19 and R.sup.21 are each independently H; C.sub.1-C.sub.8 alkyl; C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkyl; (C.sub.0-C.sub.4 alkyl)-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; (C.sub.0-C.sub.4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C.sub.1-C.sub.6 alkyl and C(O)C.sub.1-C.sub.6 alkyl; (C.sub.0-C.sub.4 alkyl)-O-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; and (C.sub.0-C.sub.4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C.sub.1-C.sub.6 alkyl or C(O)C.sub.1-C.sub.6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C.sub.1-C.sub.4 alkoxy, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6 alkyl or C(O)N(C.sub.1-C.sub.6 alkyl).sub.2; or R.sup.19 and R.sup.21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O).sub.2-aryl; S(O).sub.2—C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy; and C(O)OC.sub.1-C.sub.6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy.

17. The method according to claim 16, wherein A is CR.sup.4a.

18. The method according to claim 16, wherein R.sup.1 is C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; halogen; NR.sup.11R.sup.12, C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-5 to 6 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclic groups are each optionally substituted by one or more Z substituents.

19. The method according to claim 16, wherein R.sup.1 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; or halogen.

20. The method according to claim 16, wherein R.sup.1 is aryl, wherein aryl is phenyl optionally substituted by one or more Z substituents.

21. The method according to claim 16, wherein R.sup.2 is CF.sub.3.

22. The method according to claim 16, wherein R.sup.4 is H or C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; R.sup.5 is C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; —(CH.sub.2).sub.m—NR.sup.17R.sup.18, —(CH.sub.2).sub.m—OR′; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl heterocyclyl groups is optionally substituted by one or more Z substituents; R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; or —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl wherein the aryl is optionally substituted by one or more Z substituents; or R.sup.4 and R.sup.6 together with the carbon atoms to which they are bound form a 3 to 6 membered carbocyclic ring system; or R.sup.5 and R.sup.6 together with the carbon atoms to which they are bound form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; m is 0 or 1; R.sup.17 and R.sup.18 are each independently H or C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms.

23. The method according to claim 16, wherein A is CR.sup.4a; R.sup.1 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; or C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; R.sup.2 is CF.sub.3; R.sup.3 is H, CH.sub.3 or CF.sub.3; R.sup.4 is H or Me; R.sup.4a is H; R.sup.5 is —NR.sup.17R.sup.18 or OH, and R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms.

24. A method for the treatment of chronic bronchitis in a subject in need thereof, comprising administering an effective amount of at least one compound of Formula II, ##STR00119## or a pharmaceutically acceptable salt thereof; wherein A is N or CR.sup.4a; R.sup.4a is H or C.sub.1-C.sub.4 alkyl; R.sup.1 is C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; halogen; NR.sup.11R.sup.12; C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-5 to 6 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclic groups are each optionally substituted by one or more Z substituents; R.sup.11 is H, C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.3-C.sub.10 cycloalkyl; or —(C.sub.1-C.sub.4 alkyl)-C.sub.3-C.sub.8 cycloalkyl; R.sup.12 is H; C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.2-C.sub.8 alkenyl; C.sub.2-C.sub.8 alkynyl; C.sub.3-C.sub.10 cycloalkyl; C.sub.5-C.sub.10 cycloalkenyl; —C.sub.1-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or R.sup.11 and R.sup.12 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents; Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C.sub.1-C.sub.6 alkyl optionally substituted by one or more OH groups or NH.sub.2 groups, C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms, C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy, (SO.sub.2)NR.sup.19R.sup.21, (SO.sub.2)R.sup.21, C(O)NR.sup.19R.sup.21, NR.sup.19R.sup.21, C(O)OR.sup.19, C(O)R.sup.19, SR.sup.19, OR.sup.19, oxo, CN, NO.sub.2, halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; R.sup.19 and R.sup.21 are each independently H; C.sub.1-C.sub.8 alkyl; C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkyl; (C.sub.0-C.sub.4 alkyl)-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; (C.sub.0-C.sub.4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C.sub.1-C.sub.6 alkyl and C(O)C.sub.1-C.sub.6 alkyl; (C.sub.0-C.sub.4 alkyl)-O-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; and (C.sub.0-C.sub.4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C.sub.1-C.sub.6 alkyl or C(O)C.sub.1-C.sub.6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C.sub.1-C.sub.4 alkoxy, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6 alkyl or C(O)N(C.sub.1-C.sub.6 alkyl).sub.2; or R.sup.19 and R.sup.21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O).sub.2-aryl; S(O).sub.2—C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy; and C(O)OC.sub.1-C.sub.6 alkyl, wherein the aryl and heterocyclic substituent groups are optionally substituted by C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy; R.sup.3 is H or CH.sub.3; ##STR00120## ##STR00121##

25. A method for the treatment of chronic bronchitis in a subject in need thereof, comprising administering an effective amount of at least one compound selected from the group consisting of: 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; 3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; and 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; or a pharmaceutically acceptable salt thereof.

26. The method according to claim 25, wherein the compound is 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide having the following structure ##STR00122## or a pharmaceutically acceptable salt thereof.

27. The method according to claim 25, wherein the compound is 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide having the following structure ##STR00123## or a pharmaceutically acceptable salt thereof.

28. The method according to claim 16, wherein the compound is in free form.

29. The method according to claim 16, wherein the compound is a pharmaceutically acceptable salt.

30. The method according to claim 16 further comprising administration of a second drug substance.

31. The method according to claim 30, wherein the second drug substance is an osmotic agent, an ENaC blocker, an anti-inflammatory agent, a bronchodilatory agent, an antihistamine agent, an anti-tussive agent, an antibiotic agent and/or a DNase drug substance.

32. The method according to claim 30, wherein the second drug substance is administered separately, before, simultaneously with, or after the other drug substance.

33. The method according to claim 25, wherein the compound is in free form.

34. The method according to claim 25, wherein the compound is a pharmaceutically acceptable salt.

35. The method according to claim 25 further comprising administration of a second drug substance.

36. The method according to claim 35, wherein the second drug substance is an osmotic agent, an ENaC blocker, an anti-inflammatory agent, a bronchodilatory agent, an antihistamine agent, an anti-tussive agent, an antibiotic agent and/or a DNase drug substance.

37. The method according to claim 35, wherein the second drug substance is administered separately, before, simultaneously with, or after the other drug substance.

Description

EXAMPLES

General Conditions:

[0324] Mass spectra were run on LC-MS systems using electrospray ionization. These were either Agilent 1100 HPLC/Micromass Platform Mass Spectrometer combinations or Waters Acquity UPLC with SQD Mass Spectrometer. [M+H].sup.+ refers to mono-isotopic molecular weights.

[0325] NMR spectra were run on open access Bruker AVANCE 400 NMR spectrometers using ICON-NMR. Spectra were measured at 298K and were referenced using the solvent peak.

[0326] Optical rotations were measured at 589 nm and 546 nm using an Optical activity AA-1000 polarimeter at 21° C.

[0327] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, and NMR. Abbreviations used are those conventional in the art. If not defined, the terms have their generally accepted meanings.

Abbreviations

[0328] app apparent [0329] ATP adenosine 5-triphosphate [0330] BINAP racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [0331] BOC tertiary butyl carboxy [0332] br broad [0333] d doublet [0334] dd doublet of doublets [0335] DCM dichloromethane [0336] DIEA diethylisopropylamine [0337] DIPEA diisopropylethylamine [0338] DMF N,N-dimethylformamide [0339] DMSO dimethylsulfoxide [0340] DTT dithiothreitol [0341] ESI electrospray ionization [0342] EtOAc ethyl acetate [0343] eq equivalent [0344] h hour(s) [0345] HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate [0346] HPLC high pressure liquid chromatography [0347] IR infrared spectroscopy [0348] LCMS liquid chromatography and mass spectrometry [0349] MeOH methanol [0350] MS mass spectrometry [0351] MW microwave [0352] m multiplet [0353] min minutes [0354] ml milliliter(s) [0355] m/z mass to charge ratio [0356] NMR nuclear magnetic resonance [0357] ppm parts per million [0358] PS polymer supported [0359] rac racemic [0360] RT room temperature [0361] Rt retention time [0362] s singlet [0363] SCX-2 strong cation exchange (e.g. Isolute® SCX-2 columns from Biotage) [0364] t triplet [0365] TEA triethylamine [0366] TFA trifluoroacetic acid [0367] THF tetrahydrofuran

[0368] Referring to the examples that follow, compounds of the preferred embodiments were synthesized using the methods described herein, or other methods, which are known in the art.

[0369] The various starting materials, intermediates, and compounds of the preferred embodiments may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise stated, all starting materials are obtained from commercial suppliers and used without further purification. Salts may be prepared from compounds by known salt-forming procedures.

[0370] It should be understood that the organic compounds according to the preferred embodiments may exhibit the phenomenon of tautomerism. As the chemical structures within this specification can only represent one of the possible tautomeric forms, it should be understood that the preferred embodiments encompasses any tautomeric form of the drawn structure.

[0371] If not indicated otherwise, the analytical HPLC conditions are as follows:

Method 10minLC_v001

TABLE-US-00002 Column Waters BEH C18 100 × 2.1 mm, 1.7 μm Column 50° C. Temp. Eluents A: H.sub.2O, B: acetonitrile, both containing 0.1% TFA Flow Rate 0.7 ml/min Gradient 0.25 min 5% B; 5% to 95% B in 7.75 min, 1.00 min 95% B
Method 10minLC_v002

TABLE-US-00003 Column Waters BEH C18 50 × 2.1 mm, 1.7 μm Column 50° C. Temperature Eluents A: H.sub.2O, B: methanol, both containing 0.1% TFA Flow Rate 0.8 ml/min Gradient 0.20 min 5% B; 5% to 95% B in 7.80 min, 1.00 min 95% B
Method 10minLC_v003

TABLE-US-00004 Column Waters BEH C18 50 × 2.1 mm, 1.7 μm Column 50° C. Temperature Eluents A: H.sub.2O, B: acetonitrile, both containing 0.1% TFA Flow Rate 0.8 ml/min Gradient 0.20 min 5% B; 5% to 95% B in 7.80 min, 1.00 min 95% B
Method 2minLC_v001

TABLE-US-00005 Column Waters BEH C18 100 × 2.1 mm, 1.7 μm Column 50° C. Temp. Eluents A: H.sub.2O, B: acetonitrile, both containing 0.1% TFA Flow Rate 0.7 ml/min Gradient 0.25 min 5% B; 5% to 95% B in 1.00 min, 0.25 min 95% B
Method 2minLC_v002

TABLE-US-00006 Column Waters BEH C18 50 × 2.1 mm, 1.7 μm Column 50° C. Temperature Eluents A: H.sub.2O, B: methanol, both containing 0.1% TFA Flow Rate 0.8 ml/min Gradient 0.20 min 5% B; 5% to 95% B in 1.30 min, 0.25 min 95% B
Method 2minLC_v003

TABLE-US-00007 Column Waters BEH C18 50 × 2.1 mm, 1.7 μm Column 50° C. Temperature Eluents A: H.sub.2O, B: acetonitrile, both containing 0.1% TFA Flow Rate 0.8 ml/min Gradient 0.20 min 5% B; 5% to 95% B in 1.30 min, 0.25 min 95% B
Method 10minC18

TABLE-US-00008 Column: Gemini C18 100 × 3 mm, 3 micron Column 50° C. Temperature Eluents: A: H.sub.2O, B: Methanol, 0.1% formic acid Flow rate: 1 ml/min Gradient: 0.00 min 0% B, 10.00 min 95% B

Method AD25IPA_DEA

[0372]

TABLE-US-00009 Mobile Phase: 25% isopropanol + 0.1% v/v DEA/75 % CO.sub.2 Column: Chiralpak AD-H, 250 × 10 mm id, 5 μm Detection: UV @ 220 nm Flow rate: 10 ml/min

[0373] Example compounds of the present invention include

Preparation of Final Compounds

Example 1.0

3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

[0374] ##STR00017##

[0375] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate A) (397 mg, 1.392 mmol), 3-amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride (250 mg, 1.392 mmol) and HATU (529 mg, 1.392 mmol) were dissolved in DMF (10 ml) and stirred at RT for 2 min. 4-Methylmorpholine (0.413 ml, 4.18 mmol) was added and stirring continued at RT for 3 h. The reaction mixture was poured onto ice/water (100 ml) and extracted with EtOAc (250 ml). The organic extract was washed with sat NH.sub.4C solution (˜50 ml), dried over MgSO.sub.4 and concentrated in vacuo to give a pale brown oil. The oil was dissolved in CHCl.sub.3 (˜3 ml) and loaded onto a 24 g ISCO (silica) column eluting with iso-hexane:EtOAc to afford the title product; LC-MS Rt=1.46 mins; [M+H].sup.+ 410.1, Method 2minLC_v002. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.30 (NH, t), 7.72 (1H, s), 7.29 (NH2, b s), 6.28 (OH, s), 3.68 (1H, dd), 3.47 (1H, dd), 1.24 (3H, s). .sup.19F NMR (400 MHz, DMSO-d6) δ−62.71 (CF3, s), −80.48 (CF3, s).

[0376] The compounds of the following tabulated Examples (Table 2) were prepared by a similar method to that of Example 1 from the appropriate starting compound and amine. Single enantiomers were prepared by using chiral amines or by separation of the product by Supercritical Fluid Chromatography. The preparations of the starting compounds and amines are described in the Intermediates section, unless they are commercially available. DIPEA or TEA may have been used in place of 4-methylmorpholine in some reactions.

