Pyridine and pyrazine derivative for the treatment of chronic obstructive pulmonary disease

This invention relates to pyridine and pyrazine compounds, their preparation, and their use as pharmaceuticals.

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a channel of epithelial anions activated by protein kinase A (PKA) involved in transport of salts and fluids in multiple organs, including the lung. Most cystic fibrosis (CF) mutations reduce the number of transmembrane cystic fibrosis conductance (CFTR) regulatory channels on the cell surface (for example, synthesis or processing mutations), or impair the function of the channel ( for example, gate or conductance mutations), or both. There are currently no approved therapies that address the cystic fibrosis transmembrane conductance regulator (CFTR) directly. The present invention discloses compounds that restore or improve the function of the mutant and / or wild-type cystic fibrosis transmembrane conductance regulator (CFTR) to treat cystic fibrosis, primary ciliary dipielesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (irritable bowel syndrome (IBS), irritable bowel disease (IBD), opioid-induced).

In one aspect, the invention provides the compounds according to formula I:

OR

R⁴

<img file="CU24149B1_D0001.tif" />

r² to nh₂ | or pharmaceutically acceptable salts thereof, wherein:

A is N or CR^4th;

R¹ it's H; alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; alkenyl of 2 to 8 carbon atoms; alkynyl of 2 to 8 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; cycloalkenyl of 5 to 10 carbon atoms; -alkyl of 1 to 4 carbon atoms -cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; halogen; SO2NR⁸R⁹; SO2R¹⁰; S-alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; S-aryl of 6 to 14 carbon atoms; CN; NR¹¹R¹²; C (O) NR¹³R¹⁴;

NR¹³SO2R¹⁵; NR¹³C (O) R¹⁵, CO2R¹⁵, - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, 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;

R² it is halo-alkyl of 1 to 4 carbon atoms;

R³ and R^4th are each independently H or alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms;

R⁴ it is H, or alkyl of 1 to 8 carbon atoms optionally substituted with one or more halogen atoms;

R⁵ is - (CH2) m-NR¹⁷R¹⁸, - (CH2)_m-OR '; alkoxy of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; - (alkyl of 0 to 4 carbon atoms) -C0₂R¹⁵; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms or - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the - (alkyl of 0 to 4 carbon atoms) - aryl of 6 to 14 carbon atoms, and - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, are each optionally substituted by one or more substituents Z;

R⁶ it is alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; cycloalkyl of 3 to 10 carbon atoms; -alkyl of 1 to 4 carbon atoms -cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; OH;

CN; halogen; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms, and - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, are each optionally substituted by one or more Z substituents; or

R⁶ is H, and R⁵ is - (CH2) m-NR¹⁷R¹⁸, - (CH2)_m-OR ', alkoxy of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or - (alkyl of 0 to 4 carbon atoms) -C0₂R¹⁵, wherein - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms, and - (alkyl of 0 to 4 carbon atoms) -heterocyclic group of 3 to 14 member groups are each optionally substituted by one or more substituents Z; or

R⁴ and R⁶ together with the carbon atoms with which they are attached, they form a 3- to 8-membered carbocyclic ring system;

or

R⁴ and R⁵ together they form an oxo group (C = O), and R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O, and S, where the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or

R⁵ and R⁶ together with the carbon atoms with which they are linked, they 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 substituents Z; or

R⁴ and R⁵ and R⁶ together with the carbon atoms with which they are attached, they form a 5- to 8-membered heterocyclic ring system that contains one or more heteroatoms selected from N, O, and S, wherein the ring system is optionally substituted by one or more substituents Z;

R is H, or alkyl of 1 to 8 carbon atoms optionally substituted with one or more halogen atoms;

m is 0, 1, 2 or 3;

R⁸, R¹¹, R¹³ and R¹⁷ are each independently H, alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms, cycloalkyl of 3 to 10 carbon atoms or - (alkyl of 1 to 4 carbon atoms) -cycloalkyl of 3 to 8 carbon atoms;

R⁹, R¹⁰, R¹², R¹⁴, R¹⁵, R¹⁶ and R¹⁸ they are each independently H; alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; alkenyl of 2 to 8 carbon atoms; alkynyl of 2 to 8 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; cycloalkenyl of 5 to 10 carbon atoms; -alkyl of 1 to 4 carboncycloalkyl atoms of 3 to 8 carbon atoms; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O, and S, wherein the cycloalkyl, cycloalkenyl groups, aryl, and heterocyclyl are each optionally substituted by one or more Z substituents; or

R⁸ and R⁹, R¹¹ and R¹², R¹³ and R¹⁴, and R¹⁷ and R¹⁸, together with the nitrogen atom with which they are attached, can 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, alkyl of 1 to 6 carbon atoms optionally substituted by one or more OH groups or NH groups₂, alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms, NR¹⁸(SO2) R²¹, (SO2) NR¹⁹R²¹, (SO₂) R²¹, NR¹⁸C (O) R²¹, C (O) NR¹⁹R²¹, NR¹⁸C (O) NR¹⁹

R²¹, NR¹⁸C (O) OR¹⁹, NR¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, MR¹⁹, OR¹⁹, oxo, CN, NO₂, halogen, or a 3- to 14-membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;

R¹⁹ and R²¹ they are each independently H; alkyl of 1 to 8 carbon atoms; cycloalqullo of 3 to 8 carbon atoms; alkoxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms; (alkyl of 0 to 4 carbon atoms) -aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from halogen , oxo, alkyl of 1 to 6 carbon atoms, and C (O) -alkyl of 1 to 6 carbon atoms; (alkyl of 0 to 4 carbon atoms) -O-aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; and (alkyl of 0 to 4 carbon atoms) -O-heterocyclic group of 3 to 14 members, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from from halogen, alkyl of 1 to 6 carbon atoms, or C (O) alkyl of 1 to 6 carbon atoms; wherein the alkyl groups are optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms, C (O) NH₂, C (O) NH-alkyl of 1 to 6 carbon atoms or C (O) N (alkyl of 1 to 6 carbon atoms)₂; or

R¹⁹ and R²¹ together with the nitrogen atom with which they are attached, they form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more additional 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 that includes one or more heteroatoms selected from N, O and S; SW)₂-aryl; S (0)₂-alkyl of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms; and C (O) O-alkyl of 1 to 6 carbon atoms, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by alkyl of 1 to 6 carbon atoms, halo-alkyl of 1 to 6 carbon atoms , or alkoxy of 1 to 6 carbon atoms.

Different embodiments of the invention are described herein. It will be recognized that the characteristics specified in each modality can be combined with other characteristics specified to provide additional modalities.

In one embodiment of the invention, as described elsewhere in the present, A is N.

In one embodiment of the invention, as described elsewhere in the present, A is CR^4th.

In one embodiment of the invention, as described elsewhere in the present, R¹ is selected from H; alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; halogen; aryl of 6 to 14 carbon atoms; - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; and NR¹¹R¹², wherein the aryl and heterocyclic groups are each optionally substituted by one or more Z substituents.

In one embodiment of the invention, as described elsewhere in the present, R¹ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms. For example, -CH₃ or CF₃.

In one embodiment of the invention, as described elsewhere in the present, R¹ it is alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms. For example, -OCH₃ u -OCF₃.

In one embodiment of the invention, as described elsewhere in the present, R¹ it is aryl, wherein aryl is phenyl optionally substituted by one or more Z substituents, and specific examples are 4-fluoro-phenyl, 4-chloro-2-methyl-phenyl, or 2,410 dichloro-phenyl.

In one embodiment of the Invention, as described elsewhere in this, R¹ it is a 6-membered heterocyclyl group, wherein the 6-membered heterocyclyl group is pyridyl optionally substituted by one or more Z substituents, and the specific example is 1-methyl-4-pyridyl.

In one embodiment of the invention, as described elsewhere in the present, R¹ it's Br, -CH₃, -CF₃, -OCH₃, -OCF₃, 4-fluoro-phenyl, 4-chloro-2-methyl-phenyl, or 2,4-dichloro-phenyl.

In one embodiment of the invention, as described elsewhere in the present, R² it's CF₃CF₂-, (CF₃)₂CH-, CH₃CF₂-, CF₃CF₂-, CF_3i CF_2H-, CH₃-CCI₂-, CF₃CFCCIH-, CBr₃, CBr₂HCF₃CF₂CHCF₃ or cf₃cf₂cf₂cf₂-.

In one embodiment of the invention, as described elsewhere in the present, R² it's CF₃.

In one embodiment of the invention, as described elsewhere in the present, R³ It is H or methyl.

In a further embodiment of the invention, as described elsewhere in the present, R^4th it's H.

An embodiment of the invention, as defined above, provides a compound wherein R⁵ provides a heteroatom from amide nitrogen, wherein the heteroatom is oxygen or nitrogen.

An embodiment of the invention, as defined above, provides a compound according to formula I, wherein:

R⁴ is H, alkyl of 1 to 4 carbon atoms opclonally substituted by one or more halogen atoms, or not present;

R⁵ it is alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; - (CH2) m-NR¹⁷R¹⁸; - (CH2)_m-OR, or OH;

m is 0 or 1;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; OH; CN; halogen; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O, and S, where the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or

R⁴ and R⁵ together they form an oxo group (C = O); or

R⁵ and R⁶ together with the carbon atoms with which they are attached, they form a 5- to 8-membered heterocyclic ring system that contains one or more heteroatoms selected from N, O, and S, wherein the ring system is optionally substituted by one or more substituents Z;

R¹⁷ and R¹⁸ they are each independently H; or alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms.

An embodiment of the invention, as defined above, provides the compounds according to formula I, wherein:

A is CR^4th;

R¹ it is halogen, alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, or alkoxy of 1 to 4 carbon atoms opclonally substituted by one or more halogen atoms;

R² it is halo-alkyl of 1 to 4 carbon atoms;

R³ it's H;

R⁴ it's H or Me;

R^4th it's H;

R⁵ is - (CH2) m-NR¹⁷R¹⁸; - (CH2)_m-OR '; or OH; m is 0 or 1;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; or

R⁵ and R⁶ together with the carbon atoms with which they are attached, they form a 5- to 6-membered heterocyclic ring system that contains one or more heteroatoms selected from N, O, and S, wherein the ring system is optionally substituted by one or more substituents Z; and

R¹⁷ and R¹⁸ they are each independently H; or alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms.

An embodiment of the invention, as defined above, provides the compounds according to formula I, wherein:

A is CR^4th;

R¹ it is halogen, alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, or alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms;

R² it is halo-alkyl of 1 to 4 carbon atoms;

R³ it's H;

R^4th it's H;

R⁴ and R⁵ together they form an oxo group (C = O); and

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O, and S, where the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents.

An embodiment of the invention, as defined above, provides the compounds according to formula I, wherein:

A is CR^4th;

R¹ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms;

R² it is halo-alkyl of 1 to 4 carbon atoms;

R³ it's H;

R⁴ it's H or Me;

R^4th it's H;

R⁵ is - (CH2) m-NR¹⁷R¹⁸; - (CH2)_m-OR '; or OH; m is 0 or 1;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; or

R⁵ and R⁶ together with the carbon atoms with which they are attached, they form a 5- to 6-membered heterocyclic ring system that contains one or more heteroatoms selected from N, O, and S, wherein the ring system is optionally substituted by one or more substituents Z; and

R¹⁷ and R¹⁸ they are each independently H; or alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms.

An embodiment of the invention, as defined above, provides the compounds according to formula I, wherein:

A is CR^4th;

R¹ it is alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms;

R² it is halo-alkyl of 1 to 4 carbon atoms;

R³ it's H;

R⁴ it's H or Me;

R^4th it's H;

R⁵ is - (CH2) m-NR¹⁷R¹⁸; - (CH2)_m-OR; or OH; m is 0 or 1;

O, and S, wherein the ring system is optionally substituted by one or more Z substituents; and

R¹⁷ and R¹⁸ they are each independently H; or alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms.

An embodiment of the invention, as defined above, provides the compounds according to formula I, wherein:

A is CR^4th;

R¹ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms;

R² it is halo-alkyl of 1 to 4 carbon atoms;

R³ it's H;

R⁴ it's H or Me;

R^4th it's H;

R⁵ is -NR¹⁷R¹⁸; or OH;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; and

R¹⁷ and R¹⁸ they are each independently H; or alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms.

An embodiment of the invention, as defined above, provides the compounds according to formula I, wherein:

A is CR^4th;

R¹ it is alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms;

R² it is halo-alkyl of 1 to 4 carbon atoms;

R³ it's H;

R⁴ it's H or Me;

R^4th it's H;

R⁵ is -NR¹⁷R¹⁸; or OH;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; and

R¹⁷ and R¹⁸ they are each independently H; or alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms.

An embodiment of the invention, as described in any other part of the present, wherein:

Z is independently OH, alkyl of 1 to 4 carbon atoms optionally substituted by one or more OH groups or NH groups₂, alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms, NR¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, MR¹⁹, OR¹⁹, CN, NO₂, or halogen;

R¹⁹ and R²¹ they are each independently H; alkyl of 1 to 4 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; or alkoxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, wherein all alkyls are optionally substituted with halogens.

An embodiment of the invention, as described in any other part of the present, wherein:

Z is independently OH, alkyl of 1 to 4 carbon atoms optionally substituted by one or more OH groups or NH groups₂, alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms, C (O) OR¹⁹, C (O) R¹⁹, OR¹⁹, CN, or halogen;

R¹⁹ it's H; alkyl of 1 to 4 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; or alkoxy of 1 to 4 carbon atoms alkyl of 1 to 4 carbon atoms, wherein all alkyls are optionally substituted with halogens.

An embodiment of the invention, as described in any other part of the present, wherein:

Z is independently, alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms, or halogen.

Another embodiment of the invention, as defined above, provides compounds with substantially pure enantiomers with the R configuration.

Another embodiment of the invention, as defined above, provides compounds with substantially pure enantiomers with the S configuration.

Certain compounds of the formula I include the compounds of the formula II:

<img file="CU24149B1_D0002.tif" />

or a pharmaceutically acceptable salt thereof, wherein A, R¹, R² and R³ they have the definitions of formula I, and

R¹⁰¹ is:

<img file="CU24149B1_D0003.tif" />

<img file="CU24149B1_D0004.tif" />

<img file="CU24149B1_D0005.tif" />

<img file="CU24149B1_D0006.tif" />

<img file="CU24149B1_D0007.tif" />

In a further embodiment of the formula II of the invention herein, A is CR^4th, where R^4th it's H.

In a further embodiment of the formula II of the invention herein, R¹ is selected from H; alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; halogen; aryl of 6 to 14 carbon atoms; - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N,

O and S; and NR¹¹R¹², wherein the aryl and heterocyclic groups are each optionally substituted by one or more Z substituents.

A further embodiment of the formula II of the invention, wherein R¹ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; halogen; aryl of 6 carbon atoms; or 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.

A further embodiment of the formula II of the invention, wherein R¹ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; or halogen.

In a further embodiment of the formula II of the invention herein, R³ It is H or methyl.

An embodiment of the invention, as defined above, provides the compounds according to formula II, wherein:

A is CR^4th;

R¹ it is halogen;

R³ it's H;

R^4th it's H;

R¹⁰¹ is:

<img file="CU24149B1_D0008.tif" />

An embodiment of the invention, as defined above, provides the compounds according to formula II, wherein:

A is CR^4th;

R¹ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms;

R³ it's H;

R^4th it's H;

R¹⁰¹ is:

<img file="CU24149B1_D0009.tif" />

An embodiment of the invention, as defined above, provides the compounds according to formula II, wherein:

A is CR^4th;

R¹ it is alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms;

R³ it's H; R^4th it's H; R¹⁰¹ is:

<img file="CU24149B1_D0010.tif" />

An embodiment of the invention, as defined above, provides the compounds according to formula II, wherein:

A is CR^4th;

R¹ it is halogen, alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, or alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms;

R³ it's H;

R^4th it's H;

<img file="CU24149B1_D0011.tif" />

<img file="CU24149B1_D0012.tif" />

<img file="CU24149B1_D0013.tif" />

An embodiment of the invention, as defined above, provides the compounds according to formula II, wherein:

A is CR^4th;

R¹ it is halogen, alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, or alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms;

R³ it's H;

R^4th it's H;

R¹⁰¹ is:

<img file="CU24149B1_D0014.tif" />

<img file="CU24149B1_D0015.tif" />

<img file="CU24149B1_D0016.tif" />

An embodiment of the invention, as defined above, provides the compounds according to formula II, wherein:

A is CR^4th;

R¹ it is halogen, alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, or alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms;

R³ it's H;

R^4th it's H;

R¹⁰¹ is:

<img file="CU24149B1_D0017.tif" />

<img file="CU24149B1_D0018.tif" />

<img file="CU24149B1_D0019.tif" />

Another embodiment of the invention, as defined above, provides the compounds according to formula I and formula II, represented by:

3-amino-6-bromo-N- (imidazo- [1,2-a] -pyridin-2-yl-methyl) -5 (trifluoro-methyl) -pyrazin-2-carboxamide;

3-amino-6-bromo-N - ((1-methyl-1 H-imidazol-4-yl) -methyl) -5 (trifluoro-methyl) -pyrazin-2-carboxamide;

3-amino-6-bromo-N - ((1 -methyl 1-1 H-pyrazol-3-yl) -methyl) -5- (trlfluoro27 methyl) -prazin-2-carboxamide;

3-a mino-N- (2- (4-fluoro-phenyl) -2-oxo-eti 1) -6- (1 - met 1-1 H-indole-6i l) -5- (trifluoro-meti l) -p! choline measures;

3-amino-6-bromo-N - ((1-methyl-1 H-imidazol-2-yl) -methyl) -5 (trifluoro-methyl) -pyrazin-2-carboxamide;

3-amino-6- (6- (3- (dimethyl-amino) -propoxy) -pyridin-3-yl) -N- (2- (4-fluoro-phenyl) -2-oxo-ethyl) -5- (trifluoro -methyl) -pyrazin-2-carboxamide;

(R) -3-amino-6-bromo-N - ((4-methyl-piperazin-2-yl) -methyl) -5 (trifluoro-methyl) -pyrazin-2-carboxamide;

3-amino-6-bromo-N - ((1 -methyl 1-1 H-imidazol-5-yl) -methyl) -5 (trifl uoro-methyl) -pyrazin-2-carboxam gives;

3-amino-6- (3- (N, N-dimethyl-sulfamoyl) -phenyl) -N- (2- (4-fluoro-phenyl) 2-oxo-ethyl) -5- (trifluoro-methyl) -picolinamide ;

3-amino-6-bromo-N-isobutyl-N-methyl-5- (trifluoro-methyl) -pyrazin-2-carboxamide;

3-amino-6-bromo-N - ((1-methyl-1 H -pyrazol-5-yl) -methyl) -5- (trifluoromethyl) -pyrazin-2-carboxamide;

(3-amino-6-bromo-5- (trifluoro-methyl) -pyrazin-2-yl) - (4-methylpiperazin-1 -iI) -methane na;

3-amino-6-bromo-N- (2- (pyridin-4-yl) -ethyl) -5- (trifluoro-methyl) pyrazin-2-carboxamide;

3-am i non-N- (2- (4-fluorophenyl) -2-oxo-eti 1) -6- (1-oxo-1,2,3,4-tetrahydro-isoquinoline-6-yl) -5 - (trifluoro-methyl) -picolinamide;

3-amino-6- (4-carbamoyl-2-methyl-phenyl) -N- (2- (4-fluoro-phenyl) -2oxo-ethyl) -5- (trifluoro-methyl) -picol inamide;

3-amino-6-bromo-N- (2- (pyridin-3-yl) -ethyl) -5- (trifluoro-methyl) pyrazin-2-carboxamide;

3-amino-6- (3,4-dimethyl-phenyl) -N- (2- (4-fluoro-phenyl) -2-oxo-ethyl) -5 (trifluoro-methyl) -polyamine;

3-amino-N-benzyl-6-bromo-N-methyl-5- (trifluoro-methyl) -pyrazin-2-carboxamide;

(S) -3-amino-6-bromo-N - ((1 -eti l-pi rrol id in-2-il) -m eti I) -5- (tr¡fl uo rometil) -pyrazin-2- carboxamide; or

3-amino-6-bromo-N- (imidazo- [1,5-a] -pyridin-1-yl-methyl) -5 (trifluoro-methyl) -pyrazin-2-carboxamide.

Another embodiment of the invention, as defined above, provides the compounds according to formula 1, represented by:

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

(3-amino-6-methoxy-5-trifluoro-methyl-p¡ (3-amino-6-methoxy-5-trifluoro-methyl-p¡ (3) ridin-2-carboxylic;

3- (3-Amino-6-bromo-5- (trifluoro-methyl) -picolinamido) -pro methyl bread;

3-amino-N- (benzo- [d] -isoxazol-3-yl-methyl) -6-bromo-5- (trifluoromethyl) -picol inamide;

3-amino-6- (oxazol-2-1) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoro-methyl) -pico lina measure;

3-amino-6-bromo-N- (3,3,3-trifluoro-2-methoxy-2-methyl-propyl) -5 (trifluoro-methyl) -picolinamide;

3-amino-N- (2-hydroxy-3-methyl-2- (tril^:luoro-methyl) -butyl) -6-methoxy5- (trifluoro-methyl) -picol inamide;

3-amino-6-cyclopropyl-N- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) 5- (trifluoro-methyl) -polynamide;

3-amino-6-methoxy-N- (3,3,3-trifluoro-2-hydroxy-2- (trifluoro-methyl) propyl) -5- (methyl trifluoro) -pico lina measure;

5-amino-N- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -3- (trifluoromethyl) -2,4'-bipridin-6-carboxamide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (3-methyl-2-oxo-butyl) -amide;

3-Amino-6-bromo5-trifluoro-methyl-pyrazine-2-carboxylic acid [2- (4-fluoro-phenyl) -2-oxo-ethyl] -amide;

3-Amino-6-furan-2-yl-5-trifluoro-methyl-pyrazin-2-carboxylic acid [2- (2-methoxy-phenyl) -ethyl] -amide;

3-amin o-6- (1 -methyl 1-1 H-pyrazol-4-yl) -N- (3,3,3-trifluoro-2-hydroxy2-methyl-propyl) -5- (trifluoro-methyl) -picolinamide;

3-amino-N- (3_&gt;3,3-Trifluoro-2-hydroxy-2-methyl-propyl) -5,6-bis (trifluoro-methyl) -pyrazin-2-carboxamide;

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

3-amino-6-bromo-N- (2-morpholino-ethyl) -5- (trifluoro-methyl) -pyrazin-2-carboxamide;

(S) -3-amino-6-ethoxy-N- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) 5- (trifluoro methyl) -p, coli na measure;

3-amin or-6- (pyrrolidin-1-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methyl-30-propyl) -5- (trifluoro-methyl) -p¡ co lina measure;

3-amino-N- (2-amino-3,3,3-trifluoro-2-methyl-propyl) -6-methoxy-5 (trifluoro-methyl) -picolinamide; or

3-amino-6-methoxy-N- (3,3,3-trifluoro-2- (4-methoxy-benzyl-amino) 2-methyl-propyl) -5- (trifluoro-methyl) -picolinam gives.

It is understood that any and all modalities of the present invention may be taken in conjunction with any other modality to describe additional modalities of the present invention. Additionally, it is intended that any elements of one modality be combined with any and all other elements of any of the modalities, to describe additional modalities. It is understood by those skilled in this field that substituent combinations where they are not possible are not an aspect of the present invention.

Especially preferred specific compounds of the formula (I) or of the formula (II) are those described hereinafter in the Examples.

Definitions

The terms used in the specification have the following meanings:

Optionally substituted means that the referred group may be substituted in one or more positions by any or any combination of the radicals listed below.

"Optionally substituted by one or more Z groups" denotes that the relevant group may include one or more substituents, each independently selected from the groups included within the definition of Z. Therefore, when there are two or more group substituents Z, these may be the same or different.

Halo or halogen, as used herein, may be fluorine, chlorine, bromine or iodine.

Alkyl of 1 to 8 carbon atoms, as used herein, denotes straight or branched chain alkyl having 1 to 8 carbon atoms. If a different number of carbon atoms is specified, such as C₆ or C₃, then the definition should be amended in accordance with the same, such that alkyl of 1 to 4 carbon atoms will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl and tertiary butyl.

Alkoxy of 1 to 8 carbon atoms, as used herein, denotes straight or branched chain alkoxy having 1 to 8 carbon atoms. If a different number of carbon atoms is specified, such as C₆ or C₃, then the definition must be amended in accordance with the same, such as alkoxy of 1 to 4 carbon atoms will represent methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, and tertiary butoxy.

Halo-alkyl of 1 to 4 carbon atoms, as used herein, denotes straight or branched chain alkyl having 1 to 4 carbon atoms with at least one hydrogen substituted with a halogen. If a different number of carbon atoms is specified, such as C₆ or C₃, then the definition should be amended in accordance with the same, such as halo-alkyl of 1 to 4 carbon atoms will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl and tertiary butyl having at least one substituted hydrogen with halogen, such as where the halogen is fluorine: CF₃CF₂-, (CF₃)₂CH-, CH₃-CF₂-, CF₃CF₂-, CF₃, CF₂H-, CF₃CF₂CHCF₃ or cf₃cf₂cf₂cf₂-,

Cycloalkyl group of 3 to 15 carbon atoms, as used herein, denotes a cycloalkyl group having 3 to 15 carbon atoms of the ring that is saturated or partially saturated, such as a cycloalkyl of 3 to 8 carbon atoms . Examples of cycloalkyl of 3 to 15 carbon atoms include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclo-octyl, or a bicyclic group, such as bicyclooctyl, bicyclononyl, including indanyl and indenyl, and bicyclodecyl. If a different number of carbon atoms is specified, such as C₆, then the definition should be amended in accordance with the same.

"Aryl or aromatic carbocyclic group of 6 to 15 carbon atoms, as used herein, denotes an aromatic group having 6 to 15 ring carbon atoms. Examples of the aromatic carbocyclic groups of 6 to 15 carbon atoms include, but are not limited to, phenyl, phenylene, benzene-tri-yl, naphthyl, naphthylene, naphthalene-tri-yl, or antrylene. If a different number of carbon atoms is specified, such as C₁₀, then the definition should be amended in accordance with the same.

"Heterocyclic group of 4 to 8 members", "heterocyclic group of 5 to 6 members", "heterocyclic group of 3 to 10 members", "heterocyclic group of 3 to 14 members", "heterocyclic group of 4 to 14 members and group 5 to 14-membered heterocyclic ”, refers, respectively, to 4 to 8-membered heterocyclic rings, 5 to 6 members, 3 to 10 members, 3 to 14 members, 4 to 14 members, and 5 to 14 members containing at least one heteroatom of the ring selected from the group consisting of nitrogen, oxygen and sulfur, which may be saturated, partially saturated or unsaturated (aromatic). The heterocyclic group includes individual ring groups, fused ring groups, and bridged groups. Examples of these heterocyclic groups include, but are not limited to, furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazol, thiadiazole, sotlazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine. , pyrimidine, piperazine, pyrrolidine, pyrrolidinone, morpholine, triazine, oxazine, tetrahydro-furan, tetrahydro-thiophene, tetrahydro-thiopyran, tetrahydro-pyran, 1,4-dioxane, 1,4-oxathian, indazole, quinoline, indazole, indole , 8-aza-bicyclo- [3.2.1] -octane or thiazole.

A second aspect of the invention provides a compound of the formula (I), (II) or (III), as defined elsewhere in the present, for use as a pharmaceutical product.

A further aspect of the invention provides a compound of the formula (I), (II) or (III), for use in the treatment of an inflammatory or allergic condition, in particular an inflammatory or obstructive disease of the respiratory tract or for the mucosal hydration. These conditions include, for example, cystic fibrosis, primary ciliary dipielesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (irritable bowel syndrome (IBS), disease of irritable bowel (IBD), opioid-induced).

A still further aspect of the present invention provides the use of a compound of the formula (I), (II) or (III), as defined in any of the aforementioned modalities, in free form or pharmaceutically acceptable salt, for the preparation of a medicament for the treatment of an inflammatory or allergic condition, in particular an inflammatory or obstructive disease of the respiratory tract or for the hydration of the mucous membranes.

An embodiment of the present invention provides the use of a compound of the formula (I), (II) or (III), as defined in any of the aforementioned modalities, in free form or pharmaceutically acceptable salt, for the preparation of a medicament for the treatment of an inflammatory or allergic condition selected from cystic fibrosis, primary ciliary dipielesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis slre, or constipation (irritable bowel syndrome (IBS), irritable bowel disease (IBD), opioid-induced).

An embodiment of the present invention provides a method for the prevention or treatment of a condition or disease mediated by the cystic fibrosis transmembrane conductance regulator (CFTR), which comprises administering an effective amount of at least one compound as described in the present a subject who needs such treatment. This condition or disease mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) is selected from cystic fibrosis, primary ciliary dipielesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (irritable bowel syndrome (IBS), irritable bowel disease (IBD), opioid-induced).

Throughout this specification and in the claims that follow, unless the context requires otherwise, the word comprises, or variations, such as comprising or understanding, should be understood to imply the inclusion of an integer or step or group of integers or steps mentioned, but not the exclusion of any other integer or step or group of integers or steps.

The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this invention, and which are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of the amino and / or carboxyl groups, or groups similar thereto.

