Pyridine and pyrazine derivative for the treatment of cf

[0001] The invention relates to pyridine and pyrazine compounds, their preparation and use as pharmaceuticals.

[0002] Cystic fibrosis (CF) is a lethal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), an epithelial anion channel activated by protein kinase A (PKA) involved in salt and fluid transport in many organs, including the lung. Most CF mutations either reduce the number of CFTR channels on the cell surface (e.g. synthesis or processing mutations) or weakens channel function (e.g., gating or conductivity mutations) or both. There are currently no approved therapies that target directly CFTR. The present invention discloses compounds that restore or enhance the activity of mutant and / or wild type CFTR to treat cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infection, lung cancer, xerostomy and dry eye syndrome or constipation (IBS, IBD, opioid-induced). [0003] In one aspect, the invention provides compounds of formula I:

<img file="PL2547656T3_D0001.tif" />

or a pharmaceutically acceptable salt thereof, where:

A is N or CR^4a;

R¹ is H; C1-C8 alkyl optionally substituted with one or more halogen atoms; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; -C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted with one or more halogen atoms; halogen; 2 NR⁸R⁹; SO 2 R¹⁰; S-C1-C8alkyl optionally substituted with one or more halogen atoms; S-C6-C14 aryl; CN; NO¹¹R¹²; C (O) NR¹³R¹⁴; NO¹³SO 2 R¹⁵; NO¹³C (O) R¹⁵, CO2R¹⁵, - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or - (C 0 -C 4 alkyl) -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted with one or more Z substituents; R² is C1-C4 haloalkyl;

R³ and R^4a are each independently H or C1-C8 alkyl optionally substituted with one or more halogen atoms;

R⁴ is H or C1-C8 alkyl optionally substituted with one or more halogen;

R⁵ means - (CH2) m-NR¹⁷R¹⁸, - (CH2) m-OR '; C1-C8 alkoxy optionally substituted with one or more halogen atoms; - (C 0 -C 4 alkyl) -CO 2 R¹⁵; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl or -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein - (C 0 -C 4 alkyl) -C 6 -C 14 aryl and - (C 0 -C 4 alkyl) -3 to 14 membered heterocyclic group each are optionally substituted with one or more Z substituents;

R⁶ is C1-C8 alkyl optionally substituted with one or more halogen atoms; C3-C10 cycloalkyl; -C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted with one or more halogen atoms; OH; CN; halogen; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or - (C 0 -C 4 alkyl) -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, - (C 0 -C 4 alkyl) -C 6 -C 14 aryl and - (C 0 -C 4 alkyl) - 3 to 14 membered heterocyclic group each are optionally substituted with one or more Z substituents; or

R⁶ is H and R⁵ means - (CH2) m-NR¹⁷R¹⁸, - (CH2) m-OR ', C1-C8 alkoxy optionally substituted with one or more halogen atoms; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; - (C 0 -C 4 alkyl) -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or - (C 0 -C 4 alkyl) -CO 2 R¹⁵wherein (C 0 -C 4 alkyl) -C 6 -C 14 aryl and - (C 0 -C 4 alkyl) - 3 to 14 membered heterocyclic group each are optionally substituted with one or more Z substituents; or

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

R⁴ and R⁵ together they form an oxo group (C = O) and R⁶ is C1-C4 alkyl optionally substituted with one or more halogen atoms; C1-C4 alkoxy optionally substituted with one or more halogen atoms; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or - (C 0 -C 4 alkyl) -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, where aryl and heterocyclic groups are each optionally substituted with one or more Z substituents; or

R⁵ and R⁶ together with the carbon atom to which they are attached 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 with one or more Z substituents; or

R⁴ and R⁵ and R⁶ together with the carbon atom to which they are attached 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 with one or more Z substituents;

R is H, or C1-C8 alkyl optionally substituted with one or more halogens;

m is 0, 1, 2 or 3;

R⁸, R¹¹, R¹³ and R¹⁷ are independently H, C1-C8 alkyl optionally substituted with one or more halogen atoms, C3-C10 cycloalkyl or - (C1-C4 alkyl) -C3-C8 cycloalkyl; R⁹, R¹⁰, R¹², R¹⁴, R¹⁵, R¹⁶ and R¹⁸ are each independently H; C₁-C₈ alkyl optionally substituted with one or more halogen atoms; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; -C1-C4 alkyl-C3-C8 cycloalkyl; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or (C 0 -C 4 alkyl) -3 to 14 membered heterocyclic group, where the heterocyclic group contains at least one heteroatom selected from N, O and S, where cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted with one or more Z substituents ; or

R⁸ and R⁹, R¹¹ and R¹², R¹³ and R¹⁴, and R¹⁷ and R¹⁸ together with the nitrogen atom to which they are attached, they can form a 4 to 14 membered heterocyclic group optionally substituted with one or more Z substituents;

Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted with one or more OH groups or NH2 groups, C1-C6 alkyl optionally substituted with one or more halogen atoms, C1-C6 alkoxy optionally substituted with one or more OH or C1-C4 alkoxy groups, NR¹⁸(SO2) R²¹, (SO2) NR¹⁹R²¹, (SO2) R²¹, NO¹⁸C (O) R²¹, C (O) NR¹⁹R²¹, NO¹⁸C (O) NR¹⁹R²¹, NO¹⁸C (O) OR¹⁹, NO¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, SR¹⁹, 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 are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4 alkoxyC1-C4 alkyl; (C 0 -C 4 alkyl) -aryl optionally substituted with one or more groups selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; A 3- to 14-membered heterocyclic group with - (C 0 -C 4 alkyl) -, wherein the heterocyclic group contains one or more heteroatoms selected from N, O and S, optionally substituted with one or more groups selected from halogen, oxo, C 1 -C 6 alkyl and C (O) C1-C6 alkyl; (C 0 -C 4 alkyl) -O-aryl optionally substituted with one or more groups selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; and a 3- to 14-membered heterocyclic group with (C 0 -C 4 alkyl) -O-, wherein the heterocyclic group contains one or more heteroatoms selected from N, O and S, optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl or C (O) C1-C6 alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C 1 -C 4 alkoxy, C (O) NH 2, C (O) NHC 1 -C 6 alkyl or C (O) N (C 1 -C 6 alkyl) 2; or

R¹⁹ and R²¹ together with the nitrogen atom to which they are attached, they form a 5- to 10-membered heterocyclic group, the heterocyclic group containing one or more additional heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted by one or more substituents selected from OH; halogen; aryl; A 5- to 10-membered heterocyclic group containing one or more heteroatoms selected from N, O and S; S (O) 2-aryl; S (O) 2-C 1 -C 6 alkyl; C1-C6 alkyl optionally substituted with one or more halogen atoms; C1-C6 alkoxy optionally substituted with one or more OH or C1C4 alkoxy groups; and C (O) OC1-C6 alkyl, where the aryl and heterocyclic substituent groups are themselves optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

[0004] Various embodiments of the invention are described herein. It will be seen that the features listed in each embodiment can be combined with other specified features to form further embodiments.

[0005] In an embodiment of the invention as described elsewhere herein, A is N.

[0006] In an embodiment of the invention as described elsewhere herein, A is CR^4a.

[0007] In an embodiment of the invention as described elsewhere herein, R¹is selected from H; C1-C8 alkyl optionally substituted with one or more halogen atoms; C1-C8 alkoxy optionally substituted with one or more halogen atoms; halogen; C6-C14 aryl; - (C 0 -C 4 alkyl) -3 to 14 membered heterocyclic group, 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 with one or more Z substituents.

[0008] In an embodiment of the invention as described elsewhere herein, R¹is C1-C4 alkyl optionally substituted with one or more halogen atoms. E.g. CH3 or CF3.

[0009] In an embodiment of the invention as described elsewhere herein, R¹ is C1-C4 alkoxy optionally substituted with one or more halogen atoms.

E.g., -OCH3 or -OCF3.

[0010] In an embodiment of the invention as described elsewhere herein, R¹is aryl, where aryl is phenyl optionally substituted with one or more Z substituents, suitable examples are 4-fluorophenyl, 4-chloro-2-methylphenyl or 2,4-dichlorophenyl.

[0011] In an embodiment of the invention as described elsewhere herein, R¹is a 6-membered heterocyclyl group, where the 6-membered heterocyclyl group is pyridyl optionally substituted with one or more Z substituents, a suitable example is 1-methyl-4-pyridyl.

[0012] In an embodiment of the invention as described elsewhere herein, R¹is Br, -CH3, -CF3, -OCH3, -OCF3, 4-fluorophenyl, 4-chloro-2-methylphenyl or 2,4-dichlorophenyl.

[0013] In an embodiment of the invention as described elsewhere herein, R²means CF3CF2-, (CF3) 2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CH3-CCl2-, CF3CFCClH-, CBr3, CBr2H-CF3CF2CHCF3 or CF3CF2CF2CF2-.

[0014] In an embodiment of the invention as described elsewhere herein, R²means CF3.

[0015] In an embodiment of the invention as described elsewhere herein, R³is H or methyl.

[0016] In another embodiment of the invention as described elsewhere herein, R^4a means H.

[0017] An embodiment of the invention as defined above provides a compound where R⁵ provides heteroatom two carbons from amide nitrogen, where heteroatom is oxygen or nitrogen.

[0018] An embodiment of the invention as defined above provides a compound of Formula I where R⁴ is H, C 1 -C 4 alkyl optionally substituted with one or more halogen atoms or absent;

R⁵ is C1-C4 alkoxy optionally substituted by one or more halogen atoms; - (CH2) m-NR¹⁷R¹⁸; - (CH2) m-OR 'or OH; m is 0 or 1;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen atoms; C1-C4 alkoxy optionally substituted with one or more halogen atoms; OH; CN; halogen; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or - (C 0 -C 4 alkyl) -3 to 14 membered heterocyclic group, where the heterocyclic group contains at least one heteroatom selected from N, O and S, where aryl and heterocyclyl groups are each optionally substituted with 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 atom to which they are attached 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 with one or more Z substituents;

R¹⁷ and R¹⁸ are each independently H; or C1-C4 alkyl optionally substituted with one or more halogen atoms.

[0019] An embodiment of the invention as defined above provides compounds of Formula I where A is CR^4a;

R¹ is halogen, C1-C4 alkyl optionally substituted with one or more halogen atoms, or C1-C4 alkoxy optionally substituted with one or more halogen atoms;

R² is C1-C4 haloalkyl;

R³ is H;

R⁴ is H or Me;

R^4a is H;

R⁵ means - (CH2) m-NR¹⁷R¹⁸; - (CH2) m-OR '; or OH;

m is 0 or 1;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen atoms; or

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

R¹⁷ and R¹⁸ are each independently H; or C1-C4 alkyl optionally substituted with one or more halogen atoms.

[0020] An embodiment of the invention as defined above provides compounds of Formula I where A is CR^4a;

R¹ is halogen, C1-C4 alkyl optionally substituted with one or more halogen atoms, or C1-C4 alkoxy optionally substituted with one or more halogen atoms;

R² is C1-C4 haloalkyl;

R³ is H;

R^4a is H;

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

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen atoms; C1-C4 alkoxy optionally substituted with one or more halogen atoms; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or - (C 0 -C 4 alkyl) -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, where aryl and heterocyclyl groups are each optionally substituted with one or more Z substituents.

[0021] An embodiment of the invention as defined above provides compounds of Formula I, wherein

A means CR^4a;

R¹ is C1-C4 alkyl optionally substituted with one or more halogen atoms; R² is C1-C4 haloalkyl;

R³ is H;

R⁴ is H or Me;

R^4a is H;

R⁵ means - (CH2) m-NR¹⁷R¹⁸; - (CH2) m-OR '; or OH;

m is 0 or 1;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen atoms; or

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

R¹⁷ and R¹⁸ are each independently H; or C1-C4 alkyl optionally substituted with one or more halogen atoms.

[0022] An embodiment of the invention as defined above provides compounds of Formula I, wherein

A means CR^4a;

R¹ is C1-C4 alkoxy optionally substituted by one or more halogen atoms;

R² is C1-C4 haloalkyl;

R³ is H;

R⁴ is H or Me;

R^4a is H;

R⁵ means - (CH2) m-NR¹⁷R¹⁸; - (CH2) m-OR; or OH;

m is 0 or 1;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen atoms;

or

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

R¹⁷ and R¹⁸ are each independently H; or C1-C4 alkyl optionally substituted with one or more halogen atoms.

[0023] An embodiment of the invention as defined above provides compounds of Formula I where A is CR^4a;

R¹ is C1-C4 alkoxy optionally substituted by one or more halogen atoms;

R² is C1-C4 haloalkyl;

R³ is H;

R⁴ is H or Me;

R^4a is H;

R⁵ means -NR¹⁷R¹⁸; or OH;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen atoms; or

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

R¹⁷ and R¹⁸ are each independently H; or C1-C4 alkyl optionally substituted with one or more halogen atoms.

[0024] An embodiment of the invention as defined above provides compounds of Formula I where A is CR^4a;

R¹ is C1-C4 alkyl optionally substituted with one or more halogen atoms; R² is C1-C4 haloalkyl;

R³ is H;

R⁴ is H or Me;

R^4a is H;

R⁵ means -NR¹⁷R¹⁸; or OH;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen atoms; and

R¹⁷ and R¹⁸ are each independently H; or C1-C4 alkyl optionally substituted with one or more halogen atoms.

[0025] An embodiment of the invention as defined above provides compounds of Formula I where A is CR^4a;

R¹ is C1-C4 alkoxy optionally substituted by one or more halogen atoms;

R² is C1-C4 haloalkyl;

R³ is H;

R⁴ is H or Me;

R^4a is H;

R⁵ means -NR¹⁷R¹⁸; or OH;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen atoms; and

R¹⁷ and R¹⁸ are each independently H; or C1-C4 alkyl optionally substituted with one or more halogen atoms.

[0026] In an embodiment of the invention as described elsewhere herein, where Z is independently OH, C1-C4 alkyl optionally substituted with one or more OH groups or NH2 groups, C1-C4 alkyl optionally substituted with one or more halogen atoms, C1-C4 alkoxy optionally substituted with one or more OH or C1-C4 alkoxy groups, NR¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, SR¹⁹, OR¹⁹, CN, NO2, or halogen;

R¹⁹ and R²¹ are each independently H; C1-C4 alkyl; C3-C6 cycloalkyl; or C1-C4 alkoxy-C1-C4 alkyl, wherein all alkyl are optionally substituted with halogen.

[0027] In an embodiment of the invention as described elsewhere herein, where Z is independently OH, C1-C4 alkyl optionally substituted with one or more OH groups or NH2 groups, C1-C4 alkyl optionally substituted with one or more halogen atoms, C1-C4 alkoxy optionally substituted with one or more OH or C1C groups₄ alkoxy, C (O) OR¹⁹, C (O) R¹⁹, OR¹⁹, CN or halogen; R¹⁹ is H; C1-C4 alkyl; C3-C6 cycloalkyl; or C1-C4 alkoxy-C1-C4 alkyl, wherein all alkyl are optionally substituted with halogen.

[0028] In an embodiment of the invention as described elsewhere herein, wherein Z is independently C 1 -C 4 alkyl optionally substituted with one or more halogen, C 1 -C 4 alkoxy or halogen.

[0029] Other embodiments of the invention as defined above provide compounds with substantially pure enantiomers in the R configuration.

[0030] Other embodiments of the invention as defined above provide compounds with substantially pure enantiomers in the S configuration.

[0031] Certain compounds of Formula I contain compounds of Formula II:

<img file="PL2547656T3_D0002.tif" />

or a pharmaceutically acceptable salt thereof, wherein A, R¹, R² and R³ have definitions for Formula 5 I and

R¹⁰¹ means

<img file="PL2547656T3_D0003.tif" />

<img file="PL2547656T3_D0004.tif" />

<img file="PL2547656T3_D0005.tif" />

<img file="PL2547656T3_D0006.tif" />

<img file="PL2547656T3_D0007.tif" />

<img file="PL2547656T3_D0008.tif" />

<img file="PL2547656T3_D0009.tif" />

<img file="PL2547656T3_D0010.tif" />

<img file="PL2547656T3_D0011.tif" />

[0032] In another embodiment of Formula II according to the invention herein, A is CR^4awhere R^4a means H.