TABLE-US-00010 TABLE 2 Retention Time, [M + H].sup.+, Ex. Structure Name 1H NMR 1.1 [00018] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro- 2-hydroxy-propyl)- amide (Separated by SFC, second eluted peak) R.t 3.26 mins; Method = AD25IPA_DEA 1H NMR (DMSO) δ 3.4 (1H, m), 3.6 (1H, m), 4.3 (1H, m), 6.5 (1H, s), 7.3 (2H, s), 7.7 (1H, s), 8.6 (1H, t), 1.2 [00019] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid (3,3,3-trifluoro-2- hydroxy-propyl)-amide (Racemate) Rt 1.42 mins; [M + H].sup.+ 398 Method: 2 minLC_v002 1H NMR (DMSO) δ 3.4 (1H, m), 3.6 (1H, m), 4.3 (1H, m), 6.5 (1H, d), 7.3 (2H, s), 7.7 (1H, s), 8.6 (1H, t), 1.3 [00020] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid ((S)-3,3,3- trifluoro-2-hydroxy- propyl)-amide Prepared using (S)-3- Amino-1,1,1-trifluoro- propan-2-ol Rt 1.41 mins; [M + H].sup.+ 398 Method: 2 minLC_v002 1H NMR (DMSO) δ 3.4 (1H, m), 3.6 (1H, m), 4.3 (1H, m), 6.5 (1H, d), 7.3, (2H, s), 7.7 (1H, s), 8.6 (1H, t) 1.4 [00021] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid [(R)-1- (tetrahydro-furan-2- yl)methyl]-amide Prepared using (R)-(−)- tetrahydrofurfurylamine Rt 1.51 mins; [M + H].sup.+ 370 Method: 2 minLC_v002 1H NMR (DMSO) δ 1.6 (1H, m), 1.9, (3H, m), 3.4, (2H, m), 3.7, (1H, m), 3.8, (1H, m), 4.1, (1H, m), 7.3, (2H, s), 7.7, (1H, s), 8.4, (1H, t) 1.5 [00022] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid ([1,3]dioxolan-2- ylmethyl)-amide Rt 1.42 mins; [M + H].sup.+ 370 Method: 2 minLC_v002 1H NMR (DMSO) δ3.4, (2H, t), 3.8, (2H, m), 3.9, (2H, m), 5.0, (1H, t), 7.3, (2H, br), 7.7, (1H, s), 8.4, (1H, t), 1.6 [00023] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid [(S)-1- (tetrahydro-furan-2- yl)methy]-amide Prepared using (S)- (+)-Tetrahydrofurfurylamine Rt 1.52 mins; [M + H].sup.+ 370 Method: 2 minLC_v002. 1H NMR (DMSO) 1.6, (1H, m), 1.9, (3H, m), 3.3, (2H, m), 3.6, (1H, m), 3.8, (1H, m), 4.0, (1H, m), 7.4, (2H, s), 7.7, (1H, s), 8.4, (1H, d) 1.7 [00024] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid (tetrahydro-furan- 2-ylmethyl)-amide Rt 1.49 mins; [M + H].sup.+ 368 Method: 2 minLC_v002. 1H NMR (DMSO) δ1.55, (1H, m), 1.8, (3H, m), 3.3, (2H, m), 3.6, (1H, m), 3.8, (1H, m), 4.0, (1H, m), 7.3, (2H, s), 7.7, (1H, s), 8.4, (1H, t) 1.8 [00025] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid (2-methyl-2- piperidin-1-yl-propyl)- amide Rt 1.14 mins; [M + H].sup.+ 423 Method: 2 minLC_v002 1H NMR (DMSO) δ 1.3, (6H, s), 1.4, (1H, m), 1.7, (3H, m), 1.9, (2H, m), 2.9, (2H, m), 3.6, (2H, m), 3.7, (2H, m), 7.3, (2H, s), 7.7, (1H, s), 8.7, (1H, t) 1.9 [00026] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid (2-hydroxy- propyl) amide Rt 4.06 mins; [M + H].sup.+ 344. Method: 10 minLC_v002 1H NMR. ([400 MHz], [DMSO- d6]) δ 8.30 (1H, t), 7.69 (1H, s), 7.28 (2H, br s), 4.84 (1H, d), 3.78 (1H, m), 3.29 (1H, m), 3.14 (1H, m), 1.05 (3H, d). 1.10 [00027] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid (2-hydroxy-2- methyl-propyl)-amide Rt 4.35 mins; [M + H].sup.+ 338. Method: 10 minLC_v002 1H NMR. ([400 MHz], [DMSO- d6]) δ 8.14 (1H, t), 7.70 (1H, s), 7.29 (2H, br s), 4.70 (1H, s), 3.24 (1H, d), 1.10 (6H, s). 1.11 [00028] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid (2-methyl- tetrahydro-furan-2- ylmethyl)-amide Rt 1.53 mins; [M + H].sup.+ 384 Method: 2 minLC_v002. 1H NMR. ([400 MHz], [DMSO- d6]) δ 8.12 (1H, t), 7.70 (1H, s), 7.28 (2H, br s), 3.76 (2H, t), 3.33 (2H, d), 1.88 (2H, m), 1.80 (1H, m), 1.60 (1H, m), 1.13 (3H, s). 1.12 [00029] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid(2-methoxy- ethyl)-amide Rt 1.43 mins; [M + H].sup.+ 342; Method: 2 minLC_v002. 1H NMR. ([400 MHz], [DMSO- d6]) δ □ □8.41 (1H, t), 7.69 (1H, s), 7.28 (2H, br s), 3.44 (4H, m), 3.27 (3H, s). 1.13 [00030] 3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid (2-methyl- tetrahydro-furan-2- ylmethyl)-amide Rt 1.52 mins; [M + H].sup.+ 385; Method: 2 minLC_v002. 1H NMR. ([400 MHz], [DMSO- d6]) δ □ □8.35 (1H, t), 8.09 (2H, br s), 3.76 (2H, t), 3.34 (2H, d), 1.86 (3H, m), 1.58 (1H, m), 1.13 (3H, s). 1.14 [00031] 3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid [2-(4-fluoro- phenyl)-2-morpholin- 4-yl-ethyl]-amide Rt 4.29 mins; [M + H].sup.+ 492. Method: 10 minLC_v002. .sup.1H NMR (400 MHz, MeOD) δ.sub.H 7.61-7.64 (2H, m, 2 × Ar′H (AA′BB′X system)), 7.28-7.32 (2H, m, 2 × Ar′H (AA′BB′X system)), 4.65-4.73 (1H, br m, NHCH.sub.AH.sub.BCH.sub.XN (Ar′)), 4.31 (1H, dd.sub.ABX, J = 6.5/14.4 Hz, NHCH.sub.AH.sub.BCH.sub.XN(Ar′)), 3.70- 4.14 (6H, m, NHCH.sub.AH.sub.BCH.sub.XN (Ar′) + 5 × morpholine CH), 3.00-3.30 (3H, m, 3 × morpholine CH). 1.15 [00032] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid [2-(4-fluoro- phenyl)-2-morpholin- 4-yl-ethyl]-amide Rt 4.39 mins; [M + H].sup.+ 491 Method: 10 minLC_v002. .sup.1H NMR (400 MHz, MeOD) δ.sub.H 8.37-8.38 (1H, m, ArC(O)NHCH.sub.2), 7.68 (1H, s, ArH-1), 7.35 (2H, m (AA′BB′X system), 2 × Ar′H-2), 7.17-7.25 (4H, br s + m (AA′BB′X system), ArNH.sub.2 + 2 × Ar′H-3), 3.73-3.81 (2H, m, NHCH.sub.AH.sub.BCH(N)Ar′ + NHCH.sub.AH.sub.BCH(N)Ar′), 3.53- 3.58 (5H, morpholine 2 × CH.sub.2 + NHCH.sub.AH.sub.BCH(N)Ar′), 2.34- 2.43 (4H, m, 2 × morpholine CH.sub.2). 1.16 [00033] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid (2-morpholin-4-yl- 2-phenyl-ethyl)-amide Rt 4.20 mins; [M + H].sup.+ 473 Method 10 minLC_v002. 1H NMR (400 MHz, DMSO- d6) δ 8.46 (1H, s broad), 7.70 (1H, s), 7.32 (7H, m broad), 3.75 (2H, m broad), 3.59 (4H, broad), 2.40 (2H, broad), 2.30 (2H, broad). 1.17 [00034] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid (2- dimethylamino-2- phenyl-ethyl)-amide Rt 4.25 mins; [M + H].sup.+ 431; Method; 10 minLC_v002. 1H NMR (400 MHz, DMSO- d6) δ 10.20 (1H, s), 8.72 (1H, t), 7.71 (1H, s), 7.60 (2H, s broad), 7.50 (3H, s broad)7.30 (2H, s broad), 4.67 (1H, m), 4.19 (1H, qui), 3.83 (m), 2.80 (3H, d), 2.61 (3H, d). 1.18 [00035] 3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid (3-methyl-2- morpholin-4-yl-butyl)- amide Rt 3.39 mins; [M + H].sup.+ 442. Method 10 minLC_v002. 1H NMR (400 MHz, DMSO- d6) δ 9.03 (1H, s), 9.10 (1H, s), 8.12 (2H, s), 4.00-3.20 (12H, broad), 1.10 (3H, broad), 1.00 (3H, broad). 1.19 [00036] 3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid (2-methyl-2- morpholin-4-yl-propyl)- amide Rt 2.83 mins; [M + H].sup.+ 428; Method 10 minLC_v002. 1H NMR (400 MHz, DMSO- d6) δ 9.04 (1H, s), 8.95 (1H, s), 8.10 (2H, s), 4.04 (2H, d), 3.75 (2H, t), 3.60 (4H + broad water signal underneath), 3.20 (2H, q), 1.35 (6H, s). 1.20 [00037] 3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid (1-morpholin-4-yl- cyclohexylmethyl)- amide Rt 3.59 mins; [M + H].sup.+ 466. Method 10 minLC_v002. 1H NMR (400 MHz, DMSO- d6) δ 9.00 (1H, broad), 8.90 (1H, broad), 8.10 (1H, s), 4.02- 3.35 (20H, very broad) 1.21 [00038] 3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid (2-morpholin-4-yl- 2-phenyl-ethyl)-amide Rt 6.09 mins; [M + H].sup.+ 474 Method 10 minC18 1.22 [00039] 3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid (2- dimethylamino-2- phenyl-ethyl)-amide Rt 5.42 mins; [M + H].sup.+ 432 Method 10 minC18 1.23 [00040] 3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid [2-(4-methoxy- phenyl)-2-pyrrolidin-1- yl-ethyl]-amide Rt 5.64 mins; [M + H].sup.+ 488 Method 10 minC18 1.24 [00041] 3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid [2-dimethylamino- 2-(4-methoxy-phenyl)- ethyl]-amide Rt 5.51 mins; [M + H].sup.+ 462; Method 10 minC18 1.25 [00042] 3-Amino-6-(4-fluoro- phenyl)-5- trifluoromethyl- pyridine-2-carboxylic acid (3,3,3-trifluoro-2- hydroxy-2-methyl- propyl)-amide Rt 5.41 mins; [M + H].sup.+ 426; Method10 minLC_v002. .sup.1H NMR δ 8.42 (1H, m), 7.72 (1H, s), 7.5 (2H, m), 7.3 (2H, t), 7.22 (2H, br s), 6.24 (1H, s), 3.68 (1H, m), 3.46 (1H, m), 1.24 (3H, s) 1.26 [00043] 3-Amino-5- trifluoromethyl- pyridine-2-carboxylic acid (3,3,3-trifluoro-2- hydroxy-2-methyl- propyl)-amide Rt 4.18 mins; [M + H].sup.+ 332; Method 10 minLC_v002. .sup.1H NMR δ 8.58 (1H, t), 8.1 (1H, s), 7.56 (1H, s), 7.2 (2H, br s), 6.29 (1H, s), 3.61-3.7 (1H, m), 3.42-3.5 (1H, m), 1.26 (3H, s). 1.27 [00044] 3-Amino-6-(4-chloro- 2-methyl-phenyl)-5- trifluoromethyl- pyridine-2-carboxylic acid ((R)-3,3,3- trifluoro-2-hydroxy- propyl)-amide Prepared using (R)-3- amino-1,1,1- trifluoropropan-2-ol Rt 1.59 mins; [M + H].sup.+ 442 Method: 2 minLC_v002. 1H NMR. ([400 MHz], [DMSO- d6]) δ 8.54 (1H, br), 7.69 (1H, s), 7.41 (1H, d), 7.30 (1H, dd), 7.24 (2H, br s), 7.20 (1H, d), 6.40 (1H, br), 4.19(1H, m), 3.54 (1H, m), 3.36 (1H, m), 2.01 (3H, s). 1.28 [00045] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid (3,3,3-trifluoro-2- hydroxy-2- trifluoromethyl-propyl)- amide Rt 1.59 mins; [M + H].sup.+ 466; Method 2 minLC_v002. .sup.1H NMR (400 MHz, DMSO- d6) δ 8.50 (1H, t), 8.30 (1H, s), 7.72 (1H, s), 7.30 (2H, s), 4.00 (2H, d) 1.29 [00046] 5-Amino-6′-methyl-3- trifluoromethyl- [2,3′]bipyridinyl-6- carboxylic acid (3,3,3- trifluoro-2-hydroxy-2- methyl-propyl)-amide Rt 1.16 mins; [M + H].sup.+ 423; Method 2 minLC_v002. .sup.1H NMR (400 MHz, DMSO- d6) δ 8.53 (1H, d), 8.45 (1H, t), 7.75 (1H, d), 7.71 (1H, s), 7.34 (1H, d), 7.25 (2H, s), 6.21 (1H, s), 3.69 (1H, dd), 3.42 (1H, dd), 2.54 (3H, s), 1.22 (3H, s). 1.30 [00047] Methyl 3-(3-amino-6- bromo-5- (trifluoromethyl) picolinamido)propanoate. Rt 4.64 mins; [M + H].sup.+ 372.1; Method 10 minLCv002. .sup.1H NMR (400 MHz, DMSO- d6) δ 8.56 (1H, t), 7.68 (1H, s), 7.27 (2H, br s), 3.61 (3H, s) 3.50 (2H, q), 2.60 (2H, t). 1.31 [00048] 3-Amino-N- (benzo[d]isoxazol-3- ylmethyl)-6-bromo-5- (trifluoromethyl) picolinamide Rt 4.18 mins; [M + H].sup.+ 417.1; Method 10 minLC_v002. .sup.1H NMR (400 MHz, DMSO- d6) δ 9.32 (NH, t), 7.96 (1H, dt), 7.74 (1H, dt), 7.70 (1H, s), 7.65-7.62 (1H, m), 7.40- 7.36 (1H, m), 7.29 (NH2, b s), 4.88 (2H, d) 1.32 [00049] 3-Amino-6-(oxazol-2- yl)-N-(3,3,3-trifluoro-2- hydroxy-2- methylpropyl)-5- (trifluoromethyl)picolinamide Rt 3.44 mins; [M + H].sup.+ 399.1; Method 10 minLC_v003. 1.33 [00050] Single enantiomer of 3-Amino-6-bromo-N- (3,3,3-trifluoro-2- methoxy-2- methylpropyl)-5- (trifluoromethyl)picolinamide (Separated by SFC, second eluted peak) 1H NMR (400 MHz, DMSO- d6) δ 8.24 (1H, t), 7.72 (1H, s), 7.29 (2H, s), 3.65 (2H, m), 3.37 (3H, s), 1.35 (3H, s) 1.34 [00051] Single enantiomer of 3-amino-N-(2-hydroxy- 3-methyl-2- (trifluoromethylbutyl)- 6-methoxy-5- (trifluoromethyl)picolinamide (Separated by SFC, first eluted peak) Rt 4.48 mins; [M + H].sup.+ 390.3; Method 10 minLC_v003. .sup.1H NMR (400 MHz, DMSO- d6) δ 8.21 (1H, m), 7.69 (1H, s), 6.59 (2H, s), 6.26 (1H, s), 3.91 (3H, s), 3.68 (2H, m), 2.02 (1H, m), 1.02 (6H, m) 1.35 [00052] 3-Amino-6- cyclopropyl-N-(3,3,3- trifluoro-2-hydroxy-2- methylpropyl)-5- (trifluoromethyl)picolinamide Rt 1.23 mins; [M + H].sup.+ 372.2; Method 2 minLC_v003. .sup.1H NMR (400 MHz, DMSO- d6) δ 8.29 (1H, m), 7.56 (1H, s), 6.9 (2H, br s), 6.3 (1H, s), 3.62 (1H, m), 3.48 (1H, m), 2.1 (1H, m), 1.24 (3H, s), 0.9-1.1 (4H, m) 1.36 [00053] 3-Amino-6-methoxy- N-(3,3,3-trifluoro-2- hydroxy-2- (trifluoromethyl)propyl)- 5-(trifluoro methyl) picolinamide Rt 4.27 mins; [M + H].sup.+ 416.3; Method 10 minLC_v003. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.39 (1H, t), 8.32 (1H, br s), 7.69 (1H, s), 6.70 (2H, br s), 3.99 (2H, d), 3.93 (3H, s), 1.37 [00054] Single enantiomer of 5-amino-N-(3,3,3- trifluoro-2-hydroxy-2- methylpropyl)-3- (trifluoromethyl)-2,4′- bipyridine-6- carboxamide (Separated by SFC, first eluted peak) Rt 0.86 mins; [M + H].sup.+ 409.1; Method 2 minLC_v003. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.70 (2H, d), 8.45 (1H, t), 7.75 (1H, s), 7.50 (2H, d), 7.33 (2H, s), 6.22 (1H, s), 3.69 (1H, dd), 3.43 (1H, dd), 1.21 (3H, s). 1.38 [00055] 3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid (3-methyl-2-oxo- butyl)-amide Rt 1.18 mins; [M + H].sup.+ 368; Method 2 minLC_v003. .sup.1H NMR (400 MHz, DMSO-d6) δ 8.64 (1H, t), 7.71 (1H, s), 7.29 (2H, broad s), 4.2 (2H, d), 2.7-2.8 (1H, m), 1.08 (6H, d, 2 × CH3). 1.39 [00056] 3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid [2-(4-fluoro- phenyl)-2-oxo-ethyl]- amide .sup.1H NMR (400 MHz, DMSO-d6) δ 9.0 (1H, t, NH), 8.1 ( 4H, m, NH2, Ar—H), 7.4 (2H, t, Ar—H), 4.8 ( 2H, 5, CH2)

Example 2 and 3

[0377] These compounds namely,

3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide. (Ex. 2)

[0378] ##STR00057##

and 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide. (Ex. 3)

##STR00058##

are prepared by chiral separation of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide. (Example 1) using Supercritical Fluid Chromatography under the following conditions:
Mobile Phase: 12% isopropanol+0.1% DEA/88% CO.sub.2

Column: Chiralpak OJ-H, 250×10 mm id, 5 μm

Detection: UV @ 220 nm

[0379] Flow rate: 10 ml/min
Sample concentration: 347 mg in 5 ml EtOH.
Injection volume: 50 μl

[0380] Example 2: First eluted peak: 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide.

[0381] LC-MS: Rt=4.97 min [M+H]+ 410.1/412.2 (Method 10minLC_v002).

[0382] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.30 (NH, t), 7.72 (1H, s), 7.29 (NH2, b s), 6.28 (OH, s), 3.68 (1H, dd), 3.47 (1H, dd), 1.24 (3H, s)

[0383] .sup.19F NMR (400 MHz, DMSO-d6) d −62.70 (CF3, s), −80.47 (CF3, s)

[0384] Optical rotation [α].sup.21 at 589 nm+14.4° (c=0.522, MeOH).

[0385] Example 3: Second eluted peak: 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide.

[0386] LC-MS Rt=4.94 min [M+H]+ 412.1 (Method 10minLC_v002).

[0387] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.30 (NH, t), 7.72 (1H, s), 7.29 (NH2, b s), 6.28 (OH, s), 3.68 (1H, dd), 3.47 (1H, dd), 1.24 (3H, s)

[0388] .sup.19F NMR (400 MHz, DMSO-d6) d −62.70 (CF3, s), −80.48 (CF3, s).

[0389] The stereochemistry of this compound was confirmed by X-ray crystallography.