Pharmaceutically acceptable acid addition salts may be formed with inorganic acids and organic acids, for example, the acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride salts, chlorteophilonate, citrate, ethane disulphonate, fumarate, gluceptate, gluconate, glucuronate, hipurate, iodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsilate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / phosphate acid / diacid phosphate, polygalacturonate, propionate, stearate, succinate, sulphosalicylate, tartrate, tosylate, acetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid , mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the Periodic Table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; Particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.

The organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. . Certain organic amines include isopropyl amine, benzathine, colinate, diethanolamine, diethyl amine, Usine, meglumine, piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic fraction, by conventional chemical methods. Generally speaking, these salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as hydroxide, carbonate, Na, Ca, Mg, or K bicarbonate, or the like) , or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. These reactions are typically carried out in water or in an organic solvent, or in a mixture of both. In general terms, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, where practicable, is desirable. Lists of additional suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20^to Edition, Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Additionally, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or they can include other solvents used for their crystallization.

The compounds of the invention, that is, the compounds of the formula (I), (II) or (III) containing groups capable of acting as donors and / or acceptors for hydrogen bonds, may be able to form co- crystals with suitable co-crystal formers. These co-crystals can be prepared from the compounds of the formula (I), (II) or (III) by known co-crystal formation procedures. These procedures include milling, heating, co-sublimation, co-fusion, or solution contact of the compounds of the formula (I), (II) or (III) with the co-crystal former under crystallization conditions, and the isolation of co-crystals formed in this way. Suitable co-crystal formers include those described in International Publication Number WO 2004/078163. Accordingly, the invention further provides co-crystals, which comprise a compound of the formula (I), (II) or (III).

As used herein, the term "isomers" refers to different compounds that have the same molecular formula, but differ in the arrangement and configuration of atoms. Also as used herein, the term "an optical isomer or a stereoisomer" refers to any of the different stereoisomeric configurations that may exist for a given compound of the present invention, and includes geometric isomers. It is understood that a substituent can be attached at a chiral center of a carbon atom. Accordingly, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are mirror images that cannot be superimposed on each other. A 1: 1 mixture of a pair of enantiomers is a racemic mixture. ” The term is used to designate a racemic mixture where appropriate. Diastereoisomers ”are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry in each chiral carbon atom can be specified by any of R or S. The solved compounds whose absolute configuration is unknown, can be designated as (+) or (-) depending on the direction (dextrógira or levógira) in which the polarized light rotates in the plane at the wavelength of the sodium line D. Some of the compounds described herein contain one or more asymmetric centers and, therefore, may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry, such as (R) or (S).

The present invention is intended to include all possible isomers, including racemic mixtures, optically pure forms, and mixtures of intermediates. Optically active (R) and (S) isomers can be prepared using chiral syntons or chiral reagents, or can be resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a substituted dicycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. It is also intended to include all tautomeric forms.

Any asymmetric atom (for example, of carbon, or the like) of the compounds of the present invention may be present in a racemic or enantiomerically enriched configuration, for example in the configuration (R), (S) or (R, S). In certain embodiments, each asymmetric atom has at least an enantiomeric excess of 50 percent, at least an enantiomeric excess of 60 percent, at least an excess

<td>enantiomeric</td><td>of the</td><td> 70</td><td>by</td><td>hundred,</td><td>when</td><td>less</td><td>a</td><td>excess</td>

<td>enantiomeric</td><td>of the</td><td> 80</td><td>by</td><td>hundred,</td><td>when</td><td>less</td><td>a</td><td>excess</td>

<td>enantiomeric</td><td>of the</td><td> 90</td><td>by</td><td>hundred,</td><td>when</td><td>less</td><td>a</td><td>excess</td>

<td>enantiomeric</td><td>of the</td><td> 95</td><td>by</td><td>hundred, or</td><td>when</td><td>less</td><td>a</td><td>excess</td>

<td>enantiomeric</td><td colspan="4">of 99 percent in the</td><td colspan="2">configuration (R)</td><td> 0</td><td>(S) The</td>

<td>substituents</td><td>in the</td><td colspan="2">atoms</td><td colspan="3">with unsaturated links, yes</td><td>is</td><td>possible,</td>

they can be present in the form c / s (Z) or trans (E).

In accordance with the foregoing, as used herein, a compound of the present invention may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as geometric isomers (c / so trans) substantially pure, diastereomers, optical isomers (antipodes), racemates, or mixtures thereof.

Any resulting mixtures of isomers can be separated based on the physicochemical differences of the constituents, pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

Any racemates resulting from the final products or intermediates can be resolved in the optical antipodes by known methods, for example, by separating the diastereomeric salts thereof, obtained with an optically active acid or base, and releasing the acidic compound. or optically active basic. In particular, therefore, a basic fraction can be used to solve the compounds of the present invention in their optical antipodes, for example, by fractional crystallization of a salt formed with an optically active acid, for example tartaric acid, dibenzoyltartaric acid, diacetyl tartaric acid, di-O acid, O'-p-toluoyl-tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, for example, high pressure liquid chromatography (HPLC), using a chiral adsorbent.

Because the compounds of the invention are intended for use in pharmaceutical compositions, it will be readily understood that each is preferably provided in a substantially pure form, for example at least 60 percent pure, in a more suitable manner at least the 75 percent pure, and preferably at least 85 percent, especially at least 98 percent pure (the percentages are on a weight by weight basis). Impure preparations of the compounds can be used for the preparation of the purest forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1 percent, more suitably at least 5 percent, and preferably 10 to 59 percent of a compound of the invention.

The compounds of the present invention are obtained either in the free form, as a salt thereof, or as pro-drug derivatives thereof.

When both a basic group and an acid group are present in the same molecule, the compounds of the present invention can also form internal salts, for example, zwitterionic molecules.

Any formula given herein is also intended to represent unlabelled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures illustrated by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of the isotopes that can be incorporated into the compounds of the invention include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ²H ³H ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ^3SCI, ¹²⁵l respectively. The invention includes different isotopically labeled compounds as defined herein, for example those where radioactive isotopes are present, such as³H ¹³C, and ¹⁴C. These isotopically labeled compounds are useful in metabolic studies (with ¹⁴C), in reaction kinetics studies (with, for example ²H or ³H), in the detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate distribution tests in tissue , or in the radioactive treatment of patients. In particular, a¹⁸F or a labeled compound may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of this invention can be prepared in general terms by carrying out the procedures disclosed in the schemes or in the Examples and in the preparations described below, by using an easily labeled isotopically reagent. available to replace a non-isotopically labeled reagent.

In addition, replacement with heavier isotopes, in particular deuterium (i.e. ²H or D) may provide certain therapeutic advantages resulting from increased metabolic stability, for example an increase in half-life in vivo or reduced dosage requirements or an improvement in the therapeutic index. It is understood that deuterium in this context is considered as a substituent of a compound of the formula (I), (II) or (III). The concentration of this heavier isotope, specifically deuterium, can be defined by the isotopic enrichment factor. The term isotopic enrichment factor, as used herein, means the ratio between isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted as deuterium, this compound has an isotopic enrichment factor for each designated deuterium atom of at least 3,500 (52.5 percent incorporation of deuterium into each designated deuterium atom), from when minus 4000 (60 percent of deuterium incorporation), of at least 4500 (67.5 percent of deuterium incorporation), of at least 5000 (75 percent of deuterium incorporation), of at least 5500 (82.5 percent of deuterium incorporation), of at least 6000 (90 percent of deuterium incorporation), of at least 6333.3 (95 percent of deuterium incorporation), of at least 6466.7 (97 percent of incorporation of deuterium), of at least 6600 (99 percent of incorporation of deuterium), or of at least 6633.3 (99.5 percent of incorporation of deuterium).

Isotopically labeled compounds of the formula (I), (II) or (III) can be prepared in general terms by conventional techniques known to those skilled in this field or by processes analogous to those described in the examples and accompanying preparations, using reagents Isotopically labeled appropriate instead of the unlabeled reagent previously used.

Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be isotopically substituted, for example, D₂O d₆-acetone, d₆-DMSO.

Synthesis

In general terms, the compounds according to formula I, II or III can be synthesized by the routes described in Schemes 1, 2 and 3 and in the Examples.

When A is CH the pyridinyl fraction can be synthesized according to the general scheme 1 shown below.

Scheme 1

<img file="CU24149B1_D0020.tif" />

<img file="CU24149B1_D0021.tif" />

When to synthesize from

A is nitrogen, according to the pyrazine fraction, general scheme 2 shown below can be shown.

Scheme 2

<img file="CU24149B1_D0022.tif" />

The right side of the fraction is typically added by means of an amide formation reaction as shown below in general scheme 3.

Scheme 3

<img file="CU24149B1_D0023.tif" />

HATU (2- (1 H-7-azabenzotriazol-1-yl) - ~ 1,1,3,3-tetramethyl-uronium / Methaminium hexafluorophosphate) is a peptide coupling agent. An expert would understand that possibly other coupling agents could work. The halogen group in the above schemes can be replaced with other groups by selecting the appropriate nucleophile and catalyst. The protection of the aryl group NH may be required₂, and is represented by P. The following schemes 4 to 7 are some representative examples.

<img file="CU24149B1_D0024.tif" />

MeOH

NaOH

<img file="CU24149B1_D0025.tif" />

P

Scheme 5

<img file="CU24149B1_D0026.tif" />

<img file="CU24149B1_D0027.tif" />

R¹-B (OH) 2

Pd Cat base

<img file="CU24149B1_D0028.tif" />

Scheme 7

<img file="CU24149B1_D0029.tif" />

CF3- TMS

Cu Cat R2

NH

I

P

OR

<img file="CU24149B1_D0030.tif" />

The skilled person will appreciate that the general synthetic routes detailed above show the common reactions to transform the starting materials as required. Specific reaction conditions are not provided, but these are well known to those skilled in this field, and the appropriate conditions are considered within the common general knowledge of the skilled person.

The starting materials are either the commercially available compounds, or they are the known compounds and can be prepared from the procedures described in the art of organic chemistry.

The compounds of the formula (I), (II), or (III), in free form, can be converted to the salt form, and vice versa, in a conventional manner understood by those skilled in the art. The compounds in free form or salt can be obtained in the form of hydrates or solvates containing a solvent used for crystallization. The compounds of the formula (I), (II), or (III), can be recovered from the reaction mixtures, and purified in a conventional manner. Isomers, such as stereoisomers, can be obtained in a conventional manner, for example, by fractional crystallization or asymmetric synthesis from the correspondingly asymmetrically substituted starting materials, for example, optically active.

The compounds of the formula (I), (II), or (III), can be prepared, for example, using the reactions and techniques described below and in the Examples. The reactions can be carried out in a solvent suitable for the reagents and materials used, and suitable for the transformations that are being carried out. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule must be consistent with the proposed transformations. This will sometimes require a trial to modify the order of the synthetic steps or to select a particular process scheme over another, in order to obtain a desired compound of the invention.

The different substituents on synthetic Intermediaries and the final products shown in the following reaction schemes may be present in their fully elaborated forms, with suitable protecting groups where required, as will be understood by an expert in this field, or in forms precursors that can subsequently be prepared in their final forms by familiar methods for an expert in the field. Substituents can also be added at different stages throughout the entire synthetic sequence or after completing the synthetic sequence. In many cases, manipulations of functional groups commonly used to transform an intermediate into another intermediate, or a compound of the formula (I), (II), or (III), into another compound of the formula (I) can be employed , (II), or (III). Examples of these manipulations are the conversion of an ester or a ketone to an alcohol; the conversion of an ester to a ketone; interconversions of esters, acids and amides; alkylation, acylation and sulfonylation of alcohols and amines; and many others. Substituents can also be added using common reactions, such as alkylation, acylation, halogenation or oxidation. These manipulations are well known in this field, and many reference works summarize the procedures and methods for these manipulations. Some reference works that give examples and references to the primary literature of organic synthesis for many functional group manipulations, as well as other transformations commonly used in the technique of organic synthesis are March's Organic Chemistry, 5th. Edition, Wiley and Chichester, Editors (2001); Comprehensive Organic Transformations, Larock, Editor, VCH (1989); Comprehensive Organic Functional Group Transformations, Katritzky et al. (Series editors), Pergamon (1995); and Comprehensive Organic Synthesis, Trost and Fleming (series editors), Pergamon (1991). It will also be recognized that another important consideration in the planning of any synthetic route in this field is the judicious choice of the protective group used for the protection of the reactive functional groups present in the compounds described in this invention. Multiple protecting groups can be selected within the same molecule, such that each of these protective groups can be removed without the removal of other protective groups in the same molecule, or that several protective groups can be removed using the same step of reaction, depending on the desired result. A report with authority that describes many alternatives for the trained professional is Greene and Wuts, Protective Groups in Organic Synthesis, Wiley and Sons (1999).

Pharmacological Activity

Considering their modulation of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), the compounds of the formula (I), in free form or pharmaceutically acceptable salt, referred to herein below in an alternative manner as the agents of the invention, are useful in the treatment of conditions that respond to the modulation of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), in particular the conditions that benefit from the hydration of the mucous membranes, such as cystic fibrosis.

Diseases mediated by the modulation of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) include diseases associated with the regulation of fluid volumes through epithelial membranes. For example, the volume of the superficial liquid of the respiratory tract is a key regulator of mucociliary cleaning and maintenance of lung health. The modulation of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) will promote the accumulation of fluid on the mucous side of the airway epithelium, thereby promoting mucus clearance, and preventing mucus and sputum accumulation in the respiratory tissues (including the pulmonary airways). These diseases include respiratory diseases, such as cystic fibrosis, primary ciliary dipielesia, chronic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, respiratory tract infections (acute and chronic; viral and bacterial), and lung carcinoma. Diseases mediated by the modulation of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) also include diseases other than respiratory diseases that are associated with abnormal fluid regulation through an epithelium, perhaps involving an abnormal physiology of protective surface fluids on its surface, for example, Sjógren's syndrome, xerostomia (dry mouth) or keratoconjunctivitis sire (dry eye). Additionally, modulation of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) in the kidney could be used to promote diuresis and thus induce a hypotensive effect.

The treatment according to the invention can be symptomatic or prophylactic.

Asthma includes intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma, and induced asthma followed by bacterial infection. It should also be understood that asthma treatment encompasses the treatment of subjects, for example, less than 4 or 5 years of age, who exhibit panting symptoms and are diagnosed or diagnosable as panting babies, a category of established patient of significant concern medical and now frequently identified as early or early stage asthmatics. (For added convenience, this particular asthmatic condition is referred to as a panting baby syndrome.)

The prophylactic efficacy in the treatment of asthma will be evidenced by a reduced frequency or severity of the symptomatic attack, for example, of the acute asthmatic or bronchoconstrictor attack, improvements in the pulmonary function, or better hyperreactivity of the respiratory tract. It can also be evidenced by a reduced requirement of another symptomatic therapy, that is, therapy for, or intended to, restrict or abort the symptomatic attack when, for example, anti-inflammatory (for example, corticosteroid) or bronchodilator is present. The prophylactic benefit in asthma may be evident, in particular, in subjects susceptible to morning drowning. Morning drowning is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics, and characterized by asthma attack, for example, between the hours of approximately 4 to 6 am, that is, in a time normally substantially distant from any symptomatic asthma therapy previously administered.

Chronic obstructive pulmonary disease includes chronic bronchitis or dyspnea associated with it, emphysema, as well as exacerbation of hyper-reactivity of the airways as a result of another drug therapy, in particular, another therapy with inhaled drugs. The invention is also applicable to the treatment of bronchitis of any type or genesis, including, for example, acute, arachidic, catarrhal, croupus, chronic, or ftinoid bronchitis.

Dry eye disease is characterized by a decrease in watery tear production and abnormal lipid, protein and mucin profiles of the tear film. There are many causes for dry eye, some of which include age, laser eye surgery, arthritis, medications, chemical / thermal burns, allergies, and diseases, such as cystic fibrosis and Sjógren's syndrome. Increased secretion of anions through the cystic fibrosis transmembrane conductance regulator (CFTR) would improve fluid transport from the endothelial cells of the cornea and from the secretory glands surrounding the eye to increase hydration of the cornea. This would help relieve the symptoms associated with dry eye disease.

Sjógren's syndrome is an autoimmune disease where the immune system attacks the moisture-producing glands throughout the body, including eyes, mouth, skin, respiratory tissue, liver, vagina, and intestine. Symptoms include dry eye, dry mouth, and dry vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymyositis / dermatomyositis. It is believed that defective protein trafficking causes disease, for which treatment options are limited. The modulators of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) can hydrate the different organs affected by the disease, and can help alleviate the associated symptoms.

The suitability of the modulators of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) as the treatment of a disease that benefits from mucosal hydration can be proven by determining the movement of chloride ions in a suitable cell based assay. For example, individual cells can be used by individual cells or the confluent epithelium, which expresses endogenously, or that is designed to over-express the cystic fibrosis transmembrane conductance regulator (CFTR), in order to evaluate the function of the canal , using electrophysiological techniques or ion flow studies. See the methods described in: Hirsh et al., J Pharm Exp Ther (2004); Moody et al., Am J Physiol Cell Physiol (2005).

The modulators of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), including the compounds of the formula (I), are also useful as therapeutic co-agents for use in combination with other drug substances, such as drug substances anti-inflammatory, bronchodilators, anti-histamines, or anti-tusives, in particular in the treatment of cystic fibrosis or obstructive or inflammatory diseases of the respiratory tract, such as those mentioned above herein, for example, as enhancers of the therapeutic activity of such drugs, or as a means to reduce the required dosage or potential side effects of these drugs.

The compounds of the formula (I), (II) or (III) can be mixed with the other drug substance in a pharmaceutical composition, or they can be administered separately, before, simultaneously with, or after, the Another drug substance.

In accordance with the foregoing, the invention includes, as an additional aspect, a combination of a modulator of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) with osmotic agents (hypertonic saline, dextran, mannitol, xylitol), blockers of ENaC, an anti-inflammatory, bronchodilator, anti-histamine, antitussive, antibiotic and / or DNase drug substance, wherein the modulator of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) and the additional drug substance may be in the same or different pharmaceutical composition.

Suitable antibiotics include macrolide antibiotics, for example, tobramycin (TOBI^MR).

Suitable DNase drug substances include dornase-alpha (Pulmozyme^MR), a highly purified solution of recombinant human deoxyribonuclease I (rhDNAsa), which selectively cleaves DNA. Dornase-alpha is used to treat cystic fibrosis.

Other useful combinations of the modulators of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) with anti-inflammatory drugs are those with chemokine receptor antagonists, for example, CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists, such as Schering antagonists -Plough SC-351125, SCH-55700 and SCH-D; Takeda antagonists, such as N - [[4 - [[[6,7-dihydro-2- (4-methyl-phenyl) -5H-benzocyclohepten-8-yl] -carbonyl] -amino] -phenyl] chloride] -methyl] -tetrahydro-N, N-dimethyl2H-pyran-4-aminium (TAK-770); and CCR-5 antagonists described in United States Patent Number

USP 6,166,037 (in particular in claims 18 and 19), and in International Publications Numbers WO 00/66558 (in particular in claim 8), WO 00/66559 (in particular in claim 9), WO 04/018425 and WO 04/026873.

Suitable anti-inflammatory drugs include spheroids, in particular glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or the spheroids described in International Publications Nos. WO 02/88167, WO

02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/35668, WO 03/48181, WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; non-steroidal glucocorticoid receptor agonists, such as those described in Patent Nos. DE 10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO 03 / 101932, WO 04/05229, WO 04/18429, WO 04/19935 and WO 04/26248; antagonists of LTD4, such as montelukast and zafirlukast; PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKIine), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plow), Arophilin (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD12-281 (Asta Medica), CDC-801 (Celgene), SelCID (TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and those disclosed in International Publications Numbers WO 92/19594, WO 93/19749,

<td colspan="2">WO 93/19750, '</td><td colspan="2">WO 93/19751, WO 98/18796,</td><td>WO</td><td> &gt; 99/16766,</td><td>WO</td>

<td> 01/13953,</td><td>WO</td><td> 03/104204,</td><td>WO 03/104205,</td><td>WO</td><td> 03/39544,</td><td>WO</td>

<td> 04/000814,</td><td>WO</td><td> 04/000839,</td><td colspan="2">WO 04/005258, WO</td><td> 04/018450,</td><td>WO</td>

<td> 04/018451,</td><td>WO</td><td> 04/018457,</td><td>WO 04/018465,</td><td>WO</td><td> 04/018431,</td><td>WO</td>

04/018449, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607 and WO 04/037805; A2B adenosine receptor antagonists, such as those described in International Publication Number WO 02/42298; and beta-2 adrenoceptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially, formoterol, carmoterol and pharmaceutically acceptable salts thereof, and the compounds (in free form or salt or solvate) of the formula (I) of International Publication Number WO 0075114, whose document is incorporated herein by reference, preferably the compounds of the Examples thereof, especially indacaterol and the pharmaceutically acceptable salts thereof, as well as the compounds (in free or salt or solvate form) of the formula (I) of International Publication Number WO 04/16601, and also the compounds of Patent Numbers EP 1440966, JP 05025045, WO 93/18007, WO 99/64035, USP 2002/0055651, WO 01/42193, WO

01/83462, WO 02/66422, WO 02/70490, WO 02/76933, WO 03/24439, WO 03/42160, WO 03/42164, WO 03/72539, WO 03/91204, WO 03/99764, WO 04/16578, WO 04/22547, WO 04/32921, WO 04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618, WO 04/46083, WO 04/80964, WO 04/108765 and WO 04/108676.

Suitable bronchodilator drugs include anticholinergic or antimuscarinic agents, in particular, ipratropium bromide, oxytropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in Patent Nos. EP 424021, USP 3,714,357, USP 5,171,744,

WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO

03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422 and WO 04/05285.

Suitable double anti-inflammatory drugs and bronchodilators include beta-2 adrenoceptor agonists / double muscarinic antagonists, such as those disclosed in United States Patent No. USP 2004/0167167, and in International Publications Numbers WO 04/74246 and WO 04/74812.

Suitable anti-histamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine, and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastin, asin, and thymine, as well as michlorine, as well as michlorine, as well as protein in the case of myelin. disclosed in Japanese Patent Number JP 2004107299, and in International Publications Numbers WO 03/099807 and WO

04/026841.

In accordance with the foregoing, the invention also provides, as an additional aspect, a method for the treatment of a condition that responds to the modulation of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), for example, the associated diseases with the regulation of fluid volumes through epithelial membranes, in particular an obstructive disease of the respiratory tract, which comprises administering to a subject, in particular to a human subject, who needs it, a compound of the formula (I), (II), or (III), in free form or in the form of a pharmaceutically acceptable salt.

In another aspect, the invention provides a compound of the formula (I), (II), or (III), in free form or in the form of a pharmaceutically acceptable salt, for use in the preparation of a medicament for the treatment of a condition that responds to the modulation of the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), in particular an obstructive airway disease, for example, cystic fibrosis and chronic obstructive pulmonary disease (COPD).

The agents of the invention can be administered by any appropriate route, for example, orally, for example, in the form of a tablet or capsule; parenterally, for example, intravenously; by inhalation, for example, in the treatment of obstructive airways disease; intranasally, for example, in the treatment of allergic rhinitis; topically to the skin; or rectally. In a further aspect, the invention also provides a pharmaceutical composition, which comprises a compound of the formula (I), in free form or in the form of a pharmaceutically acceptable salt, optionally, together with a pharmaceutically acceptable diluent or carrier for the same. The composition may contain a co-therapeutic agent, such as an anti-inflammatory, bronchodilator, anti-histamine, or anti-tuslvo drug as described hereinbefore. These compositions can be prepared using conventional diluents or excipients and techniques known in the galenic field. Accordingly, oral dosage forms may include tablets and capsules. Formulations for topical administration may take the form of creams, ointments, gels, or transdermal delivery systems, for example, patches. Compositions for inhalation may comprise aerosol formulations or other atomizable formulations, or dry powder formulations.

When the composition comprises an aerosol formulation, it preferably contains, for example, a hydro-fluoroalkane (HFA) propellant, such as HFA134a or HFA227 or a mixture thereof, and may contain one or more co-solvents known in the techniques, such as ethanol (up to 20 percent by weight), and / or one or more surfactants, such as oleic acid or sorbitan trioleate, and / or one or more bulking agents, such as lactose. When the composition comprises a dry powder formulation, it preferably contains, for example, the compound of the formula (I), (II), or (III), with a particle diameter of up to 10 microns, optionally, together with a diluent or carrier, such as lactose, of the desired particle size distribution, and a compound that helps protect against deterioration of product performance due to moisture, for example, magnesium stearate. When the composition comprises a nebulized formulation, it preferably contains, for example, the compound of the formula (I), (II), or (III), either dissolved or suspended in a vehicle containing water, a cosolvent, such as ethanol or propylene glycol, and a stabilizer, which can be a surfactant.

Other aspects of the invention include:

(a) a compound of the formula (I), (II), (III), in an inhalable form, for example, in an aerosol or atomizable composition, or in an inhalable particulate, for example, in a micronized form;

(b) an inhalable medicament comprising a compound of the formula (I), (II), or (III), in an inhalable form;

(c) a pharmaceutical product comprising a compound of the formula (I), (II), or (III), in an inhalable form in association with an inhalation device; and (d) an inhalation device containing a compound of the formula (I), (II), or (III), in an inhalable form.

The dosages of the compounds of the formula (I), (II), or (III), employed in the practice of the present invention, of course, will vary depending, for example, on the particular condition to be treated, the desired effect, and the mode of administration. In general, the daily dosages suitable for administration by inhalation are of the order of 0.005 to 10 milligrams, while for oral administration, the appropriate daily doses are of the order of 0.05 to 100 milligrams.

Pharmaceutical Use and Testing

The compounds of the formula (I), (II) or (III), and their pharmaceutically acceptable salts, referred to herein below in an alternative manner as the agents of the invention, are useful as pharmaceuticals. In particular, the compounds are modulators of the activity of the appropriate cystic fibrosis transmembrane conductance regulator (CFTR), and can be tested in the following tests.

Membrane potential test

The activity of the cystic fibrosis transmembrane conductance regulator (CFTR) can be quantified by measuring the transmembrane potential. Means for measuring transmembrane potential in a biological system can employ a number of methods, including electrophysiological membrane potential assays and based on optical fluorescence.

The optical membrane potential test uses a negatively charged potentiometric dye, such as FLIPR membrane potential dye (FMP) (see Baxter DF, Kirk M, García AF, Raimondi A, Holmqvist MH, Flint KK, Bojanic D, Distefano PS, Curtís R, Xie Y. 'A novel membrane potential-sensitive fluorescent dye improves cell-based assays for ion channels.' J Biomol Screen. February 2002; 7 (1): 79-85), e, which, When it is extracellular, it binds to a quenching agent. After cell depolarization, the negatively charged dye is redistributed into the intracellular compartment, detaching itself from the impervious membrane quenching agent, providing an increase in fluorescence. This change in fluorescence is proportional to the change in transmembrane potential that may result from the activity of the cystic fibrosis transmembrane conductance regulator (CFTR). Fluorescence changes can be monitored in real time by an appropriately equipped fluorescence detector, such as the FLIPR (fluorometric image plate reader) on 96 or 384 well microtiter plates.

Cell culture:

Chinese hamster ovary (CHO) cells stably expressing the AF508-CFTR channel were used for membrane potential experiments. The cells were maintained at 37 ° C in CO₂ at 5 percent by volume / volume, with 100 percent humidity, in the middle of Modified Eagle (MEM) supplemented with 8 percent fetal calf serum by volume / volume, 100 micrograms / milliliter methotrexate, and 100 Units / milliliter of penicillin / streptomycin. Cells were grown in 225 cm tissue culture flasks². For membrane potential tests, cells were seeded in 96-well plates at 40,000 cells per well, allowed to adhere, and then maintained at 26 ° C for 48 hours in order to facilitate channel insertion.

Enhancer Test:

The membrane potential screening assay used an extracellular solution containing low chloride ion (approximately 5 mM) combined with a double addition protocol. The first addition was from the regulator with or without the test compound, followed, 5 minutes later, by an addition of Forskolin (from 1 to 20 μ -) - this protocol favors the maximum efflux of chloride in response to the activation of AF508-CFTR. The chloride ion efflux mediated by AF508-CFTR leads to membrane depolarization, which is monitored optically by dye

FMP

Solutions:

Extracellular low chloride (mM): sodium gluconate 120, CaCI₂ 1.2, KH₂PO₄ 3.3, K₂HPO₄ 0.8, MgCI₂ 1.2, D-glucose 10.0, HEPES 20.0, pH 7.4 with NaOH.

FMP dye: made according to the manufacturers instructions in the extracellular solution of low chloride detailed above, at a final concentration 10x, and stored as aliquots of 1 milliliter at -20 ° C.

LonWorks Quattro trial:

The activity of the cystic fibrosis transmembrane conductance regulator (CFTR) can also be electrophysiologically quantified using the whole cell configuration of the patch fastener technique (Hamill et al., Pflugers Archive 1981). This assay directly measures the currents associated with the flow of chloride through the cystic fibrosis transmembrane conductance regulator channels (CFTR), while maintaining or adjusting the transmembrane voltage. This assay can use either individual glass micropipettes, or parallel flat arrangements to measure the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) from the native or recombinant cellular systems. Currents measured using parallel flat arrays can be quantified using an appropriately equipped instrument, such as the LonWorks Quattro (Molecular Devices) or the Qpatch (Sophion). The Quattro system can measure the currents of the cystic fibrosis transmembrane conductance regulator (CFTR) from either a single cell per recording well (HT configuration), or alternatively, from a population of 64 cells per Well (Population Patch Clamp) (Finkel A, Wittel A, Yang N, Handran S, Hughes J, Costantin J. 'Population patch clamp improves data consistency and success rates in the measurement of ionic currents'. J Biomol Screen. August 2006; 11 (5): 488-96).