[0033] In another embodiment of Formula II according to the invention herein, R¹ is selected from H; C1-C4 alkyl optionally substituted by one or more halogen atoms; C1-C4 alkoxy optionally substituted with one or more halogen atoms; halogen; C6-C14 aryl; - (C 0 -C 4 alkyl) -3 to 14 membered heterocyclic group, 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 with one or more Z substituents.

[0034] In another embodiment of Formula II according to the invention, wherein R¹ is C1-C4 alkyl optionally substituted with one or more halogen atoms, C1-C4 alkoxy optionally substituted with one or more halogen atoms; halogen; C6 aryl; or a 6-membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, where the aryl and heterocyclic groups each are optionally substituted with one or more Z substituents.

[0035] In another embodiment of Formula II according to the invention, wherein R¹ is C1-C4 alkyl optionally substituted with one or more halogen atoms, C1-C4 alkoxy optionally substituted with one or more halogen atoms; or halogen.

[0036] In another embodiment of Formula II according to the invention herein, R³is H or methyl.

[0037] An embodiment of the invention as defined above provides compounds of Formula II where A is CR^4a;

R¹ is halogen;

R³ is H;

R^4a is H;

R¹⁰¹ means

<img file="PL2547656T3_D0012.tif" />

or

<img file="PL2547656T3_D0013.tif" />

[0038] An embodiment of the invention as defined above provides compounds of Formula II where A is CR^4a;

R¹ is C1-C4 alkyl optionally substituted with one or more halogen atoms; R³ is H;

R^4a is H;

R¹⁰¹ means

<img file="PL2547656T3_D0014.tif" />

[0039] An embodiment of the invention as defined above provides compounds of Formula II where A is CR^4a;

R¹ is C1-C4 alkoxy optionally substituted by one or more halogen atoms;

R³ is H;

R^4a is H;

R¹⁰¹ means

<img file="PL2547656T3_D0015.tif" />

[0040] An embodiment of the invention as defined above provides compounds of Formula II where A is CR^4a;

R¹ is halogen, C1-C4 alkyl optionally substituted with one or more halogen atoms, or C1-C4 alkoxy optionally substituted with one or more halogen atoms;

R³ is H;

R^4a is H;

<img file="PL2547656T3_D0016.tif" />

[0041] An embodiment of the invention as defined above provides compounds of Formula II where A is CR^4a;

R¹ is halogen, C1-C4 alkyl optionally substituted with one or more halogen atoms, or C1-C4 alkoxy optionally substituted with one or more halogen atoms;

R³ is H;

R^4a is H;

<img file="PL2547656T3_D0017.tif" />

[0042] An embodiment of the invention as defined above provides compounds of Formula II where A is CR^4a;

R¹ is halogen, C1-C4 alkyl optionally substituted with one or more halogen atoms, or C1-C4 alkoxy optionally substituted with one or more halogen atoms;

R³ is H;

R^4a is H;

<img file="PL2547656T3_D0018.tif" />

[0043] Other embodiments of the invention as defined above provide compounds of Formula I and Formula II, represented by 3-amino-6-bromo-N- (imidazo [1,2-a] pyridin-2-ylmethyl) - 5- (trifluoromethyl) pyrazine-2-carboxamide;

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

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

3-amino-N- (2- (4-fluorophenyl) -2-oxoethyl) -6- (1-methyl-1H-indol-6-yl) -5- (trifluoromethyl) picolinamide;

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

3-Amino-6- (6- (3- (dimethylamino) propoxy) pyridin-3-yl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

(R) -3-amino-6-bromo-N - ((4-methylpiperazin-2-yl) methyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

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

3-amino-6- (3- (N, N-dimethylsulfamoyl) phenyl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) picolinamide;

3-amino-6-bromo-N-isobutyl-N-methyl-5- (trifluoromethyl) pyrazine-2-carboxamide;

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

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

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

3-amino-N- (2- (4-fluorophenyl) -2-oxoethyl) -6- (1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -5- (trifluoromethyl) picolinamide;

3-Amino-6- (4-carbamoyl-2-methylphenyl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) picolinamide;

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

3-Amino-6- (3,4-dimethylphenyl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) picolinamide;

3-amino-N-benzyl-6-bromo-N-methyl-5- (trifluoromethyl) pyrazine-2-carboxamide;

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

3-amino-6-bromo-N- (imidazo [1,5-a] pyridin-1-ylmethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide.

[0044] Other embodiments of the invention as defined above provide compounds of Formula I represented by 3-amino-6-methoxy ((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide -5trifluorometylopirydyno-2-carboxylic acid amide;

3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

Methyl 3- (3-amino-6-bromo-5- (trifluoromethyl) picolinamido) propanoate;

3-amino-N- (benzo [d] isoxazol-3-ylmethyl) -6-bromo-5- (trifluoromethyl) picolinamide;

3-amino-6- (oxazol-2-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

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

3-amino-N- (2-hydroxy-3-methyl-2- (trifluoromethyl) butyl) -6-methoxy-5- (trifluoromethyl) picolinamide;

3-amino-6-cyclopropyl-N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

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

5-amino-N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -3- (trifluoromethyl) -2,4'-bipirydyno6-carboxamide;

3-amino-6-bromo-5-trifluoromethyl-pyridine-217 carboxylic acid (3-methyl-2-oxobutyl) -amide;

3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (4-fluorophenyl) 2-oxo-ethyl] -amide;

3-amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (2-methoxyphenyl) -ethyl] -amide;

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

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

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

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

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

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

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

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

[0045] It is understood that any and all embodiments of the present invention may be taken together with any other embodiment to describe additional embodiments of the present invention. In addition, each element of the embodiment is intended to be combined with any and all other elements of any embodiment to describe additional embodiments. Those skilled in the art understand that combinations of substituents, where this is not possible, do not form an aspect of the present invention.

[0046] Particularly preferred suitable compounds of formula (I) or formula (II) are those described hereinafter in the Examples.

Definitions [0047] The terms used in the description have the following meanings:

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

"Optionally substituted with one or more Z groups" means that the given group may contain one or more substituents, each independently selected from the groups included in the definition of Z. Thus, where two or more substituents from the group Z are present, they may be the same or different.

"Halo" or "halogen" as used herein may be fluoro, chloro, bromo or iodo.

"C1-C8-Alkyl," as used herein, describes a straight or branched chain alkyl having 1-8 carbon atoms. If a different number of carbon atoms are mentioned, such as C6 or C3, then the definition should be modified accordingly, such as "C1-C4-alkyl" will mean methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl .

"C1-C8-Alkoxy," as used herein, describes a straight or branched chain alkoxy having 1-8 carbon atoms. If a different number of carbon atoms are mentioned, such as C6 or C3, then the definition should be modified accordingly, such as "C1-C4-Alkoxy" will mean methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy .

"C1-C4-Haloalkyl," as used herein, describes a straight or branched chain alkyl having 1-4 carbon atoms with at least one halogen substituted hydrogen. If different numbers of carbon atoms are exchanged, such as C6 or C3, then the definition should be modified accordingly, such as "C1-C4-haloalkyl" will mean methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl which has at least one halogen substituted hydrogen atom, such as when the halogen is fluorine: CF3CF2-, (CF3) 2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CF3CF2CHCF3 or CF3CF2CF2CF2-.

"C3-C15-cycloalkyl" as used herein, describes a cycloalkyl group having 3 to 15 carbon atoms in the ring that is saturated or partially saturated, such as C3-C8-cycloalkyl. Examples of C3-C15 -cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl or a bicyclic group such as bicyclooctyl, bicyclononyl, including indanyl and indenyl and bicyclodecyl. If different numbers of carbon atoms are exchanged, such as C6, then the definition should be modified accordingly.

"Aryl" or "C6-C15 aromatic carbocyclic group" as used herein describes an aromatic group having 6- to 15-carbon ring atoms. Examples of C6C15 aromatic carbocyclic groups include, but are not limited to, phenyl, phenylene, benzenetriyl, naphthyl, naphthylene, naphthalenetriyl or anthrylene. If different numbers of carbon atoms are exchanged, such as C10, then the definition should be modified accordingly.

"4- to 8-membered heterocyclic group", "5- to 6-membered heterocyclic group", "3- to 10-membered heterocyclic group", "3- to 14-membered heterocyclic group", "4- to 14-membered group heterocyclic "and" 5- to 14-membered heterocyclic group "refers to 4- to 8-membered, 5- to 6-membered, 3- to 10-membered, 3- to 14-membered, respectively, 4- to 14-membered and 5- to 14-membered heterocyclic rings containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, which may be saturated, partially saturated or unsaturated (aromatic). The heterocyclic group contains monocyclic groups, linked ring groups and bridging groups. Examples of heterocyclic groups include, but are not limited to, furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazoles, oxadiazoles, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyridazine, pyridazine, pyrrolidine, pyrrolidinone, morpholine, triazine, oxazine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1,4-oxatate, indazole, quinoline, indazole, indole, 8-aza-bicyclo [3.2.1] octane or thiazole.

[0048] A second aspect of the present invention provides a compound of Formula (I), (II) or (III) as defined elsewhere herein for use as a pharmaceutical.

[0049] A further aspect of the present invention provides a compound of Formula (I), (II) or (III) for use in the treatment of inflammatory or allergic condition, particularly inflammatory or obstructive airways disease or mucosal hydration. Such states contain, e.g. cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory infections, lung cancer, xerostomy and dry eye or constipation syndrome (IBS, IBD, opiate-induced). [0050] Still another aspect of the present invention provides the use of a compound of formula (I), (II) or (III) as defined in any of the above-mentioned embodiments in the form of a free or pharmaceutically acceptable salt in the manufacture of a medicament for the treatment of inflammation or allergic, especially inflammatory or obstructive airway disease or hydration of the mucosa.

[0051] An embodiment of the present invention provides the use of a compound of formula (I), (II) or (III) as defined in any of the aforementioned embodiments, in the form of a free or pharmaceutically acceptable salt, in the manufacture of a medicament for the treatment of inflammation or allergy , selected from cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory infection, lung cancer, xerostomy and dry eye syndrome or constipation (IBS, IBD, opiate-induced).

[0052] An embodiment of the present invention provides a method of preventing or treating a CFTR-mediated condition or disease comprising administering an effective amount of at least one compound as described herein to a subject in need of such treatment. CFTR-mediated condition or disease is selected from cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infection, lung cancer, xerostomy, and dry eye or constipation (IBS, IBD, opiate-induced) ). [0053] Throughout this specification and the following claims, unless the context requires otherwise, the word "include", or variants such as "includes" or "including", should be understood to mean the inclusion of a designated integer or stage or groups of integers or stages, but without excluding any other integer or stage or group of integers or stages. [0054] As used herein, the term "pharmaceutically acceptable salts" refers to salts that maintain the biological effectiveness and properties of the compounds of the invention and which are usually not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts due to the advantage of the presence of amino and / or carboxyl groups or groups similar thereto.

[0055] Pharmaceutically acceptable acid addition salts may be formed from inorganic acids and organic acids, e.g. salts of acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chloroteophylate, citrate, ethanedisulfonate, fumarate, gluceptanate, iodate, gluconate, gluconate, iodate , lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalactouronate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoracetate.

[0056] Inorganic acids from which salts can be obtained contain, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.

[0057] Organic acids from which salts can be obtained contain, e.g., acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, acid mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid and sulfosalicylic acid.

[0058] Pharmaceutically acceptable base addition salts may be formed from inorganic and organic bases.

[0059] Inorganic bases from which salts may be obtained contain, e.g., ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are obtained from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

[0060] The organic bases from which salts can be obtained contain, e.g., primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like. Some organic amines contain isopropylamine, benzatin, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0061] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, a basic or acidic particle, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate or the like), or by reacting the free base form of these compounds with stoichiometric amount of the corresponding acid. Such reactions are usually carried out in water or an organic solvent, or in a mixture of the two. In general, it is desirable to use non-aqueous agents such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile where applicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th 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).

[0062] In addition, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or containing other solvents used for their crystallization.

[0063] Compounds of the invention, i.e. compounds of formula (I), (II) or (III) that contain groups capable of acting as donors and / or acceptors for hydrogen bonds, may be capable of forming co-crystals with suitable forming agents kokryształ. These co-crystals can be prepared from compounds of formula (I), (II) or (III) by known procedures for co-crystal formation. Such procedures include milling, heating, co-sublimation, melting or contacting in solution of compounds of formula (I), (II) or (III) with the co-crystal former under crystallization conditions and isolation of the co-crystals thus formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence, the invention further provides co-crystals comprising a compound of formula (I), (II) or (III).

[0064] As used herein, the term "isomers" refers to various compounds that have the same molecular formula but differ in atomic order and configuration. Also, as used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention and contain geometric isomers. It is understood that a substituent can be attached at the chiral center of a carbon atom. Thus, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. The 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to describe a racemic mixture where appropriate. "Diastereomers" are stereo isomers that have at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry is specified according to the RS Cahn-Ingold-Relog system. When the compound is a pure enantiomer, stereochemistry at each chiral carbon can be specified as either R or S. Separated compounds whose absolute configuration is unknown can be marked (+) or (-) depending on the direction (right-or left-handed) in which they twist the plane of polarized light at the wavelength of the D line of sodium. Certain compounds described herein contain one or more asymmetric centers or axes and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms, which can be referred to in terms of absolute stereochemistry as (R) - or (S) -. The present invention is intended to contain all such possible isomers, including racemic mixtures, optically pure forms and mixtures of intermediates. Optically active (R) - and (S) - isomers can be made using chiral synthons or chiral reagents, or separated using conventional techniques. If the compound has a double bond, the substituent may have the E or Z configuration. If the compound has a disubstituted cycloalkyl substituent, the cycloalkyl may have the cis- or trans-configuration. All tautomeric forms are also to be included.

[0065] Any asymmetric atom (e.g. carbon or the like) of the compound (s) of the present invention may exist in a racemic or enantiomerically enriched configuration, e.g. the (R) -, (S) - or (R, S) - . In certain embodiments, each asymmetric atom has at least a 50% enantiomeric excess, at least 60% an enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess. , or at least a 99% enantiomeric excess in the (R) - or (S) - configuration. Substituents on atoms with unsaturated bonds may, if possible, be in the form of cis- (Z) - or trans- (E) -.

[0066] Accordingly, as used herein, the compound of the present invention may exist in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, e.g. as substantially pure geometric (cis or trans) isomers , diastereomers, optical isomers (antipodes), racemates or mixtures of the foregoing.

[0067] Any resulting mixture of isomers can be separated, based on physicochemical differences in the components, into pure or substantially pure geometric or optical isomers, diastereomers, racemates, e.g. using chromatography and / or fractional crystallization.

[0068] Any resulting racemates of intermediate products or intermediates can be separated into optical antipodes by known methods, e.g., by separation of the diastereomeric salts of the above obtained from an optically active acid or base, and the release of an optically active acid or base compound. In particular, the basic particle can thus be used to separate compounds of the present invention into their optical antipodes, e.g. by fractional crystallization of a salt formed from an optically active acid, e.g. tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O, O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be separated by chiral chromatography, e.g. high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0069] Since the compounds of the invention are intended for use in pharmaceutical compositions, it will be readily understood that each of them is preferably provided in substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are weight percent). Impure preparations of the compounds can be used to make the purer forms used in pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably 10 to 59% of the compound of the invention.

[0070] The compounds of the present invention are obtained either in free form as its salt or as a prodrug derivative thereof.

[0071] When both a basic group and an acid group are present in the same molecule, the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.