Example 4, 5 and 6

[0390] This compound namely,

[0391] 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide. (Ex. 4),

##STR00059##

was prepared according to the following procedure:

[0392] A solution comprising 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D)(4 g, 16.94 mmol) and 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (Intermediate R) (3.04 g, 16.94 mmol) in NMP (188 ml) was treated with HATU (7.73 g, 20.33 mmol) followed by dropwise addition (2 ml portions) of DIPEA (8.88 ml, 50.8 mmol) over 1 hour. After stirring for a further hour, the reaction mixture was poured into water (450 ml) and EtOAc (450 ml). The aqueous phase was acidified with 5M HCl (50 ml) and the layers were separated. The organic portion was washed with 2M NaOH (200 ml), water (4×200 ml), brine (2×100 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford a brown solid. Purification of the solid by chromatography on silica (220 g pre-packed silica cartridge) eluting with 0-50% EtOAc in iso-hexane afforded the racemate, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (Ex. 4) as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, t), 7.7 (1H, s), 6.7 (2H, s), 6.2 (1H, s), 3.9 (3H, s), 3.7 (1H, m), 3.5 (1H, m), 1.2 (3H, s).

[0393] LC-MS: Rt 1.24 min; MS m/z 362.4 [M+H]+; Method 2minLC_v003.

[0394] Chiral separation of the racemate by Supercritical Fluid Chromatography was carried out using the following conditions to afford the compounds listed hereinafter:

Mobile Phase: 12% 2-propanol+0.1% DEA/50% CO.sub.2
Column: Chiralcel OD-H, 250×10 mm id, 5 μm (2 columns linked in series)

Detection: UV @ 220 nm

[0395] Flow rate: 10 ml/min
Sample concentration: 3.5 g in 30 ml EtOH
Injection volume: 100 μl

Examples 5 and 6 are Entantiomers

[0396] Example 5: First eluted peak Rt=7.30 minutes. 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide:

##STR00060##

[0397] 1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, t), 7.6 (1H, s), 6.6 (2H, broad), 6.2 (1H, s), 3.9 (3H, s), 3.6 (1H, m), 3.5 (1H, m), 1.3 (3H, s);

[0398] LC-MS Rt=1.15 mins, [M+H]+ 362.4 (Method 2minLC_v003).

[0399] Optical rotation [α].sup.21 at 589 nm −20.83° (c=0.513, MeOH).

[0400] The stereochemistry of this compound was confirmed by X-ray crystallography.

[0401] Example 6: Second eluted peak Rt=8.29 minutes. 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

##STR00061##

[0402] 1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, t), 7.6 (1H, s), 6.6 (2H, broad), 6.2 (1H, s), 3.9 (3H, s), 3.6 (1H, m), 3.5 (1H, m), 1.3 (3H, s);

[0403] LC-MS Rt=1.15 mins [M+H]+ 362.4 (Method 2minLC_v003).

[0404] Alternatively, Example 5 may be prepared according to the following method:

[0405] To a solution of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D) (10 g, 42.3 mmol) and (S)-3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (Intermediate RA)(7.60 g, 42.3 mmol) in NMP (400 ml) was added HATU (19.3 g, 50.8 mmol) followed by dropwise addition of DIPEA (22.19 ml, 127 mmol) over ˜1 hr. After stirring at room temperature for 30 min, the mixture was added to EtOAc (2 L), washed with 1M NaOH (2×1 L), water (1 L), brine (1 L), dried (MgSO.sub.4) and evaporated under reduced pressure to give the crude product as a dark brown oil. Purification by chromatography on silica eluting with a gradient of 1 to −25% of EtOAc in iso-hexane afforded a yellow oil. Recrystallisation of the oil from iso-hexane/DCM afforded 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide as a crystalline solid;

[0406] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.28 (1H, t), 7.66 (1H, s), 6.67 (2H, s), 6.27 (1H, s), 3.91 (3H, s), 3.65 (1H, m), 3.45 (1H, m), 1.24 (3H, s).

[0407] .sup.19F NMR (376 MHz, DMSO-d6) −62.58 ppm (s), −80.43 ppm (s)

Example 7

3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

[0408] ##STR00062##

[0409] A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (Ex. 3)(100 mg, 0.244 mmol), 4-fluorophenylboronic acid (37.5 mg, 0.268 mmol) and 1,1′bis(diphenylphosphoshio) ferrocenepalladium dichloride (19.90 mg, 0.024 mmol) was suspended in THF (2 ml) and 1M Cs.sub.2CO.sub.3 (0.667 ml). The vial was flushed with N.sub.2, sealed and heated at 160° C. using microwave radiation for 15 minutes. The mixture was partitioned between EtOAc (50 ml) and water (50 ml). The organic portion was separated and washed with brine (30 ml), dried (MgSO.sub.4), filtered through Celite® (filter material) and concentrated in vacuo. The crude residue was dissolved in DMSO (2 ml) and purified by mass directed LCMS using MeCN/Water/0.1% TFA eluent to afford clean product. The product fraction obtained as MeCN/Water/0.1% TFA solution was poured into EtOAc (50 ml) and washed with saturated NaHCO.sub.3 (50 ml) to free base the product. The organic portion were combined, dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound as a pale orange crystalline solid; 1H NMR (400 MHz, DMSO-d6) δ 8.4 (1H, m), 7.7 (1H, s), 7.49 (2H, m), 7.29 (2H, t), 7.2 (2H, br s), 6.22 (1H, s), 3.68 (1H, m), 3.44 (1H, m), 1.22 (3H, s); LC-MS Rt 4.41 mins [M+H]+ 426 (Method 10minLC_v003).

Example 8

3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

[0410] ##STR00063##

[0411] This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (Ex. 2) analogously to Example 8. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (1H, m), 7.7 (1H, s), 7.5 (2H, m), 7.3 (2H, t), 7.21 (2H, br s), 6.24 (1H, s), 3.68 (1H, m), 3.44 (1H, m), 1.22 (3H, s); LC-MS Rt=4.39 mins [M+H]+ 426 (Method 10minLC_v003).

Example 9 and 10

[0412] The enantiomers of 3-amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide were prepared from 3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate H) and 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride analogously to Example 1 and separated by chiral separation using Supercritical Fluid Chromatography:

[0413] Example 9: First eluted peak. Entantiomer 1 of 3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide:

##STR00064##

[0414] 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.60 (d, 1H), 7.54 (d, 1H), 7.39 (br s, 2H), 6.25 (br s, 1H). 3.71 (dd, 1H), 3.48 (dd, 1H), 1.26 (s, 3H); LC-MS Rt=1.65 mins [M+H]+ 476 (Method 2minLC_v002).

[0415] Example 10: Second eluted peak. Enantiomer 2 of 3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide.

##STR00065##

[0416] 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.60 (d, 1H), 7.54 (d, 1H), 7.39 (br s, 2H), 6.25 (br s, 1H). 3.71 (dd, 1H), 3.48 (dd, 1H), 1.26 (s, 3H); LC-MS Rt 1.65 mins [M+H]+=476.1 (Method 2minLC_v002).

Example 11

3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide

[0417] ##STR00066##

[0418] To a stirred suspension of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide (Ex. 1.10) (180 mg, 0.505 mmol) and 4-fluorophenylboronic acid (106 mg, 0.758 mmol) in a 2:1 mixture of toluene:EtOH (12 ml) under nitrogen was added 2M Na.sub.2CO.sub.3(aq) (1.011 ml, 2.022 mmol) followed by Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 adduct (41 mg, 0.051 mmol). The reaction mixture was heated using microwave radiation at 140° C. for 1 hour and then allowed to cool to RT. The mixture was diluted with EtOAc (100 ml) and washed with water (100 ml). The organic phase was separated, filtered through Celite® (filter material) dried (MgSO.sub.4) and concentrated in vacuo to yield a brown oil/solid. Purification by chromatography on silica eluting with MeOH/DCM yielded a yellow oil/solid. This was passed through a 500 mg Isolute® Si-TMT cartridge (2,4,6-trimercaptotriazine silica, pre-wetted with DCM) eluting with 30% MeOH/DCM (50 ml) to afford a yellow oil/solid. The crude product was dried in vacuo and slurried in ˜0.5 ml DCM. The resulting suspension was removed by filtration and the filtrate was evaporated to yield the title compound as a light yellow/brown foam-like solid; LC-MS Rt=5.30 mins [M+H]+ 372 (Method 10minLC_v002). 1H NMR (400 MHz, DMSO-d6), δ 8.29 (1H, t), 7.69 (1H, s), 7.49 (2H, t), 7.29 (2H, t), 7.22 (2H, s), 4.63 (1H, s), 3.24 (2H, d), 1.08 (6H, s).

Example 12

3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-propyl)-amide

[0419] ##STR00067##

Step 1: 3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-propyl)-amide

[0420] This compound was prepared from 3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D2) and 3-amino-1,1,1-trifluoropropan-2-ol analogously to Example 1; LC-MS Rt=1.50 mins [M+H]+ 426 (Method 2minLC_v002).

Step 2: 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-propyl)-amide

[0421] 3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-propyl)-amide (350 mg, 0.823 mmol) was dissolved in EtOH (14 ml) and water (7 ml). Hydroxylamine hydrochloride (572 mg, 8.23 mmol) was added followed by TEA (167 mg, 1.646 mmol) and the mixture was heated at reflux overnight. After cooling the RT, the mixture was purified by reverse phase chromatography eluting with MeOH; water (0.1% TFA) to afford the title compound as a pale yellow solid; LC-MS Rt=4.20 min [M+H]+ 348.2 (Method 10minLC_v002)

[0422] 1H NMR (400 MHz, DMSO-d6) δ 8.47 (NH, t), 7.66 (1H, s), 6.68 (NH2, b s), 6.51 (OH, d), 4.27-4.20 (1H, m), 3.93 (3H, s), 3.64-3.58 (1H, m), 3.44-3.37 (1H, m)

[0423] 19F NMR (400 MHz, DMSO-d6) d −62.67 (CF3, s), −77.05 (CF3, s), Trace TFA.

Example 14

5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propyl)-amide

[0424] ##STR00068##

[0425] This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propyl)-amide (Ex. 1.28) and 2-methylpyridine-5-boronic acid analogously to Example 8. LC-MS Rt 1.28 min; 477[M+H]+; (Method 2minLC_v002); .sup.1H NMR (400 MHz, MeOD) δ 8.50 (1H, s), 7.85 (1H, dd), 7.69 (1H, s), 7.40 (1H, d), 4.00 (2H, s), 2.62 (3H, s).

Example 15

5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

[0426] ##STR00069##

[0427] This compound was prepared by chiral separation of 5-amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (Example 1.29) using Supercritical Fluid Chromatography; LC-MS Rt 3.15 min [M+H]+ 423; (Method 10minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, s), 8.49 (1H, t), 7.75 (1H, d), 7.71 (1H, s), 7.35 (1H, d), 7.25 (2H, s), 6.22 (1H, s), 3.69 (1H, dd), 3.42 (1H, dd), 2.54 (3H, s), 1.22 (3H, s). SFC Retention Time: 4.87 min.

Example 16 and 17

3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide and 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

[0428] ##STR00070##

Step 1: 3-(2,5-Dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylicacid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

[0429] To a stirred solution of 3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate M) (1.16 g, 3.29 mmol) in NMP (32 ml) was added 3-Amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride (commercially available) (591 mg, 3.29 mmol) followed by HATU (1.25 g, 3.29 mmol) and NEt.sub.3 (918 ul, 6.59 mmol) and the reaction mixture was left to stir at RT. After 1 h a further 0.2 equiv. NEt.sub.3 was added. After 15 min a further 0.4 equiv. NEt.sub.3 and 0.2 equiv. amine were added. After 30 min a further 0.1 equiv HATU was added. After 30 min most of the starting material had been consumed. The reaction mixture was added to EtOAc (50 ml), washed with 0.1M NaOH and the aqueous layer was back extracted with EtOAc (2×50 ml). The combined organic extracts were washed with water (2×150 ml), brine (100 ml), dried (MgSO.sub.4) and concentrated in vacuo to give the crude product as an orange oil.

[0430] The crude material was purified by chromatography on silica eluting with 0-15% EtOAc in iso-hexane to afford the title product as a yellow solid; LC-MS Rt 1.32 min; MS m/z 478.2 [M+H]+; Method 2minLC_v003.

Step 2: 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

[0431] To a stirred solution of 3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (985 mg, 2.064 mmol) in 2:1 EtOH/H.sub.2O (7.5 ml) was added hydroxylamine hydrochloride (1.43 g, 20.64 mmol) followed by NEt (575 ml, 4.13 mmol). The reaction mixture was heated to reflux (˜98° C.) for 11.5 hours and then allowed to cool to RT. The solvent was removed in vacuo and the resulting residue was partitioned between EtOAc (25 ml) and water (25 ml). The aqueous layer was separated and extracted with EtOAc (2×25 ml) and the combined organic extracts were washed with brine (50 ml), dried (MgSO.sub.4) and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 0-25% EtOAc in iso-hexane to afford the title product as a pale yellow solid; LC-MS: Rt 1.24 min; MS m/z 400.0 [M+H]+; Method 2minLC_v003.

Step 3: 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide and 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylicacid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

[0432] ##STR00071##

[0433] These compounds were prepared by chiral separation of 3-amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; Enantiomer 1: LC-MS Rt 1.23 min; MS m/z 400.0 [M+H]+; Method 2minLC_v003. SFC Retention Time 5.07 min.

[0434] Enantiomer 2: LC-MS Rt 1.23 min; MS m/z 400.0 [M+H]+; Method 2minLC_v003. SFC Retention Time 5.13 min.

Example 18

3-Amino-6-methoxy-N-(3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methylpropyl)-5-(trifluoromethyl)picolinamide

[0435] ##STR00072##

[0436] The title compound was prepared analogously to Example 1 from 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D) and 3,3,3-trifluoro-N2-(4-methoxybenzyl)-2-methylpropane-1,2-diamine (Intermediate N). DIPEA was used in this reaction. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (1H, m), 7.68 (1H, s), 7.25 (2H, d), 6.83 (2H, d), 6.70 (2H, s), 3.85 (3H, s), 3.75 (2H, m), 3.72 (3H, s), 3.70 (1H, m), 3.47 (1H, m), 2.80 (1H, t), 1.24 (3H, s)

Example 19

3-Amino-N-(2-amino-3,3,3-trifluoro-2-methylpropyl)-6-methoxy-5-(trifluoromethyl) picolinamide

[0437] ##STR00073##

[0438] A mixture comprising 3-amino-6-methoxy-N-(3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methylpropyl)-5-(trifluoromethyl)picolinamide (Ex. 18) (0.9 g, 1.873 mmo) in TFA (50 ml) was heated to 50° C. for 2 h. After cooling to RT, the pH was adjusted to pH 12 using 2M NaOH. The product was extracted with DCM and the organic extract was washed with water, dried over MgSO.sub.4 and concentrated in vacuo. The crude product was loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo and dried under vacuum to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (1H, m), 7.67 (1H, s), 6.67 (2H, s), 3.93 (3H, s), 3.58 (1H, m), 3.40 (1H, m), 2.22 (2H, s), 1.14 (3H, s).

[0439] LC-MS Rt 0.94 min; MS m/z 361.2 [M+H]+; Method 2minLC_v003.

Example 20

3-Amino-6-(pyrrolidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

[0440] ##STR00074##

Step 1: 3-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(pyrrolidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

[0441] The title compound was prepared from Intermediate DA analogously to Example 1; LC-MS Rt 1.42 min; MS m/z 479.3 [M+H]+; Method 2minLC_v003.

Step 2: 3-Amino-6-(pyrrolidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

[0442] This compound was prepared from 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(pyrrolidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide analogously to Intermediate D (final step). The resulting racemate was separated by SFC to afford the title compound; First eluted peak:

[0443] 1H NMR (400 MHz, DMSO-d6) δ 8.24 (1H, m), 7.6 (1H, s), 6.4 (2H, br s), 6.32 (1H, s), 3.64 (1H, m), 3.48 (1H, m), 3.35 (4H), 1.88 (4H, m), 1.25 (3H, s);

[0444] LC-MS Rt 3.87 min; MS m/z 401.3 [M+H]+; Method 10minLC_v003.

Example 21

(S)-3-amino-6-ethoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoro methyl)picolinamide

[0445] ##STR00075##

[0446] The title compound was prepared from Intermediate DB and Intermediate R analogously to Example 20; 1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, t), 7.7 (1H, s), 6.6 (2H, broad), 6.3 (1H, s), 4.4 (2H, q), 3.6 (1H, mult), 3.5 (1H, mult), 1.3 (3H, t), 1.2 (3H, s).

[0447] LC-MS Rt 1.20 min; MS m/z 376.2 [M+H]+; Method 2minLC_v003.