Cell culture:

Chinese hamster ovary (CHO) cells stably expressing the AF508-CFTR channel were used for experiments with lonWorks Quattro. The cells were maintained at 37 ° C in CO₂ 5 percent by volume / volume, with 100 percent humidity, in D-MEM supplemented with 10 percent fetal calf serum (FCS) (100 volume / volume), 100 Units / milliliter Penicillin / Streptomycin, NEAA at 1 percent (volume / volume), 1 milligram / milliliter of Zeocin, and 500 micrograms / milliliter of Hygromycin B. For the experiments, the cells were grown in 225 cm tissue culture flasks² until almost the confluence, and then they were cultivated at 26 ° C for 48 to 72 hours in order to facilitate the insertion of the canal. The cells were removed from the flask, and resuspended in either the extracellular recording solution for immediate experimentation, or alternatively, in the culture medium supplemented with 10 percent dimethyl sulfoxide by volume / volume, and frozen at -80 ° C as aliquots of 1 to 2 milliliters for use at a later date.

Enhancer Test:

The cells, at a density of 1.5 to 3 million per milliliter, were placed in the Quattro system, added to the flat patch arrangement, and the seals allowed to set for 5 to 10 minutes. After evaluating the resistance of the seals (commonly&gt; 50 ΜΩ), access to the entire cell was obtained by drilling with 100 micrograms / milliliter of amphotericin B. Baseline currents were measured by pre-scanning the compound obtained by applying a voltage ramp from -100 to +100 mV. This was followed by the addition of either the regulator or the test compound diluted in the extracellular solution supplemented with 20 pM forskolin, to each of the 384 wells of the flat patch arrangement. After the incubation step (5 to 20 minutes), the currents after the compound were measured again, by applying a voltage ramp from

-100 to +100 mV. The difference in the currents between the before and after the compound scans defined the effectiveness of the potentiation of the cystic fibrosis transmembrane conductance regulator (CFTR).

Solutions:

Extracellular solution (ECS): 145 mM NaCI, 4 mM CsCI, 5 mM Dglucose, 10 mM TES, CaCI₂ 1 mM, MgCI₂ 1 mM, pH 7.4,

NaOH

Intracellular regulator (ICS): 113 mM L-aspartic acid, 113 mM CsOH, 27 mM CsCI, 1 mM NaCI, MgCI₂ 1 mM, 1 mM EGTA, 10 mM TES. pH 7.2, with CsOH. It was filter sterilized before use. Ion transport test:

Another method to measure the function of the cystic fibrosis transmembrane conductance regulator (CFTR) is the measurement of the short-circuit current of the Ussing chamber. Designed or native epithelial cells are grown to a confluent monolayer on a semi-permeable filter, and are sandwiched between two Perspex blocks. The flow of chloride ions by means of the cystic fibrosis transmembrane conductance regulator (CFTR) from one side of the epithelium to the other, can be quantified by measuring the current flow, while maintaining the transepithelial potential at 0 mV . This is achieved using KCI-filled agar-based electrodes both to hold the cell monolayer and to measure the flow of currents.

Cell culture:

FRT cells stably expressing AF508-CFTR were grown on plastic in Coon-modified F-12 medium supplemented with NaHCO₃ 32 mM, 10 percent fetal bovine serum by volume / volume, 2 mM L-glutamine, 100

Units / milliliter of penicillin, 100 micrograms / milliliter of streptomycin, and 30 micrograms / milliliter of hygromycin B as the culture medium. For the Ussing chamber experiments, the cells were cultured as the polarized epithelium on the Snapwell permeable support inserts (500,000 cells / insert in the culture medium), and cultured for 7 to 9 days. The inserts were fed with the fresh Coon modified F-12 culture medium every 48 hours, and 24 hours before the experiment in the Ussing chamber. To increase the protein expression of AF508-CFTR on the cell surface, the plates were incubated at 27 ° C for 48 hours before conducting a Ussing chamber experiment. Enhancer Test:

Fischer rat thyroid epithelial cells (FRT), which stably expressed human AF508-CFTR, were used as monolayer cultures on permeable supports. The Cr current was measured using the short circuit current technique, under a gradient of basolateral to apical IC imposed in the Ussing chambers. To measure stable IC currents, Fischer rat thyroid epithelial cells (FRT) were cultured during

48 hours at 27 ° C to facilitate the insertion of AF508-CFTR into the plasma membrane. Ussing chamber studies were conducted in the same way at 27 ° C. Under these conditions, the effects of the cumulative additions of the test compounds on the AF508-CFTR currents could be quantified, with both the power and efficiency endpoints. The compounds were added to both the apical and basolateral sides after the addition of 10 μΜ forskolin. The efficacy of the compounds was compared with that of a known enhancer, such as gensitein.

Solutions:

Ringer Basolateral (mM) solution: NaCI 126, NaHCO₃ 24, KH₂PO₄ 0.38, K₂HPO₄ 2.13, MgSO₄ 1, CaCI₂ 1, and glucose 10.

Ringer Apical (mM) solution: sodium gluconate 140, MgSO₄ 1, CaCI₂ 2, HCI 1, glucose 10, and NaHCO₃ 24.

The compounds can also be tested to determine their ability to stimulate the insertion of AF508-CFTR into the cell membrane using the above assays. For these tests, the protocols were identical except that the cells were not cultured at a low temperature (26 ° C or 27 ° C), but instead were incubated with the test compounds for 12 to 24 hours before the assay.

The compounds of the Examples that are found hereinafter, in general terms, have EC values₅₀in the data measurements described above below 10 μΜ. Table 1 provides a list of representative compounds with their EC value₅₀.

Table 1

<td>Example No.</td><td>EC_Sor pM</td><td>Example No.</td><td>EC₆₀</td>

<td> 2</td><td> 0.015</td><td> 9</td><td> 0.090</td>

<td> 3</td><td> 0.055</td><td> 10</td><td> 0.112</td>

<td> 4</td><td> 0.076</td><td> 11</td><td> 0.037</td>

<td> 5</td><td> 0.05</td><td> 12</td><td> 0.035</td>

<td> 6</td><td> 0.426</td><td> 14</td><td> 0.115</td>

<td> 7</td><td> 0.040</td><td> 15</td><td> 0.051</td>

<td> 8</td><td> 0.060</td><td> 16</td><td> 0.008</td>

<td></td><td></td><td> 17</td><td> 0.010</td>

The compounds listed below are within the scope of the broadest claim, and the EC values₅₀ of the cystic fibrosis transmembrane conductance regulator (CFTR) in the data measurements described above were above 5μΜ:

3-amino-6-bromo-N- (imidazo- [1,2-a] -pyridin-2-yl-methyl) -5 (trifluoro-methyl) -pyrazin-2-carboxamide;

3-amino-6-bromo-N - ((1-methyl 1-1 H-imidazol-4-yl) -methyl) -5 (trifluoro-methyl) -pyrazin-2-carboxamide;

2- (3-Amino-6-bromo-5- (trifluoro-methyl) -pyolinamide) acetic acid;

3-amino-6-bromo-N - ((1-methyl-1 H -pyrazol-3-iI) -methyl) -5- (trifluoromethyl) -pyrazin-2-carboxamide;

3-am i no-N- (2- (4-fl uoro-fen il) -2-oxo-et¡ 1) -6- (1 -meta 1-1 H-indole-6il) -5- (trifluoro -methyl) -picolinamide;

3-amino-6-bromo-N - ((1-methyl-1 H-imidazol-2-yl) -methyl) -5 (trifluoro-methyl) -pyrazin-2-carboxamide;

6 - ((3H- [1,2,3] -triazolo- [4,5-b] -pyridin-3-yl) -oxy) -3- (2,5-dimethyl-1H-pyrrol-1-yl) - N- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -5- (trifluoromethyl) -picol inamide;

3-amino-6- (6- (3- (dimethyl-amino) -propoxy) -pyridin-3-yl) -N- (2- (4-fluoro-phenyl) -2-oxo-ethyl) -5- (trifluoro -methyl) -pyrazin-2-carboxamide;

(R) -3-amino-6-bromo-N - ((4-methyl-piperazin-2-yl) -methyl) -5 (trifluoro-methyl) -pyrazin-2-carboxamide;

3-amino-6-bromo-N - ((1-methyl-1 H-imidazol-5-yl) -methyl) -5 (trifluoro-methyl) -pyrazin-2-carboxamide;

3-amino-6- (3- (N₁N-dimethyl-sulfamoyl) -phenyl) -N- (2- (4-fluoro-phenyl) 2-oxo-ethyl) -5- (trifluoro-methyl) -picol inamide;

3-amino-6-bromo-N-isobutyl-N-methyl-5- (trifluoro-methyl) -pyrazin-2-carboxamide;

3-amino-6-bromo-N - ((1-methyl-1 H -pyrazzo l-5-yl) -methyl) -5- (trifl uoromethyl) -pyrazin-2-carboxamide;

6-Bromo-3- (methyl-amino) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoro-methyl) -picolinamide;

(3-amino-6-bromo-5- (trifluoro-methyl) -pyrazin-2-yl) - (4-methylpiperazin-1-yl) -methanone;

3-amino-6-bromo-N- (2- (pyridin-4-yl) -ethyl) -5- (trifluoro-methyl) pyrazine-2-carboxamide;

3-amino-N- (2- (4-fluoro-phenyl) -2-oxo-eti 1) -6- (1 -oxo-1,2,3,4tetrah ¡dro-isoqu¡ no l¡n-6 -¡L) -5- (trfluoro-methyl) -polcol amide;

3-amino-6- (4-carbamoyl-2-methyl-phenyl) -N- (2- (4-fluoro-phenyl) -2oxo-eti 1) -5- (trifluoro-methyl) -picol inamide;

3-amino-6-bromo-N- (2- (pyridin-3-yl) -ethyl) -5- (trifluoro-methyl) pyrazin-2-carboxamide;

3-amino-6- (3,4-dimethyl-phenyl) -N- (2- (4-fluoro-phenyl) -2-oxo-ethyl) -5 (trifluoro-methyl) -picolinamide;

3-amino-N-benzyl-6-bromo-N-methyl-5- (trifluoro-methyl) -prazin-2-carboxamide;

3-amino-6-hydroxy-N- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -5 (trifluoro-methyl) -picolinamide;

3-amino-6-hydroxy-N- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -5 (trifluoro-methyl) -picolinamide;

(3-amino-6-bromo-5- (trifluoro-methyl) -pyrazin-2-yl) - (4-methyl-3-phenyl-piperazin-1-yl) -methanone;

(S) -3-amino-6-bromo-N - ((1-ethyl-pyrrolidin-2-yl) -methyl) -5- (trifluoromethyl) -pyrazin-2-carboxamide; and

3-amino-6-bromo-N- (imidazo- [1,5-a] -pyridin-1-yl-methyl) -5 (trifluoro-methyl) -pyrazin-2-carboxamide.

The invention is illustrated by the following examples.

Examples

General conditions:

Mass spectra were run in LC-MS systems using electrospray ionization. These were either combinations of Agilent 1100 HPLC / Micromass Platform Mass Spectrometer or Waters Acquity UPLC with SQD Mass Spectrometer. [M + H]⁺ They refer to monoisotopic molecular weights.

NMR spectra were run on Bruker spectrometers

ADVANCE 400 NMR of open access using ICON-RMN. The spectra were measured at 298K and referenced using the solvent peak.

Optical rotations were measured at 589 nanometers and 546 nanometers using an AA-1000 optical activity polarimeter at

21 ° C

The following examples are intended to illustrate the invention and should not be construed as limitations on it. Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are carried out under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20 to 133 mbar). The structure of the final products, intermediates and starting materials is confirmed by conventional analytical methods, for example, microanalysis and spectroscopic characteristics, for example, MS, IR, and NMR. The abbreviations used are those conventional in the field. If not defined, the terms have their generally accepted meanings.

Abbreviations:

<td>ap</td><td>apparent</td>

<td>ATP</td><td>5'-adenosine triphosphate</td>

<td>BINAP</td><td>2,2'-bis- (diphenyl phosphino) -1,1 '-binafti lo racemic</td>

<td>BOC</td><td>terbutyl carboxyl</td>

<td>br</td><td>wide</td>

<td>d</td><td>doublet</td>

<td>dd</td><td>double double</td>

<td>DCM</td><td>dichloromethane</td>

<td>DIEA</td><td>diethyl isopropyl amine</td>

<td>DIPEA</td><td>di-i soprop i l-eti I-amine</td>

<td>DMF</td><td>N, N-dimethylformamide</td>

<td>DMSO</td><td>dimethyl sulfoxide</td>

<td>DTT</td><td>dithioerythritol</td>

<td>ESI</td><td>electrospray ionization</td>

<td>EtOAc</td><td>ethyl acetate</td>

<td>eq</td><td>equivalent</td>

<td>h</td><td>hours)</td>

<td>HEY YOU</td><td>2- (7-aza-1H- hexafluorophosphate) benzotriazol-1-yl) -1,1,3,3-tetramethyl-uronium</td>

HPLC

TO GO

LCMS

MeOH

MS

MW m

mln mi m / z

NMR ppm

PS rae

RT

Rt s

SCX-2 t

TORCH

TFA

THF high pressure liquid chromatography infrared spectroscopy liquid chromatography and mass spectrometry methanol mass spectrometry microwave multiplet minutes my I i I (tro) proportion of the mass to the nuclear magnetic resonance charge parts per million supported by racemic polymer temperature environment retention time singlet strong cation exchange (for example, Biotage Isolute® SCX-2 columns) triplet triethyl amine trifluoroacetic acid tetrahydrofuran

Referring to the following Examples, the compounds of the preferred embodiments were synthesized using the methods described herein, or other methods that are known in the art.

The different starting materials, intermediates, and compounds of the preferred embodiments, can be isolated and purified, where appropriate, using conventional techniques, such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise reported, all starting materials are obtained from commercial suppliers, and used without further purification. The salts can be prepared from the compounds by known salt formation procedures.

It should be understood that organic compounds according to preferred embodiments may exhibit the phenomenon of tautomerism. Because the chemical structures within this specification can only represent one of the possible tautomeric forms, it should be understood that the preferred modalities encompass any tautomeric form of the traced structure.

If not indicated otherwise, the conditions of the analytical HPLC are as follows:

Method 10minLC_v001

Column: Waters BEH C18, 100 x 2.1 mm,

1.7 microns

Column temperature: 50 ° C

<td>Eluents:</td><td>A: H₂O, B: acetonitrile, both containing trifluoroacetic acid at 0.1 percent</td>

<td>Flow rate:</td><td>0.7 milliliters / minute.</td>

<td>Gradient:</td><td>0.25 minutes with 5 percent of B; from 5 percent to 95 percent of B in 7.75 minutes, 1.00 minutes with 95 per percent of B.</td>

<td>10minLC_v002 method</td><td></td>

<td>Column:</td><td>Waters BEH C18, 50 x 2.1 mm, 1.7 microns</td>

<td>Column temperature:</td><td>50 ° C</td>

<td>Eluents:</td><td>A: H₂Or, B: methanol, both containing 0.1 percent trifluoroacetic acid.</td>

<td>Flow rate:</td><td>0.8 milliliters / minute.</td>

<td>Gradient:</td><td>0.20 minutes with 5 percent of B; from 5 percent to 95 percent of B in 7.80 minutes, 1.00 minutes with 95 per percent of B.</td>

<td>10minLC_v003 method</td><td></td>

<td>Column:</td><td>Waters BEH C18, 50 x 2.1 mm, 1.7 microns</td>

<td>Column temperature:</td><td>50 ° C</td>

<td>Eluents:</td><td>A: H₂O, B: acetonitrile, both</td>

containing trifluoroacetic acid at

<td></td><td>0.1 percent</td>

<td>Flow rate:</td><td>0.8 milliliters / minute.</td>

<td>Gradient:</td><td>0.20 minutes with 5 percent of B; from 5 percent to 95 percent of B in 7.80 minutes, 1.00 minutes with 95 per percent of B.</td>

<td>Method 2minLC_v001</td><td></td>

<td>Column</td><td>Waters BEH C18, 100 x 2.1 mm, 1.7 microns</td>

<td>Column temperature:</td><td>50 ° C</td>

<td>Eluents:</td><td>A: H₂O, B: acetonitrile, both containing trifluoroacetic acid at 0.1 percent</td>

<td>Flow rate:</td><td>0.7 milliliters / minute.</td>

<td>Gradient:</td><td>0.25 minutes with 5 percent of B; from 5 percent to 95 percent of B in 1.00 minutes, 0.25 minutes with 95 per percent of B.</td>

<td>Method 2minLC_v002</td><td></td>

<td>Column:</td><td>Waters BEH C18, 50 x 2.1 mm, 1.7 microns</td>

<td>Column temperature:</td><td>50 ° C</td>

<td>Eluents:</td><td>A: H₂Or, B: methanol, both containing 0.1 percent trifluoroacetic acid.</td>

<td>Flow rate:</td><td>0.8 milliliters / minute.</td>

<td>Gradient:</td><td>0.20 minutes with 5 percent of B; from 5 percent to 95 percent of B in 1.30 minutes, 0.25 minutes with 95 per percent of B.</td>

<td>Method 2minl_C_vOO3</td><td></td>

<td>Column:</td><td>Waters BEH C18, 50 x 2.1 mm, 1.7 microns</td>

<td>Column temperature:</td><td>50 ° C</td>

<td>Eluents:</td><td>A: H₂O, B: acetonitrile, both containing trifluoroacetic acid at 0.1 percent</td>

<td>Flow rate:</td><td>0.8 milliliters / minute.</td>

<td>Gradient:</td><td>0.20 minutes with 5 percent of B; from 5 percent to 95 percent of B in 1.30 minutes, 0.25 minutes with 95 per percent of B.</td>

<td>10minC18 method</td><td></td>

<td>Column:</td><td>Gemini C18, 100 x 3 mm, 3 you love</td>

<td>Column temperature:</td><td>50 ° C</td>

<td>Eluents:</td><td>A: H₂O, B: Methanol, 0.1 formic acid percent.</td>

<td>Flow rate:</td><td>1 milliliter / minute</td>

<td>Gradient:</td><td>0.00 minutes with 0 percent of B, 10.00 minutes with 95 percent of B.</td>

AD25IPA DEA method

Mobile phase percent of isopropanol + DEA at

0.1 percent by volume / volume / 75 percent CO₂.

Column:

Chiralpak AD-H, 250 x 10 mm internal diameter, 5 microns.

Detection:

UV approximately 220 nanometers.

Flow rate:

milliliters / minute

Example compounds of the present invention include:

Preparation of Final Compounds

Example 3-amino6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide

OR

<img file="CU24149B1_D0031.tif" />

F

F

3-Amino-6-bromo-5-trifluoro-methyl-pyridin-2-carboxylic acid (Intermediary A) (397 milligrams, 1,392 millimoles), 3-amino-1,1,1-trifluoro-2- methyl-propan hydrochloride -2-ol (250 milligrams, 1,392 millimoles), and HATU (529 milligrams, 1,392 millimoles), dissolved in

Ν, Ν-dimethylformamide (10 milliliters), and stirred at room temperature for 2 minutes. 4-methyl-morpholine (0.413 milliliters, 4.18 millimoles) was added, and stirring was continued at room temperature for 3 hours. The reaction mixture was poured onto ice / water (100 milliliters), and extracted with EtOAc (250 milliliters). The organic extract was washed with a saturated NH solution₄CI (approximately 50 milliliters), dried over MgSO₄, and concentrated in vacuo, to give a pale brown oil. The oil was dissolved in CHCI₃ (approximately 3 milliliters), and loaded onto an ISCO 24g column (silica) eluting with iso-hexane: EtOAc, to provide the title product; LC-MS Rt = 1.46 minutes; [M + H]⁺410.1, Method 2minLC_v002. ¹H NMR (400 MHz, DMSO-d6) δ 8.30 (NH, t), 7.72 (1H, s), 7.29 (NH2, bs), 6.28 (OH, s), 3.68 (1H, dd), 3.47 (1H, dd), 1.24 (3H, s). ^{19F NMR} (400 MHz, DMSO-d₆) δ -62.71 (CF3, s), - 80.48 (CF3, s).

The compounds of the following tabulated Examples (Table 2) were prepared by a method similar to that of Example 1 from the appropriate starting compound and amine. Individual enantiomers were prepared using chiral amines or by separation of the product by Super-Critical Fluid Chromatography. Preparations of starting compounds and amines are described in the Intermediaries section, unless they are commercially available. Di-isopropyl-ethyl-amine or triethyl-amine may have been used instead of 4-methylmorpholine in some reactions.

Table 2

Ex.

Structure

First name

Retention time, [M + H] *, 'H NMR

1.1

<img file="CU24149B1_D0032.tif" />

((R) -3,3,3-Trifluoro-2-hydroxy-propyl) acid amide

3-amino-6-bromo-5-trifluoro-methylpyridin-2-carboxylic acid (Separated by SFC, second eluted peak)

Rt 3.26 minutes;

Method =

AD25IPA_DEA Ή NMR (DMSO) δ 3.4 (1H, m), 3.6 (1H, m), 4.3 (1H, m), 6.5 (1 H, s), 7.3 (2H, s), 7.7 (1H, s), 8.6 (1H, t),

<img file="CU24149B1_D0033.tif" />

3-Amino-6-bromo-5-trifluoro-methylpyridine-2Rt-2Rt acid acid (3,3,3-trifluoro2-hydroxypropyl) -amide 1.42 minutes; [M + H] * 398 Method:

2minLC_v002 Ή NMR (DMSO) δ 3.4 (1H, m), 3.6 (1H, m), 4.3 (1H,

<td>Ex.</td><td colspan="2">Structure</td><td>First name</td><td>Time of retention, [M + Hf, 'H NMR</td>

<td></td><td></td><td></td><td>carboxylic</td><td>m), 6.5 (1H, d),</td>

<td></td><td></td><td></td><td>(Racemate)</td><td>7.3 (2H, s), 7.7</td>

<td></td><td></td><td></td><td></td><td>(1H, s), 8.6 (1H,</td>

<td></td><td></td><td></td><td></td><td>t),</td>

<td></td><td></td><td></td><td>((S) -3,3,3-</td><td></td>

<td></td><td></td><td></td><td>trifluoro-2-</td><td></td>

<td></td><td></td><td></td><td>hydroxypropyl) -</td><td>Rt 1.41 minutes;</td>

<td></td><td></td><td></td><td>acid amide</td><td>[M + H] ⁺ 398</td>

<td></td><td></td><td></td><td>3-amino-6-</td><td>Method:</td>

<td></td><td></td><td>OF II U^p</td><td>bromine-5-</td><td>2minLC_v002</td>

<td></td><td>Br.</td><td></td><td></td><td></td>

<td></td><td></td><td>lf γκγ^ρ</td><td>trifluoro-methyl-</td><td>¹H NMR (DMSO) δ</td>

<td> 1.3</td><td>F ^ /</td><td>LL OH</td><td></td><td></td>

<td></td><td>F ^ l</td><td>nh₂</td><td>pyridin-2-</td><td>3.4 (1H, m), 3.6</td>

<td></td><td>F</td><td></td><td>carboxylic</td><td>(1H, m), 4.3 (1H,</td>

<td></td><td></td><td></td><td>Ready</td><td>m), 6.5 (1H, d),</td>

<td></td><td></td><td></td><td>using (S) -3-</td><td>7.3, (2H, s), 7.7</td>

<td></td><td></td><td></td><td>amino-1,1,1-</td><td>(1H, s), 8.6 (1H, t)</td>

<td></td><td></td><td></td><td>trifluoro-propan-</td><td></td>

<td></td><td></td><td></td><td>2-ol</td><td></td>

Ex.

Structure

First name

Retention time, [M + H]⁺, 'H NMR

1.4

<img file="CU24149B1_D0034.tif" />

[(R) -1 (tetrahydrofuran2- l) -methyl] acid amide

3- amino-6bromo-5trifluoro-methylpyridine-2-carboxylic acid

Prepared using (R) (-) - tetrahydrofurfuryl-amine

<img file="CU24149B1_D0035.tif" />

3-amino-6-bromo5-trifluoro-methylpyridine-2-carboxylic acid (1,3-diioxolan2-yl-methyl) -amide

Rt 1.51 minutes; [M + H]⁺ 370

Method:

2minLC_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)

Rt 1.42 minutes; [M + H]⁺ 370 Method:

2minLC_v002 ¹H NMR (DMSO) δ3.4, (2H, t), 3.8, (2H, m), 3.9, (2H, m), 5.0, (1H, t),

<td>Ex.</td><td colspan="5">Structure</td><td>First name</td><td>Time of retention, [M + H]⁺, ¹H NMR</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>7.3, (2H, br), 7.7,</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>(1 H, s), 8.4, (1 H,</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>t),</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>[(S) -1-</td><td>Rt 1.52 minutes;</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>(tetrahydrofuran-</td><td>[M + H]⁺ 370</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>2-yl) -methyl] -</td><td>Method:</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>acid amide</td><td>2minl_C_vOO2.</td>

<td></td><td></td><td></td><td></td><td rowspan="2"> 0</td><td></td><td>3-amino-6-</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>¹H NMR (DMSO)</td>

<td> 1.6</td><td>F,</td><td>Br.</td><td> 0</td><td colspan="2"></td><td>bromine-5- trifluoro-methyl-</td><td>1.6, (1H, m), 1.9,</td>

<td></td><td></td><td></td><td></td><td>nh₂</td><td></td><td></td><td>(3H, m), 3.3, (2H,</td>

<td></td><td>Γ</td><td>F</td><td></td><td></td><td></td><td>pyridin-2-</td><td>m), 3.6, (1H, m),</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>carboxylic</td><td>3.8, (1H, m), 4.0,</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>Ready</td><td>(1H, m), 7.4, (2H,</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>using (S) -</td><td>s), 7.7, (1H, s),</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>(+) - tetrahydro-</td><td>8.4, (1H, d)</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>furfuryl-amine</td><td></td>

<td></td><td></td><td></td><td></td><td> 0</td><td></td><td>(tetrahydrofuran-</td><td>Rt 1.49 minutes;</td>

<td></td><td></td><td>Br ^</td><td></td><td>TO</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>(Γ</td><td>H</td><td>f&gt;</td><td>2-l-methyl) -amide</td><td>[M + H]⁺ 368</td>

<td> 1.7</td><td>F.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>F'</td><td></td><td></td><td>nh₂</td><td></td><td>of acid 3-</td><td>Method:</td>

<td></td><td></td><td>F</td><td></td><td></td><td></td><td>amino-6-bromo-</td><td>2minLC v002.</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Ex.</td><td>Structure</td><td>First name</td><td>Time of retention, [M + H]⁺, ¹H NMR</td>

<td></td><td></td><td>5-trifluoro-methyl- pyridi n-2- carboxylic</td><td>¹H NMR (DMSO) 61.55, (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)</td>

<td> 1.8</td><td>_s Ύ ° Br .N. J H NHj F</td><td>(2-methyl-2- pi perid i n-1 -il- propyl) -amide of acid 3- amino-6-bromo- 5-trifluoro-methyl- p¡ rid¡ n-2- carboxylic</td><td>Rt 1.14 minutes; [M + H]⁺ 423 Method; 2minLC_v002¹H 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)</td>

<td>Ex-</td><td colspan="5">Structure</td><td>First name</td><td>Time of retention, [M + Hf, ¹H NMR</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Rt 4.06 minutes;</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>[M + Hf 344.</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Method:</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>(2-hydroxy-</td><td>10minl_C v002</td>

<td></td><td></td><td></td><td></td><td></td><td>OH &lt;</td><td>propyl) -amide</td><td>¹H NMR.</td>

<td></td><td></td><td></td><td></td><td>HN</td><td> \</td><td></td><td></td>

<td></td><td></td><td>Br.</td><td></td><td>Λ</td><td></td><td>of acid 3-</td><td>([400MHz],</td>

<td> 1.9</td><td>F</td><td></td><td></td><td></td><td></td><td>amino-6-bromo-</td><td>[DMSO-d₆]) δ 8.30</td>

<td></td><td></td><td></td><td></td><td>nh₂</td><td></td><td>5-trifluoro-methyl-</td><td>(1H, t), 7.69 (1 H,</td>

<td></td><td>F</td><td>F</td><td></td><td></td><td></td><td>pyridin-2-</td><td>s), 7.28 (2H, br s),</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>carboxylic</td><td>4.84 (1H, d), 3.78</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>(1H, m), 3.29 (1H,</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>m), 3.14 (1 H, m),</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>1.05 (3H, d).</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>(2-hydrox¡-2-</td><td>Rt 4.35 minutes;</td>

<td></td><td></td><td></td><td></td><td>0 II</td><td></td><td>methyl propyl) -</td><td>[M + Hf 338.</td>

<td></td><td></td><td>^Br\.</td><td></td><td>TO.</td><td>OH /</td><td>acid amide</td><td>Method:</td>

<td></td><td></td><td></td><td></td><td>N</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>H</td><td></td><td></td><td></td>