[0072] Any formula given herein is also intended to mean unlabelled forms as well as isotope-labeled forms of the compounds. Isotope-labeled compounds have the structures described by the formulas given herein, except that one or more atoms is replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H ³H ¹¹C ¹³C ¹⁴C ¹⁵N ¹⁸F ³¹P ³²P ³⁵S ³⁶Cl, ¹²⁵And accordingly. The invention includes various isotopes of these labeled compounds as defined herein, e.g., those in which radioactive isotopes exist, such as³H ¹³C and ¹⁴C. Such isotopically labeled compounds are useful in metabolic studies (z ¹⁴C), in studies of kinetic reactions (with, e.g. ²H or ³H), in detection or imaging techniques such as positron emission tomography (PET) or single photon emission tomography (SPECT), including drug or substrate tissue distribution tests, or in patient radiotherapy. In particular,¹⁸F or labeled compound may be particularly desirable for PET or SPECT testing. The radiolabeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparations described below, by substituting an easily available radiolabeled reagent with a non-radiolabeled reagent.

[0073] Then, substitution with heavier isotopes, especially deuterium (i.e., ²H or D) may provide some therapeutic benefits resulting from greater metabolic stability, e.g. increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood that deuterium in this context is considered a substituent of a compound of formula (I), (II) or (III). The concentration of such a heavy isotope, specifically deuterium, can be determined by the isotope enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic occurrence and the natural occurrence of a given isotope. If a substituent in a compound of the invention is designated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium attachment at each assigned deuterium atom), at least 4000 (60% deuterium attachment), which at least 4500 (67.5% deuterium connection), at least 5000 (75% deuterium connection), at least 5500 (82.5% deuterium connection), at least 6000 (90% deuterium connection), at least 6333.3 (95% deuterium attachment), at least 6466.7 (97% deuterium attachment), at least 6600 (99% deuterium attachment) or at least 6633.3 (99.5% deuterium attachment).

[0074] Isotope-labeled compounds of formula (I), (II) or (III) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Formulations using appropriate isotopically labeled reagents instead of the unlabelled reagent used previously.

[0075] The pharmaceutically acceptable solvates of the invention contain those in which the crystallization solvent may be isotopically substituted, e.g. D2O, d6-acetone, d6DMSO.

Synthesis [0076] In general, compounds of Formula I, II or III can be synthesized by the routes described in Schemes 1, 2 and 3 and in the Examples.

[0077] When A is CH, the pyridinyl moiety can be synthesized according to the general scheme 1 shown below.

Diagram 1

<img file="PL2547656T3_D0019.tif" />

[0078] When A is nitrogen, the pyrazine particle may be synthesized according to the general scheme 2 shown below.

Diagram 2

<img file="PL2547656T3_D0020.tif" />

[0079] The right side of the particle is usually added using an amide forming reaction as shown below in general scheme 3.

<img file="PL2547656T3_D0021.tif" />

[0080] HATU (Methanaminium 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) is a peptide coupling agent. The skilled person will know that other coupling agents could probably work. The halogen group in the above schemes can be replaced by other groups, by selecting the appropriate nucleophile and catalyst. Protection of the NH2 Aryl group may be necessary and is represented by P. Schemes 4-7 below are some representative examples.

Diagram 4

<img file="PL2547656T3_D0022.tif" />

<img file="PL2547656T3_D0023.tif" />

R^1,R^1JNH

Pd Cat rule

<img file="PL2547656T3_D0024.tif" />

<img file="PL2547656T3_D0025.tif" />

Diagram 7

<img file="PL2547656T3_D0026.tif" />

[0081] The skilled person will appreciate that the general synthetic pathways detailed above show typical reactions transforming starting materials as needed. Specific reaction conditions are not given, but they are well known to those skilled in the art, and the appropriate conditions considered are within the ordinary general knowledge of those skilled in the art. [0082] The starting materials are either commercially available compounds or known compounds and can be prepared by procedures described in the field of organic chemistry.

[0083] Compounds of formula (I), (II) or (III), in free form, can be converted into the salt form and vice versa, in a conventional manner understood by one of ordinary skill in the art. The compounds in free or salt form may be obtained in the form of hydrates or solvates containing the solvent used for crystallization. Compounds of formula (I), (II) or (III) can be recovered from reaction mixtures and purified in a conventional manner. Isomers, such as stereoisomers, can be obtained in a conventional manner, e.g. by fractional crystallization or asymmetric synthesis from suitably asymmetrically substituted, e.g. optically active, starting materials.

[0084] Compounds of formula (I), (II) or (III) can be prepared, e.g., using the reactions and techniques described below and in the Examples. The reactions can be carried out in a solvent suitable for the reagents used and the materials used, and appropriate for effective transformation. A specialist in the field of organic synthesis will be aware that the functionality present on the molecule should be consistent with the proposed transformations. This will sometimes require evaluation to modify the order of the synthetic steps or to select one particular process scheme relative to another to obtain the desired compound of the invention.

[0085] The various substituents on synthetic intermediates and the end products shown in the following reaction schemes can be in their fully developed forms, with appropriate protecting groups, if necessary, as understood by one of ordinary skill in the art, or in precursor forms, which may be later develop into final forms by methods known to those skilled in the art. Substituents can also be added at various stages of the synthesis sequence or after the synthesis sequence is completed. In many cases, commonly used functional group manipulations can be used to convert one intermediate into another intermediate, or one compound of formula (I), (II) or (III) into another compound of formula (I), (II) or (III). Examples of such manipulations are the conversion of an ester or ketone into alcohol; conversion of the ester to a ketone; transformations between esters, acids and amides; alkylation, acylation and sulfonylation of alcohols and amines; and many more. Substituents can also be added using conventional reactions such as alkylation, acylation, halogenation or oxidation. Such manipulations are well known in the art, and many references deal with procedures and methods for such manipulations. Some literature references that give examples and references to basic literature on organic synthesis in terms of many functional group manipulations, as well as other transformations commonly used in the field of organic synthesis, are March's Organic Chemistry, 5th edition, Wiley and Chichester, ed. (2001); Comprehensive Organic Transformations, Larock, ed., VCH (1989);

Comprehensive Organic Functional Group Transformations, Katritzky et al. (publisher of the series), Pergamon (1995); and Comprehensive Organic Synthesis, Trost and Fleming (series publishers), Pergamon (1991). It should also be appreciated that another important consideration in planning any synthesis pathway in this field is the legitimate choice of protecting group used to protect the reactive functional group present in the compounds described in this invention. Multiple protecting groups can be selected within the same molecule, such that each of these protecting groups can either be removed without removing the other protecting group in the same molecule, or several protecting groups can be removed using the same reaction step, depending on the desired result . The authoritative report describing many alternatives to a skilled practitioner is Greene and Wuts, Protective Groups in Organic Synthesis, Wiley and Sons (1999).

Pharmacological Activity [0086] Given their modulation of CFTR activity, the compounds of formula (I), in the form of free or pharmaceutically acceptable salt, referred to alternatively as "agents of the invention", are useful in the treatment of conditions that respond to modulation of CFTR activity , especially conditions that benefit from mucosal hydration, such as cystic fibrosis.

[0087] Diseases mediated by modulation of CFTR activity include diseases associated with fluid volume regulation across epithelial membranes. For example, fluid volume of the airway surface is a key regulator of mucociliary clearance and lung health. Modulation of CFTR activity will stimulate fluid accumulation on the mucosal side of the airway epithelium, thereby stimulating mucus clearance and preventing the accumulation of mucus and phlegm in the respiratory tissues (including lung airways). Such diseases include respiratory diseases such as cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, respiratory tract infections (acute and chronic; viral and bacterial) and lung cancer. Diseases mediated by modulation of CFTR activity also contain diseases other than respiratory diseases that are associated with abnormal fluid regulation by the epithelium, probably associated with abnormal physiology of protective surface fluids on their surface, e.g. Sjogren's syndrome, xerostomy (dry mouth ) or dry eye syndrome (dry eye). In addition, modulation of CFTR activity in the kidneys can be used to stimulate diuresis and thereby induce a hypotensive effect.

[0088] The therapy according to the invention may be symptomatic or prophylactic.

[0089] Asthma includes inborn (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, post-exercise asthma, occupational asthma and induced asthma after bacterial infection. Asthma therapy is also understood to include the treatment of subjects, e.g. younger than 4 or 5 years, showing signs of wheezing and diagnosed or possible to diagnose as "babies with wheezing", an established category of patients with special medical needs and currently commonly identified as early or early stage asthmatics. (For convenience, these individual asthma states are referred to as "wheezing syndrome in infants.") [0090] Prophylactic efficacy in asthma therapy will be demonstrated by the lower frequency or severity of the symptomatic attack, eg, acute asthmatic attack or bronchoconstriction, improved lung function or improvement respiratory hyperactivity. This may be further demonstrated by the less need for other symptomatic therapy, i.e., therapy for or intended to limit or remove symptomatic attack when it occurs, e.g. anti-inflammatory (e.g. corticosteroid) or bronchodilator. The prophylactic benefit in asthma can be seen, in particular, in subjects prone to "morning dipping". The "morning crisis" is a known asthmatic syndrome, typical of a significant percentage of asthmatics, and is characterized by an asthma attack, e.g., between about 4am and 6am, i.e., at a time normally significantly distant from any previously administered symptomatic asthma therapy.

[0091] Chronic obstructive pulmonary disease includes chronic bronchitis or associated dyspnoea, emphysema, as well as exacerbation of hyperactivity of the respiratory tract as a consequence of therapy with another drug, in particular therapy with another inhalation drug. The invention may also be used to treat bronchitis of any type or origin, including, e.g. acute bronchitis, caused by irritating to peanuts, catarrhal, croup, chronic or tuberculosis.

[0092] Dry eye disease is characterized by a decrease in tear production and an abnormal profile of lipid, protein and mucin tear film. There are many causes for dry eye, some of which include age, laser eye procedures, arthritis, medication, chemical / thermal burns, allergies, and diseases such as cystic fibrosis and Sjogren's Syndrome. Increased anion secretion by CFTR will enhance fluid transport from corneal endothelial cells and secretory glands surrounding the eye, increasing corneal hydration. This will help relieve the symptoms associated with dry eye disease.

[0093] Sjogren's syndrome is an autoimmune disease in which the immune system attacks the glands that produce moisture throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and intestines. Symptoms include dry eye, dry mouth and dry vagina as well as lung disease. The disease is also associated with rheumatoid arthritis, lupus erythematosus, systemic sclerosis and polymyositis / dermatomyositis. Malfunctioning protein transfer is considered to be the cause of the disease, whose treatment options are limited. Modulators of CFTR activity can hydrate various affected organs and help alleviate accompanying symptoms.

[0094] The suitability of CFTR activity modulators as a treatment for disease benefiting from mucosal hydration can be tested by determining the chloride ion movement in an appropriate cell based assay. For example, single cells or confluent epithelia that are endogenously expressed or reconstructed to overexpress CFTR can be used to assess channel function using electrophysiological techniques or ion flow testing. See, the methods described in: Hirsh et al., J Pharm Exp Ther (2004); Moody et al., Am J Physiol Cell Physiol (2005).

[0095] Modulators of CFTR activity, including compounds of formula (I), are also useful as co-therapeutic agents for use in combination with other medicinal substances such as anti-inflammatory drug substances, bronchodilators, antihistamines or antitussives, especially in the treatment of cystic fibrosis or disease Respiratory tract with bronchospasm or inflammation such as those previously mentioned, e.g. as enhancers of the therapeutic activity of such drugs or as agents reducing the necessary dose or potential side effects of such drugs.

[0096] The compounds of Formula (I), (II) or (III) can be mixed with other drug substances in a solid pharmaceutical composition or can be administered separately, before, simultaneously with or after other drug substances.

[0097] Accordingly, the invention includes, as an additional aspect, a combination of a modulator of CFTR activity with osmotic agents (hypertonic saline, dextran, mannitol, xylitol), ENaC blockers, anti-inflammatory, bronchodilators, antihistamines, anti-cough, antibiotics and / or substances drug DNases, where the CFTR activity modulator and other drug substances can be present in the same or different pharmaceutical composition.

[0098] Suitable antibiotics include macrolide antibiotics, e.g. tobramycin (TOBI ™).

[0099] Suitable DNase drug substances include dornase alfa (Pulmozyme ™), a highly purified solution of recombinant human deoxyribonuclease I (rhDNase) that selectively cleaves DNA. Dornase alfa is used to treat cystic fibrosis.

[0100] Other useful combinations of CFTR activity modulators with anti-inflammatory drugs are those with chemokine receptor antagonists, e.g. 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, especially antagonists CCR-5, such as antagonists SC-351125, SCH55700 and SCH-D from Schering-Plow; antagonists from Taked, such as N - [[4 [[[6,7-dihydro-2- (4-methyl-phenyl) -5H-benzo-cyclohepten-8-yl] carbonyl] amino] phenyl] methyl] tetrahydro chloride -N, N-dimethyl-2H-pyran-4-amine (TAK-770); and CCR-5 antagonists described in USP 6,166,037 (especially claims 18 and 19), WO 00/66558 (especially claim 8), WO 00/66559 (especially claim 9), WO 04/018425 and WO 04/026873.

[0101] Suitable anti-inflammatory drugs include steroids, in particular, glucocorticosteroids such as budesonide, beclometasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate or the steroids described in 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; nonsteroidal glucocorticoid receptor agonists such as those described in 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; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors, such as cilomilast (Ariflo^® GlaxoSmithKline), Roflumilast (Taurus Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plow), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12 -281 (Asta Medica), CDC-801 (Celgene), SeICID (TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and these disclosed in WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO

03/104205, WO 03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO

04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/018431, WO

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 WO 02/42298; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol, carmoterol and its pharmaceutically acceptable salts, and compounds (in free or salt or solvate form) of formula (I) of WO 0075114, which document is hereby incorporated by reference, preferably the compounds of the Examples above, in particular indacaterol and its pharmaceutically acceptable salts, as well as compounds (in free or salt or solvate form) of formula (I) of WO 04/16601, as well as compounds of 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.

[0102] Suitable bronchodilators containing anticholinergic or antimuscarinic agents, in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021, USP 3,714,357, USP 5,171,744 / 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.

[0103] Suitable dual anti-inflammatory and bronchodilatory drugs include the dual beta-2 adrenoceptor agonist / muscarinic antagonist such as disclosed in USP 2004/0167167, WO 04/74246 and WO 04/74812.

[0104] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activstine, astemizole, azelastine, ebastine, epinastine, w, tefa, and also tefin 03/099807 and WO 04/026841.

[0105] Accordingly, the invention also provides, as another aspect, a method of treating a condition responsive to modulation of CFTR activity, e.g., diseases associated with fluid volume regulation across epithelial membranes, particularly a disease involving airway spasm, which includes administration to a subject, particularly a subject being a human in need of the above compound of formula (I), (II) or (III), in free form or in the form of a pharmaceutically acceptable salt.

[0106] In another aspect, the invention provides a compound of formula (I), (II) or (III), in free form or in pharmaceutically acceptable salt form, for use in the manufacture of a medicament for treating a condition responsive to modulation of CFTR activity, particularly diseases with airway spasm, e.g. cystic fibrosis and COPD.

The agents of the invention may be administered by any appropriate route, e.g. orally, e.g. in the form of a tablet or capsule; parenterally, e.g. intravenously; by inhalation, e.g. in the treatment of a disease with airway spasm; intranasally, e.g., in the treatment of allergic rhinitis; topically to the skin; or into the rectum. In another aspect, the invention also provides a pharmaceutical composition comprising a compound of formula (I), in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier therefor. The composition may contain a co-therapeutic agent such as anti-inflammatory, bronchodilator, antihistamine or antitussive drug as described hereinbefore. Such compositions can be prepared using conventional diluents or excipients and methods known in the galenical technique. Thus oral dosage forms may contain tablets and capsules. Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g. patches. Inhalable compositions may include aerosol or other sprayable formulations or dry powder formulations.

[0108] When the composition comprises an aerosol formulation, it preferably contains, e.g.

a hydrofluoroalkane (HFA) propellant, such as HFA134a or HFA227, or a mixture thereof, and may contain one or more co-solvents known in the art, such as ethanol (up to 20% 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, e.g. a compound of formula (I), (II) or (III) with a particle diameter of up to 10 microns, optionally together with a diluent or carrier such as lactose, with a desirable particle size distribution, and a compound that helps prevent deterioration of product yield due to moisture e.g. magnesium stearate. When the composition comprises a nebulized formulation, it preferably contains, e.g. a compound of formula (I), (II) or (III) or dissolved or suspended in a carrier containing water, a co-solvent such as ethanol or propylene glycol and a stabilizer which may be a surfactant.