Example 22

3-Amino-6-bromo-N-(2-morpholinoethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide

[0448] ##STR00076##

[0449] To a stirred solution of 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate C) (250 mg, 0.874 mmol) in NMP (8 ml) was added 4-(2-aminoethyl)morphonline (138 ul, 1.049 mmol) followed by DIPEA (763 ul, 4.37 mmol). To this solution was then added HATU (499 mg, 1.311 mmol) in portions and the reaction mixture was left to stir at RT for 1 hour. A further 1 equiv. of 4-(2-aminoethyl)morphonline was added. After a further 1.5 hr, 0.5 equiv. HATU (166 mg, 0.425 mmol) was added and the RM was left to stir for a further 30 min. The mixture was added to EtOAc (50 ml) and washed with 0.1M NaOH (50 ml). The aqueous layer was back extracted with EtOAc (50 ml). The combined organics were washed with water (50 ml), brine (50 ml), dried over magnesium sulfate and evaporated under reduced pressure to give a brown oil (418 mg). The crude product was purified by chromatography (Biotage-silica 20 g/70 ml column, 3:1 EtOAc/iso-hexane). The resulting yellow residue was loaded onto an SCX-2 cartridge (10 g) that had been pre-wetted with MeOH. The cartridge was washed with MeOH (140 ml) and eluted with 3.5M ammonia in methanol solution (70 ml). The appropriate fractions were evaporated under reduced pressure to give a solid. This solid was dissolved in EtOAc and filtered under vacuum. The filtrate was evaporated under reduced pressure and then dried in vacuo to afford the title compound as a yellow solid;

[0450] LC-MS: Rt 2.61 min; MS m/z 398.2 [M+H]+; Method 10minLC_v002

[0451] 1H NMR (400 MHz, DMSO-d6) δ 8.70 (1H, s), 8.10 (2H, s), 3.58 (4H. t), 3.40 (2H, q), 2.45 (2H, m), 2.40 (4H, s).

Example 23

N-(2-(1H-imidazol-2-yl)propyl)-3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carboxamide

[0452] ##STR00077##

[0453] The title compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate C) and 2-(1H-imidazol-2-yl)propan-1-amine (prepared according to the procedure of Steffens, Robert; Schunack, Walter. Histamine analogs, XXVI. Racemic histamine H1-agonists. Archiv der Pharmazie (Weinheim, Germany) (1984), 317(9), 771-6; 1H NMR (400 MHz, DMSO-d6) δ 11.8 (1H, s), 9.0 (1H, t), 8.1 (2H, s), 7.0 (1H, s), 6.8 (1H, s), 3.55 (2H, m), 3.15 (1H, m), 1.2 (3H, d). LC-MS [M+H]+ 393.0/395.1

Example 24a and 24b

Enantiomers of 3-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5,6-bis(trifluoromethyl) pyrazine-2-carboxamide

[0454] ##STR00078##

[0455] The title compound was prepared from Intermediate BA and 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol analogously to Example 4. Chiral separation of the racemate by Supercritical Fluid Chromatography afforded the title compound;

[0456] Example 24a: First eluted peak: Enantiomer 1 of 3-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5,6-bis(trifluoromethyl) pyrazine-2-carboxamide;

[0457] 1H NMR (400 MHz, DMSO-d6) δ 8.61-8.74 (1H, broad hump), 8.5-8.61 (1H, broad hump), 8.46 (1H, t), 6.3 (1H, s), 3.69 (1H, m), 3.5 (1H, m), 1.29 (3H, s)

[0458] LC-MS: Rt 4.23 min; MS m/z 401.2 [M+H]+; Method 10minLC_v003.

[0459] Example 24b: Second eluted peak: Enantiomer 2 of 3-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5,6-bis(trifluoromethyl) pyrazine-2-carboxamide;

[0460] 1H NMR (400 MHz, DMSO-d6) δ 8.61-8.76 (1H, broad hump), 8.5-8.60 (1H, broad hump), 8.46 (1H, t), 6.3 (1H, s), 3.69 (1H, m), 3.5 (1H, m), 1.29 (3H, s)

[0461] LC-MS: Rt 4.24 min; MS m/z 401.2 [M+H]+; Method 10minLC_v003.

[0462] Optical rotation [α].sup.21 at 589 nm+22.0° (c=0.517, MeOH).

Example 25

3-Amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

[0463] ##STR00079##

Step 1: 3-Amino-6-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)picolinic acid

[0464] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (500 mg, 1.672 mmol), PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (205 mg, 0.251 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (383 mg, 1.839 mmol) and Cs.sub.2CO.sub.3 (6.69 ml, 6.69 mmol) in THF (12 ml) under N.sub.2, was heated using microwave radiation at 150° C. for 10 minutes. 2M NaOH (5 ml) was added and the mixture was stirred at RT overnight. The mixture was filtered through Celite® (filter material) and the organic solvent was removed. The resulting aqueous layer was washed with EtOAc and acidified to pH1. The product was extracted with DCM and concentrated in vacuo to afford the title compound;

Step 2: 3-Amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

[0465] The title compound was prepared from 3-amino-6-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoro methyl)picolinic acid and 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol analogously to Example 4 1H NMR (400 MHz, Methanol-d4) δ 7.97 (1H, s), 7.85 (1H, s), 7.60 (1H, s), 3.97 (3H, s), 3.77 (1H, m), 3.56 (1H, m), 1.37 (3H, s)

[0466] LC-MS: Rt 3.22 min; MS m/z 412.3 [M+H]+; Method 10minLC_v003.

Example 26

3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylicacid[2-(2-methoxy-phenyl)-ethyl]-amide

[0467] ##STR00080##

[0468] The title compound was prepared from 3-amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate PA) and the appropriate amine; MS m/z 406.93[M+H]+

Preparation of Intermediates

Intermediate A

3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid

[0469] ##STR00081##

Intermediate A1: 2-Bromo-3-nitro-5-trifluoromethyl-pyridine

[0470] 3-Nitro-5-(trifluoromethyl)pyridin-2-ol (31.00 g, 149 mmol) was dissolved in acetonitrile (250 ml) to give a dark brown solution. Phosphorus (V) oxybromide (85 g, 298 mmol) was added and the mixture was heated at reflux for 4.5 hours and then stirred at RT overnight. The reaction mixture was quenched by pouring into vigorously stirring water (600 ml) containing sodium hydrogencarbonate (110 g). The dark brown mixture was extracted with DCM (3×200 ml) and the organic phase was washed with water (200 ml) and brine (100 ml), dried (MgSO.sub.4) and concentrated in vacuo to afford the title product as a brown oil. .sup.1H-NMR: [400 MHz, CDCl.sub.3, δ.sub.H 8.87 (1H, d, J=1.4 Hz, ArH), 8.39 (1H, d, J=1.9 Hz, ArH).

Intermediate A2: 3-Nitro-5-trifluoromethyl-pyridine-2-carbonitrile

[0471] 2-Bromo-3-nitro-5-trifluoromethyl-pyridine (10.00 g, 36.87 mmol) was dissolved in toluene (250 ml) with stirring to give a pale yellow solution. Tetrabutylammonium bromide (11.90 g, 36.9 mmol) was added followed by copper(I) cyanide (9.92 g, 111 mmol) and the mixture was heated at reflux for 10 h. After cooling to RT, the reaction mixture was partitioned between water (750 ml) and EtOAc (750 ml). The organic fractions were combined, washed with water (2×250 ml) and brine (100 ml), dried (MgSO.sub.4) and concentrated in vacuo to afford the title product. .sup.1H-NMR: [400 MHz, DMSO-d.sub.6 δ.sub.H 9.55 (1H, m, ArH), 9.24 (1H, m, ArH)

Intermediate A3: 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester

[0472] 3-Nitro-5-trifluoromethyl-pyridine-2-carbonitrile (6.5 g, 29.9 mmol) was dissolved in EtOAc (150 ml) to give a pale yellow solution and placed under an atmosphere of nitrogen. 10% Palladium on activated carbon (3.19 g, 2.99 mmol) was added and the reaction mixture stirred under an atmosphere of hydrogen for 18 hours. The reaction mixture was filtered and concentrated in vacuo. The crude residue was dissolved in HCl conc. (45 ml) and heated to reflux for 24 hours. The reaction mixture was allowed to cool to RT and concentrated in vacuo. The solid was dissolved in MeOH (300 ml) and sulfuric acid (14.4 ml) was added. The resulting solution was heated at reflux for 48 hours. The reaction was allowed to cool to RT, then neutralised by addition of 10% NaHCO.sub.3(aq) (600 ml). The product was extracted into DCM (3×200 ml) and the combined organic phases were washed with water (200 ml), brine (50 ml), (MgSO.sub.4) and concentrated in vacuo. The resulting solid was purified by chromatography on silica: Eluant gradient: isohexane (500 ml), 10% EtOAc in isohexane (1000 ml), 20% EtOAc in isohexane (1500 ml) to afford the titled compound as a pale yellow solid .sup.1H-NMR: [400 MHz, DMSO-d.sub.6, δ.sub.H 8.13 (1H, d, J=1.7 Hz, ArH), 7.60 (1H, d, J=1.3 Hz, ArH), 7.01 (2H, br, NH.sub.2), 3.85 (3H, s, ArOCH.sub.3), m/z 221.1 [M+H].sup.+

Intermediate A4: 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester

[0473] 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (9.49 g, 43.16 mmol) was suspended in water (300 ml). Sulfuric acid (4.60 ml, 86 mmol) was added followed by dropwise addition over 30 minutes of a solution of bromine (2.222 ml, 43.1 mmol) in acetic acid (29.6 ml, 517 mmol). The reaction mixture was stirred at RT for 18 hours. A further 100 ml of water was added, followed by a further 0.25 equivalents of the bromine/AcOH mixture (550 μL bromine in 7.4 ml AcOH) and the reaction mixture stirred at RT for an additional 90 minutes. The reaction mixture was diluted with 500 ml water and neutralised by addition of solid NaHCO.sub.3 (85 g). The suspension was extracted with DCM (3×300 ml) and the combined organic phases washed with sat.NaHCO.sub.3(aq) (250 ml), water (250 ml) and brine (100 ml), dried (MgSO.sub.4) and concentrated in vacuo. The crude material was recrystallised from boiling MeOH (˜300 ml) to give the title product as a pale orange solid m/z 301.0 [M+H].sup.+1H-NMR: [400 MHz, DMSO-d.sub.6 δ.sub.H 7.77 (1H, s, ArH), 7.17 (2H, s, NH.sub.2), 3.86 (3H, s, ArCO.sub.2CH.sub.3).

Intermediate A: 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid

[0474] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.40 g, 4.68 mmol) was suspended in MeOH (15 ml); Sodium hydroxide (2.0 M aqueous solution) (14.04 ml, 28.1 mmol) was added and the suspension was stirred at RT overnight. The mixture was concentrated in vacuo and the resulting residue was dissolved in water (100 ml) and then acidifed by the addition of 5.0M HCl(aq). The product was extracted into ethyl acetate (2×75 ml) and the combined organic extracts were washed with water (50 ml), brine (25 ml), dried (MgSO.sub.4) and concentrated in vacuo to afford the title product as a yellow solid. .sup.1H-NMR: [400 MHz, DMSO-d.sub.6, δ.sub.H 13.24 (1H, br s, CO.sub.2H), 7.74 (1H, s, ArH), 7.17 92H, br s ArNH.sub.2). m/z 285.1, 287.1 [M+H].sup.+

Intermediate B

3-Amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester

[0475] ##STR00082##

Intermediate E1: Carbamimidoyl-nitroso-acetic acid ethyl ester

[0476] To a solution of 2M ammonia in Ethanol (152 ml, 0.304 mmol) at 0° C. to 5° C., ethyl ethoxycarbonylacetimidate HCl (25 g, 0.127 mmol) was added over 30 minutes. The reaction was stirred vigorously at this temperature for 3 hours, after which a solution of sodium nitrite in water (9.63 g, 0.139 mmol) was added in a single portion. The pH of the mixture was adjusted to pH6 with the addition of 5N HCl. The reaction mixture was left to stir at RT overnight. The yellow precipitate formed was filtered under vacuum, washed with water and dried to give the title compound;

[0477] .sup.1H NMR (400 MHz, DMSO-d6) δ 10.1 (2H, br s), 7.6 (2H, br s), 4.3 (2H, q), 1.3 (3H, t).

Intermediate B2: Amino-carbamimidoyl-acetic acid ethyl ester

[0478] To a solution of carbamimidoyl-nitroso-acetic acid ethyl ester (5.5 g, 31.4 mmol) in ethanol/5M HCl (1:1 ratio, 250 ml) was added 10% Pd/C (1.3 g). The reaction mixture was hydrogenated (H.sub.2(g) at low pressure over 2 nights. The Pd/C was filtered through Celite® (filter material) and the filtrate reduced in vacuo to give the title compound as a white solid. This was taken through to the next step as crude.

Intermediate B: 3-Amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester

[0479] To a mixture of amino-carbamimidoyl-acetic acid ethyl ester (2 g, 9.22 mmol) and water (50 ml), a 20% aqueous solution of trifluoropyruvic aldehyde (2.32 g, 18.43 mmol) was added. To this mixture, sodium acetate (5.29 g, 64.52 mmol) was added (pH of the reaction mixture was pH5). The reaction mixture was left to stir at RT overnight. The resultant precipitate was filtered under vacuum purification by chromatography on silica eluting with iso-hexane: EtOAc (gradient of 0 to 10% EtOAc) afforded the title compound

[0480] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.4 (1H, s), 7.8 (2H, br s), 4.4 (2H, q), 1.4 (3H, t).

Intermediate BA

3-Amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylic acid

[0481] ##STR00083##

Step 1: Ethyl 3-amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylate

[0482] The title compound was prepared from amino-carbamimidoyl-acetic acid ethyl ester (Intermediate B2) and 1,1,1,4,4,4-hexafluorobutane-2,3-dione analogously to Intermediate B; 10 LCMS Rt=4.72 minutes, [M+H]+ 304.2/326.1 Method 10minLC_v002.

Step 2: 3-Amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylic acid

[0483] To a stirring solution of ethyl 3-amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylate (300 mg, 0.990 mmol) in EtOH (10 ml), 2M NaOH (0.495 ml, 0.990 mmol) was added dropwise over 1 minute. After stirring at RT for 30 minutes the reaction mixture was poured into water (30 ml) and the pH was adjusted to pH 4 by addition of 1M HCl. The mixture was extracted with EtOAc (2×50 ml) and the combined organic extracts were washed with brine (30 ml), dried over MgSO.sub.4 (5 g), filtered and concentrated in vacuo to afford the title compound as an off white crystalline solid;

[0484] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.6-9.2 (2H, broad hump), 7.8-8.3 (2H, broad hump), 4.4 (2H, q), 1.32 (3H, t).

Intermediate C

3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid

[0485] ##STR00084##

Intermediate C1: 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester

[0486] To a solution of 3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Intermediate B) (30 mg, 0.13 mmol) in acetic acid (5 ml), sodium carbonate (15 mg, 0.14 mmol) was added. To this mixture, half the contents of a solution of bromine (7 μL, 0.13 mmol) in acetic acid (5 ml) were added, followed by the addition of sodium carbonate ((15 mg, 0.14 mmol). The remaining solution of bromine in acetic acid was added and the reaction mixture was left to stir at RT for 2 hours. The mixture was diluted with water and the resulting yellow precipitate was filtered under vacuum to afford the title compound.

Intermediate C: 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid

[0487] To a stirring solution of 3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (10 g, 31.8 mmol) in ethanol (20 ml), 2M NaOH (20 ml, 31.8 mmol) was added. The resulting solution was stirred at RT for 5 minutes and poured into water (50 ml). The pH was adjusted to pH6 with the addition of 1M HCl. The resulting suspension was filtered under vacuum, washed with water (20 ml) and dried to afford the title compound; MS m/z 287[M+H]+. .sup.1H NMR (400 MHz, DMSO-d6) δ 7.98 (2H, s).

Intermediate D

3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid

[0488] ##STR00085##

Intermediate D1: 6-Bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester

[0489] ##STR00086##

[0490] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (2 g, 6.69 mmol) was suspended in toluene (8 ml), and treated with p-toluenesulfonic acid (TsOH) (0.115 g, 0.669 mmol) and acetonylacetone (0.941 ml, 8.03 mmol). The reaction mixture was heated at reflux for 2 hours (using Dean-Stark apparatus) and allowed to cool to RT overnight. The resulting dark red/black solution was concentrated in vacuo to remove toluene and the crude residue diluted with EtOAc (200 ml), washed with NaHCO.sub.3 (50 ml), dried (MgSO.sub.4) and concentrated in vacuo to give a brown solid. Purification of the solid by chromatography on silica eluting with EtOAc/iso-hexane afforded the title compound; LC-MS Rt=5.58 min [M+H]+ 377/379 (Method 10minLC_v002).

[0491] 1H NMR (400 MHz, DMSO-d6) δ 8.50 (1H, s), 7.77 (2H, s), 5.83 (3H, s), 1.90 (6H, s);

[0492] 19F NMR (400 MHz, DMSO-d6) δ-62.26 (CF3, s).