<td></td><td>F_s</td><td></td><td></td><td></td><td>I</td><td>3-amino-6-</td><td>lOminLC v002</td>

<td> 1.10</td><td>F'</td><td>F</td><td></td><td>'nh₂</td><td></td><td>bromine-5-</td><td>¹H NMR.</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>trifluoro-methyl-</td><td>([400MHz],</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>pyridin-2-</td><td>[DMSO-d₆]) δ 8.14</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>carboxylic</td><td>(1H, t), 7.70 (1H,</td>

<td>Ex-</td><td>Structure</td><td>First name</td><td>Time of retention, [M + Hf, 'H NMR</td>

<td></td><td></td><td></td><td>s), 7.29 (2H, br s), 4.70 (1H, s), 3.24 (1H, d), 1.10 (6H, s) -</td>

<td> 1.11</td><td>0 nh₂FI F</td><td>(2-methyl- tetrahydrofuran- 2-yl-methyl) -amide of acid 3- amino-6-bromo- 5-trifluoro-methyl- pyridin-2- carboxylic</td><td>Rt 1.53 minutes; [M + Hf 384 Method: 2minl_C_vOO2.¹H NMR. ([400MHz], [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 (1 H, m), 1.60 (1H, m), 1.13 (3H, s).</td>

<td>Ex.</td><td colspan="5">Structure</td><td>First name</td><td>Time of retention, [M + Hf, 'H NMR</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Rt 1.43 minutes;</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>[M + H]⁺ 342;</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>(2-methoxy-ethyl) -</td><td>Method:</td>

<td></td><td></td><td></td><td></td><td></td><td>n</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>HN ^ -</td><td></td><td>acid amide</td><td>2minLC_vOO2.</td>

<td></td><td></td><td>^Br\</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>Τι h</td><td> 0</td><td></td><td>3-amino-6-</td><td>'H NMR.</td>

<td> 1.12</td><td>F.</td><td></td><td></td><td>^ nh₂</td><td></td><td>bromine-5-</td><td>([400MHz],</td>

<td></td><td>F</td><td>F</td><td></td><td></td><td></td><td>trifluoro-methyl-</td><td>[DMSO-d₆]) δ 8.41</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>pyridin-2-</td><td>(1H, t), 7.69 (1H,</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>carboxylic</td><td>s), 7.28 (2H, br s),</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>3.44 (4H, m), 3.27</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>(3H, s).</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Rt 1.52 minutes;</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>(2-methyl-</td><td>[M + H]⁺ 385;</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>tetrahydrofuran-</td><td>Method:</td>

<td></td><td></td><td></td><td></td><td> 0</td><td></td><td>2-yl-methyl) -amide</td><td></td>

<td></td><td></td><td></td><td>TO</td><td colspan="2">^Λυη</td><td>of acid 3-</td><td>2minLC_v002.</td>

<td></td><td>F,</td><td></td><td></td><td></td><td>or</td><td></td><td>'H NMR.</td>

<td> 1.13</td><td>F'</td><td>TO F</td><td>N</td><td>'' NHj</td><td></td><td>amino-6-bromo-</td><td>([400MHz],</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>5-trifluoro-methyl-</td><td>[DMSO-d₆]) δ 8.35</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>pyrazin-2-</td><td>(1H, t), 8.09 (2H,</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>carboxylic</td><td>br s), 3.76 (2H, t),</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>3.34 (2H, d), 1.86</td>

<td>Ex.</td><td>Structure</td><td>First name</td><td>Time of retention, [M + Hf, ¹H NMR</td>

<td></td><td></td><td></td><td>(3H, m), 1.58 (1H, m), 1.13 (3H, s).</td>

<td> 1.14</td><td>^F</td><td>[2- (4-fluoro- fen i 1) -2- morfolin-4-ll- ethyl] -amide 3-amino- acid 6-Bromo-5- trifluoro-methyl- pyrazin-2- carboxylic</td><td>Rt 4.29 minutes; [M + H]⁺ 492 Method: 10minl_C_v002.¹H NMR (400 MHz, MeOD) δ_Η7.61-7.64 (2H, m, 2 x Ar'H (system AA'BB'X)), 7.28- 7.32 (2H, m, 2 x Ar'H (system AA'BB'X)), 4.65- 4.73 (1 H, br m, ΝΗΟΗ_αΗ_βΟΑ ^ Ν (Ar ')), 4.31 (1H, ddABXi J ⁼6.5 / 14.4Hz, NHCH ^ HbCHxN (Ar ')), 3.70-4.14</td>

<td>Ex.</td><td>Structure</td><td>First name</td><td>Time of retention, [M + H]⁺, ¹H NMR</td>

<td></td><td></td><td></td><td>(6H, m, nhc / x, h_bch_xn (Ar ') + 5 x morpholine CH), 3.00-3.30 (3H, m, 3 x morpholine CH).</td>

<td> 1.15</td><td> ._γ. »Λ_{! Ύ}σ '^F í u</td><td>[2- (4-fluoro- feni l) -2- morfolin-4-il- ethylj-amide 3-amino- acid 6-Bromo-5- trifluoro-methyl- pyridin-2- carboxylic</td><td>Rt 4.39 minutes; [M + H]⁺ 491 Method: 10minLC_v002.¹H NMR (400 MHz, MeOD) δ_Η8.37-8.38 (1H, m, ArC (O) NHCH₂), 7.68 (1H, s, ArH- 1), 7.35 (2H, m (system AA'BB'X), 2 x Ar'H-2), 7.17-7.25 (4H, br s + m (system</td>

<td>Ex.</td><td>Structure</td><td>First name</td><td>Time of retention, [M + H]⁺, ¹H NMR</td>

<td></td><td></td><td></td><td>AA'BB'X), ArNH₂ + 2 x Ar'H-3), 3.73- 3.81 (2H, m, ΝΗΟΗαΗ_βΟΗ (Ν) Αγ ' + NHCHaHbCH (N) Ar '), 3.53-3.58 (5H, 2 x morpholine CH₂ + NHCHaHbCH (N) Ar '), 2.34-2.43 (4H, m, 2 x morpholine CH₂).</td>

<td> 1.16</td><td>that</td><td>(2-morfoli n-4-I- 2- fen il-ethyl) - acid amide 3- amino-6- bromine-5- trifluoro-methyl- pyridin-2- carboxylic</td><td>Rt 4.20 minutes; [M + H]⁺ 473 Method 10minLC_v002.¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (1H, s wide), 7.70 (1 H, s), 7.32 (7H, m</td>

<td>Ex-</td><td>Structure</td><td>First name</td><td>Time of retention, [M + Hf, ¹H NMR</td>

<td></td><td></td><td></td><td>wide), 3.75 (2H, m wide), 3.59 (4H, wide), 2.40 (2H, wide), 2.30 (2H, wide).</td>

<td> 1.17</td><td>Br., N. JJ Ti ii h nh₂F</td><td>(2-dimethyl- amino-2-phenyl- et¡l) -am¡da del 3-amino- acid 6-Bromo-5- trifluoro-methyl- pyridin-2- carboxylic</td><td>Rt 4.25 minutes; [M + H]⁺ 431; Method; 1 0minLC_v002.¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (1H, s), 8.72 (1H, t), 7.71 (1H, s), 7.60 (2H, s wide), 7.50 (3H, wide s) 7.30 (2H, s wide), 4.67 (1 H, m), 4.19 (1H, quintet), 3.83 (m), 2.80 (3H, d),</td>

<td>Ex.</td><td>Structure</td><td>First name</td><td>Time of retention, [M + H]⁺, 'H NMR</td>

<td></td><td></td><td></td><td>2.61 (3H, d).</td>

<td> 1.18</td><td>0 0 TO F</td><td>(3-methyl-2- morfolin-4-il- but¡l) -amide 3-amino- acid 6-Bromo-5- trifluoro-methyl- pyrazin-2- carboxylic</td><td>Rt 3.39 minutes; [M + Hf 442. Method 10minl_C_v002.¹H NMR (400 MHz, DMSO-de) δ 9.03 (1H, s), 9.10 (1H, s), 8.12 (2H, s), 400-3.20 (12H, wide), 1.10 (3H, wide), 1.00 (3H, wide).</td>

<td> 1.19</td><td>_:; xxA ° F</td><td>(2-methyl-2- morfolin-4-il- prop¡l) -amlda of acid 3- amino-6-bromo- 5-trifluoro-methyl- pyrazin-2-</td><td>Rt 2.83 minutes; [M + Hf 428; Method 10minLC_v002.¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (1H, s), 8.95</td>

<td>Ex.</td><td>Structure</td><td>First name</td><td>Time of retention, [M + H]⁺, 'H NMR</td>

<td></td><td></td><td>carboxylic</td><td>(1H, s), 8.10 (2H, s), 4.04 (2H, d), 3.75 (2H, t), 3.60 (4H + signal from wide water below), 3.20 (2H, q), 1.35 (6H, s).</td>

<td> 1.20</td><td>F</td><td>(1-morpholin-4-yl- cyclohexyl- metl) -amide of 3-amino- acid 6-Bromo-5- trifluoro-methyl- pyrazin-2- carboxylic</td><td>Rt 3.59 minutes; [M + H]⁺ 466. Method 10minLC_v002.¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (1 H, wide), 8.90 (1 H, wide), 8.10 (1H, s), 4.02 - 3.35 (20H, very wide)</td>

<td>Ex-</td><td>Structure</td><td>First name</td><td>Time of retention, [M + Hf, ¹H NMR</td>

<td> 1.21</td><td>_F¥^^{n nh}&gt;</td><td>(2-morpholin-4-yl- 2- fen il-ethyl) - acid amide 3- amino-6- bromine-5- trifluoro-methyl- pyrazin-2- carboxylic</td><td>Rt 6.09 minutes; [M + Hf 474 10minC18 method</td>

<td> 1.22</td><td>^ΒΓγ^ΝΎ ^ ϊι ^ ; Υ ^ νΑη₂ /ⁿ^ F</td><td>(2-dimethyl- amino-2-phenyl- ethyl) -amide 3-amino- acid 6-Bromo-5- trifluoro-methyl- pyrazin-2- carboxylic</td><td>Rt 5.42 minutes; [M + Hf 432 10minC18 method</td>

<td> 1.23</td><td>⁰ PT γ-Α ^ χΜ _FY ^ "" · Q</td><td>[2- (4-methox¡- phenyl) -2- pyrrolidin-1-yl eti |] -amide of</td><td>Rt 5.64 minutes; [M + Hf 488 10minC18 method</td>

100

<td>Ex.</td><td>Structure</td><td>First name</td><td>Time of retention, [M + H] *, ¹H NMR</td>

<td></td><td></td><td>3-amino- acid 6-Bromo-5- trifluoro-methyl- pyrazin-2- carboxylic</td><td></td>

<td> 1.24</td><td>NH₂F</td><td>[2-dimethyl- amino-2- (4- methoxy-phenyl) - ethyl] -amide 3-amino- acid 6-Bromo-5- trifluoro-methyl- pyrazin-2- carboxylic</td><td>Rt 5.51 minutes; [M + H] * 462; 10minC18 method</td>

<td> 1.25</td><td>F 'ΎΗι ^ΗΐΧ ^^ρΜγ^Νγ ^₀^0HF</td><td>(3,3,3-trifluoro- 2-hydrox¡-2- methyl propyl) - acid amide 3-amino-6- (4- fluoro-phenyl) -5-</td><td>Rt 5.41 minutes; [M + H] * 426; Method 10minLC_v002.¹H NMR δ 8.42 (1H, m),</td>

101

<td>Ex.</td><td>Structure</td><td>First name</td><td>Time of retention, [M + H] *, Ή NMR</td>

<td></td><td></td><td>uoro-methyl trifl pirid ¡n-2- carboxylic</td><td>7.72 (1 H, s), 7.5 (2H, m), 7.3 (2H, t), 7.22 (2H, br s), 6.24 (1H, s), 3.68 (1 H, m), 3.46 (1 H, m), 1.24 (3H, s)</td>

<td> 1.26</td><td>0 F^F AA ^H ^^ohF</td><td>(3,3,3-triF I uo ro- 2- hydroxy-2- methyl propyl) - acid amide 3- amino-5- trifluoro-methyl- pyridin-2- carboxylic</td><td>Rt 4.18 minutes; [M + Hf 332; Method 10minLC_v002. 'H 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).</td>

102

<td>Ex.</td><td colspan="3">Structure</td><td>First name</td><td>Time of retention, [M + Hf, Ή NMR</td>

<td></td><td></td><td></td><td></td><td></td><td>Rt 1.59 minutes;</td>

<td></td><td></td><td></td><td></td><td>((R) -3,3,3-</td><td>[M + H]⁺ 442</td>

<td></td><td></td><td></td><td></td><td>trifluoro-2-</td><td>Method;</td>

<td></td><td></td><td></td><td></td><td>h id roxi-propil) -</td><td>2minLC v002.</td>

<td></td><td></td><td></td><td></td><td>acid amide</td><td>¹H NMR.</td>

<td></td><td></td><td></td><td></td><td>3-amino-6- (4-</td><td>([400MHz],</td>

<td></td><td></td><td></td><td></td><td>chloro-2-methyl-</td><td></td>

<td></td><td>γγ ⁰</td><td></td><td rowspan="2">_ZOH</td><td rowspan="2">feni l) -5-</td><td>[DMSO-d₆]) δ 8.54</td>

<td></td><td>kA /^NFOR - Τι ⁿ l</td><td></td><td>(1 H, br), 7.69 (1H,</td>

<td> 1.27</td><td>F</td><td></td><td></td><td>trifluoro-methyl-</td><td></td>

<td></td><td>^χνη₂ F</td><td></td><td></td><td></td><td>s), 7.41 (1H, d),</td>

<td></td><td colspan="2">r I Γ F</td><td></td><td>pyridin-2-</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>7.30 (1H, dd),</td>

<td></td><td></td><td></td><td></td><td>carboxylic</td><td>7.24 (2H, br s),</td>

<td></td><td></td><td></td><td></td><td>Ready</td><td>7.20 (1H, d), 6.40</td>

<td></td><td></td><td></td><td></td><td>using (R) -3-</td><td>(1H, br), 4.19</td>

<td></td><td></td><td></td><td></td><td>amino-1,1,1-</td><td>(1H, m), 3.54 (1H,</td>

<td></td><td></td><td></td><td></td><td>trifluoro-propan-</td><td>m), 3.36 (1H, m),</td>

<td></td><td></td><td></td><td></td><td>2-ol</td><td>2.01 (3H, s).</td>

<td></td><td colspan="2">F</td><td></td><td rowspan="2">(3,3,3-trifl uoro-</td><td>Rt 1.59 minutes;</td>

<td></td><td>HO</td><td></td><td></td><td></td>

<td></td><td rowspan="2">^HfX</td><td> &lt;</td><td>^XF</td><td>2-hydrox¡-2-</td><td>[M + H]⁺ 466;</td>

<td></td><td></td><td>-F</td><td></td><td></td>

<td> 1.28</td><td>Br. ^ N. Γ</td><td></td><td></td><td>trifluoro-methyl-</td><td>Method</td>

<td></td><td>_¥ V ^⁰ ¿</td><td></td><td>F</td><td></td><td></td>

<td></td><td>F. JI</td><td></td><td></td><td>propyl) -amide</td><td>2minLC_v002.</td>

<td></td><td>nh₂</td><td></td><td></td><td></td><td></td>

<td></td><td>F |</td><td></td><td></td><td>of acid 3-</td><td>¹H NMR</td>

<td></td><td>F</td><td></td><td></td><td></td><td></td>

103

<td>Ex-</td><td>Structure</td><td>First name</td><td>Time of retention, [M + Hf, ¹H NMR</td>

<td></td><td></td><td>amino-6-bromo-</td><td>(400 MHz, DMSO-</td>

<td></td><td></td><td>5-trifluoro-methyl-</td><td>d₆) δ 8.50 (1H, t),</td>

<td></td><td></td><td>pyridin-2-</td><td>8.30 (1H, s), 7.72</td>

<td></td><td></td><td>carboxylic</td><td>(1H, s), 7.30 (2H,</td>

<td></td><td></td><td></td><td>s), 4.00 (2H, d)</td>

<td></td><td></td><td></td><td>Rt 1.16 minutes;</td>

<td></td><td></td><td></td><td>[M + Hf 423;</td>

<td></td><td></td><td></td><td>Method</td>

<td></td><td></td><td>(3,3,3-trifl uo ro-</td><td>2minl_C_vOO2.</td>

<td></td><td></td><td>2-hydrox¡-2-</td><td>¹H NMR</td>

<td></td><td>F Lf</td><td>methyl propyl) -</td><td>(400 MHz, DMSO-</td>

<td></td><td>ΗΓΤ F I OH¹</td><td>acid amide</td><td>d₆) δ 8.53 (1H, d),</td>

<td> 1.29</td><td> (1 °</td><td>5-amino-6'-</td><td>8.45 (1H, t), 7.75</td>

<td></td><td>F 1</td><td>methyl-3-trifluoro-</td><td>(1H, d), 7.71 (1H,</td>

<td></td><td>F</td><td>meti l- [2,3 '] -</td><td>s), 7.34 (1H, d),</td>

<td></td><td></td><td>bipyridinyl-6-</td><td>7.25 (2H, s), 6.21</td>

<td></td><td></td><td>carboxylic</td><td>(1H, s), 3.69 (1H,</td>

<td></td><td></td><td></td><td>dd), 3.42 (1 H, dd),</td>

<td></td><td></td><td></td><td>2.54 (3H, s), 1.22</td>

<td></td><td></td><td></td><td>(3H, s).</td>

104

<td>Ex ·</td><td colspan="2">Structure</td><td>First name</td><td>Time of retention, [M + Hf, ¹H NMR</td>

<td></td><td></td><td></td><td></td><td>Rt 4.64 minutes;</td>

<td></td><td></td><td></td><td></td><td>[M + H]⁺ 372.1;</td>

<td></td><td></td><td></td><td></td><td>Method</td>

<td></td><td></td><td></td><td>3- (3-am-no-6-</td><td></td>

<td></td><td></td><td> 0</td><td></td><td>lOminLC v002.</td>

<td></td><td></td><td rowspan="2"></td><td>bromine-5-</td><td>¹H NMR</td>

<td></td><td></td><td>(trifluoro-methyl) -</td><td></td>

<td> 1.30</td><td>^Br\</td><td></td><td></td><td rowspan="2">(400 MHz, DMSO-</td>

<td></td><td></td><td>Ίι ⁰</td><td>picolinamide) -</td>

<td></td><td>F</td><td></td><td>propanoate of</td><td>d₆) δ 8.56 (1H, t),</td>

<td></td><td>r |</td><td></td><td></td><td rowspan="2">7.68 (1H, s), 7.27</td>

<td></td><td>F</td><td></td><td>methyl.</td>

<td></td><td></td><td></td><td></td><td>(2H, br s), 3.61</td>

<td></td><td></td><td></td><td></td><td>(3H, s) 3.50 (2H,</td>

<td></td><td></td><td></td><td></td><td>q). 2.60 (2H, t).</td>

<td></td><td></td><td></td><td></td><td>Rt 4.18 minutes;</td>

<td></td><td></td><td></td><td></td><td>[M + H]⁺ 417.1;</td>

<td></td><td></td><td></td><td>3-amino-N-</td><td>Method</td>

<td></td><td></td><td></td><td>(benzo- [dj-</td><td></td>

<td></td><td></td><td> 0</td><td>isoxazol-3-yl-</td><td>10minLC_v002.</td>

<td></td><td>Br.</td><td>.N. Jl</td><td></td><td>¹H NMR</td>

<td> 1.31</td><td></td><td>I ^H</td><td rowspan="2">methyl) -6-bromine-</td><td></td>

<td></td><td>F. X</td><td>NH₂ To and</td><td>(400 MHz, DMSO-</td>

<td></td><td>F</td><td>0 \ z</td><td>5- (trifluoro-</td><td>d₆) δ 9.32 (NH, t),</td>

<td></td><td></td><td></td><td>methyl) -</td><td>7.96 (1H, dt), 7.74</td>

<td></td><td></td><td></td><td>picolinamide</td><td>(1H, dt), 7.70 (1H,</td>

<td></td><td></td><td></td><td></td><td>s), 7.65-7.62 (1H,</td>

105

<td>Ex.</td><td colspan="4">Structure</td><td>First name</td><td>Time of retention, [M + H]⁺, 'H NMR</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>m), 7.40-7.36 (1H,</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>m), 7.29 (NH2, b</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>s), 4.88 (2H, d)</td>

<td></td><td></td><td></td><td></td><td></td><td>3-amino-6-</td><td></td>

<td></td><td></td><td rowspan="2">-N.</td><td>0 F II L</td><td>zF</td><td>(oxazol-2-yl) -N-</td><td>Rt 3.44 minutes;</td>

<td></td><td> 0</td><td></td><td>F</td><td>(3,3,3-trifluoro-</td><td>[M + H]⁺ 399.1;</td>

<td></td><td></td><td>i I</td><td>HN</td><td></td><td></td><td></td>

<td> 1.32</td><td>F</td><td></td><td>OH nh₂</td><td></td><td>2-hydroxy-2-</td><td>Method</td>

<td></td><td>F</td><td></td><td></td><td></td><td>methyl propyl) -5-</td><td>10minl_C_vOO3.</td>

<td></td><td></td><td></td><td></td><td></td><td>(trifluoro-methyl) -</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>picolinamide</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>A single</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>enantiomer of</td><td></td>

<td></td><td></td><td></td><td>F</td><td></td><td>3-amino-6-</td><td>'H NMR (400</td>

<td></td><td></td><td></td><td></td><td>-F</td><td>Bromo-N- (3,3,3-</td><td>MHz, DMSO-d₆) δ</td>

<td></td><td></td><td></td><td></td><td>'F</td><td></td><td></td>

<td> 1.33</td><td>Br.</td><td>, N. i Ά</td><td>l or ^^ 0 \</td><td></td><td>trifluoro-2-</td><td>8.24 (1H, t), 7.72</td>

<td></td><td>F</td><td></td><td rowspan="2">^xnh₂</td><td></td><td>methoxy-2-methyl-</td><td>(1H, s), 7.29 (2H,</td>

<td></td><td>F'U</td><td></td><td></td><td>propyl) -5-</td><td>s), 3.65 (2H, m),</td>

<td></td><td>F</td><td></td><td></td><td></td><td>(trifluoro-methyl) -</td><td>3.37 (3H, s), 1.35</td>

<td></td><td></td><td></td><td></td><td></td><td>picolinamide</td><td>(3H, s)</td>

<td></td><td></td><td></td><td></td><td></td><td>(Separated</td><td></td>

106

<td></td><td colspan="4">Structure</td><td>First name</td><td>Time of retention, [M + H] *, &lt;H NMR</td>

<td></td><td></td><td></td><td></td><td></td><td>through SFC,</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>second peak</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>eluted)</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>A single</td><td>Rt 4.48 minutes;</td>

<td></td><td></td><td></td><td></td><td></td><td>enantiomer of</td><td>[M + H] * 390.3;</td>

<td></td><td></td><td></td><td></td><td></td><td>3-amino-N- (2-</td><td>Method</td>

<td></td><td></td><td></td><td></td><td></td><td>hydroxy-3-methyl-</td><td>1 0minLC_v003.</td>

<td></td><td></td><td></td><td></td><td></td><td>2- (trifluoro-</td><td>¹H NMR</td>

<td></td><td>I</td><td></td><td> 0</td><td>F</td><td></td><td></td>

<td></td><td>I or</td><td>N</td><td></td><td>I .F</td><td>put I) -butyl) -6-</td><td>(400 MHz, DMSO-</td>

<td></td><td></td><td> &lt;</td><td></td><td>^ F</td><td></td><td></td>

<td> 1.34</td><td></td><td>i</td><td>^H HO</td><td></td><td>methoxy-5-</td><td rowspan="2">d₆) δ 8.21 (1H, m),</td>

<td></td><td>FJ</td><td></td><td></td><td></td><td></td>

<td></td><td>FI</td><td></td><td>ΡίΠ ^</td><td></td><td>(trifluoro-methyl) -</td><td rowspan="2">7.69 (1H, s), 6.59</td>

<td></td><td>F</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>picolinamide</td><td>(2H, s), 6.26 (1H,</td>

<td></td><td></td><td></td><td></td><td></td><td>(Separated</td><td>s), 3.91 (3H, s),</td>

<td></td><td></td><td></td><td></td><td></td><td>through SFC,</td><td>3.68 (2H, m), 2.02</td>

<td></td><td></td><td></td><td></td><td></td><td>first peak</td><td>(1H, m), 1.02 (6H,</td>

<td></td><td></td><td></td><td></td><td></td><td>eluted)</td><td>m)</td>

<td></td><td></td><td></td><td> 0</td><td>F I</td><td>3-amino-6-</td><td>Rt 1.23 minutes;</td>

<td></td><td></td><td></td><td></td><td>TO</td><td></td><td></td>

<td></td><td></td><td>í</td><td>or</td><td> &lt; ^F</td><td>cyclopropyl-N-</td><td>[M + H] * 372.2;</td>

<td> 1.35</td><td>F.</td><td></td><td></td><td>OH</td><td></td><td></td>

<td></td><td>f'i</td><td></td><td>NH₂</td><td></td><td>(3,3,3-trifluoro-</td><td>Method</td>

<td></td><td>F</td><td></td><td></td><td></td><td>2-hydroxy-2-</td><td>2minLC v003.</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

107

<td>Ex.</td><td>Structure</td><td>First name</td><td>Time of retention, [M + H] *, 'H NMR</td>

<td></td><td></td><td>metyl-propyl) -5- (trifluoro-methyl) - picolinamide</td><td>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)</td>

<td> 1.36</td><td>.0 ^ .N. OH Ύ ⁰F</td><td>3-amino-6- methoxy-N- (3,3,3- trifluoro-2- hydroxy-2- (trifluoro-methyl) - propyl) -5- (methyl trifluoro) - picolinamide</td><td>Rt 4.27 minutes; [M + H] * 416.3; Method 10minLC_v003.¹H NMR (400 MHz, DMSO-de) 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),</td>

108

<img file="CU24149B1_D0036.tif" />

<td>First name</td><td>Time of retention, [M + Hf, ¹H NMR</td>

<td>A single</td><td>Rt 0.86 minutes;</td>

<td>enantiomer of</td><td>[M + H]⁺ 409.1;</td>

<td>5-amino-N-</td><td>Method</td>

<td>(3,3,3-trifluoro-</td><td>2minLC_v003.</td>

<td>2-h¡drox¡-2-</td><td>¹H NMR (400</td>

<td>methyl-propyl) -3-</td><td>MHz, DMSO-d₆) δ</td>

<td>(trifluoro-methyl) -</td><td>8.70 (2H, d), 8.45</td>

<td>2,4'-bi pi r¡d¡ n-6-</td><td>(1H, t), 7.75 (1H,</td>

<td>carboxamide</td><td>s), 7.50 (2H, d),</td>

<td>(Separated</td><td>7.33 (2H, s), 6.22</td>

<td>through SFC,</td><td>(1H, s), 3.69 (1 H,</td>

<td>first peak</td><td>dd), 3.43 (1H, dd),</td>

<td>eluted)</td><td>1.21 (3H, s).</td>

<td>(3-methyl-2-oxo- butyl) -amide 3-amino- acid 6-Bromo-5- trifluoro-methyl- pyridin-2- carboxylic</td><td>Rt 1.18 minutes; [M + H]⁺ 368; Method 2minLC_v003.¹H NMR (400 MHz, DMSO -de) δ 8.64 (1H, t), 7.71 (1H, s), 7.29 (2H,</td>

109

<td>Ex.</td><td>Structure</td><td>First name</td><td>Time of retention, [M + Hf, ¹H NMR</td>

<td></td><td></td><td></td><td>wide s), 4.2 (2H, d), 2.7 - 2.8 (1H, m), 1.08 (6H, d, 2 x CH₃).</td>

<td> 1.39</td><td>.x / = 'í^CrNH₂F</td><td>[2- (4-fluoro- phenyl) -2-oxo- ethylj-amide 3-amino- acid 6-Bromo-5- trifluoro-methyl- pyrazin-2- carboxylic</td><td>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)</td>

Examples 2 and 3

These compounds, that is,

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

110

<img file="CU24149B1_D0037.tif" />

and 3-amino-6-bromo-5-trifluoro-methyl- ((S) -3,3,3-trfluoro-2-hydroxyl-2-methyl-propyl) -amamide pyridine-2-carboxylic acid, (Example 3),

<img file="CU24149B1_D0038.tif" />

they are prepared by chiral separation of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro2-hydroxy-2-methyl-propyl) -amide, (Example 1 ), using Super-Critical Fluid Chromatography under the following conditions:

Mobile phase: 12 percent of isopropanol + 0.1 percent DEA / 88 percent CO₂.

Chiralpak OJ-H, 250 x 10 mm internal diameter, 5 microns.

UV approximately 220 nanometers.

milliliters / minute

347 milligrams in 5 milliliters of EtOH.

Column:

Detection:

Flow rate:

Sample concentration:

Injection Volume:

microliters

111

Example 2: First eluted peak: 3-amino-6-bromo-5-trifluoro-methylpyridin-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydrox-2-methyl-propyl) -amide .

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

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

^{19F NMR} (400 MHz, DMSO-d6) d -62.70 (CF3, s), -80.47 (CF3, s). Optical rotation [a]²¹D at 589 nanometers + 14.4 ° (c = 0.522,

MeOH).