[0109] Other aspects of the invention include:

1. (a) a compound of formula (I), (II) or (III) in inhalable form, e.g. in an aerosol or other atomizable composition, or in inhalable particulate, e.g. micronized form;

2. (b) an inhalable drug comprising a compound of formula (I), (II) or (III) in inhalable form;

3. (c) a pharmaceutical product comprising a compound of formula (I) in inhalable form together with an inhalation device; and

4. (d) an inhalation device containing a compound of formula (I), (II) or (III) in inhalable form.

[0110] The dosage of the compounds of formula (I), (II) or (III) used in practicing the present invention will of course vary depending upon, e.g., the particular condition to be treated, the effect desired and the mode of administration. Generally, suitable daily doses for administration by inhalation are on the order of 0.005-10 mg, while for oral administration suitable daily doses are on the order of 0.05-100 mg. Pharmaceutical Use and Test [0111] The compounds of formula (I), (II) or (III) and their pharmaceutically acceptable salts, hereinafter referred to alternatively as "agents of the invention", are useful as pharmaceuticals. In particular, the compounds are suitable modulators of CFTR activity and can be tested by the following tests.

Membrane Potential Test [0112] CFTR activity can be quantified by measuring membrane potential. Means for measuring membrane potential in a biological system can utilize a variety of methods, including electrophysiological membrane potential tests and based on optical fluorescence.

[0113] The membrane potential optical test uses a negatively charged potentiometric dye, such as FLIPR membrane potential dye (FMP) (see Baxter DF,

Kirk M, Garcia AF, Raimondi A, Holmqvist MH, Flint KK, Bojanic D, Distefano PS, Curtis R,

Xie Y. 'A novel membrane potential-sensitive fluorescent dye improves cell-based tests for ion channels.' J Biomol Screen. 2002 Feb; 7 (1): 79-85), which is bound to the quenching agent outside the cell. During cell depolarization, the negatively charged dye is redistributed to the cellular compartment, separating from the membrane non-penetrating quenching agent, resulting in increased fluorescence. This change in fluorescence is proportional to the change in membrane potential, which may be due to CFTR activity. Changes in fluorescence can be monitored in real time by a suitably equipped fluorescence detector, such as FLIPR (fluorimetric plate imaging reader) in 96 or 384 well microtiter plates.

Cell culture:

[0114] Chinese hamster ovary (CHO) cells with stable ΔF508CFTR channel expression were used for membrane potential experiments. Cells were maintained at 37 ° C in 5% v / v CO₂ at 100% humidity in Modified Eagles Medium (MEM) supplemented with 8% v / v fetal calf serum, 100 μg / ml methotrexate and 100U / ml penicillin / streptomycin. Cells were grown in 225 cm²tissue culture flasks. For membrane potential testing, cells were plated into 96 well plates at 40,000 cells per well, allowed to adhere and then held at 26 ° C for 48 hours to facilitate channel insertion.

Strengthening test:

[0115] The membrane potential screening test used an extracellular solution containing a low concentration of chloride ions (~ 5 mM) in combination with a double addition protocol. Buffer with or without test compound was added for the first time, then 5 minutes later forskolin (1-20 μΜ) was added - this protocol promotes maximum chloride outflow in response to activation of ΔF508-CFTR. The efflux of chloride ions via ΔF508-CFTR leads to membrane depolarization, which is optically monitored by the FMP dye.

solutions:

Extracellular, low chloride (mM): 120 Na-gluconate, 1.2 CaCl2, 3.3 KH2PO4, 0.8 K2HPO4, 1.2 MgCl2, 10.0 D-glucose, 20.0 HEPES, pH 7.4 with NaOH FMP dye: made as per the manufacturer's instructions in the extracellular solution with low chloride concentration, specified above, at 10x final concentration and stored as 1 ml solutions of equal volume separated into tubes at -20 ° C.

IonWorks Quattro test:

[0117] CFTR activity can also be quantified electrophysiologically using the whole cell configuration using a patch technique (Hamill and other Pflugers Acrhive 1981).

This test directly measures the currents associated with chloride flow through CFTR channels while either maintaining or tuning transmembrane voltage. This assay can use either single glass micropipettes or parallel planar sets to measure CFTR activity from native or recombinant cell systems. Currents measured using parallel planar sets can be quantified using an appropriately equipped instrument such as IonWorks Quattro (Molecular Devices) or Qpatch (Sophion). The Quattro system can measure CFTR currents either from a single cell of a measured groove (HT configuration) or alternatively from a population of 64 cells per groove (Population Patch Clamp PPC) (Finkel A, Wittel A, Yang N, Handran S, Hughes J, Costantin J. 'Population patch clamp improves data consistency and success rates in measurement of ionic currents.' J Biomol Screen. 2006 Aug; 11 (5): 488-96).

Cell culture:

[0118] Chinese hamster ovary (CHO) cells with stable ΔF508CFTR channel expression were used for the IonWorks Quattro experiments. Cells were maintained at 37 ° C in 5% v / v CO2 and 100% humidity in D-MEM supplemented with 10% (v / v) FCS, 100 U / ml Penicillin / Streptomycin, 1% (v / v) NEAA, 1 mg / ml Zeocin and 500 ug / ml Hygromycin B. Cells for experiments were cultured in 225 cm tissue culture flasks² until near confluence and then cultured at 26 ° C for 48-72 hours to facilitate channel insertion. Cells were removed from the flask and resuspended either in extracellular solution for immediate experiments or alternatively, in growth medium supplemented with 10% v / v DMSO and frozen to -80 ° C as 1-2 ml solutions of equal volume separated into tubes for later use.

Strengthening test:

[0119] Cells, 1.5-3 million per ml, were placed in a Quattro system, added to the planar patch set and sealed allowed to stabilize for 5-10 min. After assessing the closure resistance (typically&gt; 50 ΜΩ), whole cell access was obtained by perforation of 100 μg / ml amphotericin B. Baseline currents were measured by scanning before adding the compound, obtained by applying a voltage increase from -100 to +100 mV. Then either buffer or test compound diluted in the extracellular solution supplemented with 20 μΜ forskolin was added to each of the 384 grooves of the planar patch kit. After the incubation step (5-20 minutes), the currents after addition of the compound were measured again by applying a voltage increase from -100 to +100 mV. The difference in currents between the scans before and after the addition of the compound defined the CFTR gain efficiency.

solutions:

[0120] Extracellular solution (ECS): 145 mM NaCl, 4 mM CsCl, 5 mM D-glucose, 10 mM TES, 1 mM CaCl2, 1 mM MgCl2, pH 7.4 NaOH intracellular buffer (ICS): 113 mM acid L Asparagine, 113 mM CsOH, 27 mM CsCl, 1 mM NaCl, 1 mM MgCl2, 1 mM EGTA, 10 mM TES. pH 7.2 with CsOH. The filter was sterilized before use.

Ion transport test:

[0121] Another method of measuring the CFTR function is by measuring the current in the Ussing short circuit chamber. Developed or native epithelial cells are cultured into a confluent single layer on a semi-permeable filter and layered between two blocks of Plexiglas. The flow of chloride ions through CFTR from one side of the epithelium to the other can be quantified by measuring the current flow while maintaining the trans-epithelial potential at 0 mV. This is achieved thanks to KCl-filled agar electrodes on both terminals of a single cell layer and measurement of current flow.

Cell culture:

[0122] FRT cells with stable expression of ΔF508-CFTR were grown on plastic in modified F-12 Coon medium supplemented with 32 mM NaHCO3, 10% v / v fetal bovine serum, 2 mM L-glutamine, 100 U / ml penicillin, 100 μg / ml streptomycin and 30 μg / ml hygromycin B as growth medium. For experiments with the Ussing chamber, cells were grown as polarized epithelials on permeable supports for Snapwell inserts (500,000 cells / insert in growth medium) and cultured for 7 to 9 days. The cartridges were fed with fresh F-12 Coon growth medium every 48 hours and 24 hours before the Ussing chamber experiment. To increase CFTR TRF508 protein expression on the cell surface, the plates were incubated at 27 ° C for 48 hours before conducting the Ussing chamber experiment.

Strengthening test:

[0123] Fischer Rat Thyroid (FRT) epithelial cells, stably expressing human ΔF508CFTR, were used as monolayer cultures on permeable bases. Cl. Current was measured^- using short circuit current techniques with imposed Cl gradientbasolateral to apical, in Ussing chambers. For measuring constant currents Cl^-, FRT cells were cultured for 48 hours at 27 ° C to facilitate the introduction of ΔF508 CFTR into the plasma membrane. Tests with the Ussing chamber were carried out similarly at 27 ° C. Under these conditions, the effect of the combined addition of test compounds on the ΔF508 CFTR currents could be assessed with both strength and efficacy endpoints. Compounds were added to both the apical and basolateral sides after adding 10μΜ of forskolin. The efficacy of the compounds was compared to known enhancers such as genistein. solutions:

[0124] Ringer basal solution (mM): 126 NaCl, 24 NaHCO3, 0.38 KH2PO4, 2.13 K2HPO4, 1 MgSO4, 1 CaCl2 and 10 glucose.

[0125] Top Ringer's solution (mM): 140 Na-gluconate, 1 MgSO4, 2 CaCl2, 1 HCl, 10 glucose and 24 NaHCO3.

[0126] The compounds can also be tested for their ability to stimulate the introduction of ΔF508 CFTR into the cell membrane using the above assays. For these tests, the protocols were identical except that the cells were not grown at low temperature (26 or 27 ° C) but instead they were incubated with test compounds for 12-24 hours. before the test.

[0127] The compounds of the Examples, herein below, generally have EC50 values ​​in the measurement data described above, below 10 μΜ. Table 1 provides a list of representative compounds with their EC50 value.

Table 1

<td>Example No.</td><td>EC50 μΜ</td><td>Example No.</td><td>EC50</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>

[0128] The compounds listed below are within the scope of the broadest claim, and the EC50 CFTR values ​​in the measurement data described above were above 5 μΜ:

3-amino-6-bromo-N- (imidazo [1,2-a] pyridin-2-ylmethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

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

2- (3-amino-6-bromo-5- (trifluoromethyl) picolinamido) acetic acid;

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

3-amino-N- (2- (4-fluorophenyl) -2-oxoethyl) -6- (1-methyl-1H-indol-6-yl) -5- (trifluoromethyl) picolinamide;

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

6 - ((3H- [1,2,3] triazolo [4,5-b] pyridine-3-yl) oxy) -3- (2,5-dimethyl-1H-pyrrol-1-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

3-Amino-6- (6- (3- (dimethylamino) propoxy) pyridin-3-yl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

(R) -3-amino-6-bromo-N - ((4-methylpiperazin-2-yl) methyl) -5- (trifluoromethyl) pyrazine-2-carboxamide;

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

3-amino-6- (3- (N, N-dimethylsulfamoyl) phenyl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) picolinamide;

3-amino-6-bromo-N-isobutyl-N-methyl-5- (trifluoromethyl) pyrazine-2-carboxamide;

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

6-bromo-3- (methylamino) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

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

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

3-amino-N- (2- (4-fluorophenyl) -2-oxoethyl) -6- (1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -5- (trifluoromethyl) picolinamide;

3-Amino-6- (4-carbamoyl-2-methylphenyl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) picolinamide;

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

3-Amino-6- (3,4-dimethylphenyl) -N- (2- (4-fluorophenyl) -2-oxoethyl) -5- (trifluoromethyl) picolinamide;

3-amino-N-benzyl-6-bromo-N-methyl-5- (trifluoromethyl) pyrazine-2-carboxamide;

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

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

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

(S) -3-amino-6-bromo-N - ((1-ethylpyrrolidin-2-yl) methyl) -5- (trifluoromethyl) pyrazine-2-carboxamide; and

3-amino-6-bromo-N- (imidazo [1,5-a] pyridin-1-ylmethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide.

[0129] The invention is illustrated by the following examples.

Examples

General conditions:

[0130] Mass spectra were run on LC-MS using electrospray ionization. They were either a combination of Agilent 1100 HPLC / Micromass Platform Mass Spectrometer or Waters Acquity UPLC with SQD Mass Spectrometer. [M + H]⁺ refers to monoisotopic molecular masses.

[0131] NMR spectra were run on Bruker AVANCE 400 NMR open access spectrometers using ICON-NMR. Spectra were measured at 298 K and related to the solvent peak.

[0132] Optical rotation was measured at 589nm and 546nm using an Optical activity AA-1000 polarimeter at 21 ° C.

[0133] The following examples are intended to illustrate the invention and should not be construed as limiting. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporations are carried out under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of end products, intermediates and starting materials is confirmed by standard analytical methods, e.g. microanalysis and spectroscopic characteristics, e.g. MS, IR and NMR. The abbreviations used are conventional in the art. If not defined, the terms have their generally accepted meanings.

abbreviations:

[0134] app visible (apparent)

ATP adenosine 5'-triphosphate

BINAP racemic 2,2'-bis (diphenylphosphine) -1,1'-binaphthyl

BOC tertiary butyl carboxyl br broad (broad) d doublet dd

DCM

DIEA

DIPEA

DMF

DMSO

DTT

ESI

EtOAc eq h

HATU

HPLC

IR

LCMS

MeOH

MS

MW

doublet doublet dichloromethane diethylisopropylamine diisopropylethylamine

N, N-dimethylformamide, dimethyl sulfoxide dithiothreitol

Ionization with electrospray ethyl acetate equivalent hour (s)

2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate high pressure liquid chromatography

Infrared spectroscopy liquid chromatography and mass spectrometry methanol mass spectrometry microwave multiplet min minutes ml milliliter (milliliters) m / z mass / charge ratio

NMR

Nuclear magnetic resonance imaging parts per million

PS polymer supported racemic

RT

Room temperature

rt

Retention time p

singlet

SCX-2 strong cation exchange (e.g. Isolute® SCX-2 columns from Biotage) vol

triplet

TEA triethylamine

TFA

Trifluoroacetic acid

THF tetrahydrofuran [0135] Regarding the examples that follow, compounds of preferred embodiments were synthesized using methods described herein or other methods that are known in the art.

[0136] Various starting materials, intermediates, and compounds of preferred embodiments can be isolated and purified, if appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. Unless otherwise specified, all starting materials are obtained from market suppliers and used without further purification. Salts can be prepared from compounds by known salt formation procedures.

[0137] It should be understood that organic compounds according to preferred embodiments may exhibit the phenomenon of tautomerism. Since the chemical structures in this list can only mean one of the possible tautomeric forms, it should be understood that preferred embodiments include any tautomeric form with the structure drawn.