Intermediate D2: 3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid

[0493] ##STR00087##

[0494] 6-Bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (2 g, 5.30 mmol) was dissolved in MeOH (40 ml) and treated with 2M NaOH (20 ml) to give a suspension which was stirred at RT for 1 h to afford a clear solution. The solvent was removed in vacuo and the resulting residue was acidified to pH1 with 5M HCl. The mixture was extracted with EtOAc (200 ml) and the organic extract was dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound as a dark brown solid which was used in the next step without further purification; LC-MS Rt=1.50 min [M+H]+ 315.2.1/316.2 (Method 2minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ14.42-12.61 (COOH, b), 8.25 (1H, s), 5.84 (2H, s), 4.13 (3H, s), 1.97 (6H, s); 19F NMR (400 MHz, DMSO-d6) δ-62.43 (CF3, s).

Intermediate D: 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid

[0495] 3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (2.1 g, 6.68 mmol) was dissolved in EtOH (40 ml) and water (20 ml). To this mixture was added TEA (2.79 ml, 20.05 mmol) followed by hydroxylamine hydrochloride (4.64 g, 66.8 mmol). The resulting mixture was heated at reflux for 5 hours. After cooling to RT, the mixture was diluted with EtOAc (100 ml) and washed with aqueous HCl (1M, 100 ml). The aqueous phase was back extracted with EtOAc (100 ml) and the combined organic phases washed with brine (100 ml), dried (MgSO.sub.4) and concentrated in vacuo to afford the product as an orange solid. The material can be used crude or recrystallised from isohexane-EtOAc (10:1) LC-MS Rt=1.0 min [M+H]+ 237 (Method 2minLC_v003) 1H NMR (400 MHz, DMSO-d6) δ 8.5 (NH2, b), 7.70 (1H, s), 3.89 (3H, s).

Intermediate DA

3-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(pyrrolidin-1-yl)-5-(trifluoromethyl)picolinic acid

[0496] ##STR00088##

Step 1:6-Bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)picolinic acid

[0497] 6-Bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.9 g, 5.04 mmol) and 2M NaOH (2.52 ml, 5.04 mmol) in THF (10 ml) was stirred at RT for 1 hour. The reaction mixture was poured into water (50 ml) and the pH was adjusted to pH 4 by addition of 1M HCl. The mixture was extracted with EtOAc (2×50 ml) and the organic portion was washed with brine (30 ml), dried over MgSO.sub.4 (5 g), filtered and concentrated to give the title compound as a crystalline orange solid; LC_MS Rt=1.21 min [M+H]+ 363.1 (Method 2minLC_v003).

Step 2: 3-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(pyrrolidin-1-yl)-5-(trifluoromethyl)picolinic acid

[0498] To a stirring solution of 6-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl) picolinic acid (300 mg, 0.826 mmol) in THF (1 ml), pyrrolidine (0.136 ml, 1.652 mmol) was added. The orange solution was stirred at RT overnight. The reaction mixture was partitioned between 0.5M HCl (30 ml) and EtOAc (30 ml) and shaken. The organic portion was separated and washed with brine (30 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to give a red oil. The crude product was purified on silica eluting with 0-40% EtOAc in iso-hexane to afford the title product;

[0499] 1H NMR (400 MHz, DMSO d6) δ 13.45 (1H, br s), 7.88 (1H, s), 5.74 (2H, s), 3.58 (5H, br s), 1.88-2.0 (11H, unresolved peaks).

Intermediate DB

3-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-ethoxy-5-(trifluoromethyl)picolinic acid

[0500] ##STR00089##

Step 1: Methyl 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methoxy-5-(trifluoromethyl)picolinate

[0501] 3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D2)(500 mg, 1.591 mmol) in methanol (15.91 ml) was treated with H.sub.2SO.sub.4 (0.0424 ml, 0.795 mmol) and the solution was heated at reflux for overnight.

[0502] The solvent removed was removed in vacuo and the resulting brown oil was neutralised to pH 7 using saturated sodium bicarbonate. The mixture was extracted with EtOAc (20 ml) and the combined organic extracts were washed with water (20 ml), brine (20 ml), passed though a phase separator and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with iso-hexane: EtOAc (gradient of 0 to 10% EtOAc) afforded the title compound as an off-white powder.

[0503] 1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, s), 5.8 (2H, s), 4.1 (3H, s), 3.6 (3H, s), 1.9 (6H, s).

Step 2: Methyl 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-hydroxy-5-(trifluoromethyl)picolinate

[0504] Methyl 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methoxy-5-(trifluoromethyl)picolinate (100 mg, 0.305 mmol) in acetonitrile (3.05 ml) was treated with KI (202 mg, 1.218 mmol) and TMS-Chloride (0.156 ml, 1.221 mmol) and heated at reflux for 6 hours. The solvent removed was in vacuo and the crude product was dissolved in EtOAc (20 ml) and washed with water (2×10 ml) and brine (10 ml), dried over a phase separator and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with iso-hexane: EtOAc (gradient of 0 to 30% EtOAc) afforded the title compound as an yellow powder. LC-MS Rt=1.11 mins [M+H]+ 315.4 (Method 2minLC_v003).

Step 3: Methyl 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-ethoxy-5-(trifluoromethyl)picolinate

[0505] Methyl 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-hydroxy-5-(trifluoromethyl)picolinate (62 mg, 0.168 mmol) in 1,4-dioxane (1.5 ml) (dry) was treated with EtOH (0.020 ml, 0.335 mmol) and triphenylphosphine (88 mg, 0.335 mmol) and the solution stirred. DEAD (0.053 ml, 0.335 mmol) was added dropwise and the reaction mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo and purification of the crude product by chromatography on silica eluting with iso-hexane: EtOAc (gradient of 0 to 10% EtOAc) afforded the title compound;

[0506] 1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, s), 5.8 (2H, s), 4.5 (2H, q), 3.6 (3H, s), 1.9 (6H, s), 1.4 (3H, t).

Step 4: 3-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-ethoxy-5-(trifluoromethyl)picolinic acid

[0507] Methyl 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-ethoxy-5-(trifluoromethyl)picolinate (140 mg, 0.409 mmol) was dissolved in THF (2.045 ml). NaOH (0.613 ml, 1.226 mmol) was added and heated at reflux for 6 hours. The solvent was removed in vacuo and the resulting mixture was diluted with EtOAc (25 ml) was acidified to pH 1 using HCl (5M). The organic portion washed with brine, dried using a phase separator and concentrated in vacuo to afford the title compound as a yellow oil.

[0508] LC-MS Rt=1.26 mins [M+H]+ 329.2 Method 2minLC_v003.

Intermediate E

3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid

[0509] ##STR00090##

[0510] To a stirring solution of 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A3) (1 g, 4.54 mmol) in MeOH (20 ml) was added 2M NaOH (0.182 g, 4.54 mmol). The orange solution was stirred at RT for 1 minute and then into water (10 ml). The solution was acidified to pH1 with the addition of 1M HCl and the product was extracted with EtOAc (150 ml). The organic portions were combined, washed with brine (50 ml), dried over MgSO.sub.4 and concentrated in vacuo to afford the title compound as an orange solid; LC-MS Rt=0.82 mins [M+H]+ 207.1 (Method 2minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 13.9 (1H, broad hump), 8.11 (1H, s), 7.59 (1H, s), 7.08 (2H, broad hump) (trace of EtOAc present but correlates to proposed structure).

Intermediate G

3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid

[0511] ##STR00091##

[0512] A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate A) (1 g, 3.51 mmol), 4-fluorophenylboronic acid (0.736 g, 5.26 mmol) and 1,1′Bis(diphenylphosphoshio)ferrocene palladium dichloride (0.286 g, 0.351 mmol) and 1.0M Cs.sub.2CO.sub.3 (3.3 ml) in THF (10 ml) was heated to reflux for 10 hours. After cooling to RT, the mixture was partitioned between DCM (100 ml) and 1 M NaOH (2×100 ml). The aqueous phase was acidified with 5M HCl and the resulting milky solution was extracted into DCM (2×100 ml). The organic portion was separated, dried (MgSO.sub.4) and concentrated in vacuo to afford the product as a crude oil. The crude material was purified by flash chromatography on silica cartridge eluting with a gradient of DCM: MeOH from 0% to 10% MeOH to afford the title product as a pale yellow solid; .sup.1H NMR (DMSO-d6, 400 MHz) δ 12.9 (1H, brs, COOH), 7.7 (1H, s, CH, Ar—H), 7.4 (2H, m, Ar—H), 7.25 (2H, m, Ar—H), 7.1 (2H, br s, NH2).

Intermediate GA

3-Amino-6-cyclopropyl-5-(trifluoromethyl)picolinic acid

[0513] ##STR00092##

Step 1: 3-Amino-6-cyclopropyl-5-(trifluoromethyl)picolinic acid

[0514] A microwave vial was charged with amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (0.5 g, 1.754 mmol), cyclopropylboronic acid (0.753 g, 8.77 mmol), and 1,1′Bis(diphenylphosphosphino) ferrocene palladium dichloride (0.143 g, 0.175 mmol). The mixture was taken up as a solution in THF (6 ml) and flushed with N.sub.2, sealed and heated using microwave radiation at 150° C. for 20 minutes. The reaction mixture was filtered through Celite® (filter material) and washed through with EtOAc (20 ml). The filtrate was partitioned between EtOAc (30 ml) and water (50 ml). The phases were separated and the organic portion was washed with brine (30 ml), dried over MgSO.sub.4, filtered and concentrated under vacuum.

[0515] The crude material was taken up in EtOAc (20 ml) and dry loaded onto silica (2-3 g). Material then purified on the Combiflash Rf Teledyne ISCO System 100% Isohexane to 60% EtOAc:Isohexane to afford semi pure material which was used without further purification.

[0516] Step 2: 3-Amino-6-cyclopropyl-5-(trifluoromethyl)picolinic acid

[0517] To a stirring solution of 3-amino-6-cyclopropyl-5-(trifluoromethyl)picolinic acid (472 mg, 1.814 mmol) in THF (10 ml), 2M NaOH (10 ml, 20.00 mmol) was added. The orange solution was stirred at RT for 2 days. The reaction mixture was poured into water (30 ml) and the pH adjusted to pH6 with the addition of 1M HCl. The product was extracted with EtOAc (50 ml) and the organic portion was dried over MgSO.sub.4, filtered and concentrated in vacuo to give the title compound as a red/orange oil. LC-MS Rt=1.10 mins [M+H]+ 247.1 (Method 2minLC_v003);

Intermediate H

3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid

[0518] ##STR00093##

[0519] Intermediate H1: 3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (3 g, 10.03 mmol), 2,4-dichlorophenylboronic acid (2.297 g, 12.04 mmol), potassium phosphate (4.26 g, 20.06 mmol) and Fibrecat®1034A (Johnson Matthey, polymer supported palladium complex) (500 mg, 10.03 mmol) were suspended in toluene (50 ml) and water (15 ml). The reaction mixture was heated to 110° C. under vigorous stirring for 3 hours. The mixture was allowed to cool to RT and EtOAc (100 ml) was added. The organic layer was separated and washed with brine (15 ml). MP-TMT (macroporous polystyrene-bound trimercaptotriazine, 3 g, Polymern labs) was added and stirred for 1 hour at RT. MgSO.sub.4 was added and the suspension filtered off. The filtrate was concentrated in vacuo and purification of the residue by reverse phase chromatography (130 g C18 column) eluting with water/MeOH afforded the title compound as a white solid; LS-MS Rt=1.55 mins [M+H]+ 365 (Method 2minLC_v002).

Intermediate H: 3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid

[0520] 3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (0.9 g, 2.465 mmol) was suspended in MeOH (15 ml) and NaOH 2M (2.465 ml, 4.93 mmol) was added under stirring. 1,4-Dioxane (15.00 ml) was added and the solution was left standing at RT over night. The solvent was removed in vacuo and the resulting residue was dissolved in water (10 ml) and carefully acidified to pH4 with slow addition of 2M HCl (2 ml) whilst stirring. The mixture was extracted with EtOAc (20 ml) and the organic portion was washed with brine and concentrated in vacuo. The residue was purified by reverse phase chromatography (130 g C18 column) eluting with water/MeOH to afford the title compound; LS-MS Rt=1.57 mins [M+H]+ 351.0 (Method 2minLC_v002).

Intermediate I

3-Amino-6-(4-chloro-2-methyl-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester

[0521] ##STR00094##

[0522] This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) and 4-chloro-2-methylphenylboronic acid analogously to Intermediate H; LC-MS Rt=1.53 mins, [M+H]+ 331 (Method 2minLC_v002).

Intermediate J

2-Aminomethyl-1,1,1,3,3,3-hexafluoro-propan-2-ol

[0523] To a stirred mixture of 35% ammonium solution (1 ml) and diethyl ether (1 ml) was added 3,3,3-trifluoro-2-(trifluoromethyl)-1,2-propenoxide (500 mg, 2.78 mmol) dropwise and the reaction mixture was left to stir at RT for 3 hours. The reaction mixture was separated and the aqueous layer was extracted with diethyl ether (2×3 ml). The combined organic portions were dried (MgSO.sub.4) and concentrated in vacuo to give a white crystalline solid; 1H NMR (400 MHz, DMSO-d6) δ 4.20 (broad), 3.30 (broad), 3.15 (s), 3.02 (s), 2.50 (s, DMSO). 19F NMR (400 MHz, DMSO-d6) δ-85 (CF3), −84.5 (CF3).

Intermediate K

5-Amino-6′-methyl-3-(trifluoromethyl)-2,3′-bipyridine-6-carboxylic acid

[0524] ##STR00095##

Intermediate K1: 5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acid methyl ester

[0525] This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) and 2-methylpyridine-5-boronic acid analogously to 3-amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate G); LC-MS Rt 0.96 min [M+H]+ 312 (Method 2minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 8.41 (1H, s), 7.79 (1H, s), 7.69 (1H, dd), 7.32 (1H, d), 7.10 (2H, s), 3.82 (3H, s), 2.52 (3H, s).

Intermediate K: 5-Amino-6′-methyl-3-(trifluoromethyl)-2,3′-bipyridine-6-carboxylic acid

[0526] This compound was prepared from: 5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acid methyl ester analogously to 3-amino-6-(4-chloro-2-methyl-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate I); LC-MS Rt 0.90 min; [M+H]+ 298 (Method 2minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 12.90 (1H, broad), 8.45 (1H, s), 7.72 (2H), 7.32 (1H, d), 7.12 (2H, broad), 2.51 (3H).

Intermediate KA

5-Amino-3-(trifluoromethyl)-2,4′-bipyridine-6-carboxylic acid

[0527] ##STR00096##

[0528] The title compound was prepared analogously to Intermediate K using the appropriate boronic acid in step 1; 1H NMR (400 MHz, DMSO-d6) δ 13.00 (1H, broad), 8.65 (2H, d), 7.65 (1H, s), 7.43 (2H, d), 7.18 (2H, broad).

Intermediate M

3-(2,5-Dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid

[0529] ##STR00097##

Intermediate M1: 3-(2,5-Dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid methyl ester

[0530] A stirred mixture of KF (2.12 g, 5.62 mmol) and CuI (0.490 g, 8.43 mmol) was heated in a sealed 10.0-20.0 ml microwave vial under vacuum until a slight greenish colour began to appear. The vial was then placed under nitrogen to cool. A solution 6-bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate D) (2.64 ml, 16.86 mmol) in 1:1 dry DMF/dry NMP (14 ml) was then added, followed by TMS-CF.sub.3 (2.64 ml, 16.86 mmol). A new septum was then used to seal the vial and the reaction mixture was heated using microwave radiation with stirring at 100° C. for 3 h and allowed to cool. The mixture was added to 5M NH3 solution (50 ml) and then extracted with diethyl ether (4×50 ml). The combined organic extracts were washed with 5M NH.sub.3 solution (3×20 ml), 1M HCl (50 ml), sat. sodium bicarbonate solution (2×50 ml), brine (50 ml), dried (MgSO.sub.4) and concentrated in vacuo to give a brown oil. The crude material was purified by chromatography on silica eluting with Iso-hexane/EtOAc, 0-10% to afford the title compound as an orange solid; LC-MS Rt 1.37 min; MS m/z 367.1 [M+H]+; Method 2minLC_v003.

Intermediate M: 3-(2,5-Dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid

[0531] To a stirred solution 3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.28 g, 3.49 mmol) in methanol (25 ml) was added 1M NaOH (7 ml, 6.99 mmol) and the reaction mixture was left to stir at RT for 30 min. The solvent was removed in vacuo and water (20 ml) was added to the remaining residue. The pH was adjusted to pH 4/5 by the addition of 1M HCl. The mixture was extracted with EtOAc (3×20 ml) and the combined organic extracts were washed with brine (30 ml), dried (MgSO.sub.4) and concentrated in vacuo and dried in a vacuum oven (50° C.) overnight to give the crude title product as an orange solid which was used without further purification; LC-MS: Rt 1.23 min; MS m/z 353.1 [M+H]+; Method 2minLC_v003.