Example 3: Eluted second peak: 3-amino-6-bromo-5-trifluoro-methylpyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide.

LC-MS Rt = 4.94 minutes [M + H] + 412.1 (Method

10minLC_v002).

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

19F NMR _{(400 MHz DMSO}-d₆) d -62.70 (CF3, s), -80.48 (CF3, s). The stereochemistry of this compound was confirmed by X-ray crystallography.

Examples 4, 5 and 6

This compound, i.e. 3-amino-6-methoxy-5-trifluoro-methyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide, (Example 4 ),

112

<img file="CU24149B1_D0039.tif" />

It was prepared according to the following procedure:

A solution comprising 3-amino-6-methoxy-5-trifluoro-methyl-pyridine-2-carboxylic acid (Intermediate D) (4 grams, 16.94 mmol), and 3-amino-1,1,1-trifluoro- hydrochloride 2-methyl-propan-2ol (Intermediary R) (3.04 grams, 16.94 millimoles) in NMP (188 milliliters), was treated with HATU (7.73 grams, 20.33 millimoles), followed by drip addition (2 milliliter portions) of diisopropyl ethyl amine (8.88 milliliters, 50.8 mmol) for 1 hour. After stirring for an additional hour, the reaction mixture was poured into water (450 milliliters) and EtOAc (450 milliliters). The aqueous phase was acidified with 5M HCI (50 milliliters), and the layers were separated. The organic portion was washed with 2M NaOH (200 milliliters), water (200 milliliters, 4 times), brine (100 milliliters, 2 times), dried over MgSO₄, was filtered, and concentrated in vacuo, to provide a brown solid. Purification of the solid by chromatography on silica (previously packed 220 gram silica cartridge) eluting with 0 to 50 percent EtOAc in

113 Sohexane, provided the racemate, 3-amino-6-methoxy-5-trifluoro-methyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -amide (Example 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).

LC-MS: Rt 1.24 minutes; MS m / z 362.4 [M + H] +; Method

Column:

2minl_C_vOO3.

Chiral separation of the racemate by Super-Critical Fluid Chromatography was carried out using the following conditions, to provide the compounds listed hereinafter:

Mobile phase: 12 percent of 2-propanol + 0.1 percent DEA / 50 percent CO₂.

Chiralcel OD-H, 250 x 10 mm internal diameter, 5 microns (2 columns linked in series).

UV approximately 220 nanometers.

milliliters / minute

3.5 grams in 30 milliliters of EtOH.

Detection:

Flow rate:

Sample concentration:

Injection volume: 100 microliters.

Examples 5 and 6 are enantiomers.

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

114

<img file="CU24149B1_D0040.tif" />

¹H NMR (400MHz, dimethyl sulfoxide - d₆) δ 8.3 (1H, t), 7.6 (1H, s), 6.6 (2H, wide), 6.2 (1H, s), 3.9 (3H, s), 3.6 (1H, m), 3.5 (1H, m) , 1.3 (3H, s);

LC-MS Rt = 1.15 minutes, [M + H] + 362.4 (Method

2minLC_v003).

Optical rotation [a]²¹D at 589 nanometers -20.83 ° (c = 0.513, MeOH).

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

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

<img file="CU24149B1_D0041.tif" />

¹H NMR (400MHz, dimethyl sulfoxide - d₆) δ 8.3 (1H, t), 7.6

115 (1H, s), 6.6 (2Η, wide), 6.2 (1H, s), 3.9 (3H, s), 3.6 (1H, m), 3.5 (1H, m), 1.3 (3H, s);

LC-MS Rt = 1.15 minutes [M + H] + 362.4 (Method 2minLC_vOO3). Alternatively, Example 5 can be prepared according to the following method:

To a solution of 3-amino-6-methoxy-5-trifluoro-methylpyridin-2-carboxylic acid (Intermediate D) (10 grams, 42.3 mmol), and (S) -3-amino-1,1,1 hydrochloride -trifluoro-2-methyl-propan-2-ol (RA Intermediary) (7.60 grams, 42.3 millimoles) in NMP (400 milliliters), HATU (19.3 grams, 50.8 millimoles) was added, followed by drip addition of di -isopropyl-ethyl-amine (22.19 milliliters, 127 millimoles) for about 1 hour. After stirring at room temperature for 30 minutes, the mixture was added to EtOAc (2 liters), washed with 1M NaOH (1 liter, 2 times), water (1 liter), brine (1 liter), dried (MgSO₄), 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 percent EtOAc in isohexane, provided a yellow oil. Recrystallization of the oil from iso-hexane / dichloromethane, provided the ((S) 3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide of 3-amino-6-methoxy acid -5-trifluoro-methyl-pyridine-2-carboxylic acid as a crystalline solid.

'H NMR (400MHz, dimethyl sulfoxide - 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),

116

3.45 (1 H, m), 1.24 (3Η, s).

19F rmn (37θ | \ / | (- |_ζ dimethyl sulfoxide - d₆) -62.58 ppm (s), 80.43 ppm (s).

Example 3am ino-6- (4-f lu oro-fen i I) -5-trif I ((S) -3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide uoro-methyl-pyridin-2-carboxylic acid.

<img file="CU24149B1_D0042.tif" />

A mixture comprising the ((S) -3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide of 3-amino-6-bromo-5-trifluoro-methylpyridine-2-carboxylic acid (Example 3 ) (100 milligrams, 0.244 millimoles), 4-fluoro-phenyl-boronic acid (37.5 milligrams, 0.268 millimoles), and 1,1'-bis- (diphenyl phosphonium) -ferrocene-palladium dichloride (19.90 milligrams, 0.024 millimoles ), was suspended in tetrahydrofuran (2 milliliters), and Cs₂CO₃ 1M (0.667 milliliters). The bottle was flooded with N₂, was sealed and heated at 160 ° C using microwave radiation for 15 minutes. The mixture was partitioned between EtOAc (50 milliliters), and water (50 milliliters). The organic portion was separated and washed with brine (30 milliliters), dried (MgSO₄), filtered through Celite® (filter material), and concentrated in vacuo. The crude residue was dissolved in dimethyl sulfoxide (2 milliliters), and purified by mass directed LC-MS, using MeCN / Water / acid

117 0.1 percent trifluoroacetic as eluent, to provide the clean product. The fraction of the product obtained as a solution of MeCN / Water / trifluoroacetic acid a! 0.1 percent, poured into EtOAc (50 milliliters), and washed with NaHCO₃ saturated (50 milliliters) to the free base of the product. The organic portion was combined, dried (MgSO₄), and concentrated in vacuo, to provide the title compound as a pale orange crystalline solid; ¹H NMR (400MHz, dimethyl sulfoxide - 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 minutes [M + H] + 426 (Method 10minLC_v003).

Example 3 ((R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-propyl) -amide of 3-amino-6- (4-fluoro-phenol) -5-trifluoro- methyl pyridine-2-carboxylic.

<img file="CU24149B1_D0043.tif" />

This compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyridin-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide (Example 2), in a manner analogous to Example 8. ¹H NMR (400MHz, dimethyl sulfoxide - 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 minutes

118 [Μ + Η] + 426 (Method 10minLC_v003).

Examples 9 and 10

The enantiomers of 3-amino-6- (2,4-dichloro-phenyl) -5-trifluoro-methyl- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) amide Pyridine-2-carboxylic acid were prepared from 3-amino-6- (2,4-dichlorophenyl) -5-trifluoro-methyl-pyridine-2-carboxylic acid (Intermediary H), and 3-amino-1,1 hydrochloride, 1-Trifluoro-2-methyl-propan-2-ol, in a manner analogous to Example 1, and separated by chiral separation using Super-Critical Fluid Chromatography:

Example 9: First eluted peak. Enantiomer 1 of 3-amino-6- (2,4-dichloro-phenyl) -5-trifluoro-methyl-pridin-2 (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide -carboxylic:

<img file="CU24149B1_D0044.tif" />

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, 1 HOUR). 3.71 (dd, 1H), 3.48 (dd, 1H), 1.26 (s, 3H); LC-MS Rt = 1.65 minutes [M + H] + 476 (Method 2minLC_v002).

Example 10: Eluted second peak. Enantiomer 2 of 3-amino-6- (2,4d-chloro-nyl) -5-trifluoro- (3,3,3-trifluoro-2-hydroxy-2-methyl-propll) -amide met¡lp¡rid¡n-2-carboxylic.

119

<img file="CU24149B1_D0045.tif" />

'H NMR (400 MHz, DMSO-d₆) δ 8.38 (t, 1 Η), 7.83 (s, 1 Η), 7.78 (s, 1 Η), 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 minutes [M + H] + = 476.1 (Method 2minLC_vOO2).

Example 3-Amino-6- (4-fluorophenyl) -5-trifluoro-methyl-1-pyrid in-2-carboxylic acid (2-hydroxy-2-methyl-propyl) -amide

<img file="CU24149B1_D0046.tif" />

To a stirred suspension of 3-amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl) -amide (Example 1.10) (180 milligrams, 0.505 millimoles), and 4-fluorophenyl boronic acid (106 milligrams, 0.758 millimoles) in a mixture of

120

2: 1 toluene: EtOH (12 milliliters) under nitrogen, Na was added₂CO₃(aqueous) 2M (1,011 milliliters, 2,022 millimoles), followed by Pd adduct (dppf) CI₂»CH₂CI₂ (41 milligrams, 0.051 millimoles). The reaction mixture was heated using microwave radiation at

140 ° C for 1 hour, and then allowed to cool to room temperature. The mixture was diluted with EtOAc (100 milliliters), and washed with water (100 milliliters). The organic phase was separated, filtered through Celite® (filter material), dried (MgSO₄), and concentrated in vacuo, to provide a brown oil / solid. Purification by chromatography on silica, eluting with MeOH / DCM provided a yellow oil / solid. This was passed through a 500-milligram Isolute® Si-TMT cartridge (2,4,6-trimercapto-triazine / silica, previously moistened with dichloromethane), eluting with 30 percent methanol / dichloromethane (50 milliliters), to provide a yellow oil / solid. The crude product was dried under vacuum, and formed on a paste in approximately 0.5 milliliters of dichloromethane. The resulting suspension was removed by filtration, and the filtrate was evaporated, to give the title compound as a yellow / light brown foam-like solid; LC-MS Rt = 5.30 minutes [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).

121

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

<img file="CU24149B1_D0047.tif" />

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

This compound was prepared from 3- (2,5-dimethylpyrrol-1-yl) -6-methoxy-5-trifluoro-methyl-pyridine-2-carboxylic acid (Intermediary D2), and 3-amino-1,1 , 1-trifluoro-propan-2-ol, in a manner analogous to Example 1; LC-MS Rt = 1.50 minutes [M + H] + 426 (Method 2minLC_v002).

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

3- (2,5-dimethyl-pyrrole-1-yl) -6-methoxy-5-trifluoro-methyl-pyridin-2 (3,3,3-trifluoro-2-hydroxy-propyl) -amide -carboxylic (350 milligrams, 0.823 millimoles) was dissolved in EtOH (14 milliliters) and water (7 milliliters). Hydroxylamine hydrochloride (572 milligrams, 8.23 ​​millimoles) was added, followed by triethyl amine (167 milligrams, 1646 millimoles), and the mixture was heated at reflux overnight. After cooling to room temperature, the mixture is

122 purified by reverse phase chromatography, eluting with MeOH: water (0.1 percent trifluoroacetic acid), to provide the title compound as a pale yellow solid; LC-MS Rt = 4.20 minutes [M + H] + 348.2 (Method 10minLC_v002).

¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (NH, t), 7.66 (1H, s), 6.68 (NH2, bs), 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).

19F NMR _{(400 MHz DMSO}._d6) _d -62.67 (CF3, s), -77.05 (CF3, s), Trace of trifluoroacetic acid (TFA).

Example 14-3,3-Trifluoro-2-hydroxy-2-trifluoro-methyl-propyl) -amide of 5-amino-6'-methyl-3-trifluoro-methyl- [2,3 '] - bipiridinii-6-carboxylco

<img file="CU24149B1_D0048.tif" />

This compound was prepared from 3-amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-trifluoro-methyl-propyl) -amlda (Example 1.28), and 2-methylpyridin-5-boronic acid, in a manner analogous to Example 8. LC-MS Rt 1.28 minutes; 477 [M + H] +; (Method 2minLC_v002);¹H NMR (400

123

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 15-3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide of 5-amino6'-methyl-3-trifl uoro-methyl- [2,3 '] - bipir¡ d¡n¡l-6-carboxylic

F

This compound was prepared by chiral separation of 5-amino-6'methyl-3-trifluoro-methyl- [2, 3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide [2, 3 '] - bipyridinyl-6-carboxylic acid (Example 1.29) using Super-Critical Fluid Chromatography; LC-MS Rt 3.15 minutes [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 minutes. Examples 16 and 17 (3am ino-5, G-bis-trifluoro acid (3) 3,3,3-trifluoro-2-hydroxyl-2-methyl-propyl) 3-Amino-5,6bis-trifluoro-methyl-pyridin-2- (-R-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide -methyl-pyridin-2-carboxylic acid carboxylic

124

<img file="CU24149B1_D0049.tif" />

<img file="CU24149B1_D0050.tif" />

Step 1: 3- (2,5-dimethl-pyrro 1-1-yl) -5,6-bis (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide -trifluoro-methyl-pyridine-2-carboxylic acid

To a stirred solution of 3- (2,5-dimethyl-pyrrol-1-yl) -5,6bis-trifluoro-methyl-pyridine-2-carboxylic acid (Intermediary M) (1.16 grams, 3.29 mmol) in NMP (32 milliliters), 3-amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride (commercially available) (591 milligrams, 3.29 millimoles) was added, followed by HATU (1.25 grams, 3.29 millimoles ), and NEt₃ (918 microliters, 6.59 mmol), and the reaction mixture was allowed to stir at room temperature. After 1 hour, an additional 0.2 equivalents of NEt were added₃. After 15 minutes, an additional 0.4 equivalents of NEt were added₃ and 0.2 equivalents of amine. After 30 minutes, an additional 0.1 equivalent of HATU was added. After 30 minutes, most of the starting material was consumed. The reaction mixture was added to EtOAc (50 milliliters), washed with 0.1 M NaOH, and the aqueous layer was back-extracted with EtOAc (50 milliliters, 2 times). The combined organic extracts were washed with water (150

125 milliliters, 2 times), brine (100 milliliters), dried (MgSO₄), and concentrated in vacuo, to give the crude product as an orange oil.

The crude material was purified by chromatography on silica, eluting with 0 to 15 percent EtOAc in isohexane, to provide the title product as a yellow solid; LCMS Rt 1.32 minutes; MS m / z 478.2 [M + H] +; Method 2minLC_v003.

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

To a stirred solution of 3- (2,5-dimethyl-pyrrole-1-yl) -5,6-bis-trifluoromethyl (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -amide -pyridin-2-carboxylic acid (985 milligrams, 2,064 millimoles) in 2: 1 EtOH / H₂Or (7.5 milliliters), hydroxylamine hydrochloride (1.43 grams, 20.64 millimoles) was added, followed by NEt₃ (575 milliliters, 4.13 millimoles). The reaction mixture was heated at reflux (approximately 98 ° C) for 11.5 hours, and then allowed to cool to room temperature. The solvent was removed in vacuo, and the resulting residue was partitioned between EtOAc (25 milliliters), and water (25 milliliters). The aqueous layer was separated and extracted with EtOAc (25 milliliters, 2 times), and the combined organic extracts were washed with brine (50 milliliters), dried (MgSO₄), and concentrated in vacuo. The crude material was purified by chromatography on silica, eluting with 0 to 25 percent EtOAc in isohexane, to provide the title product as a pale yellow solid; LC-MS: Rt 1.24 minutes; MS m / z 400.0

126 [Μ + Η] +; Method 2minLC_v003.

Step 3: ((S) -3₁3-Amino-5,6-bis-trifluoro-methyl-pyridine-2-carboxylic acid 3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide and ((R) 3,3, 3-Amino-5,6 bis-trifluoro-methyl-pyridine-2-carboxylic acid 3-trifluoro-2-hydroxy-2-methyl-propyl) -amide.

<img file="CU24149B1_D0051.tif" />

<img file="CU24149B1_D0052.tif" />

These compounds were prepared by chiral separation of the 3-amino-5,6-bis-trifluoro-methyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide .

Enantiomer 1: LC-MS Rt 1.23 minutes; MS m / z 400.0 [M + H] +; Method 2minLC_v003. SFC Retention time 5.07 minutes.

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

Example 18

3-amino-6-methox¡-N- (3,3,3-trifluoro-2- (4-methoxy-benzyl-amino) -2-methyl-propyl) -5- (trifluoro-methyl) -picolinamide

127

F

<img file="CU24149B1_D0053.tif" />

OR

The title compound was prepared in a manner analogous to Example 1, from 3-amino-6-methoxy-5-trifluoro-methylpyridin-2-carboxylic acid (Intermediary D), and 3,3,3-trifluoro- N2- (4-methoxy-benzyl) -2-methyl-propan-1,2-diamine (Intermediary N). in this reaction di-isopropyl-ethyl-amine was used.¹H NMR (400 MHz, DMSOde) 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-methyl-propyl) -6-methoxy-5 (trifluoro-methyl) -pi col inamide

F

OR

NH.

F

F

A mixture comprising 3-amino-6-methoxy-N- (3,3,3128 trifluoro-2- (4-methoxy-benzyl-amino) -2-methyl-propyl) -5- (trifluoro-methyl) picolinamide ( Example 18) (0.9 grams, 1873 mmol) in trifluoroacetic acid (50 milliliters) was heated at 50 ° C for 2 hours. After cooling to room temperature, the pH was adjusted to a pH of 12 using 2M NaOH. The product was extracted with dichloromethane, and the organic extract was washed with water, dried over MgSO₄ and concentrated in vacuo. The crude product was loaded onto an SCX-2 cartridge eluting with methanol, followed by NH₃ 2M in methanol. The methanolic ammonia fractions were concentrated in vacuo, and dried in vacuo, to provide 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).

LC-MS Rt 0.94 minutes; MS m / z 361.2 IM + H] +; Method 2minLC_v003.

Example 20

3-amino-6- (pyrrolidin-1-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifl or gold-methyl) -picolinam ida

<img file="CU24149B1_D0054.tif" />

Step 1: 3- (2,5-d got 1-1 H-pi rrol-1-yl) -6- (pyrrolidin-1-yl) -N (3,3,3-trifluoro-2-hydroxy- 2-methyl-propyl) -5- (trifluoro-methyl) 129 picolinamide

The title compound was prepared from DA Intermediary in a manner analogous to Example 1; LC-MS Rt 1.42 minutes; MS m / z 479.3 [M + HJ +; Method 2minLC_v003.

Step 2: 3-amino-6- (pyrrolidin-1-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -5- (trifluoro-methyl) -picolinamide

This compound was prepared from 3- (2,5-dimethyl-1 Hpyrrol-1-yl) -6- (pyrrolidin-1-yl) -N- (3,3,3-trifluoro-2-hydroxy- 2-methylpropyl) -5- (trifluoro-methyl) -picolinamide in a manner analogous to Intermediary D (final step). The resulting racemate was separated by SFC to provide the title compound; first eluted peak:

¹H NMR (400MHz, dimethyl sulfoxide - d_s) 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);

LC-MS Rt 3.87 minutes; 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-methyl-propyl) -5 (trifluoro methyl) -picolinamide

<img file="CU24149B1_D0055.tif" />

130

The title compound was prepared from DB Intermediary and Intermediary R, ​​in a manner analogous to Example 20; ¹H NMR (400 MHz, DMSO-d₆) δ 8.3 (1H, t), 7.7 (1H, s), 6.6 (2H, wide), 6.3 (1H, s), 4.4 (2H, q), 3.6 (1H, multiplet), 3.5 (1H, multiplet) , 1.3 (3H, t), 1.2 (3H, s).

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

Example 22

3-aml-6-bromo-N- (2-morphol-et-l) -5- (trfluoro-methyl) -pyrazin-2-carboxamide

To a stirred solution of 3-amino-6-bromo-5-trifluoromethyl-pyrazin-2-carboxylic acid (Intermediary C) (250 milligrams, 0.874 millimoles) in NMP (8 milliliters), 4- (2-amino -etll) morpholine (138 microliters, 1,049 millimoles), followed by di-isopropylethyl amine (763 microliters, 4.37 millimoles). To this solution was then added HATU (499 milligrams, 1,311 millimoles) in portions, and the reaction mixture was allowed to stir at room temperature for 1 hour. An additional equivalent of 4- (2 amino- ethyl) -morpholine was added. After an additional 1.5 hours, it

131 they added 0.5 equivalents of HATU (166 milligrams, 0.425 millimoles), and the reaction mixture was allowed to stir for an additional 30 minutes. The mixture was added to EtOAc (50 milliliters), and washed with 0.1M NaOH (50 milliliters). The aqueous layer was back extracted with EtOAc (50 milliliters). The combined organics were washed with water (50 milliliters), brine (50 milliliters), dried over magnesium sulfate, and evaporated under reduced pressure, to give a brown oil (418 milligrams). The crude product was purified by chromatography (Biotage-silica column 20 g / 70 mL, 3: 1 EtOAc / iso-hexane). The resulting yellow residue was loaded onto an SCX-2 cartridge (10 grams) that had previously been moistened with methanol. The cartridge was washed with methanol (140 milliliters), and eluted with a 3.5M solution of ammonia in methanol (70 milliliters). 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 under vacuum, to provide the title compound as a yellow solid;

LC-MS: Rt 2.61 minutes; MS m / z 398.2 [M + H] +; 10minLC_v002 method¹H 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) -pyrazin-2-carboxamide

132

<img file="CU24149B1_D0056.tif" />

<img file="CU24149B1_D0057.tif" />

F

The title compound was prepared from 3-amino-6-bromo-5-trifluoro-methyl-pyrazin-2-carboxylic acid (Intermediary C), and 2 (1 H-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-de) 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

Examples 24a and 24b

Enantiomers of 3-amino-N- (3,3,3-trifluoro-2-hydroxy-2-methylpropi l) -5,6-bis- (trif I or gold-methyl) l -pyrazin-2-carboxam ida

<img file="CU24149B1_D0058.tif" />

The title compound was prepared from Intermediary BA

133 and 3-amino-1,1,1-trifluoro-2-methyl-propan-2-ol in a manner analogous to Example 4. Chiral separation of the racemate by Super-Critical Fluid Chromatography gave the title compound;

Example 24a: First eluted peak: Enantiomer 1 of 3-amino-N (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -5,6-b-s- (trifluoro-methyl) pyrazine- 2-carboxamide;

¹H NMR (400MHz, dimethyl sulfoxide - d₆) δ 8.61 - 8.74 (1H, wide hump), 8.5 - 8.61 (1H, wide hump), 8.46 (1H, t), 6.3 (1H, s), 3.69 (1H, m), 3.5 (1H, m), 1.29 (3H, s)

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

Example 24b: Second eluted peak: Enantiomer 2 of 3-amino-N (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -5,6-bis- (trifluoro-methyl) pyrazine-2- carboxamide;

¹H NMR (400MHz, dimethyl sulfoxide - d₆) δ 8.61 - 8.76 (1H, wide hump), 8.5 - 8.60 (1H, wide hump), 8.46 (1H, t), 6.3 (1H, s), 3.69 (1H, m), 3.5 (1H, m), 1.29 (3H, s)

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

Optical rotation [a]²¹D at 589 nanometers + 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-methyl-propyl) -5- (trifluoro-methyl) -picolinam ida

134

F

<img file="CU24149B1_D0059.tif" />

F

Step 1: 3-amino-6- (1-methyl-1 H-pyrazol-4-yl) -5- (trifluoro-methyl) -polinic acid

The methyl ester of 3-amino-6-bromo-5-trifluoro-methylpyridin-2-carboxylic acid (Intermediary A4) (500 milligrams, 1,672 millimoles), PdCI adduct₂(dppf) .CH2CI₂ (205 milligrams, 0.251 thousand moles), 1-meth 1-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 Hpirazol (383 milligrams, 1,839 millimoles) , and Cs₂CO₃ (6.69 milliliters, 6.69 millimoles) in tetrahydrofuran (12 milliliters) under N₂, were heated using microwave radiation at 150 ° C for 10 minutes. 2M NaOH (5 milliliters) was added, and the mixture was stirred at room temperature 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 a pH of 1. The product was extracted with dichloromethane and concentrated in vacuo, to give the title compound;

Step 2; 3-amino-6- (1-methyl-1 H -pyrazol-4-yl) -N- (3,3,3trifluoro-2-hydroxy-2-methyl-propyl) -5- (trifluoro-methyl) -picolinamide

The title compound was prepared from 3-amino-6 (1-methyl-1 H -pyrazol-4-yl) -5- (trifluoro methyl) -picolinic acid and 3-amino-1,1,1135 trifluoro- 2-methyl-propan-2-ol, in a manner analogous 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)

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

Example 3-amino-6-furan-2-yl-5-trifluoro-methyl-1-pyrazine-2-carboxylic acid [2- (2-methoxy-phenyl) -ethyl] -amide

<img file="CU24149B1_D0060.tif" />

F

The title compound was prepared from 3-amino-6furan-2-yl-5-trifluoro-methyl-pyrazin-2-carboxylic acid (PA Intermediary), and the appropriate amine; MS m / z 406.93 [M + H] +

Intermediary Preparation

Intermediary A

3-amino-6-bromo-5-trifluoro-methyl-pyridin-2-carboxylic acid

<img file="CU24149B1_D0061.tif" />

Intermediary A1: 2-Bromo-3-nitro-5-trifluoro-methyl-pyridine

3-nitro-5- (trifluoro-methyl) -pyridin-2-ol (31.00 grams, 149

136 millimoles) was dissolved in acetonitrile (250 milliliters), to give a dark brown solution. Phosphorus oxybromide (V) (85 grams, 298 mmol) was added, and the mixture was heated at reflux for 4.5 hours, and then stirred at room temperature overnight. The reaction mixture was quenched by pouring water (600 milliliters) containing sodium acid carbonate (110 grams) with vigorous stirring. The dark brown mixture was extracted with dichloromethane (200 milliliters, 3 times), and the organic phase was washed with water (200 milliliters), and brine (100 milliliters), dried (MgSO₄), and concentrated in vacuo, to provide the title product as a brown oil. ¹H-RMN: [400MHz, CDCI₃, δ_Η 8.87 (1H, d, J = 1.4Hz, ArH), 8.39 (1H, d, J = 1.9Hz, ArH).

Intermediary A2: 3-nitro-5-trifluoro-methyl-pyridin-2-carbonitrile

2-Bromo-3-nitro-5-trifluoro-methyl-pyrdine (10.00 grams,

36.87 millimoles) was dissolved in toluene (250 milliliters) with stirring, to give a pale yellow solution. Tetrabutyl ammonium bromide (11.90 grams, 36.9 millimoles) was added, followed by copper cyanide (l) (9.92 grams, 111 millimoles), and the mixture was heated at reflux for 10 hours. After cooling to room temperature, the reaction mixture was partitioned between water (750 milliliters) and EtOAc (750 milliliters). The organic fractions were combined, washed with water (250 milliliters, 2 times) and brine (100 milliliters), dried (MgSO₄), and concentrated in vacuo, to provide the title product.¹H-RMN: [400MHz, DMSO-d₆ δ_Η 9.55 (1H, m, ArH), 9.24 (1H, m, ArH)

137 Intermediate A3: 3-amino-5-trifluoro-methylpyridin-2-carboxylic acid methyl ester

The 3-nitro-5-trifluoro-methyl-pyridin-2-carbonitrile (6.5 grams, 29.9 mmol) was dissolved in EtOAc (150 milliliters), to give a pale yellow solution, and placed under a nitrogen atmosphere. 10 percent palladium on activated carbon (3.19 grams, 2.99 mmol) was added, and the reaction mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered and concentrated in vacuo. The crude residue was dissolved in concentrated HCI (45 milliliters), and heated at reflux for 24 hours. The reaction mixture was allowed to cool to room temperature, and concentrated in vacuo. The solid was dissolved in methanol (300 milliliters), and sulfuric acid (14.4 milliliters) was added. The resulting solution was heated at reflux for 48 hours. The reaction was allowed to cool to room temperature, then neutralized by the addition of NaHCO.₃ (aqueous) at 10 percent (600 milliliters). The product was extracted in dichloromethane (200 milliliters, 3 times), and the combined organic phases were washed with water (200 milliliters), brine (50 milliliters), (MgSO₄), and concentrated in vacuo. The resulting solid was purified by chromatography on silica: Eluent gradient: isohexane (500 milliliters), 10 percent EtOAc in isohexane (1000 milliliters), 20 percent EtOAc in isohexane (1500 milliliters), to provide the title compound as a pale yellow solid¹H-RMN: [400MHz, DMSO-d₆, δ_Η 8.13 (1 H, d, J = 1.7Hz, ArH), 7.60 (1H, d, J = 1.3Hz, ArH), 7.01 (2H, br, NH₂), 3.85

138 (3Η, s, ArOCH₃), m / z 221.1 [M + Hf

Intermediary A4: 3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid methyl ester

The methyl ester of 3-amino-5-trifluoro-methyl-pyridine-2-carboxylic acid (9.49 grams, 43.16 mmol) was suspended in water (300 milliliters). Sulfuric acid (4.60 milliliters, 86 millimoles) was added, followed by dripping, for 30 minutes, of a solution of bromine (2,222 milliliters, 43.1 millimoles) in acetic acid (29.6 milliliters, 517 millimoles). The reaction mixture was stirred at room temperature for 18 hours. An additional 100 milliliters of water were added, followed by an additional 0.25 equivalents of the bromine / AcOH mixture (550 microliters of bromine in 7.4 milliliters of AcOH), and the reaction mixture was stirred at room temperature for an additional 90 minutes. The reaction mixture was diluted with 500 milliliters of water, and neutralized by the addition of NaHCO.₃ solid (approximately 85 grams). The suspension was extracted with dichloromethane (300 milliliters, 3 times), and the combined organic phases were washed with NaHCO₃(aqueous) saturated (250 milliliters), water (250 milliliters), and brine (100 milliliters), dried (MgSO₄), and concentrated in vacuo. The crude material was recrystallized from boiling methanol (approximately 300 milliliters), to give the title product as a pale orange solid; m / z 301.0 [M + H]⁺. ¹H-RMN: [400MHz, DMSO-d₆ δ_Η 7.77 (1H, s, ArH), 7.17 (2H, s, NH₂), 3.86 (3H, s, ArCO₂CH₃).