[0138] Unless otherwise stated, HPLC analytical conditions are as follows:

<td>Method 10 min LC_v001</td><td></td>

<td>Column</td><td>Waters BEH C18 100x2.1 mm, 1.7 μιτι</td>

<td>Temp. column.</td><td>50 ° C</td>

<td>eluents</td><td>A: H2O, B: acetonitrile, both contain 0.1% TFA</td>

<td>Flow rate</td><td>0.7 ml / min</td>

<td>Gradient</td><td>0.25 min 5% B; 5% to 95% B in 7.75 min, 1.00 min 95% B</td>

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

<td>Method 10 min LC_v002</td><td></td>

<td>Column</td><td>Waters BEH C18 50x2.1 mm, 1.7 μm</td>

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

<td>eluents</td><td>A: H.₂O, B: methanol, both contain 0.1% TFA</td>

<td>Flow rate</td><td>0.8 ml / min</td>

<td>Gradient</td><td>0.20 min 5% B; 5% to 95% B in 7.80 min, 1.00 min 95% B</td>

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

<td>Method 10 min LC_v003</td><td></td>

<td>Column</td><td>Waters BEH C18 50x2.1 mm, 1.7 μm</td>

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

<td>eluents</td><td>A: H2O, B: acetonitrile, both contain 0.1% TFA</td>

<td>Flow rate</td><td>0.8 ml / min</td>

<td>Gradient</td><td>0.20 min 5% B; 5% to 95% B in 7.80 min, 1.00 min 95% B</td>

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

<td>Method 2 min LC_v001</td><td></td>

<td>Method 10 min LC_v003</td><td></td>

<td>Column</td><td>Waters BEH C18 100x2.1 mm, 1.7 μιτι</td>

<td>Temp. column</td><td>50 ° C</td>

<td>eluents</td><td>A: H2O, B: acetonitrile, both contain 0.1% TFA</td>

<td>Flow rate</td><td>0.7 ml / min</td>

<td>Gradient</td><td>0.25 min 5% B; 5% to 95% B in 1.00 min, 0.25 min 95% B</td>

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

<td>Method 2 min LC_v002</td><td></td>

<td>Column</td><td>Waters BEH C18 50x2.1 mm, 1.7 μm</td>

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

<td>eluents</td><td>A: H.₂O, B: methanol, both contain 0.1% TFA</td>

<td>Flow rate</td><td>0.8 ml / min</td>

<td>Gradient</td><td>0.20 min 5% B; 5% to 95% B in 1.30 min, 0.25 min 95% B</td>

<td>Method 2 min LC_v003</td><td></td>

<td>Column</td><td>Waters BEH C18 50x2.1 mm, 1.7 μm</td>

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

<td>eluents</td><td>A: H2O, B: acetonitrile, both contain 0.1% TFA</td>

<td>Flow rate</td><td>0.8 ml / min</td>

<td>Gradient</td><td>0.20 min 5% B; 5% to 95% B in 1.30 min, 0.25 min 95% B</td>

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

<td>Method 10 min. C18</td><td></td>

<td>Column:</td><td>Gemini C18 100x3 mm, 3 microns</td>

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

<td>eluents:</td><td>A: H2O, B: Methanol, 0.1% formic acid</td>

<td>Flow rate:</td><td>1 ml / min</td>

<td>Gradient:</td><td>0.00 min 0% B, 10.00 min 95% B</td>

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

<td colspan="2">AD25IPA_DEA method</td>

<td>Mobile phase:</td><td>25% isopropanol + 0.1% by volume DEA / 75% CO2</td>

<td>Column:</td><td>Chiralpak AD-H, 250 x 10 mm id, 5 μιτι</td>

<td>Detection:</td><td>UV @ 220 nm</td>

<td>Flow rate:</td><td>10 ml / min</td>

[0139] Exemplary compounds of the present invention include Preparation of the final compounds Example 1.0 (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) 3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid amide [0140]

<img file="PL2547656T3_D0027.tif" />

[0141] 3-Amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (intermediate A) (397 mg, 1.392 mmol), 3-amino-1,1,1-trifluoro-2-methylpropane-2 hydrochloride -olu (250 mg, 1.392 mmol) and HATU (529 mg, 1.392 mmol) were dissolved in

DMF (10 ml) and stirred at RT for 2 min. 4-Methylmorpholine (0.413 mL, 4.18 mmol) was added and stirring continued at RT for 3 hours. The reaction mixture was poured onto ice / water (100 mL) and extracted with EtOAc (250 mL). The organic extract was washed with saturated NH 4 Cl (~ 50 mL), dried over MgSO 4 and concentrated in vacuo to give a pale brown oil. The oil was dissolved in

CHCl3 (~ 3 mL) and loaded onto a 24 g ISCO (silica) column, eluting with isohexane: EtOAc to give the title product; LC-MS Rt = 1.46 min; [M + H]⁺

410.1, Method 2 min LC_v002. NMR¹H (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). NMR^{10 * * * * 15 * * * 19 20}F (400 MHz, DMSO-d6) δ -62.71 (CF3, s), - 80.48 (CF3, s).

[0142] The compounds of the following examples in Table (Table 2) were prepared by a method similar to that in Example 1 from the corresponding starting compound and amine.

Single enantiomers were prepared by using a chiral amine or by product separation using Supercritical Fluid Chromatography. Preparation of starting compounds and amines are described in the Intermediates section, unless they are commercially available. In some reactions, DIPEA or TEA could be used instead of 4-methylmorpholine.

<td>Retention time, [M + H] +, NMR ¹H</td><td>Rt 3.26 min; Method = AD2 51PA_DEA NMR¹H (DMSO) δ 3.4 (1H, m), 3.6 (1H, m), 4.3 (1H, m), 6.5 (1H, s), 7.3 (2H, s), 7.7 (1H, s), 8.6 (1H, t),</td><td>Rt 1.42 min; [M + H] + 398 Method: 2 min LC_v002 NMR¹H (DMSO) δ 3.4 (1H, m), 3.6 (1H, m), 4.3 (1H, m), 6.5 (1H, d), 7.3 (2H, s), 7.7 (1H, s), 8.6 (1H, t),</td><td>Rt 1.41 min; [M + H] + 398 Method: 2 min LC_v002 NMR ¹H (DMSO) δ 3.4 (1H, m), 3.6 (1H, m), 4.3 (1H, m), 6.5 (1H, d), 7.3, (2H, s), 7.7 (1H, s), 8.6 (1H, t)</td><td>Rt 1.51 min; [M + H] + 370 Method: 2 min LC_v002 NMR ¹H (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),</td>

<td>Name</td><td>3-amino-6-bromo-5- (trifluoromethylpyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxypropyl) amide (separated by SFC, the second eluted peak)</td><td>3-amino6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxypropyl) amide (Racemate)</td><td>3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxypropyl) amide. Prepared using (S) -3-amino1,1,1-trifluoro-propan-2 ol</td><td>3-amino6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [(R) -1- (tetrahydrofuran-2-yl) methyl] amide. Prepared using (R) - (-) - tetrahydrofurfurylamine</td>

<td>Structure</td><td>LU LL ZZ _rj / ^{o =}\ ²² / co / ξ^-LL LL</td><td>LL LU ZZ _N^{o =}\ ²behind to / V LL LL</td><td>LL LL ZZ _M / ^{o =}\ ²/ Λ WHAT LL LL</td><td></td>

<td>Prov.</td><td> 1.1</td><td> 1.2</td><td> 1.3</td><td> 1.4</td>

<td>Retention time, [M + H] +, NMR * H</td><td>-M x " τ-1 00 CD x " τ-1 rP rP CD x " ΓΝ WHAT rP</td><td>Rt 1.42 min; [M + H] + 370 Method: 2 min LC_v002</td><td>NMR ¹H (DMSO) δ3,4, (2H, t), 3.8, (2H, m), 3.9, (2H,</td><td>m), 5.0, (1H, t), 7.3, (2H, br), 7.7, (1H, s), 8.4, (1H, t),</td><td>Rt 1.52 min; [M + H] + 370 Method: 2 min LC v002.</td><td>NMR ¹H (DMSO) 1.6, (1H, m), 1.9, (3H, m), 3.3, (2H,</td><td>m), 3.6, (1H, m), 3.8, (1H, m), 4.0, (1H, m), 7.4,</td><td>(2H, s), 7.7, (1H, s), 8.4, (1H, d)</td><td>Rt 1.49 min; [M + H] + 368 Method: 2 min LC v002.</td><td>NMR ¹H (DMSO) δ 1.55, (1H, m), 1.8, (3H, m), 3.3,</td><td>(2H, m), 3.6, (1H, m), 3.8, (1H, m), 4.0, (1H, m),</td><td>-M x " τ-1 00 CD x " τ-1 rP rP CD x " ΓΝ WHAT rP</td>

<td>Name</td><td></td><td>3-amino-6- ([1,3] dioxolan-2-ylmethyl) amide</td><td>bromo-5-trifluoromethyl-pyridine-2-carboxylic acid</td><td></td><td>3- (tetrahydrofuran-2-yl) methyl] amide [3- (S) -1- (tetrahydrofuran-2-yl) methyl] amide</td><td>amino-6-bromo-5-trifluoromethyl-2-</td><td>carboxylic acid Prepared using (S) - (+) -</td><td>Tetrahydrofurfurylaminy</td><td>3-amino-6- (tetrahydrofuran-2-ylmethyl) amide</td><td>bromo-5-trifluoromethyl-pyridine-2-carboxylic acid</td><td></td><td></td>

<td></td><td>° p</td><td></td><td></td><td> °0</td><td></td><td>ABOUT</td><td></td><td></td><td></td><td></td><td>FROM'·</td><td></td>

<td></td><td>zi / O = X from</td><td></td><td>ABOUT -</td><td>&lt; zi / hT yz</td><td></td><td>o =</td><td>P Z1</td><td>AND from</td><td></td><td>o =</td><td>&lt; ΣΙ</td><td>from" from</td>

<td rowspan="2">Structure</td><td>about</td><td></td><td></td><td>ABOUT</td><td></td><td></td><td>/ y from</td><td>AND</td><td></td><td></td><td>/ Γ from</td><td></td>

<td>m A ^_LLLL U-</td><td></td><td></td><td>ł_ Λ- LL ca A LL LL</td><td></td><td></td><td>Ca</td><td>A— U^-LL LL</td><td></td><td></td><td>Ca</td><td>ALL LL</td>

<td>Prov.</td><td></td><td colspan="3"> 1.5</td><td colspan="4"> 1.6</td><td colspan="4"> 1.7</td>

<td>Retention time, [M + H] +, NMR ¹H</td><td>Rt 1.14 min; [M + H] + 423 Method: 2 min LC_v002 NMR¹H (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>Rt 4.06 min; [M + H] + 344. Method: 10 min LC_v002 NMR 1H. ([400MHz], [DMSO-d6]) δ 8.30 (1H, t), 7.69 (1H, s), 7.28 (2H, br s), 4.84 (1H, d), 3 , 78 (1H, m), 3.29 (1H, m), 3.14 (1H, m), 1.05 (3H, d).</td><td>Rt 4.35 min; [M + H] + 338. Method: 10 min LC_v002 NMR ¹H. ([400MHz], [DMSO-d6]) δ 8.14 (1H, t), 7.70 (1H, s), 7.29 (2H, br s), 4.70 (1H, s), 3.24 (1H, d), 1.10 (6H, s).</td><td>Rt 1.53 min; [M + H] + 384 Method: 2 min LC v002.</td>

<td>Name</td><td>3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-methyl-2-piperidin-1-ylpropyl) amide</td><td>3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxypropyl) amide</td><td>3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methylpropyl) amide</td><td>3- (2-methyltetrahydrofuran-2-ylmethyl) amide</td>

<td>Structure</td><td>AND^ZZL N _ / τ ' o = &lt; ^from^from / ffl A. IX x</td><td>X about n ZV Z X \ f^from / LL · Ll</td><td>X r zi / hT^{o =}\ ^from^from / this XX</td><td></td>

<td>Prov.</td><td> 1.8</td><td> 1.9</td><td> 1.10</td><td> 1.11</td>

<td>Retention time, [M + H] +, NMR * H</td><td>NMR ¹H. ([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 (1H, m), 1.60 (1H, m), 1.13 (3H, s).</td><td>Rt 1.43 min; [M + H] + 342; Method: 2 min LC_v002. NMR 1H. ([400MHz], [DMSO-d6]) δ 8.41 (1H, t), 7.69 (1H, s), 7.28 (2H, br s), 3.44 (4H, m), 3.27 (3H, s).</td><td>Rt 1.52 min; [M + H] + 385; Method: 2 min LC_v002. NMR ¹H. ([400MHz], [DMSO-d6]) δ 8.35 (1H, t), 8.09 (2H, br s), 3.76 (2H, t), 3.34 (2H, d), 1.86 (3H, m), 1.58 (1H, m), 1.13 (3H, s).</td><td>Rt 4.29 min; [M + H] + 492. Method: 10 min LC_v002. NMR ¹H (400 MHz, MeOD) δH 7.61-7.64 (2H, m, 2 x Ar'H (AA'BB'X system)), 7.28-7.32 (2H, m, 2 x Ar'H (AA'BB'X system)), 4.65-4.73 (1H, br m, NHCHaHbCHN (Ar ')), 4.31 (1H, ddABx, J =</td>

<td>Name</td><td>amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic</td><td>3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-methoxyethyl) amide</td><td>3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-methyltetrahydrofuran-2-ylmethyl) amide</td><td>3 amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (4-fluorophenyl) -2-morpholin-4-ylethyl] amide</td>

<td>Structure</td><td>zi / I ™ ° ^ \ ^from^from / m A " LL LL</td><td>/ ABOUT \ // z - V z X \ 7² / «- \ -LL LL LL</td><td>? zz XLL LL</td><td></td>

<td>Prov.</td><td></td><td> 1.12</td><td> 1.13</td><td> 1.14</td>

<img file="PL2547656T3_D0028.tif" />

<td>Retention time, [M + H] +, NMR * H</td><td>NMR ¹H (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, s wide) 7.30 (2H, s wide), 4.67 (1H, m), 4.19 (1H, quintet), 3.83 (m), 2.80 (3H, d), 2.61 (3H, d).</td><td>Rt 3.39 min; [M + H] + 442. Method 10 min LC_v002. NMR¹H (400 MHz, DMSO-d6) δ 9.03 (1H, s), 9.10 (1H, s), 8.12 (2H, s), 4.00-3.20 (12H, wide), 1.10 (3H, wide), 1.00 (3H, wide).</td><td>Rt 2.83 min; [M + H] + 428; Method 10 min LC_v002. NMR ¹H (400 MHz, DMSO-d6) δ 9.04 (1H, s), 8.95 (1H, s), 8.10 (2H, s), 4.04 (2H, d), 3.75 (2H, t), 3.60 (4H + wide water signal on the bottom), 3.20 (2H, q), 1.35 (6H, s).</td><td>Rt 3.59 min; [M + H] + 466. Method 10 min LC_v002. NMR ¹H (400 MHz, DMSO-d6) δ 9.00 (1H, wide), 8.90 (1H, wide), 8.10 (1H, s), 4.02-3.35 (20H, very wide)</td>

<td>Name</td><td>bromo-5-trifluoromethyl-pyridine-2-carboxylic acid</td><td>3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (3-methyl-2-morpholin-4-yl-butyl) amide</td><td>3-amino6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-methyl-2-morpholin-4-ylpropyl) amide</td><td>3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (1-morpholin-4-ylcyclohexylmethyl) amide</td>

<td>Structure</td><td>X zł _in / ^{o =}\ ^fromv5 ώ / χ^-LU LU</td><td>ABOUT ° 1X zz XX LU LU</td><td>ABOUT AND zł M YLU LU</td><td>ABOUT P XX YLu Lu</td>

<td>Prov.</td><td></td><td> 1.18</td><td> 1.19</td><td> 1.20</td>

<td>Retention time, [M + H] +, NMR ¹H</td><td>Rt 6.09 min; [M + H] + 474 Method 10 min. C18</td><td>Rt 5.42 min; [M + H] + 432 Method 10 min. C18</td><td>Rt 5.64 min; [M + H] + 488 Method 10 min. C18</td><td>Rt 5.51 min; [M + H] + 462; Method 10 min. C18</td>

<td>Name</td><td>3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-morpholin-4-yl-2-phenylethyl) amide</td><td>3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-dimethylamino-2-phenylethyl) amide</td><td>3-amino-6-bromo-5-trifluoromethylpyrazine-2-carboxylic acid [2- (4-methoxy-phenyl) -2-pyrrolidin-1-ylethyl] amide</td><td>3-amino-6-bromo-5-trifluoromethylpyrazine-2-carboxylic acid [2-dimethylamino-2- (4-methoxyphenyl) ethyl] amide</td>

<td>Structure</td><td>&lt;4Λ / -⁰~ Z. X. X LU LU</td><td>4 Z— X zz 44 XX</td><td>/ ABOUT 4-0 with— and LL LL</td><td>/ 0 \- from Z— And Χ4 LL LL</td>