Intermediate N

3,3,3-Trifluoro-N2-(4-methoxybenzyl)-2-methylpropane-1,2-diamine

[0532] ##STR00098##

Step 1: 1-(4-methoxyphenyl)-N-(1,1,1-trifluoropropan-2-ylidene)methanamine

[0533] To a stirring solution of trifluoroacetone (7.75 g, 69.2 mmol) in diethyl ether (60 ml) at −40° C. was added 4-methoxybenzyl amine (9.49 g, 69.2 mmol) and triethylamine (14 g, 138 mmol) in diethyl ether (40 ml). A cooled (0° C.) mixture of TiCl.sub.4 (6.56 g, 34.6 mmol) in hexane (40 ml) at was added dropwise over 10 minutes and the resulting mixture was allowed to warm up to ambient temperature over 20 mins and stirred at 50° C. for 2.5 h. The inorganic precipitate was removed by filtration and washed with diethyl ether. The filtrate was concentrated in vacuo to afford a yellow oil. Purification of the crude product by chromatography on silica eluting with 0% to 25% EtOAc in iso-hexane afforded the title product.

Step 2: 3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methyl propanenitrile

[0534] To a cooled (0° C.) solution of 1-(4-methoxyphenyl)-N-(1,1,1-trifluoropropan-2-ylidene)methanamine (4.41 g, 19.07 mmol) in DCM (100 ml) was added cyanotrimethylsilane (2.84 g, 28.6 mmol) and magnesium bromide. The mixture was stirred at RT for 90 h and then diluted with sat. NaHCO.sub.3 (200 ml). After stirring at RT for 1 h, the organic phase was separated, washed with a further portion of sat. NaHCO.sub.3 (100 ml), dried over MgSO.sub.4 and concentrated in vacuo to afford the title compound.

Step 3: 3,3,3-trifluoro-N2-(4-methoxybenzyl)-2-methylpropane-1,2-diamine

[0535] To a cooled (0° C.) solution of 3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methyl propanenitrile (1.5 g, 5.81 mmol) in dry diether ether (50 ml) was added LiAlH4 (11.62 ml of a 2M solution in THF) and the resulting mixture was stirred at RT overnight. The reaction mixture was hydrolyzed by successive addition of water 15% KOH, and water. The resulting precipitate was filtered on Celite® (filter material) and the organic portion was washed with water, dried over MgSO.sub.4 and concentrated under reduced pressure to afford the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.97 (1H, s), 7.85 (1H, s), 7.60 (1H, s), 3.97 (3H, s), 3.77 (1H, m), 3.56 (1H, m), 1.37 (3H, s)

[0536] LC-MS: Rt 3.22 min; MS m/z 412.3 [M+H]+; Method 10minLC_v003.

Intermediate O

Benzo[d]isoxazol-3-ylmethanamine

[0537] ##STR00099##

[0538] The title compound was prepared according to the procedure of Pigini, Maria; Giannella, Mario; Gualtieri, Fulvio; Melchiorre, Carlo; Bolle, Paola; Angelucci, Luciano. Analogs with a 1,2-benzisoxazole nucleus of biologically active indole derivatives. Ill. Tryptamine and gramine isosteres. European Journal of Medicinal Chemistry (1975), 10(1), 29-32 (Compound 11 page 31-32).

Intermediate P

Methyl 3-amino-6-(oxazol-2-yl)-5-(trifluoromethyl)picolinate

[0539] A solution of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (500 mg, 1.672 mmol), 2-(tributylstannyl)oxazole (0.704 ml, 3.34 mmol) and tetrakis(triphenylphosphine)palladium(O) (193 mg, 0.167 mmol) in dioxane (10 ml) was heated at reflux for 13 hours. After cooling to room temperature over 8 hours, the solvent was evaporated and the resulting residue triturated with hot methanol to remove a yellow solid impurity. The remaining crude material was used without further purification. LC-MS: Rt 0.95 min; MS m/z 288 [M+H]+; Method 2minLC_v003.

Intermediate PA

3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid

[0540] ##STR00100##

Step 1: 3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid

[0541] The title compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Intermediate C1) and tributyltin-2-furylstannane analogously to methyl 3-amino-6-(oxazol-2-yl)-5-(trifluoromethyl)picolinate (Intermediate P)

Step 2: 3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid

[0542] The title compound was prepared from 3-amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid and 6M NaOH analogously to 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate C, final step).

Intermediate Q

2-Hydroxy-3-methyl-2-(trifluoromethyl)butan-1-aminium chloride

[0543] ##STR00101##

Step 1: 1,1,1-Trifluoro-3-methyl-2-(nitromethyl)butan-2-ol

[0544] A cooled (0° C.) solution of lithium hydroxide (0.048 g, 2.015 mmol) in water (20 ml) was stirred and treated with nitromethane (1.23 g, 20.15 mmol), 1,1,1-trifluoro-3-methylbutan-2-one (3.11 g, 22.17 mmol), cetyltrimethylammonium Chloride (0.871 g, 2.72 mmol) and MgSO.sub.4 (0.485 g, 4.03 mmol). The white suspension was stirred at 0° C. for 1 hr, then at RT for 2 days. The resulting biphasic mixture was separated and the more dense lower layer was collected and dissolved in diethyl ether (30 ml). The mixture was dried over MgSO.sub.4, filtered and concentrated in vacuo to give a pale yellow oil. The oil was taken up in diethyl ether (10 ml) and passed through a pre-packed SCX-2 cartridge eluting with 100% diethyl ether. The filtrate was concentrated in vacuo to afford the title compound as a colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 4.74 (1H, d), 4.59 (1H, d), 4.29 (1H, s), 2.29 (1H, m), 1.1 (6H, two sets of unresolved doublets)

Step 2: 2-Hydroxy-3-methyl-2-(trifluoromethyl)butan-1-aminium chloride

[0545] To a solution of 1,1,1-trifluoro-3-methyl-2-(nitromethyl)butan-2-ol (753 mg, 3.74 mmol) in EtOH (10 ml) in a 25 ml medium pressure glass hydrogenation vessel under N.sub.2, 10% Pd on carbon (39.8 mg, 0.374 mmol) was added. The vessel was flushed with N.sub.2, followed by H.sub.2 (22.64 mg, 11.23 mmol) at 5 bar pressure and stirred at RT for 6 days. The mixture was filtered through Celite® and washed through with EtOH (30 ml), followed by DCM (10 ml). The filtrate was concentrated under vacuum to give a colourless oil. The crude product was taken up in methanol (20 ml) and treated with a 1.25M HCl in methanol solution. The resulting colourless solution was stirred at RT for 1 hour and concentrated under vacuum to afford the title compound; 1H NMR (400 MHz, DMSO-d6) δ 8.04 (3H, broad peak), 6.74 (1H, s), 3.58 (broad peak), 3.6 (2H, m), 2.12 (1H, m), 0.99 (6H).

Intermediate R

3-Amino-1,1,1-trifluoro-2-methylpropan-2-olhydrochloride

[0546] ##STR00102##

Step 1: 1,1,1-trifluoro-2-methyl-3-nitropropan-2-ol

[0547] To LiOH (0.193 g, 8.06 mmol) in a 3-neck roundbottom flask was added water (25 ml), nitromethane (3.76 ml, 81 mmol) and trifluoroacetone (7.95 ml, 89 mmol). Cetyltrimethylammonium chloride (3.8 g, 10.88 mmol) and MgSO.sub.4 (1.9 g, 16.12 mmol) were added and the resulting yellow solution stirred at 20-25° C. for 2 days. The reaction mixture was poured into diethyl ether (120 ml) and washed with water (3×200 ml) and brine (1×100 ml). The organic portion was dried over MgSO.sub.4 and concentrated in vacuo to afford the title compound as a yellow liquid. 1H NMR (CDCl.sub.3, 400 MHz): δ 4.7 (1H d), δ 4.5 (1H, d), δ 3.7 (1H, broad), δ 1.6 (3H, s).

Step 2: 3-Amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride

[0548] Pd/C was added (1 g) to a 200 ml glass vessel. Ethanol (50 ml, dry) was added cautiously under an atmosphere of CO.sub.2. 1,1,1-Trifluoro-2-methyl-3-nitropropan-2-ol (10 g, 57.8 mmol) was dissolved in ethanol (50 ml, dry) and added to the glass vessel. The reaction mixture was put under a positive pressure of hydrogen (5 bar) at room temperature and hydrogenated for 2 days. The reaction mixture was filtered through Celite® (filter material) and washed with excess ethanol. The solvent was removed in vacuo to yield a colourless oil. The oil was dissolved in MeOH (50 ml) and treated dropwise with HCl (1M) in MeOH (30 ml). The solution was left to stir for 30 minutes and concentrated in vacuo azeotroping with MeCN to afford the title compound as a waxy white solid; 1H NMR (DMSO-d6, 400 MHz) δ 8.3 (3H, broad s), 6.9 (1H, broad), 3.0 (2H, q), 1.4 (3H, s).

Intermediate RA

(S)-3-Amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride

[0549] ##STR00103##

Step 1: Benzyl 3,3,3-trifluoro-2-hydroxy-2-methylpropylcarbamate

[0550] To a stirring suspension of amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (Intermediate R) (1.5 g, 8.35 mmol) in DCM (50 ml) was added TEA 93.54 g, 35.0 mmol) followed by benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.983 g, 7.96 mmol). The mixture was stirred at RT for 6 hours and then diluted with water. The organic portion was separated using a phase separator and concentrated in vacuo. Purification by chromatography on silica eluting with 0-70% EtOAc in iso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 7.34 (6H, m), 5.98 (1H, s), 5.05 (2H, s), 3.31 (1H, m), 3.18 (1H, m), 1.21 (3H. s) LC-MS: Rt 1.05 min; MS m/z 278.1 [M+H]+; Method 2minLC_v003.

Step 2: Separation of Enantiomers of benzyl 3,3,3-trifluoro-2-hydroxy-2-methyl propylcarbamate

[0551] Benzyl 3,3,3-trifluoro-2-hydroxy-2-methylpropylcarbamate (1.7 g) was dissolved in 2-propanol (10 ml) and purified using the following chromatographic conditions:

[0552] Mobile Phase: 10% 2-propanol/90% CO.sub.2

[0553] Column: 2× Chiralcel OJ-H, 250×10 mm id, 5 μm (columns coupled in series)

[0554] Detection: UV @ 220 nm

[0555] Flow rate: 10 ml/min

[0556] Sample concentration: 1.7 g in 10 ml 2-propanol

[0557] Injection volume: 75 μl

[0558] First eluted peak: Rt=6.94 minutes (R)-benzyl 3,3,3-trifluoro-2-hydroxy-2-methyl propylcarbamate

[0559] Second eluted peak: Rt=8.04 minutes (S)-benzyl 3,3,3-trifluoro-2-hydroxy-2-methyl propylcarbamate (Stereochemistry confirmed by analysis of final compound prepared by subsequent steps)

Step 3: (S)-3-Amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride

[0560] A mixture comprising (S)-benzyl 3,3,3-trifluoro-2-hydroxy-2-methyl propylcarbamate in EtOH (165 ml) was pumped through a H-Cube (hydrogenation reactor, 1-2 ml/min, 1 bar pressure, RT) for 8 hours using a 10% palladium on carbon catalyst cartridge. 1.25 M HCl in methanol (130 ml) was added to the mixture was stirred for 30 mins. The solvent was removed in vacuo azeotroping with MeCN to afford the title product as a white powder; 1H NMR (400 MHz, DMSO-d6) δ8.3 (3H, broad), 6.8 (1H, s), 3.0 (2H, s), 1.5 (3H, s).

[0561] Alternatively, racemic 3-Amino-1,1,1-trifluoro-2-methylpropan-2-ol can be resolved into separate enantiomers by recrystallistion with either (S)-Mandelic acid or L-tartaric acid in isopropanol or ethanol.

Intermediate S

2-Aminomethyl-1,1,1,3,3,3-hexafluoro-propan-2-ol

[0562] 3,3,3-Trifluoro-2-(trifluoromethyl)-1,2-propenoxide (1 g, 5.55 mmol) was added to a stirred solution of aqueous ammonia solution (0.88 g/ml, 3 ml) and diethyl ether (3 ml). The resulting colourless solution was stirred at room temperature for 3 hours. The biphasic mixture was separated and and the aqueous portion was further extracted with diethyl ether (2×5 ml). The combined organic layers were dried over MgSO.sub.4 and concentrated in vacuo (no heating) to afford the title compound as a white crystalline solid which was used without further purification; 1H NMR (400 MHz, DMSO-d6) signals unassigned δ 4.20 (broad), 3.15 (s).

Intermediate T

3,3,3-Trifluoro-2-methoxy-2-methylpropan-1-amine

[0563] ##STR00104##

Step 1: 2-(3,3,3-Trifluoro-2-hydroxy-2-methylpropyl)isoindoline-1,3-dione

[0564] A mixture comprising 3,3,3-trifluoro-2-hydroxy-2-methyl-propyl-ammonium (0.9 g), phthalic anhydride (1.039 g) and DIPEA (2.188 ml) in chloroform (30 ml) was heated at 70° C. for 5 hours. After cooling to RT, the mixture was washed with water and passed through a phase separator. The organic phase was reduced to dryness. The crude product was purified by chromatography on silica, eluting in a 0% to 30% iso-hexane:EtOAc removed to give the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.92 (2H, m), 7.85 (2H, m), 3.95 (2H, m), 1.36 (3H, s).

Step 2: 2-(3,3,3-Trifluoro-2-methoxy-2-methylpropyl)isoindoline-1,3-dione

[0565] To a stirring solution of 2-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)isoindoline-1,3-dione (250 mg, 0.915 mmol)) at 0° C. in THF (8 ml), NaH (80 mg, 2 mmol) was added. After 30 minutes methyl iodide (1.299, 9.15 mmol) was added. The reaction mixture was left stirring in a ice-bath and allowed to warm to 25° C. over 3.5 hours. The reaction was quenched with sat. NH.sub.4Cl and the mixture extracted with DCM. The organic extract was separated using a phase separator and purification by chromatography on silica, eluting in a 0% to 30% iso-hexane:EtOAc afforded the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.91 (2H, m), 7.85 (2H, m), 3.97 (2H, m), 3.44 (3H, s), 1.42 (3H, s); LC-MS: Rt 1.17 min; MS m/z 288.10 [M+H]+; Method 2minLC_v003.

Step 3: 3,3,3-Trifluoro-2-methoxy-2-methylpropan-1-amine

[0566] A mixture comprising 2-(3,3,3-trifluoro-2-methoxy-2-methylpropyl)isoindoline-1,3-dione (272 mg, 0.95 mmol) and hydrazine (0.033 ml, 1.045 mmol) was stirred at 75° C. for 4 hours. After cooling to RT, the mixture was filtered and the filtrate was concentrated in vacuo to afford the title product which was used without further purification (no characterisation data available).

[0567] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Embodiments/Consistory Clauses

[0568] Embodiment 1: A Compounds According to Formula I:

##STR00105##

or pharmaceutically acceptable salts thereof, wherein:

A is N or CR.SUP.4a.;

[0569] R.sup.1 is H; C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.2-C.sub.8 alkenyl; C.sub.2-C.sub.8 alkynyl; C.sub.3-C.sub.10 cycloalkyl; C.sub.5-C.sub.10 cycloalkenyl; —C.sub.1-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; halogen; SO.sub.2NR.sup.8R.sup.9; SO.sub.2R.sup.10; S—C.sub.1-C.sub.8alkyl optionally substituted by one or more halogen atoms; S—C.sub.6-C.sub.14 aryl; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; CN; NR.sup.11R.sup.12; CONR.sup.13R.sup.14; NR.sup.13SO.sub.2R.sup.15; NR.sup.13C(O)R.sup.15 and CO.sub.2R.sup.15, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents;
R.sup.2 is C.sub.1-C.sub.4 haloalkyl;
R.sup.3, R.sup.4 and R.sup.4a are each independently H or C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms;
R.sup.5 and R.sup.6 are each independently H; C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.2-C.sub.8 alkenyl; C.sub.2-C.sub.8 alkynyl; C.sub.3-C.sub.10 cycloalkyl; C.sub.5-C.sub.10 cycloalkenyl; —C.sub.1-C.sub.4alkyl-C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or —(C.sub.0-C.sub.4 alkyl)-CO.sub.2R.sup.15, wherein the cycloalkyl, cycloalkenyl, —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl and —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group groups are each optionally substituted by one or more Z substituents; or
R.sup.5 and R.sup.6 are each independently a group of the formula:

—(CH.sub.2).sub.m—NR.sup.17R.sup.18; or

R.sup.5 and R.sup.6 are each independently a group of the formula:

—(CH.sub.2).sub.m—OR.sup.4; or

R.sup.4 and R.sup.5 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or
R.sup.5 and R.sup.6 together with the carbon atoms to which they are bound form a 5 to 8 membered carbocyclic ring system or a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
R.sup.4, R.sup.5 and R.sup.6 cannot all be the same;
m is 0, 1, 2 or 3;
R.sup.8, R.sup.11, R.sup.13 and R.sup.17 are each independently H, C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms, C.sub.3-C.sub.10 cycloalkyl or —(C.sub.1-C.sub.4 alkyl)-C.sub.3-C.sub.8 cycloalkyl; R.sup.9, R.sup.10, R.sup.12, R.sup.14, R.sup.15, R.sup.16 and R.sup.18 are each independently H; C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.2-C.sub.8 alkenyl; C.sub.2-C.sub.8 alkynyl; C.sub.3-C.sub.10 cycloalkyl; C.sub.5-C.sub.10 cycloalkenyl; —C.sub.1-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
R.sup.8 and R.sup.9, R.sup.11 and R.sup.12, R.sup.13 and R.sup.14, and R.sup.17 and R.sup.18 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents; Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C.sub.1-C.sub.6 alkyl optionally substituted by one or more OH groups or NH.sub.2 groups, C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms, C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy, NR.sup.18(SO.sub.2)R.sup.21, (SO.sub.2)NR.sup.19R.sup.21, (SO.sub.2)R.sup.21, NR.sup.18C(O)R.sup.21, C(O)NR.sup.19R.sup.21, NR.sup.18C(O)NR.sup.19R.sup.21, NR.sup.18C(O)OR.sup.19, NR.sup.19R.sup.21, C(O)OR.sup.19, C(O)R.sup.19, SR.sup.19, OR.sup.19, oxo, CN, NO.sub.2, halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;
R.sup.19 and R.sup.21 are each independently H; C.sub.1-C.sub.8 alkyl; C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkyl; (C.sub.0-C.sub.4 alkyl)-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; (C.sub.0-C.sub.4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C.sub.1-C.sub.6 alkyl and C(O)C.sub.1-C.sub.6 alkyl; (C.sub.0-C.sub.4 alkyl)-O-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; and (C.sub.0-C.sub.4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C.sub.1-C.sub.6 alkyl or C(O)C.sub.1-C.sub.6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C.sub.1-C.sub.4 alkoxy, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6 alkyl or C(O)N(C.sub.1-C.sub.6 alkyl).sub.2; or
R.sup.19 and R.sup.21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O).sub.2-aryl; S(O).sub.2—C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy; and C(O)OC.sub.1-C.sub.6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy.