139

Intermediary A: 3-amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid

The methyl ester of 3-amino-6-bromo-5-trifluoro-methylpyridine-2-carboxylic acid (1.40 grams, 4.68 mmol) was suspended in methanol (15 milliliters); Sodium hydroxide (2.0 M aqueous solution) (14.04 milliliters, 28.1 mmol) was added, and the suspension was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the resulting residue was dissolved in water (100 milliliters), and then acidified by the addition of 5.0M (aqueous) HCI. The product was extracted in ethyl acetate (75 milliliters, 2 times), and the combined organic extracts were washed with water (50 milliliters), brine (25 milliliters), dried (MgSO₄), and concentrated in vacuo, to provide the title product as a yellow solid. ¹H-RMN: [400MHz, DMSO-d_s, δ_Η 13.24 (1H, br s, CO_2H), 7.74 (1H, s, ArH), 7.17 92H, br s ArNH₂). m / z 285.1, 287.1 [M + Hf Intermediary B

3-amino-5-trifluoro-methyl-pyrazin-2-carboxylic acid ethyl ester

OR

<img file="CU24149B1_D0062.tif" />

F

Intermediary B1: Carbamimidoyl nitrosoacetic acid ethyl ester

To a solution of 2M ammonia in ethanol (152 milliliters, 0.304

140 millimoles) from 0 ° C to 5 ° C, ethyl ethoxycarbonyl-acetimidate-HCI (25 grams, 0.127 mmol) was added over 30 minutes. The reaction was vigorously stirred at this temperature for 3 hours, after which, a solution of sodium nitrite in water (9.63 grams, 0.139 mmol) was added, in a single portion. The pH of the mixture was adjusted to a pH of 6 with the addition of 5N HCI. The reaction mixture was allowed to stir at room temperature overnight. The yellow precipitate formed was filtered under vacuum, washed with water, and dried, to give the title compound;

¹H NMR (400 MHz, dimethyl sulfoxide - d₆) δ 10.1 (2H, br s), 7.6 (2H, br s), 4.3 (2H, q), 1.3 (3H, t).

Intermediary B2: Ethyl ester of amino-carbamimidoylacetic acid

To a solution of ethyl ester of carbamimidoyl nitrosoacetic acid (5.5 grams, 31.4 millimoles) in 5M ethanol / HCI (1: 1 ratio, 250 milliliters), 10 percent Pd / C (1.3 grams) was added. The reaction mixture was hydrogenated (H₂{g)) at low pressure for 2 nights. The Pd / C was filtered through Celite® (filter material), and the filtrate was reduced in vacuo, to give the title compound as a white solid. This was taken to the next step as a raw material.

Intermediary B: 3-amino-5-trifluoro-methylpyrazin-2-carboxylic acid ethyl ester

A mixture of ethyl ester of amino-carbamimidoylacetic acid (2 grams, 9.22 mmol), and water (50 milliliters), is given

141 added a 20 percent aqueous solution of trifluoropyruvic aldehyde (2.32 grams, 18.43 mmol). To this mixture was added sodium acetate (5.29 grams, 64.52 mmol) (the pH of the reaction mixture was a pH of 5). The reaction mixture was allowed to stir at room temperature overnight. The resulting precipitate was filtered under vacuum by purification by chromatography on silica, eluting with iso-hexane: EtOAc (gradient from 0 to 10 percent EtOAc), to provide the title compound 'H RIVIN (400 MHz, sulfoxide). dimethyl - d₆) δ 8.4 (1H, s), 7.8 (2H, br s), 4.4 (2H, q), 1.4 (3H, t).

BA intermediary

3-amino-5,6-bis- (trifluoro-methyl) -pyrazin-2-carboxylic acid

OH '2

Step 1: ethyl 3-amino-5,6-bis- (trifluoro-methyl) -pyrazin-2-carboxylate

The title compound was prepared from amino-carbamimidoyl-acetic acid ethyl ester (Intermediary B2), and 1,1,1,4,4,4 hexafluoro-butan-2,3-dione, in a manner analogous to Intermediary B; 10 LCMS Rt = 4.72 minutes, [M + H] + 304.2 / 326.1 Method 10minLC_v002.

Step 2: 3-amino-5,6-bis- (trifluoro-methyl) -pyrazin-2142 carboxylic acid

To a stirring solution of ethyl 3-amino-5,6-bis- (trifluoro-methyl) pyrazin-2-carboxylate (300 milligrams, 0.990 millimoles) in EtOH (10 milliliters), 2M NaOH was added dropwise ( 0.495 milliliters, 0.990 millimoles), for 1 minute. After stirring at room temperature for 30 minutes, the reaction mixture was poured into water (30 milliliters), and the pH was adjusted to a pH of 4 by the addition of 1M HCI. The mixture was extracted with EtOAc (50 milliliters, 2 times), and the combined organic extracts were washed with brine (30 milliliters), dried over MgSO₄ (5g), filtered, and concentrated in vacuo, to provide the title compound as a grayish crystalline solid;

¹H NMR (400 MHz, dimethyl sulfoxide - d₆) δ 8.6 - 9.2 (2H, wide hump), 7.8 - 8.3 (2H, wide hump), 4.4 (2H, q), 1.32 (3H,

t).

Intermediary C

3-ammonium-6-bromo-5-trifluoro-methyl-pyrazine-2-carboxylic acid

OR

<img file="CU24149B1_D0063.tif" />

F

Intermediary C1: Ethyl ester of 3-amino-6-bromo-5trifluoro-methyl l-pyrazin-2-carboxylic acid

To a solution of ethyl ester of 3-amino-5-trifluoro-methyl143 pyrazin-2-carboxylic acid (Intermediary B) (30 milligrams, 0.13 mmol) in acetic acid (5 milliliters), sodium carbonate (15 milligrams, 0.14 millimoles). To this mixture, half of the content of a bromine solution (7 microliters, 0.13 mmol) in acetic acid (5 milliliters) was added, followed by the addition of sodium carbonate ((15 milligrams, 0.14 millimoles). The bromine solution in remaining acetic acid was added, and the reaction mixture was allowed to stir at room temperature for 2 hours. The mixture was diluted with water, and the resulting yellow precipitate was filtered under vacuum, to give the title compound.

Intermediary C: 3-amine-6-bromo-5-trifluoro-methylpyrazin-2-carboxylic acid

To a stirring solution of 3-aml-5-trifluoro-methyl-pyrazine-2-carboxylic acid ethyl ester (10 grams, 31.8 mmol) in ethanol (20 milliliters), 2M NaOH (20 milliliters, 31.8 millimoles) was added .

The resulting solution was stirred at room temperature for 5 minutes, and poured into water (50 milliliters). The pH was adjusted to a pH of 6 with the addition of 1M HCI. The resulting suspension was filtered under vacuum, washed with water (20 milliliters), and dried, to provide the title compound;

MS m / z 287 [M + H]⁺. ¹H NMR (400 MHz, dimethyl sulfoxide d₆) δ 7.98 (2H, s).

Intermediary D

3-amino-6-methoxy-5-trifluoro-methyl-pyridin-2-carboxylic acid

144

OH

<img file="CU24149B1_D0064.tif" />

NH₂

F

F

<img file="CU24149B1_D0065.tif" />

F

Intermediary D1: 6-Bromo-3- (2,5-dimethylpyrrol-1-yl) -5-trifluoro-methyl-pyridine-2-carboxylic acid methyl ester

OR

F

F

<img file="CU24149B1_D0066.tif" />

The methyl ester of 3-amino-6-bromo-5-trifluoro-methylpyridin-2-carboxylic acid (Intermediary A4) (2 grams, 6.69 mmol) was suspended in toluene (8 milliliters), and treated with p- toluenesulfonic (TsOH) (0.115 grams, 0.669 millimoles), and acetonyl-acetone (0.941 milliliters, 8.03 millimoles). The reaction mixture was heated at reflux for 2 hours (using a Dean-Stark apparatus), and allowed to cool to room temperature overnight. The resulting dark red / black solution was concentrated in vacuo, to remove toluene, and the crude residue was diluted with EtOAc (200 milliliters), washed with NaHCO₃ (50 milliliters), dried (MgSO₄), and concentrated in vacuo, to give a brown solid. Purification of the solid by chromatography on silica, eluting with EtOAc / isohexane, provided the title compound; LC-MS Rt = 5.58

145 minutes [M + H] + 377/379 (Method 10minLC_v002).

¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (1H, s), 7.77 (2H, s), 5.83 (3H, s), 1.90 (6H, s); ¹⁹F NMR (400 MHz, DMSO-d₆) δ -62.26 (CF3, s). Intermediary D2: 3- (2,5-dimethyl-pyrrole-1-yl) -6-methoxy-5-trifluoro-methyl-pyridine-2-carboxylic acid

<img file="CU24149B1_D0067.tif" />

The 6-bromo-3- (2,5-dimethyl-pyrrole-1-yl) -5-trifluoro-methyl-pyridine-2-carboxylic acid methyl ester (2 grams, 5.30 mmol) was dissolved in methanol (40 milliliters) , and treated with 2M NaOH (20 milliliters), to give a suspension, which was stirred at room temperature for 1 hour, to provide a clear solution. The solvent was removed in vacuo, and the resulting residue was acidified to a pH of 1 with 5M HCI. The mixture was extracted with EtOAc (200 milliliters), and the organic extract was dried (MgSO₄), and concentrated in vacuo, to provide the title compound as a dark brown solid, which was used in the next step without further purification; LC-MS Rt = 1.50 minutes [M + H] + 315.2.1 / 316.2 (Method 2minLC_v002);¹H NMR (400 MHz, DMSO-d6) δ 14.42-12.61 (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).

Intermediary D: 3-amino-6-methoxy-5-trifluoro-methyl146 pyridine-2-carboxylic acid

3- (2,5-Di-Methyl-1-pyrrol-1-yl) -6-methoxy-5-trifluoro-methyl-pyridine-2-carboxylic acid (2.1 grams, 6.68 mmol) was dissolved in EtOH (40 milliliters) and water (20 milliliters). To this mixture was added triethylamine (2.79 milliliters, 20.05 millimoles), followed by hydroxylamine hydrochloride (4.64 grams, 66.8 millimoles). The resulting mixture was heated at reflux for 5 hours. After cooling to room temperature, the mixture was diluted with EtOAc (100 milliliters), and washed with aqueous HCI (1M, 100 milliliters). The aqueous phase was back-extracted with EtOAc (100 milliliters), and the combined organic phases were washed with brine (100 milliliters), dried (MgSO₄), and concentrated in vacuo, to provide the product as an orange solid. The material can be used raw or recrystallized from isohexane-EtOAc (10: 1) LC-MS Rt = 1.0 minutes [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).

DA intermediary

3- (2,5-Dimethyl-1 H-pyrrole-1-yl) -6- (pyrrole idi n-1 -yl) -5- (trifluoromethyl) -picolic acid

<img file="CU24149B1_D0068.tif" />

Step 1:

6-Bromo-3- (2,5-dimethyl-1 H-pyrrole-1-yl) -5- (tr147 fl uo ro-methyl) 1 -nic acid

6-Bromo-3- (2,5-dimethyl-pyrrol-1-yl) -5-trifluoro-methyl-pyridine-2-carboxylic acid methyl ester (1.9 grams, 5.04 mmol), and 2M NaOH (2.52 milliliters, 5.04 mmol) in tetrahydrofuran (10 milliliters), stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 milliliters), and the pH was adjusted to a pH of 4 by the addition of 1M HCI. The mixture was extracted with EtOAc (50 milliliters, 2 times), and the organic portion was washed with brine (30 milliliters), dried over MgSO₄ (5 grams), filtered, and concentrated, to give the title compound as a crystalline orange solid; LC-MS Rt = 1.21 minutes [M + H] + 363.1 (Method 2minLC_v003).

Step 2: 3- (2,5-dimethyl-1 H-pyrrol-1-yl) -6- (pyrrolidin-1-yl) 5- (trifluoro-methyl) -picolinic acid

To a stirring solution of 6-bromo-3- (2,5-dimethyl1 H-pyrrol-1-yl) -5- (trifluoro-methyl) -picolinic acid (300 milligrams, 0.826 mmol) in tetrahydrofuran (1 milliliter) , pyrrolidine (0.136 milliliters, 1,652 millimoles) was added. The orange solution was stirred at room temperature overnight. The reaction mixture was partitioned between 0.5M HCI (30 milliliters) and EtOAc (30 milliliters), and stirred. The organic portion was separated and washed with brine (30 milliliters), dried over MgSO₄, was filtered, and concentrated in vacuo, to give a red oil. The crude product was purified on silica, eluting with 0 to 40 percent EtOAc in isohexane, to provide the title product;

148 ¹H NMR (400MHz, dimethyl sulfoxide-d₆) δ 13.45 (1H, br s), 7.88 (1H, s), 5.74 (2H, s), 3.58 (5 hours, br s), 1.88-2.0 (11 H, unresolved peaks).

DB broker

3- (2,5-Dimethyl-1 H-pyrro 1-1 -yl) -6-ethoxy-5- (trifluoro-methyl) picolinic acid

<img file="CU24149B1_D0069.tif" />

Step 1: methyl (2,5-dim eti I -1 H-pyrrole-1-yl) -6-methoxy-5- (trifluoromethyl) -picolinate

3- (2,5-Dimethyl-pyrrol-1-yl) -6-methoxy-5-trifluoro-methylpyridin-2-carboxylic acid (Intermediary D2) (500 milligrams, 1,591 millimoles) in methanol (15.91 milliliters) was treated with H₂SW₄ (0.0424 milliliters, 0.795 millimoles), and the solution was heated at reflux overnight.

The solvent was removed in vacuo, and the resulting brown oil was neutralized to a pH of 7 using saturated sodium bicarbonate. The mixture was extracted with EtOAc (20 milliliters), and the combined organic extracts were washed with water (20 milliliters), brine (20 milliliters), passed through a phase separator, and concentrated in vacuo. Purification of the crude product by chromatography on silica, eluting with iso-hexane: EtOAc

149 (gradient 0 to 10 percent EtOAc), provided the title compound as a grayish powder.

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-1 H -pyrrol-1-yl) -6-hydroxy-5- (trifluoromethyl) -picolinate

Methyl 3- (2,5-d? 1-1 H-pyrrole-1-yl) -6-methoxy-5- (trifluoro-methyl) picolinate (100 milligrams, 0.305 mmol) in acetonitrile (3.05 milliliters) was treated with Kl (202 milligrams, 1,218 millimoles), and TMS Chloride (0.156 milliliters, 1,221 millimoles), and heated at reflux for 6 hours. The solvent was removed in vacuo, and the crude product was dissolved in EtOAc (20 milliliters), and washed with water (10 milliliters, 2 times), and brine (10 milliliters), dried over a phase separator, and dried. concentrated in vacuo. Purification of the crude product by chromatography on silica, eluting with iso-hexane: EtOAc (0 to 30 percent gradient of EtOAc), provided the title compound as a yellow powder. LC-MS Rt = 1.11 minutes [M + H] + 315.4 (Method 2minLC_v003).

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

Methyl 3- (2,5-dimethyl-1 H -pyrrol-1-yl) -6-hydroxy-5- (trif I uoro-m eti I) (62 milligrams, 0.168 millimoles) in 1.4 -dioxane (1.5 milliliters) (dry), was treated with EtOH (0.020 milliliters, 0.335 millimoles), and triphenyl phosphine (88 milligrams, 0.335 millimoles), and the solution was stirred. DEAD was added by dripping (0.053 milliliters, 0.335

150 millimoles), and the reaction mixture was 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 from 0 to 10 percent EtOAc) provided the title compound;

¹H NMR (400 MHz, DMSO-d_s) 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-pyrrole-1-yl) -6-ethoxy-5- (trifluoro-methyl) -picolinic acid

Methyl 3- (2,5-dimethyl-1 H -pyrrol-1-yl) -6-ethoxy-5- (trifluoro-methyl) picolinate (140 milligrams, 0.409 millimoles) was dissolved in tetrahydrofuran (2,045 milliliters). NaOH (0.613 milliliters, 1,226 millimoles) was added, and heated at reflux for 6 hours. The solvent was removed in vacuo, and the resulting mixture was diluted with EtOAc (25 milliliters), and acidified to a pH of 1 using HCI (5M). The organic portion was washed with brine, dried using a phase separator, and concentrated in vacuo, to provide the title compound as a yellow oil.

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

Intermediary E

3-amine-5-trifluoro-methyl-pridin-2-carboxylic acid or

OH

F

151

To a stirring solution of the 3-amino5-trifluoro-methyl-pyridine-2-carboxylic acid methyl ester (Intermediate A3) (1 gram, 4.54 mmol) in methanol (20 milliliters), 2M NaOH (0.182 grams) was added , 4.54 millimoles). The orange solution was stirred at room temperature for 1 minute, and then water (10 milliliters) was added. The solution was acidified to a pH of 1 with the addition of 1M HCI, and the product was extracted with EtOAc (150 milliliters). The organic portions were combined, washed with brine (50 milliliters), dried over MgSO₄, and concentrated in vacuo, to provide the title compound as an orange solid; LC-MS Rt = 0.82 minutes [M + H] + 207.1 (Method 2minLC_v002);¹H NMR (400MHz, dimethyl sulfoxide - d₆) δ 13.9 (1H, wide hump), 8.11 (1H, s), 7.59 (1H, s), 7.08 (2H, wide hump) (trace of EtOAc present but correlates with the proposed structure).

Intermediary G

3-amine-6- (4-fluoro-phenyl) -5-trifluoro-methyl-pyridine-2-carboxylic acid

<img file="CU24149B1_D0070.tif" />

A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyridin-2-carboxylic acid (Intermediary A) (1 gram, 3.51 mmol), 4-fluoro-phenyl boronic acid (0.736 grams, 5.26 mmol), and 1,1'-bis- (diphenyl phosphonium) -ferrocene-palladium dichloride (0.286

152 grams, 0.351 millimoles), and Cs₂CO₃ 1.0M (3.3 milliliters) in tetrahydrofuran (10 milliliters), heated at reflux for 10 hours. After cooling to room temperature, the mixture was partitioned between dichloromethane (100 milliliters) and 1 M NaOH (100 milliliters, 2 times). The aqueous phase was acidified with 5M HCI, and the resulting milky solution was extracted in dichloromethane (100 milliliters, 2 times). The organic portion was separated, dried (MgSO₄), and concentrated in vacuo, to provide the product as a crude oil. The crude material was purified by flash evaporation chromatography on a silica cartridge, eluting with a gradient of DCM: methanol from 0 percent to 10 percent methanol, to provide the title product as a pale yellow solid;

¹H NMR (DMSO-d₆, 400MHz) δ 12.9 (1H, br s, 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).

GA broker

3-amino-6-cyclopropyl-5- (trifluoro-methyl) -picolinic acid

<img file="CU24149B1_D0071.tif" />

Step 1: 3-amino-6-cyclopropyl-5- (trifluoro-methyl) picolinic acid

153

A microwave flask was charged with amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid methyl ester (A4 intermediate) (0.5 grams, 1,754 millimoles), cyclopropyl-boronic acid (0.753 grams, 8.77 millimoles), and 1,1'-bis- (diphenyl phosphino) ferrocene-palladium dichloride (0.143 grams, 0.175 millimoles). The mixture was absorbed as a solution in tetrahydrofuran (6 milliliters), and flooded with N₂, was sealed, and heated using microwave radiation at 150 ° C for 20 minutes. The reaction mixture was filtered through Celite® (filter material), and washed therewith with EtOAc (20 milliliters). The filtrate was divided between EtOAc (30 milliliters) and water (50 milliliters). The phases were separated, and the organic portion was washed with brine (30 milliliters), dried over MgSO₄, filtered, and concentrated in vacuo.

The crude material was absorbed in EtOAc (20 milliliters), dried, and loaded onto silica (2 to 3 grams). The material was then purified on the Combiflash Rf Teledyne ISCO System, with 100 percent Isohexane to 60 percent EtOAcJsohexane, to provide a semi-pure material, which was used without further purification.

Step 2: 3-amino-6-cyclopropyl-5- (trifluoro-methyl) picolinic acid

To a stirring solution of 3-amino-6-cyclopropyl-5 (trifluoro-methyl) -picolinic acid (472 milligrams, 1,814 mmol) in tetrahydrofuran (10 milliliters), 2M NaOH (10 milliliters, 20.00 millimoles) was added. The orange solution was stirred at temperature

154 atmosphere for 2 days. The reaction mixture was poured into water (30 milliliters), and the pH was adjusted to a pH of 6 with the addition of 1M HCI. The product was extracted with EtOAc (50 milliliters), and the organic portion was dried over MgSO₄, filtered, and concentrated in vacuo, to give the title compound as a red / orange oil. LC-MS Rt = 1.10 minutes [M + H] + 247.1 (Method 2minLC_v003);

Intermediary H

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

<img file="CU24149B1_D0072.tif" />

Intermediary H1: Methyl ester of 3-amino-6- (2,4-dichlorophenyl) -5-trifluoro-methyl-pyridin-2-carboxylic acid

Methyl ester of 3-amino-6-bromo-5-trifluoro-methylpyridin-2-carboxylic acid (Intermediary A4) (3 grams, 10.03 mmol), 2,4-dichloro-phenyl-boronic acid (2,297 grams, 12.04 millimoles), potassium phosphate (4.26 grams, 20.06 millimoles), and Fibrecat® 1034A (Johnson Matthey, polymer-supported palladium complex) (500 milligrams, 10.03 millimoles), were suspended in toluene (50 milliliters), and water (15 milliliters) The reaction mixture was heated at 110 ° C under vigorous stirring for 3 hours. The mixture was allowed to cool to room temperature, and EtOAc (100 milliliters) was added.

155

The organic layer was separated and washed with brine (15 milliliters). MP-TMT ftrimercapto-triazine bound with macroporous polystyrene, 3 grams, Polimern labs) was added, and stirred for 1 hour at room temperature. MgSO was added₄, and the suspension was filtered. The filtrate was concentrated in vacuo, and purification of the residue by reverse phase chromatography (C18 column of 130 grams), eluting with water / MeOH, provided the title compound as a white solid; LS-MS Rt = 1.55 minutes [M + H] + 365 (Method 2minLC_v002).

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

The 3-amino-6- (2,4-dichloro-phenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (0.9 grams, 2,465 mmol) was suspended in methanol (15 milliliters), and added 2M NaOH (2,465 milliliters, 4.93 millimoles) with stirring. 1,4-dioxane (15.00 milliliters) was added, and the solution was allowed to stand at room temperature overnight. The solvent was removed in vacuo, and the resulting residue was dissolved in water (10 milliliters), and carefully acidified to a pH of 4 with the slow addition of 2M HCI (2 milliliters) with stirring. The mixture was extracted with EtOAc (20 milliliters), and the organic portion was washed with brine, and concentrated in vacuo. The residue was purified by reverse phase chromatography (C18 column of 130 grams), eluting with water / MeOH, to provide the title compound; LS-MS Rt = 1.57 minutes [M + Hj + 351.0 (Method 2minLC_v002).

156

Intermediary I

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

<img file="CU24149B1_D0073.tif" />

This compound was prepared from the 3-amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid methyl ester (Intermediary A4), and 4-chloro-2-methyl-phenyl-boronic acid, of one analogous to Intermediary H; LC-MS Rt = 1.53 minutes, [M + H] + 331 (Method 2minLC_v002).

Intermediary J

2-amino-methyl-1,1,1,3,3,3-hexafluoro-propan-2-ol

To a stirred mixture of a solution of 35 percent ammonium (1 milliliter), and diethyl ether (1 milliliter), 3,3,3-trifluoro-2- (trifluoro-methyl) -1 was added dropwise, 2-propenoxide (500 milligrams, 2.78 millimoles), and the reaction mixture was allowed to stir at room temperature for 3 hours. The reaction mixture was separated, and the aqueous layer was extracted with diethyl ether (3 milliliters, 2 times). The combined organic portions were dried (MgSO₄), 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),

157

-84.5 (CF3).

Intermediary K

5-ami no-6'-methyl-3- (tr! Uoro-methyl) -2,3'-bipyrid and n-6 ​​carboxylic acid

<img file="CU24149B1_D0074.tif" />

Intermediary K1: Methyl ester of 5-amino-6'-methyl-3trifl uoro-methyl-l- [2,3 '] - bipyrid and nyl-6-carboxylic acid

This compound was prepared from the 3a mi non-6-bromo-5-trifl uoro-methyl-1-pyrid and η-2-carboxylic acid methyl ester (Intermediary A4), and 2-methyl-pyridine-5 acid -boronic, in a manner analogous to 3-amino-6- (4-fluoro-phenyl) -5-trifluoro-methyl-pyrid and η-2-ca carboxylic acid (Intermediary G); LC-MS Rt 0.96 minutes [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) .

Intermediary K: 5-amino-6'-methyl-3- (trifluoro-methyl) -2,3'bipirid and η-6-ca carboxylic acid

This compound was prepared from the 5-amino-6'-methyl-3-trifluoro-methyl- [2,3 '] -bipyridinyl-6-carboxylic acid methyl ester in a manner analogous to the 3-amino methyl ester -6- (4-chloro-2-methylfenll) -5-trifluoro-methyl-pyridin-2-carboxylic (Intermediary I); LC-MS

158

Rt 0.90 minutes; [M + H] + 298 (Method 2minLC_v002); 'H NMR (400 MHz, DMSO-d₆) δ 12.90 (1H, wide), 8.45 (1H, s), 7.72 (2H), 7.32 (1H, d), 7.12 (2H, wide), 2.51 (3H).

KA intermediary

5-amino-3- (trifluoro-methyl) -2,4'-bipyrin-6-carboxylic acid

<img file="CU24149B1_D0075.tif" />

The title compound was prepared in a manner analogous to Intermediary K, using the appropriate boronic acid in Step 1; ¹H NMR (400 MHz, DMSO-d₆) δ 13.00 (1H, wide), 8.65 (2H, d), 7.65 (1H, s), 7.43 (2H, d), 7.18 (2H, wide).

Intermediary M

3- (2,5-Dimethyl-pyrrole-1 -i I) -5,6-b is-tr if luo ro-meti l-pi r id i n-2 carboxylic acid

<img file="CU24149B1_D0076.tif" />

Intermediary M1: 3- (2,5-Dimethyl-pyrrole-1-yl) 5,6-bis-trifluoro-methyl-pyridine-2-carboxylic acid methyl ester

A stirred mixture of KF (2.12 grams, 5.62 mmol), and Cul

159 (0.490 grams, 8.43 mmol) was heated in a sealed microwave jar of 10.0 to 20.0 milliliters in vacuo, until a light greenish color began to appear. The bottle was then placed under nitrogen to cool. Then a solution of the 6-bromo-3- (2,5-dimethyl-pyrrol-1-yl) 5-trifluoro-methyl-pyridin-2-carboxylic acid methyl ester (Intermediate D) (2.64 milliliters, 16.86 millimoles) in 1: 1 of Ν, dry Ν-dimethylformamide / dry NMP (14 m ililiters), followed by TMS-CF₃ (2.64 milliliters, 16.86 millimoles). A new septum was then used to seal the bottle, and the reaction mixture was heated using microwave radiation with stirring at 100 ° C for 3 hours, and allowed to cool. The mixture was added to an NH solution₃ 5M (50 milliliters), and then extracted with diethyl ether (50 milliliters, 4 times). The combined organic extracts were washed with an NH solution₃ 5M (20 milliliters, 3 times), 1M HCI (50 milliliters), saturated sodium bicarbonate solution (50 milliliters, 2 times), brine (50 milliliters), dried (MgSO₄), and concentrated in vacuo, to give a brown oil. The crude material was purified by chromatography on silica, eluting with Iso-hexane / EtOAc, from 0 to 10 percent, to provide the title compound as an orange solid; LC-MS Rt 1.37 minutes; MS m / z 367.1 [M + HJ +; Method 2minLC_v003. Intermediary M: 3- (2,5-dimethyl-pyrrol-1-yl) -5,6-bis-trifluoro-methyl-pyridine-2-carboxylic acid

To a stirred solution of 3- (2,5-dimethylpyrrol-1-yl) -5,6-bis-trifluoro-methyl-pyridine-2-carboxylic acid methyl ester (1.28 grams,

160

3.49 millimoles) in methanol (25 milliliters), 1M NaOH (7 milliliters, 6.99 millimoles) was added, and the reaction mixture was allowed to stir at room temperature for 30 minutes. The solvent was removed in vacuo, and water (20 milliliters) was added to the remaining residue. The pH was adjusted to a pH of 4/5 by the addition of 1M HCI. The mixture was extracted with EtOAc (20 milliliters, 3 times), and the combined organic extracts were washed with brine (30 milliliters), dried (MgSO₄), were 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 minutes; MS m / z 353.1 [M + H] +; Method 2minLC_v003.