<td>Prov.</td><td> 1.21</td><td> 1.22</td><td> 1.23</td><td> 1.24</td>

<td>Retention time, [M + H] +, NMR ¹H</td><td>Rt 5.41 min; [M + H] + 426; Method 10 min LC_v002. NMR * H δ 8.42 (1H, m), 7.72 (1H, s), 7.5 (2H, m), 7.3 (2H, t), 7.22 (2H, br s), 6.24 (1H, s), 3.68 (1H, m), 3.46 (1H, m), 1.24 (3H, s)</td><td>Rt 4.18 min; [M + H] + 332; Method 10 min LC_v002. NMR¹H 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><td>Rt 1.59 min; [M + H] + 442 Method: 2 min LC_v002. NMR ¹H. ([400MHz], [DMSO-d6]) δ 8.54 (1H, br), 7.69 (1H, s), 7.41 (1H, d), 7.30 (1H, dd), 7.24 (2H, br s), 7.20 (1H, d), 6.40 (1H, br), 4.19 (1H, m), 3.54 (1H, m), 3.36 (1H, m), 2.01 (3H, s).</td><td>Rt 1.59 min; [M + H] + 466; Method 2 min LC_v002. NMR ¹H (400 MHz, DMSO-d6) δ 8.50 (1H, t), 8.30 (1H, s), 7.72 (1H, s), 7.30 (2H, s), 4.00 (2H, d)</td>

<td>Name</td><td>3-amino-6- (4-fluoro-phenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide</td><td>3-amino-5-trifluoromethylpyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide</td><td>3 amino-6- (4-chloro-2-methylphenyl) -5-trifluoromethylpyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxypropyl) amide. Prepared using (R) -3-amino-1 1,1-trifluoro-propan-2-ol</td><td>3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropyl) amide</td>

<td>Structure</td><td>LU LU X. z — γ z FROM \ / 0 LU</td><td>LL LL Ύ ZZ / fromⁱⁿ^{o =}\ ^from0 V— ll</td><td>X O x n zz / from¹^{o =}\ ^from^from / \ - LL ABOUT "" □</td><td></td>

<td>Prov.</td><td> 1.25</td><td> 1.26</td><td> 1.27</td><td> 1.28</td>

<td>Retention time, [M + H] +, NMR * H</td><td></td><td>Rt 1.16 min; [M + H] + 423; Method 2 min LC_v002. NMR¹H (400 MHz, DMSO-d6) δ 8.53 (1H, d), 8.45 (1H, t), 7.75 (1H, d), 7.71 (1H, s), 7.34 ( 1H, d), 7.25 (2H, s), 6.21 (1H, s), 3.69 (1H, dd), 3.42 (1H, dd), 2.54 (3H, s), 1.22 (3H, s).</td><td>Rt 4.64 min; [M + H] + 372.1; 10 min method LC_v002. NMR¹H (400 MHz, DMSO-d6) δ 8.56 (1H, t), 7.68 (1H, s), 7.27 (2H, br s), 3.61 (3H, s) 3.50 (2H, q), 2.60 (2H, t).</td><td>Rt 4.18 min; [M + H] + 417.1; 10 min method</td>

<td>Name</td><td></td><td>Acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide 5-amino-6'-methyl-3-trifluoromethyl- [2,3 '] bipyridinyl-6-carboxylic</td><td>Methyl 3- (3-amino-6-bromo-5- (trifluoromethyl) picolinamido) propanoate.</td><td>3-amino-N- (benzo [d] isoxazol-3-ylmethyl) -6-bromo-5-</td>

<td>Structure</td><td>U- LL LL AX \ /² / * - \ -X m / \ LL LL</td><td>LL LL \ / x-VO \ zP \ // X from — 7 from X \ / about zy Ull</td><td>\ ° X z - V z X \ /² / m XX</td><td></td>

<td>Prov.</td><td></td><td> 1.29</td><td> 1.30</td><td> 1.31</td>

<td>Retention time, [M + H] +, NMR * H</td><td>LC_v002. NMR¹H (400 MHz, DMSO-d6) δ 9.32 (NH, t), 7.96 (1H, dt), 7.74 (1H, dt), 7.70 (1H, s), 7.657.62 ( 1H, m), 7.40-7.36 (1H, m), 7.29 (NH2, bs), 4.88 (2H, d)</td><td>Rt 3.44 min; [M + H] + 399.1; 10 min method LC_v003.</td><td>NMR ¹H (400 MHz, DMSO-d6) δ 8.24 (1H, t), 7.72 (1H, s), 7.29 (2H, s), 3.65 (2H, m), 3.37 (3H, s), 1.35 (3H, s)</td><td>Rt 4.48min; [M + H] + 390.3; Method 10 min LC_v003. NMR ¹H (400 MHz, DMSO-d6) δ 8.21 (1H, m), 7.69 (1H, s), 6.59 (2H, s), 6.26 (1H, s), 3.91 (3H, s), 3.68 (2H, m), 2.02 (1H, m), 1.02 (6H, m)</td>

<td>Name</td><td>(Trifluoromethyl) picolinamide</td><td>3-amino-6- (oxazol-2-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide</td><td>Single enantiomer of 3-amino-6-bromo-N- (3,3,3-trifluoro-2-methoxy-2-methylpropyl) -5 (trifluoromethyl) picolinamide (separated by SFC, second eluted peak)</td><td>Single enantiomer of 3-amino-N- (2-hydroxy-3-methyl-2- (trifluoromethyl) butyl) -6-methoxy-5- (trifluoromethyl) picolinamide (separated by SFC, first eluted peak)</td>

<td>Structure</td><td>AND / from zł _ / if ° ^ \ ^fromώ γ'ξ uLU LU</td><td>LU LU &gt; ZT _ / X v5 X</td><td>LU LL X. of-yz Yes^from / □ 5 LL</td><td></td>

<td>Prov.</td><td></td><td> 1.32</td><td> 1.33</td><td> 1.34</td>

<td>Retention time, [M + H] +, NMR ¹H</td><td></td><td>Rt 1.23 min; [M + H] + 372.2; Method 2 min LC_v003. NMR¹H (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>Rt 4.27 min; [M + H] + 416.3; 10 min method LC_v003. NMR¹H (400 MHz, DMSO-d6) δ 8.39 (1H, t), 8.32 (1H, br s), 7.69 (1H, s), 6.70 (2H, br s), 3.99 (2H, d), 3.93 (3H, s),</td><td>Rt 0.86 min; [M + H] + 409.1; Method 2 min LC_v003. NMR ¹H (400 MHz, DMSO-d6) δ 8.70 (2H, d), 8.45 (1H, t), 7.75 (1H, s), 7.50 (2H, d), 7.33 (2H, s), 6.22</td>

<td>Name</td><td></td><td>3-amino-6-cyclopropyl-N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide</td><td>3-amino-6-methoxy-N- (3,3,3-trifluoro-2-hydroxy-2- (trifluoromethyl) propyl) -5- (trifluoromethyl) picolinamide</td><td>Single enantiomer of 5-amino-N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -3- (trifluoromethyl) -2,4'-bipyridine-6-carboxamide (separated by SFC,</td>

<td>Structure</td><td>U-LL 'Loam ZI _ / from ^{o =}\ ^from- ° LL LL</td><td>LL LL "ł ZZ / AND¹^from / w / V- LL LL Ll</td><td>Lll \ from z — Y z I \ /^from / ° X— \ Ll</td><td></td>

<td>Prov.</td><td></td><td> 1.35</td><td> 1.36</td><td> 1.37</td>

<td>Retention time, [M + H] +, NMR ¹H</td><td>(1H, s), 3.69 (1H, dd), 3.43 (1H, dd), 1.21 (3H, s).</td><td>Rt 1.18 min; [M + H] + 368; Method 2 min LC_v003. NMR¹H (400 MHz, DMSO-d6) δ 8.64 (1H, t), 7.71 (1H, s), 7.29 (2H, wide s), 4.2 (2H, d), 2.7 -2.8 (1H, m), 1.08 (6H, d, 2 x CH3).</td><td>NMR ¹H (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>

<td>Name</td><td>first eluted peak)</td><td>3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3-methyl-2-oxobutyl) amide</td><td>3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (4-fluorophenyl) -2-oxoethyl] amide</td>

<td>Structure</td><td>LL LL 4. ZV with and \ i^from / i- (\ -U_ &lt;4Λ A z = 4</td><td>zi / T ™ from CO / Χξ U " LL LL</td><td>X 4 ZI AND AX X</td>

<td>Prov.</td><td></td><td> 1.38</td><td> 1.39</td>

Examples 2 and 3 These compounds, namely, 3-amino-6-bromo-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide. (Ex. 2)

<img file="PL2547656T3_D0029.tif" />

and 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide. (Prz.3)

<img file="PL2547656T3_D0030.tif" />

is prepared by chiral separation of 3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide. ( Example 1) using Supercritical Fluid Chromatography, under the following conditions:

<td>Mobile phase:</td><td>12% isopropanol + 0.1% DEA / 88% CO2</td>

<td>Column:</td><td>Chiralpak OJ-H, 250 x 10 mm id, 5 gm</td>

<td>Detection:</td><td>UV @ 220nm</td>

<td>Flow rate:</td><td>10 ml / min</td>

<td>Sample Concentration:</td><td>347 mg in 5 ml EtOH.</td>

<td>Injection Volume:</td><td>50 gl</td>

[0144] Example 2: First eluted peak: 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide.

[0145] LC-MS: Rt = 4.97min [M + H] + 410.1 / 412.2 (Method 10 min LC_v002).

NMR ¹H (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)

NMR ^{15 * * * 19 20}F (400 MHz, DMSO-d6) d -62.70 (CF3, s), -80.47 (CF3, s)

Optical rotation [a]²¹D at 589 nm + 14.4 ° (c = 0.522, MeOH).

Example 3: Second eluted peak: 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide.

LC-MS Rt = 4.94 min [M + H] + 412.1 (Method 10 min LC_v002).

NMR ¹H (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)

NMR ¹⁹F (400 MHz, DMSO-d6) d -62.70 (CF3, s), -80.48 (CF3, s).

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

Examples 4, 5 and 6 [0146] This compound, namely, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide (Ex. 4 )

<img file="PL2547656T3_D0031.tif" />

prepared according to the following procedure:

Solution containing 3-amino-6-methoxy-5-trifluoromethylpyridine-2-carboxylic acid (intermediate D) (4 g, 16.94 mmol) and 3-amino-1,1,1-trifluoro-2-methylpropane-2- hydrochloride olu (intermediate R) (3.04 g, 16.94 mmol) in NMP (188 mL) was treated with HATU (7.73 g, 20.33 mmol) and then dropped (2 mL portions) DIPEA (8.88 ml, 50.8 mmol) for 1 hour. After stirring for another hour, the reaction mixture was poured into water (450 mL) and EtOAc (450 mL). The aqueous phase was acidified with 5M HCl (50 ml) and the layers separated. The organic portion was washed with 2M NaOH (200 mL), water (4 x 200 mL), brine (2 x 100 mL), dried over MgSO 4, filtered and concentrated under reduced pressure to give a brown solid. Purification of the solid by silica chromatography (220 g cartridge pre-packed with silica), eluting with 0-50% EtOAc in isohexane, gave the racemate, (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) 3-amino-6 acid amide -methoxy-5-trifluoromethyl-pyridine-2-carboxyl (Ex 4) in the form of a yellow solid; NMR¹H (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 min; MS m / z 362.4 [M + H] +; Method 2 min LC_v003.

[0147] The chiral separation of the racemate by Supercritical Fluid Chromatography was carried out using the following conditions to give the compounds mentioned hereinafter:

<td>Mobile phase:</td><td>12% 2-propanol + 0.1% DEA / 50% CO2</td>

<td>Column:</td><td>Chiralcel OD-H, 250 x 10 mm id, 5 μιτι (2 columns connected in number)</td>

<td>Detection:</td><td>UV @ 220nm</td>

<td>Speed flow</td><td>10 ml / min</td>

<td>Sample Concentration:</td><td>3.5 g in 30 ml EtOH</td>

<td>Injection Volume:</td><td>100GB</td>

Examples 5 and 6 are enantiomers.

[0148] Example 5: First eluted peak Rt = 7.30 minutes. 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide:

<img file="PL2547656T3_D0032.tif" />

NMR ¹H (400MHz, DMSO-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 min, [M + H] + 362.4 (Method 2 min LC_v003).

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

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

[0149] Example 6: Second eluted peak Rt = 8.29 minutes. 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide

<img file="PL2547656T3_D0033.tif" />

NMR ¹H (400MHz, DMSO-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 min [M + H] + 362.4 (Method 2 min LC_v003).

[0150] Alternatively, Example 5 can be prepared according to the following method:

To a solution of 3-amino-6-methoxy-5-trifluoromethylpyridine-2-carboxylic acid (intermediate D) (10 g, 42.3 mmol) and (S) -3-amino-1,1,1-trifluoro- hydrochloride 2-methylpropan-2-ol (intermediate RA) (7.60 g, 42.3 mmol) in NMP (400 ml) was added

HATU (19.3 g, 50.8 mmol), after which DIPEA (22.19 mL, 127 mmol) was added dropwise over ~ 1 hour. After stirring at room temperature for 30 min, the mixture was added to EtOAc (2 L), washed with 1 M NaOH (2 x 1 L), water (1 L), brine (1 L), dried (MgSO 4) and evaporated under reduced pressure. pressure to give the crude product as a dark brown oil.

[0151] Purification by silica chromatography, eluting with a gradient of 1 to 25% EtOAc in isohexane gave a yellow oil. Recrystallization of oil from isohexane / DCM gave 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide as a crystalline solid; NMR¹H (400MHz, DMSO-d6) δ 8.28 (1H, t), 7.66 (1H, s), 6.67 (2H, s), 6.27 (1H, s), 3.91 (3H , s), 3.65 (1H, m), 3.45 (1H, m), 1.24 (3H, s).

NMR ¹⁹F (376MHz, DMSO-d6) -62.58 ppm (s), -80.43 ppm (s)

Example 7 3-Amino-6- (4-fluoro-phenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3,3-Trifluoro-2-hydroxy-2-methylpropyl) amide.

[0152]

<img file="PL2547656T3_D0034.tif" />

Mixture containing 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide (Ex. 3) (100) mg, 0.244 mmol), 4-fluorophenyl boronic acid (37.5 mg, 0.268 mmol) and 1,1'bis (diphenylphosphotio) ferrocenopalladium dichloride (19.90 mg, 0.024 mmol) suspended in THF (2 mL) and 1 M Cs2CO3 (0.667 ml). The vial was purged with N2, sealed and heated at 160 ° C using microwave irradiation for 15 minutes. The mixture was partitioned between EtOAc (50ml) and water (50ml). The organic portion was separated and washed with brine (30ml), dried (MgSO4), filtered through Celite® (filter material) and concentrated under reduced pressure. The crude residue was dissolved in DMSO (2ml) and purified by mass directed LCMS using a MeCN / water / 0.1% TFA eluent to give pure product. The fraction containing the product obtained as a MeCN / water / 0.1% TFA solution was poured into EtOAc (50 mL) and washed with saturated NaHCO3 (50 mL) to give the product as the free base. The organic portion was combined, dried (MgSO4) and concentrated in vacuo to give the title compound as a pale orange crystalline solid; NMR¹H (400MHz, DMSO-d6) δ 8.4 (1H, m), 7.7 (1H, s), 7.49 (2H, m), 7.29 (2H, t), 7.2 (2H , br s), 6.22 (1H, s), 3.68 (1H, m), 3.44 (1H, m), 1.22 (3H, s); LC-MS Rt 4.41 min [M + H] + 426 (Method 10 min LC_v003).

Example 8 (3-amino-6- (4-fluoro-phenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide.

[0154]

<img file="PL2547656T3_D0035.tif" />

[0155] This compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide (Ex. 2) analogously to example 8. NMR ¹H (400MHz, DMSO-d6) δ 8.42 (1H, m), 7.7 (1H, s), 7.5 (2H, m), 7.3 (2H, t), 7.21 (2H , br s), 6.24 (1H, s), 3.68 (1H, m), 3.44 (1H, m), 1.22 (3H, s); LC-MS Rt = 4.39 min [M + H] + 426 (Method 10 min LC_v003).