[0570] Embodiment 2: The Compound of Formula I

##STR00106##

or pharmaceutically acceptable salts thereof, wherein:

A is N or CR.SUP.4a.;

[0571] R.sup.1 is H; C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.2-C.sub.8 alkenyl; C.sub.2-C.sub.8 alkynyl; C.sub.3-C.sub.10 cycloalkyl; C.sub.1-C.sub.10 cycloalkenyl; —C.sub.1-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogenatoms; halogen; SO.sub.2NR.sup.3R.sup.9; SO.sub.2R.sup.10; S—C.sub.1-C.sub.8alkyl optionally substituted by one or more halogen atoms; S—C.sub.6-C.sub.14 aryl; CN; NR.sup.11R.sup.12; C(O)NR.sup.13R.sup.14; NR.sup.13SO.sub.2R.sup.15; NR.sup.13C(O)R.sup.15, CO.sub.2R.sup.15, —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents;
R.sup.2 is C.sub.1-C.sub.4 haloalkyl;
R.sup.3 and R.sup.4a are each independently H or C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms;
R.sup.4 is H, or C.sub.1-C.sub.8 alkyl optional substituted with one or more halogen;
R.sup.5 is —(CH.sub.2).sub.m—NR.sup.17R.sup.18, —(CH.sub.2).sub.m—OR′; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; —(C.sub.0-C.sub.4 alkyl)-CO.sub.2R.sup.15; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl or −3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl and —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents;
R.sup.6 is C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.3-C.sub.10 cycloalkyl; —C.sub.1-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl and —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; or
R.sup.6 is H, and R.sup.5 is —(CH.sub.2).sub.m—NR.sup.17R.sup.18, —(CH.sub.2).sub.m—OR′, C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or —(C.sub.0-C.sub.4 alkyl)-C.sub.2R.sup.15, wherein —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl and —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group groups are each optionally substituted by one or more Z substituents; or
R.sup.4 and R.sup.6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or
R.sup.4 and R.sup.5 together form an oxo group (C═O) and R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
R.sup.5 and R.sup.6 together with the carbon atoms to which they are bound a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; or
R.sup.4 and R.sup.5 and R.sup.6 together with the carbon atoms to which they are bound form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
R′ is H, or C.sub.1-C.sub.8 alkyl optional substituted with one or more halogen;
m is 0, 1, 2 or 3;
R.sup.8, R.sup.11, R.sup.13 and R.sup.17 are each independently H, C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms, C.sub.3-C.sub.10 cycloalkyl or —(C.sub.1-C.sub.4 alkyl)-C.sub.3-C.sub.8 cycloalkyl; R.sup.9, R.sup.10, R.sup.12, R.sup.14, R.sup.15, R.sup.16 and R.sup.18 are each independently H; C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.2-C.sub.8 alkenyl; C.sub.2-C.sub.8 alkynyl; C.sub.3-C.sub.10 cycloalkyl; C.sub.1-C.sub.10 cycloalkenyl; —C.sub.1-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
R.sup.8 and R.sup.9, R.sup.11 and R.sup.12, R.sup.13 and R.sup.14, and R.sup.17 and R.sup.18 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents;
Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C.sub.1-C.sub.6 alkyl optionally substituted by one or more OH groups or NH.sub.2 groups, C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms, C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy, NR.sup.18(SO.sub.2)R.sup.21, (SO.sub.2)NR.sup.19R.sup.21, (SO.sub.2)R.sup.21, NR.sup.18C(O)R.sup.21, C(O)NR.sup.19R.sup.21, NR.sup.18C(O)NR.sup.19R.sup.21, NR.sup.18C(O)OR.sup.19, NR.sup.19R.sup.21, C(O)OR.sup.19, C(O)R.sup.19, SR.sup.19, OR.sup.19, oxo, CN, NO.sub.2, halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;
R.sup.19 and R.sup.21 are each independently H; C.sub.1-C.sub.8 alkyl; C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkyl; (C.sub.0-C.sub.4 alkyl)-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; (C.sub.0-C.sub.4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C.sub.1-C.sub.6 alkyl and C(O)C.sub.1-C.sub.6 alkyl; (C.sub.0-C.sub.4 alkyl)-O-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; and (C.sub.0-C.sub.4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C.sub.1-C.sub.6 alkyl or C(O)C.sub.1-C.sub.6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C.sub.1-C.sub.4 alkoxy, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6 alkyl or C(O)N(C.sub.1-C.sub.6 alkyl).sub.2; or
R.sup.19 and R.sup.21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O).sub.2-aryl; S(O).sub.2—C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy; and C(O)OC.sub.1-C.sub.6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy.

[0572] Embodiment 3: The compound according to embodiment 1 or 2, wherein [0573] R.sup.1 is H; C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; halogen; C.sub.6-C.sub.14 aryl; —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or —NR.sup.11R.sup.12, wherein the aryl and heterocyclic groups are each optionally substituted by one or more Z substituents.

[0574] Embodiment 4: The compound according to embodiment 1 to 3, wherein [0575] R.sup.1 is C.sub.1-C.sub.4 alkyl optional substituted by one or more halogen atoms.

[0576] Embodiment 5: The compound according to embodiment 1 to 4, wherein [0577] R.sup.1 is —CH.sub.3 or CF.sub.3.

[0578] Embodiment 6: The compound according to embodiment 1, 2 or 3, wherein [0579] R.sup.1 is C.sub.1-C.sub.4 alkoxy optional substituted by one or more halogen atoms.

[0580] Embodiment 7: The compound according to embodiment 1, 2, 3 or 6, wherein [0581] R.sup.1 is —OCH.sub.3, —OCH.sub.2CH.sub.3 or —OCF.sub.3.

[0582] Embodiment 8: The compound according to embodiments 1, 2 or 3, wherein R.sup.1 is aryl, wherein aryl is phenyl optionally substituted by one or more Z substituents,

[0583] Embodiment 9: The compound according to embodiment 1, 2, 3 or 8, wherein R.sup.1 is 4-fluorophenyl, 4-chloro-2-methylphenyl, or 2,4-dichlorophenyl.

[0584] Embodiment 10: The compound according to embodiment 1, 2 or 3, wherein R.sup.1 is pyridyl, oxazole, pyrrolidine or pyrazole and is optionally substituted by one or more Z substituents.

[0585] Embodiment 11: The compound according to embodiment 1, 2, 3 or 10, wherein R.sup.1 is 1-methyl-4-pyridyl, oxzaoyl-2-yl, 1-methyl-1H-pyrazole-4-yl or pyrrolidin-1yl.

[0586] Embodiment 12: The compound according to embodiment 1 to 11, wherein R.sup.1 is Br, —CH.sub.3, —CF.sub.3, —OCH.sub.3, —OCH.sub.2CH.sub.3, —OCF.sub.3, 4-fluorophenyl, 4-chloro-2-methylphenyl, 2,4-dichlorophenyl, 1-methyl-4-pyridyl, 1-methyl-1H-pyrazole-4-yl, oxzaoyl-2-yl, or pyrrolidin-1yl.

[0587] Embodiment 13: The compound according to embodiment 1 to 12, wherein R.sup.5 provides a heteroatom two carbons from the amide nitrogen, wherein the heteroatom is oxygen or nitrogen.

[0588] Embodiment 14: The compound according to embodiment 1 to 13, wherein [0589] R.sup.4 is H or C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; [0590] R.sup.5 is C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; —(CH.sub.2).sub.m—NR.sup.17R.sup.18; —(CH.sub.2).sub.m—OR′, or OH; [0591] R′ is H, or C.sub.1-C.sub.4 alkyl optional substituted with one or more halogen; [0592] m is 0, 1 or 2; [0593] R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; —(C.sub.0-C.sub.4 alkyl)-C.sub.6 aryl; or —(C.sub.0-C.sub.4 alkyl)-5 to 6 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or [0594] R.sup.4 and R.sup.6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or [0595] R.sup.5 and R.sup.6 together with the carbon atoms to which they are bound a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; [0596] R.sup.17 and R.sup.18 are each independently H; or C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms.

[0597] Embodiment 15: The compound according to any proceeding embodiment, wherein [0598] R.sup.3 is H; [0599] R.sup.4 is H or Me; [0600] R.sup.4a is H; [0601] R.sup.5 is —(CH.sub.2).sub.m—NR.sup.17R.sup.18; —(CH.sub.2).sub.m—OR′; or OH; [0602] m is 0, or 1; [0603] R′ is H; [0604] R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; or [0605] R.sup.5 and R.sup.6 together with the carbon atoms to which they are bound form a 5 to 6 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; and [0606] R.sup.17 and R.sup.18 are each independently H; or C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms.

[0607] Embodiment 16: The compound according to any proceeding embodiment, wherein [0608] R.sup.3 is H; [0609] R.sup.4 is H or Me; [0610] R.sup.4a is H; [0611] R.sup.5 is —NR.sup.17R.sup.18; or OH; [0612] R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; or [0613] R.sup.5 and R.sup.6 together with the carbon atoms to which they are bound form a 5 to 6 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; and [0614] R.sup.17 and R.sup.18 are each independently H; or C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms.

[0615] Embodiment 17: The compound according to any proceeding claim, wherein [0616] R.sup.3 is H; [0617] R.sup.4 is H or Me; [0618] R.sup.4a is H; [0619] R.sup.5 is —NR.sup.17R.sup.18; or OH; [0620] R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; and [0621] R.sup.17 and R.sup.18 are each independently H; or C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms.

[0622] Embodiment 18: The compound according to embodiment 1 to 13, wherein [0623] R.sup.3 is H; [0624] R.sup.4a is H; [0625] R.sup.4 and R.sup.5 form an oxo group; [0626] R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; phenyl; or 5 to 6 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the phenyl and heterocyclyl groups are each optionally substituted by one or more Z substituents.

[0627] Embodiment 19: The compound according to embodiment 1 to 13 or 18, wherein [0628] R.sup.3 is H; [0629] R.sup.4a is H; [0630] R.sup.4 and R.sup.5 form an oxo group; [0631] R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; or phenyl, wherein the phenyl is optionally substituted by one or more Z substituents; [0632] Z is independently OH, C.sub.1-C.sub.4 alkyl optionally substituted by one or more OH groups or NH.sub.2 groups, C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms, C.sub.1-C.sub.4 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy, C(O)OR.sup.19, C(O)R.sup.19, OR.sup.19, CN, or halogen; [0633] R.sup.19 is H; C.sub.1-C.sub.4 alkyl; C.sub.3-C.sub.6 cycloalkyl; or C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkyl, wherein all alkyl are optionally substituted with halogens.

[0634] Embodiment 20: The compound according to embodiment 1 to 13 or 18 to 19, wherein [0635] R.sup.3 is H; [0636] R.sup.4a is H; [0637] R.sup.4 and R.sup.5 form an oxo group; [0638] R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; or phenyl, wherein the phenyl is optionally substituted by one or more Z substituents; [0639] Z is independently, C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms, C.sub.1-C.sub.4 alkoxy or halogen.

[0640] Embodiment 21. The compound according to embodiment 1 to 13, wherein the compound is represented by formula II,

##STR00107##

or a pharmaceutically acceptable salt thereof,
wherein,
R.sup.101 is selected from the following:

##STR00108## ##STR00109##

[0641] Embodiment 22: The compound according to embodiment 21, wherein [0642] R.sup.3 is H; [0643] R.sup.101 is

##STR00110##

[0644] Embodiment 23: The compound according to embodiment 21, wherein [0645] R.sup.3 is H; [0646] R.sup.101 is

##STR00111##

[0647] Embodiment 24: The compound according to embodiment 21, wherein [0648] R.sup.3 is H; [0649] R.sup.101 is

##STR00112##

[0650] Embodiment 25: The compound according to embodiment 21, wherein [0651] R.sup.3 is H; [0652] R.sup.101 is

##STR00113##

[0653] Embodiment 26: The compound according to embodiment 1 to 13, wherein [0654] R.sup.3 is H; [0655] R.sup.101 is —(C.sub.1-C.sub.2 alkyl)-5 to 10 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents.

[0656] Embodiment 27: The compound according to embodiment 21 or 26, wherein [0657] R.sup.3 is H; [0658] R.sup.101 is

##STR00114##

[0659] Embodiment 28: The compound of formula III

##STR00115##

or pharmaceutically acceptable salts thereof, wherein:

A is N or CR.SUP.4a.;

X is NR.SUP.y .or O;

[0660] R.sup.1 is C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.3-C.sub.10 cycloalkyl; —C.sub.1-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; halogen; CN; NR.sup.11R.sup.12; C(O)NR.sup.13R.sup.14; NR.sup.13C(O)R.sup.15, CO.sub.2R.sup.15, —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents;
R.sup.2 is C.sub.1-C.sub.4 haloalkyl;
R.sup.3 and R.sup.4a are each independently H or C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms;
R.sup.4 is H, or C.sub.1-C.sub.8 alkyl optional substituted with one or more halogen;
R.sup.5a is H, C.sub.1-C.sub.8 alkyl optional substituted with one or more halogen, —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl or −3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl and —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents;
R.sup.y is H, C.sub.1-C.sub.8 alkyl optional substituted with one or more halogen, —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl or −3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl and —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents;
R.sup.6 is C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.3-C.sub.10 cycloalkyl; —C.sub.1-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.8 alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl and —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; or
R.sup.4 and R.sup.6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or
R.sup.5a and R.sup.6 together with the atoms to which they are bound a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; or
R.sup.5a and R.sup.y together with the atoms to which they are bound a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
R.sup.11 and R.sup.13 are each independently H, C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms, C.sub.3-C.sub.10 cycloalkyl or —(C.sub.1-C.sub.4 alkyl)-C.sub.3-C.sub.8 cycloalkyl;
R.sup.12, R.sup.14, and R.sup.15 are each independently H; C.sub.1-C.sub.8 alkyl optionally substituted by one or more halogen atoms; C.sub.2-C.sub.8 alkenyl; C.sub.2-C.sub.8 alkynyl; C.sub.3-C.sub.10 cycloalkyl; C.sub.1-C.sub.10 cycloalkenyl; —C.sub.1-C.sub.4 alkyl-C.sub.3-C.sub.8 cycloalkyl; —(C.sub.0-C.sub.4 alkyl)-C.sub.6-C.sub.14 aryl; or —(C.sub.0-C.sub.4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
R.sup.11 and R.sup.12, and R.sup.13 and R.sup.14 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents;
Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C.sub.1-C.sub.6 alkyl optionally substituted by one or more OH groups or NH.sub.2 groups, C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms, C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy, NR.sup.18(SO.sub.2)R.sup.21, (SO.sub.2)NR.sup.19R.sup.21, (SO.sub.2)R.sup.21, NR.sup.18C(O)R.sup.21, C(O)NR.sup.19R.sup.21, NR.sup.18C(O)NR.sup.19R.sup.21, NR.sup.18C(O)OR.sup.19, NR.sup.19R.sup.21, C(O)OR.sup.19, C(O)R.sup.19, SR.sup.19, OR.sup.19, oxo, CN, NO.sub.2, halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;
R.sup.19 and R.sup.21 are each independently H; C.sub.1-C.sub.8 alkyl; C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkyl; (C.sub.0-C.sub.4 alkyl)-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; (C.sub.0-C.sub.4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C.sub.1-C.sub.6 alkyl and C(O)C.sub.1-C.sub.6 alkyl; (C.sub.0-C.sub.4 alkyl)-O-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; and (C.sub.0-C.sub.4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C.sub.1-C.sub.6 alkyl or C(O)C.sub.1-C.sub.6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C.sub.1-C.sub.4 alkoxy, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6 alkyl or C(O)N(C.sub.1-C.sub.6 alkyl).sub.2; or
R.sup.19 and R.sup.21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O).sub.2-aryl; S(O).sub.2—C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy; and C(O)OC.sub.1-C.sub.6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy.