Intermediary N

3,3,3-trifl uoro-N2- (4-methoxy-benzyl) -2-methyl-propa n-1,2-d-amine

<img file="CU24149B1_D0077.tif" />

Step 1: 1- (4-methoxy-phenyl) -N- (1,1,1-trifluoro-propan-2-ylidene) methanamine

To a stirring solution of trifluoroacetone (7.75 grams, 69.2 mmol) in diethyl ether (60 milliliters) at -40 ° C, were added

161

4-methox-benzyl-amine (9.49 grams, 69.2 mmol), and triethyl amine (14 grams, 138 mmol) in diethyl ether (40 milliliters). A cooled mixture (0 ° C) TiCI mixture was added dropwise₄ (6.56 grams, 34.6 mmol) in hexane (40 milliliters) for 10 minutes, and the resulting mixture was allowed to warm to room temperature for 20 minutes, and stirred at 50 ° C for 2.5 hours. The inorganic precipitate was removed by filtration, and washed with diethyl ether. The filtrate was concentrated in vacuo to provide a yellow oil. Purification of the crude product by chromatography on silica, eluting with 0 percent to 25 percent EtOAc in isohexane, provided the title product. Step 2: 3,3,3-trifluoro-2- (4-methox¡-benzyl-amino) -2-methyl-propanonitrile

To a cooled solution (0 ° C) of 1- (4-methoxy-phenyl) -N- (1,1,1-trifluoro-propan-2-ylidene) -methanamine (4.41 grams, 19.07 mmol) in dichloromethane (100 milliliters), cyano-trimethyl-silane (2.84 grams, 28.6 mmol), and magnesium bromide were added. The mixture was stirred at room temperature for 90 hours, and then diluted with NaHCO₃ saturated (200 milliliters). After stirring at room temperature for 1 hour, the organic phase was separated, washed with an additional portion of NaHCO₃ saturated (100 milliliters), dried over MgSO₄, and concentrated in vacuo, to provide the title compound.

Step 3: 3,3,3-trifluoro-N2- (4-methoxy-benzyl) -2-methyl-propan1,2-diamine

162

To a cooled solution (0 ° C) of 3,3,3-trifluoro-2- (4-methoxybenzyl-amino) -2-methyl-propane-nitrile (1.5 grams, 5.81 mmol) in diethyl ester dry (50 milliliters), LiAIH was added₄ (11.62 milliliters of a 2M solution in tetrahydrofuran), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was hydrolyzed by the successive addition of 15 percent KOH in water, and water. The resulting precipitate was filtered over Celite® (filter material), and the organic portion was washed with water, dried over MgSO₄, and concentrated under reduced pressure, to provide 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 (1 H, m), 1.37 (3H, s )

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

Intermediary O

Benzn- [d] -isoxazol-3-il-metanam ina

NH

N

The title compound was prepared according to the procedure of Pigini, Maria; Giannella, Mario; Gualtieri, Fulvio; MelcLiorre, Cario; Bolle, Paola; Angelucci, Luciano. Analogs with a 1,2-t nzisoxazole nucleus of biologically active nature derivatives. III. Tryptamine and gramine isosteres. European Journal of Medicinal Cher.istry (1975), 10 (1), 29-32 (Compound 11, pages 31-32).

163

Intermediary P

3-atr no-6- (oxazol-2-yl) -5- (trifluoro-methyl) -picol methyl innate

A solution of the methyl ester of 3-amino-6-bromo-5triflu ro-methyl-pyridin-2-carboxylic acid (Intermediary A4) (500 milligrams, 1,672 millimoles), 2- (tributyl stanyl) -oxazole (0.704 milliliters, 3.34 millimoles), and tetrakis- (triphenyl phosphine) -palladium (0) (193 milligrams, 0.167 millimoles) in dioxane (10 milliliters), was heated at reflux for 13 hours. After cooling to room temperature for 8 hours, the solvent was evaporated and the resulting residue was triturated with hot methanol to remove a yellow solid impurity. The remaining crude material was used without further purification. LC-k 3: Rt 0.95 minutes; MS m / z 288 [M + H] +; Method 2minLC_v003.

PA Intermediary

3-amino-6-furan-2-¡-5-trfluoro-methyl-pyrazine-2-carboxylic acid

OH

F

OR

<img file="CU24149B1_D0078.tif" />

^Daso 1: 3-amino-6-furan-2-yl-5-trifluoro-methyl-pyrazin-2-carboxylic acid

The title compound was prepared from the 3-amino-6-bromo-5-trifluoro-methyl-pyrazine-2-carboxylic acid ethyl ester (Inte C1), and tributyl-tin-2-furyl-stannous an analogous way to 3-amino-6- (oxazol-2-yl) -5- (trifluoro-methyl) -picolinate

164 methyl (Intermediary P)

Step 2: 3-amino-6-furan-2-yl-5-trifluoro-methyl-pyrazine-2-carboxylic acid

The title compound was prepared from 3-amino-6furan-2-yl-5-trifluoro-methyl-pyrazin-2-carboxylic acid and 6M NaOH, in a manner analogous to 3-amino-6-bromo-5 acid -trifluoro-methyl-pyrazine-2-carboxylic acid (Intermediary C, final step).

Intermediary Q

2-Hydroxy-3-methyl-2- (trifluoro-methyl) -butan-1-amino chloride

NH .HCI

Step 1: 1,1,1-trifluoro-3-methyl-2- (nitro-methyl) -butan-2-ol

A cooled solution (0 ° C) of lithium hydroxide (0.048 grams, 2015 millimoles) in water (20 milliliters) was stirred and treated with nitro-methane (1.23 grams, 20.15 millimoles), 1,1,1-trifluoro- 3-methyl-butan-2-one (3.11 grams, 22.17 millimoles), cetyltrimethyl ammonium chloride (0.871 grams, 2.72 millimoles), and MgSO₄ (0.485 grams, 4.03 millimoles). The white suspension was stirred at 0 ° C for 1 hour, and then at room temperature for 2 days. The resulting biphasic mixture was separated, and the denser lower layer was collected and dissolved in diethyl ether (30 milliliters). The mixture was dried over MgSO₄, filtered, and concentrated in vacuo, to give a pale yellow oil. The oil was absorbed in diethyl ether (10

165 milliliters), and passed through a previously packaged SCX-2 cartridge, eluting with 100 percent diethyl ether. The filtrate was concentrated in vacuo to provide the title compound as a colorless oil.¹H NMR (400MHz, CDCI₃): 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- (trifluoro-methyl) butan-1-aminium chloride

To a solution of 1,1,1-trifluoro-3-methyl-2- (nitro-methyl) -butan-2ol (753 milligrams, 3.74 millimoles) in EtOH (10 milliliters) in a medium pressure glass hydrogenation vessel 25 milliliters under N₂, 10 percent Pd on coal was added (39.8 milligrams, 0.374 millimoles). The vessel was flooded with N₂, followed by H₂ (22.64 milligrams, 11.23 millimoles) at a pressure of 5 bar, and stirred at room temperature for 6 days. The mixture was filtered through Celite®, and washed therewith with EtOH (30 milliliters), followed by dichloromethane (10 milliliters). The filtrate was concentrated in vacuo to give a colorless oil. The crude product was absorbed in methanol (20 milliliters), and treated with a solution of 1.25M HCI in methanol. The resulting colorless solution was stirred at room temperature for 1 hour, and concentrated in vacuo, to provide the title compound;

'H NMR (400MHz, dimethyl sulfoxide - 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).

166

Intermediary R

3-amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride

<img file="CU24149B1_D0079.tif" />

Step 1: 1,1,1 -trifluoro-2-methyl-3-nitro-propan-2-ol

To the LiOH (0.193 grams, 8.06 millimoles) in a 3-neck round bottom flask, water (25 milliliters), nitromethane (3.76 milliliters, 81 millimoles), and trifluoroacetone (7.95 milliliters, 89 millimoles) were added. Cetyl trimethyl ammonium chloride (3.8 grams, 10.88 mmol), and MgSO were added₄ (1.9 grams, 16.12 mmol), and the resulting yellow solution was stirred at 20-25 ° C for 2 days. The reaction mixture was poured into diethyl ether (120 milliliters), and washed with water (200 milliliters, 3 times), and brine (100 milliliters, 1 time). The organic portion was dried over MgSO₄ and concentrated in vacuo, to provide the title compound as a yellow liquid. ¹H NMR (CDCI₃, 400 MHz): δ 4.7 (1H d), δ 4.5 (1H, d), δ 3.7 (1H, wide), δ 1.6 (3H, s).

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

Pd / C (1 gram) was added to a 200 milliliter glass vessel. Ethanol (50 milliliters, dry) was added, with caution, under an atmosphere of CO₂. 1,1,1-Trifluoro-2-methyl-3-nitropropan-2-ol (10 grams, 57.8 mmol) was dissolved in ethanol (50 milliliters,

167 dry), and added to the glass bowl. The reaction mixture was placed 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 an excess of ethanol. The solvent was removed in vacuo to provide a colorless oil. The oil was dissolved in methanol (50 milliliters), and treated by dripping with HCI (1M) in methanol (30 milliliters). The solution was allowed to stir for 30 minutes and concentrated in vacuo, azeotropically distilled with MeCN, to provide the title compound as a waxy white solid; ¹H NMR (DMSOd₆, 400 MHz) δ 8.3 (3H, wide s), 6.9 (1H, wide), 3.0 (2H, q), 1.4 (3H, s).

Intermediary RA (S) -3-amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride

HO .HCI

Step 1: benzyl 3,3,3-trifluoro-2-hydroxy-2-methyl-propyl-carbamate

To a stirring suspension of amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride (Intermediary R) (1.5 grams, 8.35 mmol) in dichloromethane (50 milliliters), triethyl was added 93.54 grams amine, 35.0 millimoles), followed by benzyl 2,5-dioxo-pyrrolidin-1-ylcarbonate (1,983 grams, 7.96 millimoles). The mixture was stirred at room temperature for 6 hours, and then diluted

168 with water. The organic portion was separated using a phase separator, and concentrated in vacuo. Purification by chromatography on silica, eluting with 0 to 70 percent EtOAc in isohexane, provided the title product; Ή 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 minutes ; 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-propyl carbamate

Benzyl 3,3,3-trifluoro-2-hydroxy-2-methyl-propyl carbamate (1.7 grams) was dissolved in 2-propanol (10 milliliters), and purified using the following chromatographic conditions:

Mobile phase: 10 percent of 2-propanol / 90 percent of

CO₂

<td>Column:</td><td>2 x Chiralcel OJ-H,</td><td> 250</td><td>x 10 mm</td>

<td></td><td>internal diameter,</td><td> 5</td><td>honeys (columns</td>

<td></td><td>coupled in series).</td><td></td><td></td>

<td>Detection:</td><td>UV approximately</td><td> 220</td><td>nanometers</td>

Flow rate: 10 milliliters / minute.

Sample concentration: 1.7 grams in 10 milliliters of 2-propanol

Injection volume: 75 microliters

First eluted peak: Rt = 6.94 minutes (R) -3,3,3-trifluoro-2-hydroxy-2-methyl-propyl-carbamate benzyl

Second eluted peak: Rt = 8.04 minutes (S) -3,3,3-trifluoro-2169 hydroxy-2-methyl-propyl-benzyl carbamate (Stereochemistry confirmed by analysis of the final compound prepared by means of the following steps).

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

A mixture comprising (S) -3,3,3-trifluoro-2-hydroxy-2-methyl-propyl-carbamate in EtOH (165 milliliters) was pumped through an H-Cube (hydrogenation reactor, 1 to 2 milliliters - minute, 1 bar pressure, room temperature) for 8 hours using a 10 percent palladium catalyst cartridge on carbon. 1.25 M HCI in methanol (130 milliliters) was added, and the mixture was stirred for 30 minutes. The solvent was removed in vacuo, azeotropically distilled with MeCN, to provide the title product as a white powder; ¹H NMR (400 MHz, DMSOd₆) δ 8.3 (3H, broad), 6.8 (1H, s), 3.0 (2H, s), 1.5 (3H, s).

Alternatively, racemic 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol can be resolved in the separated enantiomers by recrystallization with (S) -mandelic acid or with L-tartaric acid in isopropanol or ethanol.

Intermediary S

2-amino-methyl-1,1,1,3,3,3-hexafluoro-propan-2-ol

3,3,3-Trifluoro-2- (trifluoro-methyl) -1,2-propenoxide (1 gram, 5.55 mmol), was added to a stirred solution of aqueous ammonia (0.88 grams / milliliter, 3 milliliters), and diethyl ether (3 milliliters). The resulting colorless solution was stirred at room temperature

170 during 3 hours. The biphasic mixture was separated, and the aqueous portion was further extracted with diethyl ether (5 milliliters, 2 times). The combined organic layers were dried over MgSO₄ and concentrated in vacuo, (without heating), to provide the title compound as a white crystalline solid, which was used without further purification; ¹H NMR (400 MHz, DMSO-d_and) unassigned signals δ 4.20 (wide), 3.15 (s).

Intermediary T

3,3,3-trif luoro-2-methoxy-2-meti l-pro pan-1-amine

<img file="CU24149B1_D0080.tif" />

Step 1: 2- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) isoindoline-1,3-dione

A mixture comprising 3,3,3-trifluoro-2-hydroxy-2-methylpropyl-ammonium (0.9g), italic anhydride (1,039 g), and di-isopropyl-ethylamine (2,188 milliliters) in chloroform (30 milliliters), It was heated at 70 ° C for 5 hours. After cooling to room temperature, 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 0 percent to 30 percent iso-hexane: EtOAc, 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).

171

Step 2: 2- (3,3,3-trifluoro-2-methoxy-2-methyl-propyl) soindoline-1,3-dione

To a stirring solution of 2- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -isoindoline-1,3-dione (250 milligrams, 0.915 millimoles) at 0 ° C in tetrahydrofuran (8 milliliters) , NaH (80 milligrams, 2 millimoles) was added. After 30 minutes, methyl iodide (1,299 grams, 9.15 millimoles) was added. The reaction mixture was allowed to stir in an ice bath, and allowed to warm to 25 ° C for 3.5 hours. The reaction was quenched with NH₄Saturated CI, and the mixture was extracted with dichloromethane. The organic extract was separated using a phase separator, and purification by chromatography on silica, eluting at 0 percent to 30 percent iso-hexane: EtOAc, provided 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 minutes; MS m / z 288.10 [M + H] +; Method 2minLC_vOO3.

Step 3: 3,3,3-trifluoro-2-methoxy-2-methyl-propan-1-amino

A mixture comprising 2- (3,3,3-trifluoro-2-methox¡-2-methylpropyl) -isoindoline-1,3-dione (272 milligrams, 0.95 millimoles), and hydrazine (0.033 milliliters, 1,045 millimoles) is stirred at 75 ° C for 4 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo, to provide the title product, which was used without further purification (no characterization data available).

172

From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, different modifications can be made without departing from the spirit and scope of the invention. In accordance with the foregoing, the invention is not limited except by the appended claims.

Modalities / Consistency Clauses

Modality 1: A compound according to formula I:

OR

R⁴

<img file="CU24149B1_D0081.tif" />

R² to NH₂ | or pharmaceutically acceptable salts thereof, wherein:

A is N or CR^4th;

R¹ it's H; alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; alkenyl of 2 to 8 carbon atoms; alkynyl of 2 to 8 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; cycloalkenyl of 5 to 10 carbon atoms; -alkyl of 1 to 4 carbon atoms -cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; halogen; SO2NR⁸R⁹; SO2R¹⁰; S-alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; S-aryl of 6 to 14 carbon atoms; - (alkyl of 0 to 4 carbon atoms) 173 aryl of 6 to 14 carbon atoms; - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; CN; NR¹¹R¹²; CONR¹³R¹⁴; NR¹³SO2R¹⁵; NR¹³C (O) R¹⁵ and CO2R¹⁵, wherein the cycloalkyl, cycloalkenyl, aryl, and heterocyclyl groups are each optionally substituted by one or more Z substituents;

R² it is halo-alkyl of 1 to 4 carbon atoms;

R³, R⁴ and R^4th are each independently H or alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms;

R⁵ and R⁶ they are each independently H; alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; alkenyl of 2 to 8 carbon atoms; alkynyl of 2 to 8 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; cycloalkenyl of 5 to 10 carbon atoms; -alkyl of 1 to 4 carbon atoms -cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; OH; CN; halogen; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or - (alkyl of 0 to 4 carbon atoms) -CO₂R¹⁵, wherein the cycloalkyl, cycloalkenyl, (alkyl of 0 to 4 carbon atoms) -aryl groups of 6 to 14 atoms of

174 carbon, and - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members are each optionally substituted by one or more Z substituents; or

<td></td><td>R⁵</td><td>and</td><td>R⁶</td><td>are</td><td>every</td><td>one independently a</td><td>group</td><td>of the</td>

<td>formula</td><td>the:</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>(CH₂)_m-NR¹⁷R¹⁸; or</td><td></td><td></td>

<td></td><td>R⁵</td><td>and</td><td>R⁶</td><td>are</td><td>every</td><td>one independently a</td><td>group</td><td>of the</td>

<td>formula</td><td>the:</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>- (CH₂)_m-OR⁴; or</td><td></td><td></td>

<td></td><td>R⁴</td><td>and</td><td>R⁵</td><td>together</td><td>with</td><td>carbon atoms with I</td><td>what</td><td>is it so</td>

together, they form a 3 to 8 member carbocyclic ring system;

or

R⁵ and R⁶ together with the carbon atoms with which they are attached, they form a 5- to 8-membered carbocyclic ring system or a 5- to 8-membered heterocyclic ring system that contains one or more heteroatoms selected from N, O, and S , wherein the ring system is optionally substituted by one or more Z substituents;

R⁴, R⁵ and R⁶ they cannot all be the same; m is 0, 1, 2 or 3;

R⁸, R¹¹, R¹³ and R¹⁷ are each independently H, alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms, cycloalkyl of 3 to 10 carbon atoms or - (alkyl of 1 to 4 carbon atoms) -cycloalkyl of 3 to 8 carbon atoms;

175

R⁹, R¹°, R¹², R¹⁴, R¹⁵, R¹⁶ and R¹⁸ they are each independently H; alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; alkenyl of 2 to 8 carbon atoms; alkynyl of 2 to 8 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; cycloalkenyl of 5 to 10 carbon atoms; -alkyl of 1 to 4 carboncycloalkyl atoms of 3 to 8 carbon atoms; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O, and S, wherein the cycloalkyl, cycloalkenyl groups, aryl, and heterocyclyl are each optionally substituted by one or more Z substituents; or

R⁸ and R⁹, R¹¹ and R¹², R¹³ and R¹⁴, and R¹⁷ and R¹⁸, together with the nitrogen atom with which they are attached, can 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, alkyl of 1 to 6 carbon atoms optionally substituted by one or more OH groups or NH groups₂, alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms, NR¹⁸(SW₂) R²¹, (SO₂) NR¹⁹R²¹, (SO₂) R²¹, NR¹⁸C (O) R²¹, C (O) NR¹⁹R²¹, NR¹⁸WITH

R¹⁹R²¹, NR¹⁸C (O) OR¹⁹, NR¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, MR¹⁹, OR¹⁹oxo

176

CN, NO₂, halogen, or a 3- to 14-membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;

R¹⁹ and R²¹ they are each independently H; alkyl of 1 to 8 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms; (alkyl of 0 to 4 carbon atoms) -aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from halogen , oxo, alkyl of 1 to 6 carbon atoms, and C (O) -alkyl of 1 to 6 carbon atoms; (alkyl of 0 to 4 carbon atoms) -O-aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; and (alkyl of 0 to 4 carbon atoms) -O-heterocyclic group of 3 to 14 members, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from from halogen, alkyl of 1 to 6 carbon atoms, or C (O) alkyl of 1 to 6 carbon atoms; wherein the alkyl groups are optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms, C (O) NH₂, C (O) NH-alkyl of 1

177 at 6 carbon atoms or C (O) N (alkyl of 1 to 6 carbon atoms)₂; or

R¹⁹ and R²¹ together with the nitrogen atom with which they are attached, they form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more additional 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 that includes one or more heteroatoms selected from N, O and S; S (0)₂-aryl; S (0)₂-alkyl of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms; and C (O) O-alkyl of 1 to 6 carbon atoms, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by alkyl of 1 to 6 carbon atoms, halo-alkyl of 1 to 6 carbon atoms , or alkoxy of 1 to 6 carbon atoms.

Modality 2: The compound of formula I:

OR

R⁴

<img file="CU24149B1_D0082.tif" />

or pharmaceutically acceptable salts thereof, wherein:

178

A is N or CR^4th;

R¹ it's H; alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; alkenyl of 2 to 8 carbon atoms; alkynyl of 2 to 8 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; cycloalkenyl of 5 to 10 carbon atoms; -alkyl of 1 to 4 carbon atoms -cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; halogen; SO2NR⁸R⁹; SO2R¹⁰; S-alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; S-aryl of 6 to 14 carbon atoms; CN; NR¹¹R¹²; C (O) NR¹³R¹⁴;

NR¹³SO2R¹⁵; NR¹³C (O) R¹⁵, CO2R¹⁵, - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, 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;

R² it is halo-alkyl of 1 to 4 carbon atoms;

R³ and R^4th are each independently H or alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms;

R⁴ it is H, or alkyl of 1 to 8 carbon atoms optionally substituted with one or more halogen atoms;

R⁵ is - (CH2) m-NR¹⁷R¹⁸, - (CH2)_m-OR '; alkoxy of 1 to 8 atoms

179 carbon optionally substituted by one or more halogen atoms; - (alkyl of 0 to 4 carbon atoms) -CO₂R¹⁵; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms or - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the - (alkyl of 0 to 4 carbon atoms) - aryl of 6 to 14 carbon atoms, and - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, are each optionally substituted by one or more substituents Z;

R⁶ it is alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; cycloalkyl of 3 to 10 carbon atoms; -alkyl of 1 to 4 carbon atoms -cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; OH; CN; halogen; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms, and - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, are each optionally substituted by one or more Z substituents; or

R⁶ is H, and R⁵ is - (CH2) m-NR¹⁷R¹⁸, - (CH2)_m-OR ', alkoxy of 1 to 8 carbon atoms optionally substituted by one or more atoms

180 halogen; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or - (alkyl of 0 to 4 carbon atoms) -CO₂R¹⁵, wherein the groups - (alkyl of 0 to 4 carbon atoms) - aryl of 6 to 14 carbon atoms, and - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members are each optionally substituted by one or more Z substituents; or

R⁴ and R⁶ together with the carbon atoms with which they are attached, they form a 3- to 8-membered carbocyclic ring system;

or

R⁴ and R⁵ together they form an oxo group (C = O), and R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O, and S, where the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or

R⁵ and R⁶ together with the carbon atoms with which they are linked, they form a 5- to 8-membered heterocyclic ring system that contains one or more heteroatoms selected from

181 from N, O, and S, wherein the ring system is optionally substituted by one or more Z substituents; or

R⁴ and R⁵ and R⁶ together with the carbon atoms with which they are attached, they form a 5- to 8-membered heterocyclic ring system that contains one or more heteroatoms selected from N, O, and S, wherein the ring system is optionally substituted by one or more substituents Z;

R is H, or alkyl of 1 to 8 carbon atoms optionally substituted with one or more halogen atoms;

m is 0, 1, 2 or 3;

R⁸, R¹¹, R¹³ and R¹⁷ are each independently H, alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms, cycloalkyl of 3 to 10 carbon atoms or - (alkyl of 1 to 4 carbon atoms) -cycloalkyl of 3 to 8 carbon atoms;

R⁹, R¹⁰, R¹², R¹⁴, R¹⁵, R¹⁶ and R¹⁸ they are each independently H; alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; alkenyl of 2 to 8 carbon atoms; alkynyl of 2 to 8 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; cycloalkenyl of 5 to 10 carbon atoms; -alkyl of 1 to 4 carboncycloalkyl atoms of 3 to 8 carbon atoms; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom

182 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

R⁸ and R⁹, R¹¹ and R¹², R¹³ and R¹⁴, and R¹⁷ and R¹⁸, together with the nitrogen atom with which they are attached, can 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, alkyl of 1 to 6 carbon atoms optionally substituted by one or more OH groups or NH groups₂, alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms, NR¹⁸(SO2) R²¹, (SO2) NR¹⁹R²¹, (SO₂) R²¹, NR¹⁸C (O) R²¹, C (O) NR¹⁹R²¹, NR¹⁸WITH

R¹⁹R²¹, NR¹⁸C (O) OR¹⁹, NR¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, MR¹⁹, OR¹⁹, 0X0, CN, NO₂, halogen, or a 3- to 14-membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;

R¹⁹ and R²¹ they are each independently H; alkyl of 1 to 8 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms; (alkyl of 0 to 4 carbon atoms) -aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; (alkyl of 0 to 4 carbon atoms) -heterocyclic group of 3 to 14

183 members, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from halogen, oxo, alkyl of 1 to 6 carbon atoms, and C (O) -alkyl of 1 to 6 carbon atoms; (alkyl of 0 to 4 carbon atoms) -0-aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; and (alkyl of 0 to 4 carbon atoms) -O-heterocyclic group of 3 to 14 members, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from from halogen, alkyl of 1 to 6 carbon atoms, or C (O) alkyl of 1 to 6 carbon atoms; wherein the alkyl groups are optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms, C (O) NH₂, C (O) NH-alkyl of 1 to 6 carbon atoms or C (O) N (alkyl of 1 to 6 carbon atoms)₂; or

R¹⁹ and R²¹ together with the nitrogen atom with which they are attached, they form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more additional 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 that includes one or more heteroatoms selected from N, O and S; SW)₂-aryl; SW)₂-alkyl of 1 to 6 atoms of

184 carbon; alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms; and C (O) O-alkyl of 1 to 6 carbon atoms, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by alkyl of 1 to 6 carbon atoms, halo-alkyl of 1 to 6 carbon atoms , or alkoxy of 1 to 6 carbon atoms.

Modality 3: The compound according to modality 1 or 2, where:

R¹ it's H; alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; halogen; aryl of 6 to 14 carbon atoms; - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or -NR¹¹R¹², wherein the aryl and heterocyclic groups are each optionally substituted by one or more Z substituents.

Modality 4: The compound according to modalities at 3, where:

R¹ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms.

Modality 5: The compound according to modalities at 4, where:

185

R¹ is -CH₃ or CF₃.

Modality 6: The compound according to modality 1, or 3, where:

R¹ it is alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms.

Modality 7: The compound according to modality 1,

2, 3 or 6, where:

R¹ it's -OCH₃, -OCH₂CH₃ u -OCF₃.

Modality 8: The compound according to the modalities

1, 2 or 3, where R¹ is aryl, wherein aryl is phenyl optionally substituted by one or more Z substituents,

Modality 9: The compound according to modality 1,

2, 3 or 8, where R¹ it is 4-fluoro-phenyl, 4-chloro-2-methyl-phenyl, or 2,4-dichloro-phenyl.

Modality 10: The compound according to modality 1, or 3, where R¹ it is pyridyl, oxazole, pyrrolidine or pyrazole, and is optionally substituted by one or more Z substituents.

Modality 11: The compound according to modality 1,

2, 3 or 10, where R¹ it is 1-methyl-4-pyridyl, oxazol-2-yl, 1-methyl-1-pyrazol-4-yl, or pyrrolidin-1-yl.

Modality 12: The compound according to modalities at 11, where R¹ it's Br, -CH₃, -CF₃, -OCH₃, -OCH₂CH₃, -OCF₃, 4Fluoro-phenyl, 4-chloro-2-methyl-phenyl, 2,4-dichloro-phenyl, 1-methyl-4-pyridyl, 1-methyl-1 H -pyrazol-4-yl, oxazol-2-yl, or pyrrolidine -1 yl

Modality 13: The compound according to the modalities

186 to 12, where R⁵ provides a heteroatom and two carbon atoms from the amide nitrogen, wherein the heteroatom is oxygen or nitrogen.

Modality 14: The compound according to modalities 1 to 13, where:

R⁴ it is H or alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms;

R⁵ it is alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; - (CH2) m-NR¹⁷R¹⁸; - (CH2)_m-OR, or OH;

R is H, or alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms;

m is 0, 1 or 2;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; OH; CN; halogen; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 5 to 6 members, 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

R⁴ and R⁶ together with the carbon atoms with which they are attached, they form a 3- to 8-membered carbocyclic ring system;

187 or

R⁵ and R⁶ together with the carbon atoms with which they are linked, they 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 substituents Z;

R¹⁷ and R¹⁸ they are each independently H; or alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms.