Examples 9 and 10 [0156] 3-Amino-6 (2,4-dichlorophenyl) -5-trifluoromethylpyridine-2-carboxylic acid (3,3,3-trifluoro-2-methylpropyl) amide enantiomers 364 amino-6- (2,4-dichlorophenyl) -5-trifluoromethylpyridine-2-carboxyl (intermediate H) and 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride analogously to example 1 and separated by chiral separation using Supercritical Fluid Chromatography:

Example 9: First eluted peak. 3-amino-6- (2,4-dichlorophenyl) -5-trifluoromethylpyridine-2-carboxylic acid enantiomer 1 (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide:

<img file="PL2547656T3_D0036.tif" />

NMR ¹H (400 MHz, DMSO-d6) δ 8.38 (t, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.60 (d, 1H), 7.54 (d, 1H), 7.39 (br s, 2H), 6.25 (br s, 1H). 3.71 (dd, 1H), 3.48 (dd, 1H), 1.26 (s, 3H); LC-MS Rt = 1.65 min [M + H] + 476 (Method 2 min LC_v002).

[0157] Example 10: Second eluted peak. 3-amino-6- (2,4-dichlorophenyl) -5-trifluoromethylpyridine-215 carboxylic acid 2 (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide enantiomer.

<img file="PL2547656T3_D0037.tif" />

NMR ¹H (400 MHz, DMSO-d6) δ 8.38 (t, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.60 (d, 1H), 7.54 (d, 1H), 7.39 (br s, 2H), 6.25 (br s, 1H), 3.71 (dd, 1H), 3.48 (dd, 1H) , 1.26 (s, 3H); LC-MS

Rt 1.65 min [M + H] + = 476.1 (Method 2 min LC_v002).

Example 11 3-Amino-6- (4-fluorophenyl) -5-trifluoromethylpyridine-2-carboxylic acid (2-hydroxy-2-methylpropyl) amide [0158]

<img file="PL2547656T3_D0038.tif" />

To a mixed suspension of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methylpropyl) amide (Ex. 1.10) (180 mg, 0.505 mmol) and 4-fluorophenyl boronic acid (106 mg , 0.758 mmol) in 2: 1 toluene: EtOH (12ml) under nitrogen atmosphere, 2M Na2CO3 (aq) (1.011 ml, 2.022 mmol) was added followed by Pd adduct (dppf) Cl2. CH2Cl2 (41 mg, 0.051 mmol). The reaction mixture was heated using microwave irradiation at 140 ° C for 1 hour and then allowed to cool to RT. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). The organic phase was separated, filtered through Celite® (filter material) dried (MgSO4) and concentrated in vacuo to give a brown oil / solid. Purification by silica chromatography eluting with MeOH / DCM gave a yellow oil / solid. They were passed through an Isolute® Si-TMT 500 mg cartridge (silica with 2,4,6-trimercaptotriazine, pre-wetted with DCM) eluting with 30% MeOH / DCM (50 mL) to give a yellow oil / solid. The crude product was dried in vacuo and suspended in ~ 0.5ml DCM. The resulting suspension was removed by filtration and the filtrate was evaporated to give the title compound as a light yellow / brown foamy solid; LC-MS Rt = 5.30 min [M + H] + 372 (Method 10 min LC_v002). NMR ¹H (400 MHz, DMSO-d6), δ 8.29 (1H, t), 7.69 (1H, s), 7.49 (2H, t), 7.29 (2H, t), 7.22 (2H, s), 4.63 (1H, s), 3.24 (2H, d),

1.08 (6H, s).

Example 12 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-Trifluoro-2-hydroxypropyl) amide [0160]

<img file="PL2547656T3_D0039.tif" />

Step 1: 3- (2,5-Dimethylpyrrol-1-yl) -6-methoxy-5-trifluoromethylpyridine-2-carboxylic acid (3,3,3-Trifluoro-2-hydroxypropyl) amide [0161] This compound was prepared from 3 - (2,5-dimethylpyrrol-1-yl) -6-methoxy-5-trifluoromethyl-pyridine-2-carboxyl (intermediate D2) and 3-amino-1,1,1-trifluoropropan-2-ol in analogy to Example 1; LC-MS Rt = 1.50min [M + H] + 426 (Method 2 min LC_v002).

Step 2: 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxypropyl) amide 3 acid (3,3,3-Trifluoro-2-hydroxypropyl) amide - (2,5-dimethylpyrrol-1-yl) -6-methoxy-5-trifluoromethyl-pyridine-2-carboxyl (350 mg, 0.823 mmol) was dissolved in EtOH (14 mL) and water (7 mL). Hydroxylamine hydrochloride (572 mg, 8.23 ​​mmol) was added, followed by TEA (167 mg, 1.646 mmol) and the mixture was refluxed overnight. After cooling to RT, the mixture was purified by reverse phase chromatography, eluting with MeOH; water (0.1% TFA) to give the title compound as a pale yellow solid; LC-MS Rt = 4.20 min [M + H] + 348.2 (Method 10 min LC_v002)

NMR 1H (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)

NMR 19F (400 MHz, DMSO-d6) d -62.67 (CF3, s), -77.05 (CF3, s), TFA trace.

Example 14 5-Amino-6'-methyl-3-trifluoromethyl- [2,3 '] bipyridinyl-6-carboxylic acid (3,3,3-Trifluoro-2-hydroxy-2-trifluoromethylpropyl) amide [0163]

<img file="PL2547656T3_D0040.tif" />

[0164] This compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropyl) amide (Ex. 1.28) and 2-methylpyridine-5- boron, analogous to Example 8. LC-MS Rt 1.28 min; 477 [M + H] +; (Method 2 min LC_v002); NMR¹H (400 MHz,

MeOD) δ 8.50 (1H, s), 7.85 (1H, dd), 7.69 (1H, s), 7.40 (1H, d), 4.00 (2H, s), 2, 62 (3H, s).

Example 15 5-Amino-6'-methyl-3-trifluoromethyl- [2,3 '] bipyridinyl-6-carboxylic acid (3,3,3-Trifluoro-2-hydroxy-2-methylpropyl) amide [0165]

<img file="PL2547656T3_D0041.tif" />

[0166] This compound was prepared by chiral separation of 5-amino-6'-methyl-3-trifluoromethyl- [2,3 '] bipyridinyl-6-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide 1.29) using Supercritical Fluid Chromatography; LC-MS Rt 3.15 min [M + H] + 423; (Method 10 min LC_v002); NMR¹H (400 MHz, DMSO-d6) δ 8.53 (1H, s), 8.49 (1H, t), 7.75 (1H, d), 7.71 (1H, s), 7.35 ( 1H, d), 7.25 (2H, s), 6.22 (1H, s),

3.69 (1H, dd), 3.42 (1H, dd), 2.54 (3H, s), 1.22 (3H, s). SFC Retention time: 4.87 min.

Examples 16 and 17 (3-amino-5,6-bistrifluoromethyl-pyridine-2-carboxylic acid and ((R) -3,3, ((S) -3,3,3-Trifluoro-2-hydroxy-2-methylpropyl) amide 3-amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid 3-trifluoro-2-hydroxy-2-methylpropyl) amide [0167]

<img file="PL2547656T3_D0042.tif" />

Level 1: 3- (2,520 dimethylpyrrol-1-yl) -5,6-bis-trifluoromethylpyridine-2-carboxylic acid (3,3,3-Trifluoro-2-hydroxy-2-methylpropyl) amide [0168] To a mixed solution of 3- (2,5-dimethylpyrrol-1-yl) -5,6-bistrifluoromethylpyridine-2-carboxylic acid (intermediate M) (1.16 g, 3.29 mmol) in NMP (32 ml) 3-amino-1 hydrochloride was added , 1,1-trifluoro-2-methyl-propan-2-ol (commercially available) (591 mg, 3.29 mmol) followed by HATU (1.25 g, 3.29 mmol) and NEt3 (918 gl . 6.59 mmol) and the reaction mixture was allowed to stir at RT. After 1 hour, another 0.2 equivalent was added. NEt3. After 15 min, another 0.4 equivalent was added.

NEt3 and 0.2 equivalent amine. After 30 min, another 0.1 equivalent was added. HATU. After a minute, most of the starting material was consumed. The reaction mixture was added to

EtOAc (50 mL), washed with 0.1M NaOH and the aqueous layer was extracted again with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (2 x 150 mL), brine (100 mL), dried (MgSO 4) and concentrated in vacuo to give the crude product as an orange oil.

[0169] The crude material was purified by silica chromatography eluting with 015% EtOAc in isohexane to give the title product as a yellow solid; LC-MS Rt 1.32 min; MS m / z 478.2 [M + H] +; Method 2 min LC_v003.

Step 2: 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-Trifluoro-2-hydroxy-2-methylpropyl) amide [0170] To a mixed solution (3,3,3-trifluoro- 3- (2,5-Dimethylpyrrol-1-yl) -5,6-bis-trifluoromethylpyridine-2-carboxylic acid 2-hydroxy-2-methylpropyl) amide (985 mg, 2.064 mmol) in EtOH / H2O 2: 1 ( 7.5 ml) hydroxylamine hydrochloride (1.43 g, 20.64 mmol) was added, followed by NEt3 (575 ml, 4.13 mmol). The reaction mixture was heated to reflux (~ 98 ° C) for 11.5 hours and then allowed to cool to RT. The solvent was removed under reduced pressure and the obtained residue was partitioned between EtOAc (25 mL) and water (25 mL). The aqueous layer was separated and extracted with EtOAc (2 x 25 mL) and the combined organic extracts were washed with brine (50 mL), dried (MgSO 4) and concentrated in vacuo. The crude material was purified by silica chromatography, eluting with 0-25% EtOAc in isohexane to give the title product as a pale yellow solid; LC-MS: Rt 1.24 min; MS m / z 400.0 [M + H] +; Method 2 min LC_v003.

Step 3: 3-amino5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid (((S) -3,3,3-Trifluoro-2-hydroxy-2-methylpropyl) amide and ((R) -3,3,3 -Trifluoro-2-hydroxy-2-methylpropyl) 3-amino-5,6-bistrifluoromethyl-pyridine-2-carboxylic acid

<img file="PL2547656T3_D0043.tif" />

[0172] These compounds were prepared by chiral separation (3, 3-amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

Enantiomer 1: LC-MS Rt 1.23 min; MS m / z 400.0 [M + H] +; Method 2 min LC_v003. Retention time SFC 5.07 min.

[0173] Enantiomer 2: LC-MS Rt 1.23 min; MS m / z 400.0 [M + H] +; Method 2 min LC_v003. Retention time SFC 5.13 min.

Example 18

3-Amino-6-methoxy-N- (3,3,3-trifluoro-2- (4-methoxybenzylamino) -25-methylpropyl) -5- (trifluoromethyl) picolinamide [0174]

<img file="PL2547656T3_D0044.tif" />

[0175] The title compound was prepared analogously to Example 1 from 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (intermediate D) and 3,3,3-trifluoro-N2- (4-methoxybenzyl) -2-methylpropane-1 , 2-diamines (intermediate N). DIPEA was used in this reaction. NMR¹H (400 MHz, DMSO-d6) δ 8.27 (1H, m), 7.68 (1H, s), 7.25 (2H, d), 6.83 (2H, d), 6.70 ( 2H, s), 3.85 (3H, s), 3.75 (2H, m), 3.72 (3H, s), 3.70 (1H, m), 3.47 (1H, m), 2.80 (1H, t), 1.24 (3H, s)

Example 19

3-Amino-N- (2-amino-3,3,3-trifluoro-2-methylpropyl) -6-methoxy-5- (trifluoromethyl) picolinamide [0176]

<img file="PL2547656T3_D0045.tif" />

[0177] A mixture containing 3-amino-6-methoxy-N- (3,3,3-trifluoro-2- (4-methoxybenzylamino) -2-methylpropyl) -5- (trifluoromethyl) picolinamide (Ex 18) (0.9 g.

1.873 mmo) in TFA (50 mL) was heated to 50 ° C for 2 hours. After cooling to RT, the pH was adjusted to pH 12 with 2M NaOH. The product was extracted with DCM and the organic extract was washed with water, dried over MgSO 4 and concentrated in vacuo. The crude product was loaded onto an SCX-2 cartridge eluting with MeOH, then 2M NH3 in MeOHMethanolic ammonia fractions were concentrated under reduced pressure and dried under reduced pressure to give the title compound. NMR¹H (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 min; MS m / z 361.2 [M + H] +; Method 2 min LC_v003.

Example 20

3-amino-6- (pyrrolidin-1-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5 (trifluoromethyl) picolinamide [0178]

<img file="PL2547656T3_D0046.tif" />

Step 1: 3- (2,5-Dimethyl-1H-pyrrol-1-yl) -6- (pyrrolidin-1-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) - 5- (trifluoromethyl) picolinamide [0179] The title compound was prepared from intermediate DA analogously to example 1; LC-MS Rt 1.42 min; MS m / z 479.3 [M + H] +; Method 2 min LC_v003.

Step_2: 3-Amino-6- (pyrrolidin-1-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide [0180] This compound was prepared from 3- ( 2,5-dimethyl-1H-pyrrol-1-yl) -6- (pyrrolidin-1-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide analogous to intermediate D (final step). The resulting racemate was separated by SFC to give the title compound; First eluted peak:

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

LC-MS Rt 3.87 min; MS m / z 401.3 [M + H] +; Method 10 min LC_v003.

Example 21 (S) -3-Amino-6-ethoxy-N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5 (trifluoromethyl) picolinamide [0181]

<img file="PL2547656T3_D0047.tif" />

[0182] The title compound was prepared from intermediate DB and intermediate R analogously to example 20; NMR¹H (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, mult), 3.5 (1H, mult), 1.3 (3H, t), 1.2 (3H, s).

LC-MS Rt 1.20 min; MS m / z 376.2 [M + H] +; Method 2 min LC_v003.

Example 22

3-Amino-6-bromo-N- (2-morpholinoethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide [0183]

<img file="PL2547656T3_D0048.tif" />

To a mixed solution of 3-amino-6-bromo-5-trifluoromethylpyrazine-2-carboxylic acid (intermediate C) (250 mg, 0.874 mmol) in NMP (8 mL) was added 4- (215 aminoethyl) morpholine (138 µL, 1.049 mmol) followed by DIPEA (763 ul, 4.37 mmol). To this solution, HATU (499 mg, 1.311 mmol) was then added in portions and the reaction mixture was allowed to stir at RT for 1 hour. Then 1 equivalent was added. 4- (2-aminoethyl) morpholine. After another 1.5 h, 0.5 eq. HATU (166 mg, 0.425 mmol) and RM were allowed to stir for another 30 min.

The mixture was added to EtOAc (50 mL) and washed with 0.1 M NaOH (50 mL). The aqueous layer was back extracted with EtOAc (50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over magnesium sulfate and evaporated under reduced pressure to give a brown oil (418 mg). The crude product was purified by chromatography (Biotage- silica 20 g / 70 ml column, EtOAc / iso-hexane

3: 1). The resulting yellow residue was loaded onto an SCX-2 cartridge (10 g), which was pre-wetted with MeOH. The cartridge was washed with MeOH (140 ml) and eluted with 3.5M ammonia in methanol solution (70 ml). The appropriate fractions were evaporated under reduced pressure to give a solid. This solid was dissolved in

EtOAc and filtered under reduced pressure. The filtrate was evaporated under reduced pressure and then dried under reduced pressure to give the title compound as a yellow solid; LC-MS: Rt 2.61 min; MS m / z 398.2 [M + H] +; Method 10 min LC_v002

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

Example 23

N- (2- (1H-imidazol-2-yl) propyl) -3-amino-6-bromo-5- (trifluoromethyl) pyrazine-2-carboxamide [0185]

<img file="PL2547656T3_D0049.tif" />

[0186] The title compound prepared from 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (intermediate C) and 2- (1H-imidazol-2-yl) propan-1-amine (prepared according to the procedure Steffens, Robert; Schunack , Walter. Histamine analogs, XXVI. Racemic histamine H1-agonists. Archiv der Pharmazie (Weinheim, Germany) (1984), 317 (9), 771-6; NMR ¹H (400 MHz, DMSO-d6) δ 11.8 (1H, s), 9.0 (1H, t),

8.1 (2H, s), 7.0 (1H, s), 6.8 (1H, s), 3.55 (2H, m), 3.15 (1H, m), 1.2 (3H , d). LC-MS [M + H] + 393.0 / 395.1

Examples 24a and 24b

3-amino-N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5,6-bis (trifluoromethyl) pyrazine-2-carboxamide enantiomers [0187]

<img file="PL2547656T3_D0050.tif" />

[0188] The title compound was prepared from intermediate BA and 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol in analogy to Example 4. Chiral separation of the racemate by Supercritical Fluid Chromatography gave the title compound;

Example 24a: First eluted peak: 3-amino-N- (3,3,3-trifluoro-2-hydroxy2-methylpropyl) -5,6-bis (trifluoromethyl) pyrazine-2-carboxamide enantiomer;

NMR ¹H (400MHz, DMSO-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 min; MS m / z 401.2 [M + H] +; Method 10 min LC_v003.