[0661] Embodiment 29: The compound according to embodiment 28, wherein

A is N or CR.SUP.4a.;

X is NR.SUP.y .or O;

[0662] R.sup.1 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; halogen; —(C.sub.0-C.sub.4 alkyl)-C.sub.6 aryl; or —(C.sub.0-C.sub.4 alkyl)-5 to 6 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents;
R.sup.2 is C.sub.1-C.sub.4 haloalkyl;
R.sup.3 and R.sup.4a are H;
R.sup.4 is H, or C.sub.1-C.sub.4 alkyl optional substituted with one or more halogen;
R.sup.5a is H, C.sub.1-C.sub.4 alkyl optional substituted with one or more halogen, —(C.sub.0-C.sub.4 alkyl)-C.sub.6 aryl or −5 to 8 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C.sub.0-C.sub.4 alkyl)-C.sub.6 aryl and −5 to 8 membered heterocyclic group are each optionally substituted by one or more Z substituents;
R.sup.y is H, C.sub.1-C.sub.4 alkyl optional substituted with one or more halogen, —(C.sub.0-C.sub.4 alkyl)-C.sub.6 aryl or −5 to 8 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C.sub.0-C.sub.4 alkyl)-C.sub.6 aryl and −5 to 8 membered heterocyclic group are each optionally substituted by one or more Z substituents;
R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; OH; CN; —(C.sub.0-C.sub.4 alkyl)-C.sub.6 aryl; or −5 to 8 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —C.sub.6 aryl and −5 to 8 membered heterocyclic group are each optionally substituted by one or more Z substituents; or R.sup.4 and R.sup.6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or
R.sup.5a and R.sup.6 together with the atoms to which they are bound a 5 to 8 membered heterocyclic group containing one or more heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted by one or more Z substituents; or
R.sup.5a and R.sup.y together with the atoms to which they are bound a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
Z is independently OH, aryl, O-aryl, C.sub.1-C.sub.6 alkyl optionally substituted by one or more OH groups or NH.sub.2 groups, C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms, C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy, NR.sup.18C(O)R.sup.21, C(O)NR.sup.19R.sup.21, NR.sup.19R.sup.21, C(O)OR.sup.19, C(O)R.sup.19, SR.sup.19, OR.sup.19, oxo, CN, NO.sub.2, halogen or a 5 to 8 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the heterocyclic group is option substituted by halogen, C.sub.1-C.sub.4 alkyl optionally substituted by halogen, C.sub.1-C.sub.4 alkoxy or —CN;
R.sup.18 is H or C.sub.1-C.sub.4 alkyl;
R.sup.19 and R.sup.21 are each independently H; C.sub.1-C.sub.8 alkyl; C.sub.3-C.sub.8 cycloalkyl; C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkyl; (C.sub.0-C.sub.4 alkyl)-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; (C.sub.0-C.sub.4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C.sub.1-C.sub.6 alkyl and C(O)C.sub.1-C.sub.6 alkyl; (C.sub.0-C.sub.4 alkyl)-O-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; and (C.sub.0-C.sub.4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C.sub.1-C.sub.6 alkyl or C(O)C.sub.1-C.sub.6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C.sub.1-C.sub.4 alkoxy, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6 alkyl or C(O)N(C.sub.1-C.sub.6 alkyl).sub.2; or
R.sup.19 and R.sup.21 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O).sub.2-aryl; S(O).sub.2—C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy; and C(O)OC.sub.1-C.sub.6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy.

[0663] Embodiment 30: The compound according to embodiment 28 or 29, wherein

A is N or CR.SUP.4a.;

X is NR.SUP.y .or O;

[0664] R.sup.1 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; or halogen;
R.sup.2 is CF.sub.3;
R.sup.3 and R.sup.4a are H;
R.sup.4 is H, or C.sub.1-C.sub.4 alkyl optional substituted with one or more halogen;
R.sup.5a is H, C.sub.1-C.sub.4 alkyl optional substituted with one or more halogen,
R.sup.y is H, C.sub.1-C.sub.4 alkyl optional substituted with one or more halogen,
R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; OH; CN; or
R.sup.4 and R.sup.6 together with the carbon atoms to which they are bound form a 3 to 6 membered carbocyclic ring system; or
R.sup.5a and R.sup.6 together with the atoms to which they are bound a 5 to 8 membered heterocyclic group containing one or more heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted by one or more Z substituents; or
R.sup.5a and R.sup.y together with the atoms to which they are bound a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
Z is independently OH, C.sub.1-C.sub.6 alkyl optionally substituted by one or more OH groups or NH.sub.2 groups, C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms, C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy, NR.sup.19R.sup.21, C(O)OR.sup.19, C(O)R.sup.19, SR.sup.19, OR.sup.19, oxo, CN, NO.sub.2, or halogen;
R.sup.19 is H; C.sub.1-C.sub.8 alkyl; (C.sub.0-C.sub.4 alkyl)-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; (C.sub.0-C.sub.4 alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C.sub.1-C.sub.6 alkyl and C(O)C.sub.1-C.sub.6 alkyl; (C.sub.0-C.sub.4 alkyl)-O-aryl optionally substituted by one or more groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen; and (C.sub.0-C.sub.4 alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C.sub.1-C.sub.6 alkyl or C(O)C.sub.1-C.sub.6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C.sub.1-C.sub.4 alkoxy, C(O)NH.sub.2, C(O)NHC.sub.1-C.sub.6 alkyl or C(O)N(C.sub.1-C.sub.6 alkyl).sub.2; or
R.sup.19 and R.sup.21 together with the nitrogen atom to which they attached form a 5- to 6-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O).sub.2-aryl; S(O).sub.2—C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy; and C(O)OC.sub.1-C.sub.6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy.

[0665] Embodiment 31: The compound according to embodiment 28 to 30, wherein

A is N or CR.SUP.4a.;

X is NR.SUP.Y .or O;

[0666] R.sup.1 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; or halogen;
R.sup.2 is CF.sub.3;
R.sup.3 and R.sup.4a are H;
R.sup.4 is H, or C.sub.1-C.sub.4 alkyl optional substituted with one or more halogen;
R.sup.5a is H, C.sub.1-C.sub.4 alkyl optional substituted with one or more halogen,
R.sup.y is H, C.sub.1-C.sub.4 alkyl optional substituted with one or more halogen,
R.sup.6 is C.sub.1-C.sub.4 alkyl optionally substituted by one or more halogen atoms; C.sub.1-C.sub.4 alkoxy optionally substituted by one or more halogen atoms; OH; CN; or
R.sup.5a and R.sup.6 together with the atoms to which they are bound a 5 to 8 membered heterocyclic group containing one or more heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted by one or more Z substituents; or
R.sup.5a and R.sup.y together with the atoms to which they are bound a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; Z is independently OH, C.sub.1-C.sub.6 alkyl optionally substituted by one or more OH groups or NH.sub.2 groups, C.sub.1-C.sub.6 alkyl optionally substituted by one or more halogen atoms, C.sub.1-C.sub.6 alkoxy optionally substituted by one or more OH groups or C.sub.1-C.sub.4 alkoxy, oxo, CN, NO.sub.2, or halogen;

[0667] Embodiment 32: The compound according to any of the proceeding embodiments, A is N.

[0668] Embodiment 33: The compound to embodiments 1 to 31, wherein A is CR.sup.4.

[0669] Embodiment 34: The compound according to embodiment 33, wherein A is CR.sup.4a and R.sup.4a is H.

[0670] Embodiment 35: The compound according to any proceeding embodiment, wherein R.sup.2 is CF.sub.3CF.sub.2—, (CF.sub.3).sub.2CH—, CH.sub.3—CF.sub.2—, CF.sub.3CF.sub.2—, CF.sub.3, CF.sub.2H—, CH.sub.3—CCl.sub.2—, CF.sub.3CFCCIH—, CBr.sub.3, CBr.sub.2H—CF.sub.3CF.sub.2CHCF.sub.3 or CF.sub.3CF.sub.2CF.sub.2CF.sub.2—.

[0671] Embodiment 36: The compound according to any proceeding embodiment, wherein R.sup.2 is CF.sub.3.

[0672] Embodiment 37: The compound according to any proceeding embodiment, wherein the compound is a substantially pure enantiomer with the S configuration.

[0673] Embodiment 38: The compound according to embodiment 1 to 36, wherein the compound is a substantially pure enantiomer with the R configuration.

[0674] Embodiment 39: The compound according to embodiment 2, 21 or 28, wherein the compound is represented by: [0675] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0676] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-propyl)-amide; [0677] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-propyl)-amide; [0678] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [(R)-1-(tetrahydro-furan-2-yl)methyl]-amide; [0679] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ([1,3]dioxolan-2-ylmethyl)-amide; [0680] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [(S)-1-(tetrahydro-furan-2-yl)methyl]-amide; [0681] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide; [0682] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-methyl-2-piperidin-1-yl-propyl)-amide; [0683] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-propyl)-amide; [0684] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide; [0685] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-methyl-tetrahydro-furan-2-yl-methyl)-amide; [0686] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-methoxy-ethyl)-amide; [0687] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide; [0688] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-morpholin-4-yl-2-phenyl-ethyl)-amide; [0689] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-dimethylamino-2-phenyl-ethyl)-amide; [0690] 3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0691] 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0692] 3-Amino-6-(4-chloro-2-methyl-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-propyl)-amide; [0693] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propyl)-amide; [0694] 5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0695] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0696] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0697] 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0698] 3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0699] 3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0700] 3-amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0701] 3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide; [0702] 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-propyl)-amide; [0703] 5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propyl)-amide; [0704] 5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0705] 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0706] 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0707] 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0708] 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0709] Methyl 3-(3-amino-6-bromo-5-(trifluoromethyl)picolinamido)propanoate; [0710] 3-Amino-N-(benzo[d]isoxazol-3-ylmethyl)-6-bromo-5-(trifluoromethyl) picolinamide; [0711] 3-Amino-6-(oxazol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide; [0712] 3-Amino-6-bromo-N-(3,3,3-trifluoro-2-methoxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide; [0713] 3-amino-N-(2-hydroxy-3-methyl-2-(trifluoromethyl)butyl)-6-methoxy-5-(trifluoromethyl)picolinamide; [0714] 3-Amino-6-cyclopropyl-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide; [0715] 3-Amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-5-(trifluoro methyl) picolinamide; [0716] 5-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-3-(trifluoromethyl)-2,4′-bipyridine-6-carboxamide; [0717] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3-methyl-2-oxo-butyl)-amide; [0718] 3-Amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide; [0719] (S)-3-amino-6-ethoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoro methyl)picolinamide; [0720] 3-Amino-6-(pyrrolidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide; [0721] 3-Amino-N-(2-amino-3,3,3-trifluoro-2-methylpropyl)-6-methoxy-5-(trifluoromethyl) picolinamide; or [0722] 3-Amino-6-methoxy-N-(3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methylpropyl)-5-(trifluoromethyl)picolinamide.

[0723] Embodiment 40: The compound according to embodiment 39, wherein the compound is [0724] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [(R)-1-(tetrahydro-furan-2-yl)methyl]-amide; [0725] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ([1,3]dioxolan-2-ylmethyl)-amide; [0726] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [(S)-1-(tetrahydro-furan-2-yl)methyl]-amide; [0727] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide; or [0728] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-methyl-tetrahydro-furan-2-yl-methyl)-amide.

[0729] Embodiment 41: The compound according to embodiment 2, 21 or 28, wherein the compound is [0730] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide; [0731] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide; [0732] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-morpholin-4-yl-2-phenyl-ethyl)-amide; [0733] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-dimethylamino-2-phenyl-ethyl)-amide; [0734] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (3-methyl-2-morpholin-4-yl-butyl)-amide; [0735] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-methyl-2-morpholin-4-yl-propyl)-amide; [0736] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (1-morpholin-4-yl-cyclohexylmethyl)-amide; [0737] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-morpholin-4-yl-2-phenyl-ethyl)-amide; [0738] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-dimethylamino-2-phenyl-ethyl)-amide; [0739] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2-(4-methoxy-phenyl)-2-pyrrolidin-1-yl-ethyl]-amide; [0740] 3-Amino-N-(2-amino-3,3,3-trifluoro-2-methylpropyl)-6-methoxy-5-(trifluoromethyl) picolinamide; or [0741] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2-dimethylamino-2-(4-methoxy-phenyl)-ethyl]-amide.

[0742] Embodiment 42: The compound according to embodiment 2, 21 or 28, wherein the compound is [0743] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-methyl-tetrahydro-furan-2-yl-methyl)-amide; [0744] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide; [0745] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (3-methyl-2-morpholin-4-yl-butyl)-amide; [0746] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-methyl-2-morpholin-4-yl-propyl)-amide; [0747] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (1-morpholin-4-yl-cyclohexylmethyl)-amide; [0748] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-morpholin-4-yl-2-phenyl-ethyl)-amide; [0749] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-dimethylamino-2-phenyl-ethyl)-amide; [0750] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2-(4-methoxy-phenyl)-2-pyrrolidin-1-yl-ethyl]-amide; [0751] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2-dimethylamino-2-(4-methoxy-phenyl)-ethyl]-amide; [0752] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2-(4-fluoro-phenyl)-2-oxo-ethyl]-amide; [0753] 3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid [2-(2-methoxy-phenyl)-ethyl]-amide; [0754] 3-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5,6-bis(trifluoromethyl) pyrazine-2-carboxamide; [0755] N-(2-(1H-imidazol-2-yl)propyl)-3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carboxamide; [0756] 3-Amino-6-bromo-N-(2-morpholinoethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide; or [0757] 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2-(4-fluoro-phenyl)-2-oxo-ethyl]-amide.

[0758] Embodiment 43: The compound according to embodiment 39, wherein the compound is [0759] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0760] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-propyl)-amide; [0761] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-propyl)-amide; [0762] 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0763] 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0764] 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0765] 3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0766] 3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0767] 3-amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; [0768] 3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide; or [0769] 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide.

[0770] Embodiment 44: Use of a compound according to embodiment 1 to 43 in the manufacture of a medicament for use in the treatment of an inflammatory or obstructive airways disease or mucosal hydration.

[0771] Embodiment 45: Use of a compound according to embodiment 1 to 43 in the manufacture of a medicament for use in the treatment of a disease mediated by CFTR.

[0772] Embodiment 46: Use of a compound according to embodiment 42 in the manufacture of a medicament for use in the treatment of a disease mediated by CFTR, wherein the disease is CF or COPD.

[0773] Embodiment 47: Use of a compound according to embodiment 1 to 43 in the manufacture of a medicament for use in the treatment of cystic fibrosis.

[0774] Embodiment 48: A pharmaceutical composition for treating a disease or disorder mediated by CFTR, comprising: [0775] the compound according to embodiment 1 to 43 and [0776] one or more pharmaceutically acceptable excipients.

[0777] Embodiment 49: A pharmaceutical composition, according to embodiment 48, wherein the disease or disorder is cystic fibrosis or COPD.

[0778] Embodiment 49: A pharmaceutical composition, according to embodiment 49, wherein the disease or disorder is cystic fibrosis.

[0779] Embodiment 50: A pharmaceutical combination, comprising: [0780] a first active comprising the compound according to embodiment 1 to 43 and [0781] a second active selected from osmotic agents, ENaC blockers, anti-inflammatory agents, bronchodilatory agents, antihistamine agents, anti-tussive agents, antibiotic agents and DNase drug substances, wherein the first and second actives may be in the same or different pharmaceutical composition.

[0782] Embodiment 51: A pharmaceutical combination according to embodiment 50, wherein the second active agent is an EnaC blocker.

[0783] Embodiment 52: A process for the preparation of compounds of formula (I), comprising:

##STR00116## [0784] reacting a compound 1 with compound 2 in a peptide coupling reaction,

##STR00117##

wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined herein and P is a suitable amino protecting group; [0785] removing protecting groups and isolating the compound of formula I.

[0786] Embodiment 53: The process according to embodiment 48, wherein the peptide coupling condition is HATU in an aprotic solvent.