Modality 15: The compound according to any of the above modalities, where:

R³ it's H;

R⁴ it's H or Me;

R^4th it's H;

R⁵ is - (CH2) m-NR¹⁷R¹⁸; - (CH2)_m-OR'¡ or OH; m is 0 or 1;

R 'is H;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; or

R⁵ and R⁶ together with the carbon atoms with which they are attached, they form a 5- to 6-membered heterocyclic ring system that contains one or more heteroatoms selected from N, O, and S, wherein the ring system is optionally substituted by one or more substituents Z; and

R¹⁷ and R¹⁸ they are each independently H; or alkyl of 1 to

188 carbon atoms optionally substituted by one or more halogen atoms.

Modality 16: The compound according to any of the above modalities, where:

R³ it's H;

R⁴ it's H or Me;

R^4th it's H;

R⁵ is -NR¹⁷R¹⁸; or OH;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; or

R⁵ and R⁶ together with the carbon atoms with which they are attached, they form a 5- to 6-membered heterocyclic ring system that contains one or more heteroatoms selected from N, O, and S, wherein the ring system is optionally substituted by one or more substituents Z; and

R¹⁷ and R¹⁸ they are each independently H; or alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms.

Modality 17: The compound according to any of the above modalities, where:

R³ it's H;

R⁴ it's H or Me;

R^4th it's H;

R⁵ is -NR¹⁷R¹⁸; or OH;

R⁶ is alkyl of 1 to 4 carbon atoms optionally

189 substituted by one or more halogen atoms; and

R¹⁷ and R¹⁸ they are each independently H; or alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms.

Modality 18: The compound according to modalities at 13, where:

R³ it's H;

R^4th it's H;

R⁴ and R⁵ they form an oxo group;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; phenyl; or a 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.

Modality 19: The compound according to modalities at 13 or 18, where:

R³ it's H;

R^4th it's H;

R⁴ and R⁵ they form an oxo group;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; or phenyl, wherein the phenyl is optionally substituted by one or more Z substituents;

190

Z is independently OH, alkyl of 1 to 4 carbon atoms optionally substituted by one or more OH groups or NH groups₂, alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms, C (O) OR¹⁹, C (O) R¹⁹, OR¹⁹, CN, or halogen;

R¹⁹ it's H; alkyl of 1 to 4 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; or alkoxy of 1 to 4 carbon atoms alkyl of 1 to 4 carbon atoms, wherein all alkyls are optionally substituted with halogens.

Modality 20: The compound according to modalities at 13 or 18 to 19, where:

R³ it's H;

R^4th it's H;

R⁴ and R⁵ they form an oxo group;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; or phenyl, wherein the phenyl is optionally substituted by one or more Z substituents;

Z is independently, alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms, or halogen.

Modality 21: The compound according to modalities at 13, wherein the compound is represented by formula II:

191

OR

<img file="CU24149B1_D0083.tif" />

or a pharmaceutically acceptable salt thereof, wherein:

R¹⁰¹ It is selected from the following:

<img file="CU24149B1_D0084.tif" />

OR.

192

<img file="CU24149B1_D0085.tif" />

<img file="CU24149B1_D0086.tif" />

Ό

<img file="CU24149B1_D0087.tif" />

ν „

193

<img file="CU24149B1_D0088.tif" />

194

<img file="CU24149B1_D0089.tif" />

<img file="CU24149B1_D0090.tif" />

<img file="CU24149B1_D0091.tif" />

Modality 22: The compound according to the modality

21, where:

R³ it's H;

<img file="CU24149B1_D0092.tif" />

R¹⁰¹ is

195

<img file="CU24149B1_D0093.tif" />

<img file="CU24149B1_D0094.tif" />

Modality 23: The compound according to the modality

21, where:

R³ it's H;

R¹⁰¹ is:

<img file="CU24149B1_D0095.tif" />

196

<img file="CU24149B1_D0096.tif" />

Modality 24:

21, where:

R³ it's H;

R¹⁰¹ is:

The compound according to the modality

<img file="CU24149B1_D0097.tif" />

cf₃

HO CF₃

<img file="CU24149B1_D0098.tif" />

197

<img file="CU24149B1_D0099.tif" />

<img file="CU24149B1_D0100.tif" />

<img file="CU24149B1_D0101.tif" />

<img file="CU24149B1_D0102.tif" />

<img file="CU24149B1_D0103.tif" />

198

<img file="CU24149B1_D0104.tif" />

Modality 25: The compound according to the modality

21, where: R³ it's H; R¹⁰¹ is:

<img file="CU24149B1_D0105.tif" />

OR

199

<img file="CU24149B1_D0106.tif" />

Modality 26: The compound according to modalities at 1 3, where:

R³ it's H;

R¹⁰¹ is - (alkyl of 1 to 2 carbon atoms) - heterocyclic group of 5 to 10 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O, and S, where the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents.

Modality 27: The compound according to modality 21 or 26, where:

R³ it's H;

R¹⁰¹ is

<img file="CU24149B1_D0107.tif" />

Modality 28: The compound of formula III:

<img file="CU24149B1_D0108.tif" />

X

200 or pharmaceutically acceptable salts thereof, wherein:

A is N or CR^4th;

X is NR^and or OR;

R¹ it is alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; cycloalkyl of 3 to 10 carbon atoms; -alkyl of 1 to 4 carbon atoms -cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; halogen; CN; NR¹¹R¹²; C (O) NR¹³R¹⁴; NR¹³C (O) R¹⁵, CO₂R¹⁵, - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, 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;

R² it is halo-alkyl of 1 to 4 carbon atoms;

R³ and R^4th are each independently H or alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms;

R⁴ it is H, or alkyl of 1 to 8 carbon atoms optionally substituted with one or more halogen atoms;

R^5th is H, alkyl of 1 to 8 carbon atoms optionally substituted with one or more halogen atoms, - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms or-heterocyclic group of 3 to 14 members , where the heterocyclic group

201 it contains at least one heteroatom selected from N, O and S; wherein the - (alkyl of 0 to 4 carbon atoms) - aryl of 6 to 14 carbon atoms, and - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, are each optionally substituted by one or more substituents Z;

R^and is H, alkyl of 1 to 8 carbon atoms optionally substituted with one or more halogen atoms, - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms or-heterocyclic group of 3 to 14 members , wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the - (alkyl of 0 to 4 carbon atoms) - aryl of 6 to 14 carbon atoms, and - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, are each optionally substituted by one or more substituents Z;

R⁶ it is alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; cycloalkyl of 3 to 10 carbon atoms; -alkyl of 1 to 4 carbon atoms -cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; OH; CN; halogen; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms, and - (alkyl of

202 at 4 carbon atoms) - 3- to 14-membered heterocyclic group, each optionally substituted by one or more Z substituents; or

R⁴ and R⁶ together with the carbon atoms with which they are attached, they form a 3- to 8-membered carbocyclic ring system;

or

R^5th and R⁶ together with the atoms with which they are linked, they form a 5- to 8-membered heterocyclic ring system that contains 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^5th and R^and together with the atoms with which they are linked, they form a 5- to 8-membered heterocyclic ring system that contains one or more heteroatoms selected from N, O, and S, wherein the ring system is optionally substituted by one or more Z substituents;

R¹¹ and R¹³ are each independently H, alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms, cycloalkyl of 3 to 10 carbon atoms or - (alkyl of 1 to 4 carbon atoms) -cycloalkyl of 3 to 8 carbon atoms;

R¹², R¹⁴, and R¹⁵ they are each independently H; alkyl of 1 to 8 carbon atoms optionally substituted by one or more halogen atoms; alkenyl of 2 to 8 carbon atoms; alkynyl of 2 to 8 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; cycloalkenyl of 5 to 10 carbon atoms; -alkyl from 1 to

203 carbon-cycloalkyl atoms of 3 to 8 carbon atoms; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 to 14 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, wherein the heterocyclic group contains at least one heteroatom selected from N, O, and S, wherein the cycloalkyl, cycloalkenyl groups, aryl, and heterocyclyl are each optionally substituted by one or more Z substituents; or

R¹¹ and R¹², and R¹³ and R¹⁴ together with the nitrogen atom with which they are attached they can 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, alkyl of 1 to 6 carbon atoms optionally substituted by one or more OH groups or NH groups₂, alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms, NR¹⁸(SO2) R²¹, (SO2) NR¹⁹R²¹, (SO₂) R²¹, NR¹⁸C (O) R²¹, C (O) NR¹⁹R²¹, NR¹⁸WITH

R¹⁹R²¹, NR¹⁸C (O) OR¹⁹, NR¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, MR¹⁹, OR¹⁹, oxo, CN, NO₂, halogen, or a 3- to 14-membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;

R¹⁹ and R²¹ they are each independently H; alkyl of 1 to 8 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms;

204 (alkyl of 0 to 4 carbon atoms) -aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from halogen , oxo, alkyl of 1 to 6 carbon atoms, and C (O) -alkyl of 1 to 6 carbon atoms; (alkyl of 0 to 4 carbon atoms) -0-aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; and (alkyl of 0 to 4 carbon atoms) -O-heterocyclic group of 3 to 14 members, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from from halogen, alkyl of 1 to 6 carbon atoms, or C (O) alkyl of 1 to 6 carbon atoms; wherein the alkyl groups are optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms, C (O) NH₂, C (O) NH-alkyl of 1 to 6 carbon atoms or C (O) N (alkyl of 1 to 6 carbon atoms) /, or

R¹⁹ and R²¹ together with the nitrogen atom with which they are attached, they form a 5-10 membered heterocyclic group, the heterocyclic group including one or more additional heteroatoms selected from N, O, and S, the group being

205 heterocyclic optionally substituted by one or more substituents selected from OH; halogen; aryl; 5 to 10-membered heterocyclic group that includes one or more heteroatoms selected from N, O and S; SW)₂-aryl; SW)₂-alkyl of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms; and C (O) O-alkyl of 1 to 6 carbon atoms, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by alkyl of 1 to 6 carbon atoms, halo-alkyl of 1 to 6 carbon atoms , or alkoxy of 1 to 6 carbon atoms.

Modality 29: The compound according to the modality

28, where:

A is N or CR^4th;

X is NR^and or OR;

R¹ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; halogen; - (alkyl of 0 to 4 carbon atoms) -aryl of 6 carbon atoms; or - (alkyl of 0 to 4 carbon atoms) 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

206 Z substituents;

R² it is halo-alkyl of 1 to 4 carbon atoms;

R³ and R^4th they are H;

R⁴ it is H, or alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms;

R^5th is H, alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms, - (alkyl of 0 to 4 carbon atoms) -aryl of 6 carbon atoms, or-5- to 8-membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the - (alkyl of 0 to 4 carbon atoms) -aryl of 6 carbon atoms, and - heterocyclic group of 5 to 8 members are each optionally substituted by one or more Z substituents;

R^and is H, alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms, - (alkyl of 0 to 4 carbon atoms) -aryl of 6 carbon atoms, or-5- to 8-membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the - (alkyl of 0 to 4 carbon atoms) -aryl of 6 carbon atoms, and - heterocyclic group of 5 to 8 members are each optionally substituted by one or more Z substituents;

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; OH; CN; - (alkyl of 0 to 4 carbon atoms) -aryl of

207 carbon atoms; or -5 to 8-membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the -aryl of 6 carbon atoms, and-5- to 8-membered heterocyclic group are each optionally substituted by one or more Z substituents; or

R⁴ and R⁶ together with the carbon atoms with which they are attached, they form a 3- to 8-membered carbocyclic ring system;

or

R^5th and R⁶ together with the atoms with which they are linked, they form 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^5th and R^and together with the atoms with which they are linked, they form a 5- to 8-membered heterocyclic ring system that contains 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, alkyl of 1 to 6 carbon atoms optionally substituted by one or more OH groups or NH groups₂, alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms, NR¹⁸C (O) R²¹, C (O) NR¹⁹R²¹, NR¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, MR¹⁹, OR¹⁹, oxo, CN,

208

NO_2i 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 optionally substituted by halogen, alkyl of 1 to 4 carbon atoms optionally substituted by halogen, alkoxy of 1 to 4 carbon atoms, or -CN;

R¹⁸ it is H or alkyl of 1 to 4 carbon atoms;

R¹⁹ and R²¹ they are each independently H; alkyl of 1 to 8 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; alkoxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms; (alkyl of 0 to 4 carbon atoms) -aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from halogen , oxo, alkyl of 1 to 6 carbon atoms, and C (O) -alkyl of 1 to 6 carbon atoms; (alkyl of 0 to 4 carbon atoms) -O-aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; and (alkyl of 0 to 4 carbon atoms) -O-heterocyclic group of 3 to 14 members, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from

209 from halogen, alkyl of 1 to 6 carbon atoms, or C (O) alkyl of 1 to 6 carbon atoms; wherein the alkyl groups are optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms, C (O) NH₂, C (O) NH-alkyl of 1 to 6 carbon atoms or C (O) N (alkyl of 1 to 6 carbon atoms)₂; or

R¹⁸ and R²¹ together with the nitrogen atom with which they are attached, they form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more additional 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 that includes one or more heteroatoms selected from N, O and S; S (0)₂-aryl; S (0)₂-alkyl of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms; and C (0) 0-alkyl of 1 to 6 carbon atoms, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by alkyl of 1 to 6 carbon atoms, halo-alkyl of 1 to 6 carbon atoms , or alkoxy of 1 to 6 carbon atoms.

Modality 30: The compound according to modality 28 or 29, where:

A is N or CR^4th;

210

X is NR^and or OR;

R¹ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; or halogen;

R² it's CF₃;

R³ and R^4th they are H;

R⁴ it is H, or alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms;

R^5th is H, alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms,

R^and is H, alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms,

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; OH; CN; or

R⁴ and R⁶ together with the carbon atoms with which they are attached, they form a 3- to 6-membered carbocyclic ring system;

or

R^5th and R⁶ together with the atoms with which they are linked to 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

211

R^5th and R^and together with the atoms with which they are linked, they form a 5- to 8-membered heterocyclic ring system that contains 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, alkyl of 1 to 6 carbon atoms optionally substituted by one or more OH groups or NH groups₂, alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms, alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms, NR¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, MR¹⁹, OR¹⁹, oxo, CN, NO₂, or halogen;

R¹⁹ it's H; alkyl of 1 to 8 carbon atoms; (alkyl of 0 to 4 carbon atoms) -aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; (alkyl of 0 to 4 carbon atoms) - heterocyclic group of 3 to 14 members, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from halogen , oxo, alkyl of 1 to 6 carbon atoms, and C (O) -alkyl of 1 to 6 carbon atoms; (alkyl of 0 to 4 carbon atoms) -O-aryl optionally substituted by one or more groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and halogen; and (alkyl of 0 to 4 carbon atoms) -O-group

212 3 to 14-membered heterocyclic, including the heterocyclic group one or more heteroatoms selected from N, O, and S, optionally substituted by one or more groups selected from halogen, alkyl of 1 to 6 carbon atoms, or C (O) alkyl of 1 to 6 carbon atoms; wherein the alkyl groups are optionally substituted by one or more halogen atoms, alkoxy of 1 to 4 carbon atoms, C (O) NH₂, C (O) NH-alkyl of 1 to 6 carbon atoms or C (O) N (alkyl of 1 to 6 carbon atoms)₂; or

R¹⁹ yr²¹ together with the nitrogen atom with which they are attached, they form a 5- to 6-membered heterocyclic group, the heterocyclic group including one or more additional 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 that includes one or more heteroatoms selected from N, O and S; SW)₂-aryl; S (0)₂-alkyl of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms; and C (0) 0-alkyl of 1 to 6 carbon atoms, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by alkyl of 1 to 6 carbon atoms, halo-alkyl of 1 to 6 carbon atoms , or alkoxy of 1 to 6 carbon atoms.

213

Modality 31: The compound according to modalities at 30, where:

A is N or CR^4th;

X is NR^and or OR;

R¹ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; or halogen;

R² it's CF₃;

R³ and R^4th they are H;

R⁴ it is H, or alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms;

R^5th is H, alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms,

R^and is H, alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms,

R⁶ it is alkyl of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; alkoxy of 1 to 4 carbon atoms optionally substituted by one or more halogen atoms; OH; CN; or

R^Sa and R⁶ together with the atoms with which they are linked, they form 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

214

R^5th and R^and together with the atoms with which they are linked, they form a 5- to 8-membered heterocyclic ring system that contains 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, alkyl of 1 to 6 carbon atoms optionally substituted by one or more OH groups or NH groups₂, alkyl of 1 to 6 carbon atoms opclonally substituted by one or more halogen atoms, alkoxy of 1 to 6 carbon atoms optionally substituted by one or more OH groups, or alkoxy of 1 to 4 carbon atoms, oxo, CN, NO₂, or halogen;

Modality 32: The compound according to any of the above modalities, where A is N.

Modality 33: The compound according to modalities at 31, where A is CR^4th.

Modality 34: The compound according to the modality

33, where A is CR^4th, and R^4th it's H.

Modality 35: The compound according to any of the above modalities, where R² is CF3CF2-, (CF3) 2CH-, CH3-CF2-, CF3CF2-, CF3j CF2H-, CH3-CCI2-, CF3CFCCIH-, CBr3, CBR²H-CF3CF₂CHCF₃ or CF₃CF₂CF₂CF₂-,

Modality 36: The compound according to any of the above modalities, where R² it's CF₃.

Modality 37: The compound according to any of the above modalities, wherein the compound is a

215 substantially pure enantiomer with the S configuration.

Modality 38: The compound according to modalities at 36, wherein the compound is a substantially pure enantiomer with the R configuration.

Modality 39: The compound according to modality 2, or 28, wherein the compound is represented by:

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

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

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxy-propyl) -amamide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid [(R) -1- (tetrahydrofuran-2-yl) -methyl] -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (1,3-diioxolan-2-yl-methyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid [(S) -1- (tetrahydrofuran-2-yl) -meti |] -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid tetrahydrofuran-2-yl-methyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (2-methyl-2-piperidin-1-yl-propyl) -amide;

3-Amino-6-bromo-5-trifluoromethyl-pyridin-2-carboxUico (2-hydroxy-propyl) -amide;

3-Amino-6-bromo-5216 trifl uoro-methyl-pyrid and η-2-carboxylic acid (2-hydroxy-2-methyl-propyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (2-methyl-tetrahydrofuran-2-yl-methyl) -amide;

3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-methoxy-ethyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid [2- (4-fluoro-phenyl) -2-morpholin-4-yl-ethyl] -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (2-morpholin-4-yl-2-phenyl-ethyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (2-dimethyl-amino-2-phenyl-ethyl) -amide;

3-amino-6- (4-fluoro-phenyl) -5-trifluoro-methyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide;

3-amino-5-trifluoro-methyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide;

3-Amino-6 (4-chloro-2-methyl-phenyl) -5-trifluoro-methyl-pyridin-2- ((R) -3,3,3-trifluoro-2-hydroxy-propyl) -amide carboxylic;

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

Amino-6'-methyl-3-trifluoro-methyl- [2,3 '] - bipyridinyl-6-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide;

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

3-amino-6-bromo-5-trifluoro-meti l-pyrid in-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide;

217 3-Amino-6-methyl-5-trifluoro-methyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide;

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

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

3-Amino-6- (2,4-dichloro-phenyl) -5-trifluoro-methyl-lp¡ridin-2 (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide -carboxylic;

3-Amino-6- (4-fluoro10-phenyl) -5-trifluoro-methyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl) -amide;

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

5-Amino-6'-methyl-3-trifluoro-methyl- [2,3 (3,3-trifluoro-2-hydroxy-2-trifluoro-methyl-propyl) -amide [2,3^,] -bipyridine-6-carboxylic acid;

Amino-6'- methyl-3-trifluoro-methyl- [2,3 '] - bipyridinyl-6-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide ;

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

320 amino-5,6-bis-trifluoro-methyl-pyridine-2- (320) -3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide carboxylic;

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

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

3- (3-amino-6-bromo-5- (trifluoro-methyl) -polcolide) -propanoate

218 of methyl;

3-amino-N- (benzo- [d] -¡soxazol-3-l-methyl) -6-bromo-5- (trifluoromethyl) -picolinamide;

3-amino-6- (oxazol-2-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoro-methyl) -picolinamide;

3-amino-6-bromo-N- (3,3,3-trfluoro-2-methoxy-2-methyl-propyl) -5 (trifluoro-methyl) -picolinamide;

3-amino-N- (2-hydroxy-3-methyl-2- (trifluoro-methyl) -butyl) -6-methoxy5- (trifluoro-methyl) -pi col inamide;

3-amino-6-cyclopropyl-N- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) 5- (trifluoro-methyl) -picol inamide;

3-amino-6-methoxy-N- (3,3,3-trifluoro-2-hydroxy-2- (trifluoro-methyl) propyl) -5- (trifluoro methyl 1) -picolinamide;

5-amino-N- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -3- (trifluoromethyl) -2,4'-bipyridine-6-carboxamide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (3-methyl-2-oxo-butyl) -amide;

3-amino-6- (1 -methyl 1-1 H-pyrazol-4-yl) -N- (3,3,3-trfluoro-2-hydrox2-methyl-propyl) -5- (trifluoro -methyl) -picolinamide;

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

3-amino-6- (pyrrolidin-1-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoro-methyl) -picolinamide;

3-amino-N- (2-amino-3,3,3-trifluoro-2-methyl-propyl) -6-methoxy-5 (trifluoro-methyl) -picolinamide; or

219

3-amino-6-methoxy-N- (3,3,3-trifluoro-2- (4-methoxy-benzyl-amino) 2-methyl-propyl) -5- (trifluoro-methyl) -picolamide.

Modality 40: The compound according to the modality

39, where the compound is:

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid [(R) -1- (tetrahydrofuran-2-yl) -methyl] -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (1,3-diioxolan-2-yl-methyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid [(S) -1- (tetrahydrofuran-2-yl) -methyl] -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid tetrahydrofuran-2-yl-methyl) -amide; or 3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (2-methyl-tetrahydrofuran-2-yl-methyl) -amide.

Modality 41: The compound according to modality 2, or 28, wherein the compound is:

3-amino6-brom o-5-trifluoro-methyl-1-pyrazin-2-carboxylic acid [2- (4-fluoro-phenyl) -2-morpholin-4-yl-eti |] -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid [2- (4-fluoro-phenyl) -2-morpholin-4-yl-ethyl] -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (2-morpholin-4-yl-2-phenyl-ethyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (2-dimethyl-amino-2-phenyl-ethyl) -amide;

3-Amino-6-bromo220 (3-methyl-2-morpholin-4-yl-butyl) -amide

5-trifluoro-meti l-pi razin-2-carboxylic acid;

3-amino-6b rom o-5-trifluoro-m eti l-pi razin-2-carboxylic acid (2-methyl-2-morpholin-4-yl-propyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyrazin-2-carboxylic acid (1-morpholin-4-yl-cyclohexyl-methyl) -amide;

3-Amino-6-bromo-5-trifluoro-meti l-pi razin-2-carboxylic acid (2-morpholin-4-yl-2-phenyl-ethyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyrazine-2-carboxylic acid (2-dimethyl-amino-2-phenyl-ethyl) -amide;

3a mi no-6-bromo-5-trifl uoro-methyl-1-pi razin-2-carboxylic acid [2- (4-methoxy-phenyl) -2-pyrrolidin-1-yl-eti |] -amide;

3-amino-N- (2-amino-3,3,3-trifluoro-2-methyl-propyl) -6-methoxy-5 (trifl uoro-methyl-1) -picolin amide; or 3-amino-6-bromo-5-trifluoro-m eti l-pi razin-2-carboxylic acid [2-dimethyl-amino-2- (4-methoxy-phenyl) -ethyl] -amide.

Modality 42: The compound according to modality 2, 21 or 28, where the compound is:

3-Amino-6-bromo-5-trifluoro-methyl-pyrazine-2-carboxylic acid (2-methyl-tetrahydrofuran-2-yl-methyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyrazin-2-carboxylic acid [2- (4-fluoro-phenyl) -2-morpholin-4-yl-eti |] -amide;

3-Amino-6-bromo5-trifluoro-methyl-l-pi razin-2-carboxylic acid (3-methyl-2-morpholin-4-yl-butyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyrazin-2-carboxylic acid (2-methyl-2-morpholin-4-yl-propyl) -amide;

221 3-Amino-6-bromo-5-trifluoro-methyl-pyrazin-2-carboxylic acid (1-morpholin-4-yl-cyclohexyl-methyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyrazin-2-carboxylic acid (2-morpholin-4-l-2-phenyl-et-1) -am¡da;

3-Amino-6-bromo5-trifluoro-methyl-pyrazine-2-carboxylic acid (2-dimethyl-amino-2-phenyl-ethyl) -amide;

3-Amino-6-bromo-5-trifluoro-methyl-pyrazine-2-carboxylic acid [2- (4-methoxy-phenyl) -2-pyrrolidin-1-yl-ethyl] -amide;

3-amino-6-bromo-5-trifluoro-methyl-pyrazine-2-carboxylic acid [2-dimethyl-amino-2- (4-methoxy-phenyl) -ethyl |] -amide;

3-Amino-6-bromo5-trifluoro-methyl-pyrazine-2-carboxylic acid [2- (4-fluoro-phenyl) -2-oxo-ethyl] -amide;

3-Amino-6-furan-2-yl-5-trifluoro-methyl-pyrazin-2-carboxylic acid [2- (2-methoxy-phenyl) -ethyl] -amide;

3-amino-N- (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -5,6-bis- (trifluoromethyl) -pyrazin-2-carboxamide;

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

3-amino-6-bromo-N- (2-morpholino-ethyl) -5- (trifluoro-methyl) -pyrazin-2-carboxamide; or 3-Amino-6-bromo5-trifluoro-methyl-pyrazin-2-carboxylic acid [2- (4-fluoro-phenyl) -2-oxo-ethyl] -amide.

Modality 43: The compound according to the modality

39, where the compound is:

3222 amino-6-bromo-5-trifluoro-methyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide;

3-Amino-6-bromo-5-trif I-uoro-methyl-1-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-propyl) -amide;

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

(3 S) -3,3,3-Trifluoro-2-hydroxy-2-methyl-propyl) -amide of the 3-amino acid-5,6-b¡s-trofluoro-met¡lp¡nd¡n -2-carboxylic acid;

(3) R-3,3,3-Trifluoro-2-hydroxy-2-methyl-propyl) -amide of 3-amino-5,6- bis- trifluoro-methyl-pyridine-2-carboxylic acid;

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

3 (A) -3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide 3-amino-6- (4-fluoro-phenyl) -5-trifluoro-methyl-pyr acid Din-2-carboxylic;

(3) R 3 -3,3,3-Trifluoro-2-hydroxy-2-methyl-propyl) -amide 3-amino-6- (4-fluoro-phenyl) -5-trifluoro-methyl-pyridin -2-carboxylic;

3-amino-6- (2,4-dichloro-phenyl) -5-trifluoro-methyl acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide -pyridin-2-carboxylic;

3-Amino-6- (4-fluorophenyl) -5-trifluoro-methyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl) -amide; or (3 R) -3,3,3-trifluoro-2-hydroxy-2-methyl-propyl) -amide-3-amino-6-methoxy-5-trifluoro-methyl-propyl-2-2- carboxylic.

Modality 44: The use of a compound according to modalities 1 to 43, in the preparation of a medicament for use in the treatment of an inflammatory or obstructive airways disease, or for the hydration of the

223 mucous

Modality 45: The use of a compound according to modalities 1 to 43, in the preparation of a medicament for use in the treatment of a disease mediated by the cystic fibrosis transmembrane conductance regulator (CFTR).

Modality 46: The use of a compound according to modality 42, in the preparation of a medicament for use in the treatment of a disease mediated by the cystic fibrosis transmembrane conductance regulator (CFTR), wherein the disease is cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD).

Modality 47: The use of a compound according to modalities 1 to 43, in the preparation of a medicament for use in the treatment of cystic fibrosis.

Modality 48: A pharmaceutical composition for the treatment of a disease or disorder mediated by the cystic fibrosis transmembrane conductance regulator (CFTR), which comprises:

the compound according to modalities 1 to 43, and one or more pharmaceutically acceptable excipients.

Modality 49: A pharmaceutical composition, according to modality 48, wherein the disease or disorder is cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD).

224

Modality 50: A pharmaceutical composition, according to modality 49, wherein the disease or disorder is cystic fibrosis (CF).

Modality 51: A pharmaceutical combination, which comprises:

a first active agent, which comprises the compound according to modalities 1 to 43, and a second active agent selected from osmotic agents, ENaC blockers, anti-inflammatory agents, bronchodilator agents, anti-histamine agents, cough suppressants , antibiotic agents, and DNase drug substances, wherein the first and second active agents may be in the same or different pharmaceutical composition.

Modality 52: a pharmaceutical combination according to modality 51, wherein the second active agent is an EnaC blocker.

Modality 53: A process for the preparation of the compounds of the formula (I):

R ·

<img file="CU24149B1_D0109.tif" />

which includes:

225 reacting a compound 1 with compound 2 in a peptide coupling reaction, or

<img file="CU24149B1_D0110.tif" />

P

two where R¹, R², R³, R⁴, R⁵ and R⁶ they are as defined herein, and p is a suitable amino protecting group;

remove the protective groups and isolate the compound of the formula I.

Modality 54: The process according to modality 49, wherein the peptide coupling condition is HATU in an aprotic solvent.

<img file="CU24149B1_D0111.tif" />

227