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

NMR ¹H (400MHz, DMSO-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 min; MS m / z 401.2 [M + H] +; Method 10 min LC_v003.

Optical rotation [a]²¹D at 589 nm + 22.0 ° (c = 0.517, MeOH).

Example 25

3-Amino-6- (1-methyl-1H-pyrazol-4-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide [0189]

<img file="PL2547656T3_D0051.tif" />

Step_1 3-Amino-6- (1-methyl-1H-pyrazol-4-yl) -5 (trifluoromethyl) picolinic acid [0190] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (intermediate A4 ) (500 mg, 1.672 mmol), PdCl2 adduct (dppf) CH2Cl2 (205 mg, 0.251 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) -1H-pyrazole (383 mg, 1.839 mmol) and Cs2CO3 (6.69 mL, 6.69 mmol) in THF (12 mL) under N2, heated under microwave irradiation at 150 ° C for 10 minutes. 2M NaOH (5 mL) was added and the mixture was stirred at RT overnight. The mixture was filtered through Celite® (filter material) and the organic solvent removed. The resulting aqueous layer was washed with EtOAc and acidified to pH 1. The product was extracted with DCM and concentrated under reduced pressure to give the title compound;

Stage 2; 3-amino-6- (1-methyl-1H-pyrazol-4-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide [0191] The title compound was prepared from 3-amino-6- (1-methyl-1H-pyrazol-4-yl) -5 (trifluoromethyl) picolinic acid and 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol analogously to the example 4. NMR¹H (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 min; MS m / z 412.3 [M + H] +; Method 10 min LC_v003.

Example 26 3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (2-methoxyphenyl) ethyl] amide [0192]

<img file="PL2547656T3_D0052.tif" />

[0193] The title compound prepared from 3-amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid (intermediate PA) and the corresponding amine; MS m / z 406.93 [M + H] +

Preparation of intermediates

Intermediate A

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid [0194]

<img file="PL2547656T3_D0053.tif" />

Intermediate A1: 2-Bromo-3-nitro-5-trifluoromethyl-pyridine 3-Nitro-5- (trifluoromethyl) pyridin-2-ol (31.00 g, 149 mmol) was dissolved in acetonitrile (250 ml) to form a dark brown solution. Phosphorus (V) oxybromide (85 g, 298 mmol) was added and the mixture was refluxed for 4.5 hours and then stirred at RT overnight. The reaction mixture was stopped by pouring into vigorously stirred water (600 ml) containing sodium bicarbonate (110 g). The dark brown mixture was extracted with DCM (3 x 200 mL) and the organic phase was washed with water (200 mL) and brine (100 mL), dried (MgSO 4) and concentrated in vacuo to give the title product as a brown oil. NMR¹H: [400MHz, CDCfe, δH 8.87 (1H, d, J = 1.4 Hz, ArH), 8.39 (1H, d, J = 1.9 Hz, ArH).

Intermediate A2: 3-Nitro-5-trifluoromethylpyridine-2-carbonitrile [0196] 2-Bromo-3-nitro-5-trifluoromethylpyridine (10.00 g, 36.87 mmol) was dissolved in toluene (250 mL) with stirring, to give a pale yellow solution. Tetrabutylammonium bromide (11.90 g, 36.9 mmol) was added, followed by copper (I) cyanide (9.92 g, 111 mmol) and the mixture was refluxed for 10 hours. After cooling to RT, the reaction mixture was partitioned between water (750 ml) and EtOAc (750ml). The organic fractions were combined, washed with water (2 x 250ml) and brine (100ml), dried (MgSO4) and concentrated in vacuo to give the title product. NMR¹H: [400MHz, DMSO-d₆ δ_Η 9.55 (1H, m, ArH), 9.24 (1H, m, ArH)

Intermediate A3: 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester [0197] 3-Nitro-5-trifluoromethyl-pyridine-2-carbonitrile (6.5 g, 29.9 mmol) was dissolved in EtOAc (150 mL) to give pale yellow solution and placed under nitrogen. 10% palladium on activated carbon (3.19 g, 2.99 mmol) was added and the reaction mixture was stirred under an atmosphere of hydrogen for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was dissolved in conc. HCl (45 ml) and heated to reflux for 24 hours. The reaction mixture was allowed to cool to RT and concentrated under reduced pressure. The solid was dissolved in MeOH (300 mL) and sulfuric acid (14.4 mL) was added. The resulting solution was heated to reflux for 48 hours. The reaction was allowed to cool to RT, then neutralized by the addition of 10% NaHCO3 (aq) (600 mL). The product was extracted into DCM (3 x 200 mL) and the combined organic phases were washed with water (200 mL), brine (50 mL), (MgSO 4) and concentrated under reduced pressure. The resulting solid was purified by silica chromatography: eluant gradient: isohexane (500 mL), 10% EtOAc in isohexane (1000 mL), 20% EtOAc in isohexane (1500 mL) to give the title compound as a pale yellow solid NMR¹H: [400MHz, DMSO-d6, δH 8.13 (1H, d, J = 1.7 Hz, ArH), 7.60 (1H, d, J = 1.3 Hz, ArH), 7.01 (2H, br, NH2), 3.85 (3H, s, ArOCH3), m / z 221.1 [M + H]⁺Intermediate A4: 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester [0198] 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (9.49 g, 43.16 mmol) was suspended in water (300 ml). Sulfuric acid (4.60 mL, 86 mmol) was added followed by dropwise a solution of bromine (2.222 mL, 43.1 mmol) in acetic acid (29.6 mL, 517 mmol) dropwise over 30 minutes. The reaction mixture was stirred at RT for 18 hours. Then 100 ml water was added followed by a further 0.25 equivalent of the bromine / AcOH mixture (550 g bromine in 7.4 ml AcOH) and the reaction mixture was stirred at RT for an additional 90 minutes. The reaction mixture was diluted with 500 mL water and neutralized by the addition of solid NaHCO3 (~ 85 g). The suspension was extracted with DCM (3 x 300 mL) and the combined organic phases were washed with saturated NaHCO 3 (aq) (250 mL), water (250 mL) and brine (100 mL), dried (MgSO 4) and concentrated in vacuo. The crude material was recrystallized from boiling MeOH (~ 300 mL) to give the title product as a pale orange solid m / z 301.0 [M + H]⁺ NMR ¹H: [400MHz, DMSO-d6 δH 7.77 (1H, s, ArH), 7.17 (2H, s, NH), 3.86 (3H, s, ArCOzCHs).

Intermediate A: 3-Amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid [0199] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.40 g, 4.68 mmol) was suspended in MeOH (15 ml); sodium hydroxide (2.0 M aqueous solution) (14.04 mL, 28.1 mmol) was added and the suspension was stirred at RT overnight. The mixture was concentrated under reduced pressure and the obtained residue was dissolved in water (100 mL) and then acidified by the addition of 5.0 M HCl (aq). The product was extracted into ethyl acetate (2 x 75 mL) and the combined organic extracts washed with water (50 mL), brine (25 mL), dried (MgSO 4) and concentrated in vacuo to give the title product as a yellow solid. NMR¹H: [400MHz, DMSO-d6, δH 13.24 (1H, br s, CO2H), 7.74 (1H, s, ArH), 7.17 92H, br s ArNH2). m / z 285.1, 287.1 [M + H]⁺

Intermediate B

3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester [0200]

<img file="PL2547656T3_D0054.tif" />

[0201] Intermediate B1: Carbamimidoylnitrosoacetic acid ethyl ester. To a solution of 2M ammonia in ethanol (152 mL, 0.304 mmol) at 0 ° C to 5 ° C, ethyl ethoxycarbonylacetoimidate HCl (25 g, 0.127 mmol) was added over 30 minutes. The reaction was stirred vigorously at this temperature for 3 hours, after which a solution of sodium nitride in water (9.63 g, 0.139 mmol) was added in one portion. The pH of the mixture was adjusted to pH 6 by adding 5 N HCl. The reaction mixture was allowed to stir at RT overnight. The yellow precipitate formed was filtered under reduced pressure, washed with water and dried to give the title compound;

NMR ¹H (400 MHz, DMSO-d6) δ 10.1 (2H, br s), 7.6 (2H, br s), 4.3 (2H, q), 1.3 (3H, t). [0202] Intermediate B2: aminocarbamimidoylacetic acid ethyl ester. To a solution of carbamimidoylnitrosoacetic acid ethyl ester (5.5 g, 31.4 mmol) in ethanol / 5M HCl (1: 1 ratio, 250 mL) was added 10% Pd / C (1.3 g). The reaction mixture was hydrogenated (H2 (g)) under reduced pressure for 2 nights. Pd / C was filtered through Celite® (filter material) and the filtrate was reduced under reduced pressure to give the title compound as a white solid. They were taken to the next stage in raw form.

[0203] Intermediate B: 3-amino-5-trifluoromethylpyrazine-2-carboxylic acid ethyl ester. To a mixture of aminocarbamimidoylacetic acid ethyl ester (2 g, 9.22 mmol) and water (50 mL), a 20% aqueous solution of trifluoropyruvic aldehyde (2.32 g, 18.43 mmol) was added. Sodium acetate (5.29 g, 64.52 mmol) was added to this mixture (pH of the reaction mixture was 5). The reaction mixture was allowed to stir at RT overnight. The resulting precipitate was filtered under reduced pressure, purified by silica chromatography eluting with isohexane: EtOAc (gradient from 0 to 10% EtOAc) to give the title compound NMR ¹H (400 MHz, DMSO-d6) δ 8.4 (1H, s), 7.8 (2H, br s), 4.4 (2H, q), 1.4 (3H, t).

Indirect BA

3-Amino-5,6-bis (trifluoromethyl) pyrazine-2-carboxylic acid [0204]

<img file="PL2547656T3_D0055.tif" />

Step 1: Ethyl 3-amino-5,6-bis (trifluoromethyl) pyrazine-2-carboxylate [0205] The title compound prepared from aminocarbamimidoylacetic acid methyl ester (intermediate B2) and 1,1,1,4,4,4- 2,3-dione hexafluorobutane, analogous to intermediate B; 10 LCMS Rt = 4.72 minutes, [M + H] + 304.2 / 326.1 Method 10 min LC_v002.

Step 2: Ethyl 3-amino-5,6-bis (trifluoromethyl) pyrazine-2-carboxylic acid To a mixed solution of ethyl 3-amino-5,6-bis (trifluoromethyl) pyrazine-2-carboxylate (300 mg, 0.990 mmol) in EtOH (10 mL), 2M NaOH (0.495 mL, 0.990 mmol) was added dropwise over 1 minute. After stirring at RT for 30 minutes, the reaction mixture was poured into water (30 mL) and the pH was adjusted to pH 4 by the addition of 1 M HCl. The mixture was extracted with EtOAc (2 x 50ml) and the combined organic extracts washed with brine (30ml), dried over MgSO4 (5g), filtered and concentrated under reduced pressure to give the title compound as a off-white crystalline solid;

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

Intermediate C

3-amino-6-bromo-5-trifluoromethylpyrazine-2-carboxylic acid [0207] ο

F

F

<img file="PL2547656T3_D0056.tif" />

OH

E

Intermediate C1: 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester [0208] To solution of 3-amino-5-trifluoromethyl-pyrazine-carboxylic acid methyl ester (intermediate B) (30 mg, 0.13 mmol) in acetic acid (5 ml), sodium carbonate (15 mg, 0.14 mmol) was added. To this mixture, half the bromine solution (7 g, 0.13 mmol) in acetic acid (5 mL) was added, followed by the addition of sodium carbonate (15 mg, 0.14 mmol). The remaining bromine in acetic acid solution was added and the reaction mixture was allowed to stir at RT for 2 hours. The mixture was diluted with water and the resulting yellow precipitate was filtered under reduced pressure to give the title compound.

Intermediate C: 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [0209] To a mixed solution of 3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester (10 g, 31.8 mmol) in ethanol (20 ml) 2M was added

NaOH (20 mL, 31.8 mmol).

[0210] The resulting solution was stirred at RT for 5 minutes and poured into water (50 ml). The pH was adjusted to 6 by adding 1 M HCl. The resulting suspension was filtered under reduced pressure, washed with water (20ml) and dried to give the title compound; MS m / z 287 [M + H]⁺. NMR¹H (400 MHz, DMSO-d6) δ 7.98 (2H, s).

Intermediate relationship D

3-amino-6-methoxy-5-trifluoromethylpyridine-2-carboxylic acid [0211]

OH

F

Intermediate D1: 6-Bromo-3- (2,5-dimethylpyrrol-1-yl) -5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester [0212]

<img file="PL2547656T3_D0057.tif" />

[0213] 3-Amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid methyl ester (intermediate A4) (2 g, 6.69 mmol) was suspended in toluene (8 mL) and treated with p-toluenesulfonic acid (TsOH) ( 0.115 g, 0.669 mmol) and acetonylacetone (0.941 mL, 8.03 mmol). The reaction mixture was refluxed for 2 hours (using a Dean-Stark apparatus) and allowed to cool to RT overnight. The resulting dark red / black solution was concentrated under reduced pressure to remove toluene, and the crude residue was diluted with EtOAc (200 mL), washed with NaHCO3 (50 mL), dried (MgSO4) and concentrated under reduced pressure to give a brown solid. Purification of the solid by silica chromatography, eluting with the EtOAc / isohexane mixture, gave the title compound; LC-MS Rt = 5.58 min [M + H] + 377/379 (Method 10 min LC_v002). NMR¹H (400 MHz, DMSO-d6) δ 8.50 (1H, s), 7.77 (2H, s), 5.83 (3H, s), 1.90 (6H, s); NMR¹⁹F (400 MHz, DMSO-d6) δ -62.26 (CF3, s).

Intermediate D2: 3- (2,5-Dimethylpyrrol-1-yl) -6-methoxy-5-trifluoromethylpyridine-2-carboxylic acid [0214]

<img file="PL2547656T3_D0058.tif" />

[0215] 6-Bromo-3- (2,5-dimethylpyrrol-1-yl) -5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (2 g, 5.30 mmol) was dissolved in MeOH (40 mL) and treated with 2M NaOH (20 mL) to form a suspension, which was stirred at RT for 1 h to give a clear solution. The solvent was removed under reduced pressure and the obtained residue was acidified to pH 1 with 5 M HCl. The mixture was extracted with EtOAc (200 mL) and the organic extract dried (MgSO 4) and concentrated under reduced pressure to give the title compound as a dark brown solid which was used in the next step without further purification; LC-MS Rt = 1.50 min [M + H] + 315.2.1 / 316.2 (Method 2 min LC_v002); NMR¹H (400 MHz, DMSO-d6) δ14.42-12.61 (COOH, b), 8.25 (1H, s), 5.84 (2H, s), 4.13 (3H, s),

1.97 (6H, s); NMR¹⁹F (400 MHz, DMSO-d6) δ -62.43 (CF3, s).

Intermediate D: 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid 3- (2,5-Dimethyl-pyrrol-1-yl) -6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (2, 1g, 6.68 mmol) was dissolved in EtOH (40 mL) and water (20 mL). To this mixture, TEA (2.79 mL, 20.05 mmol) was added, followed by hydroxylamine hydrochloride (4.64g, 66.8 mmol). The resulting mixture was heated to reflux for 5 hours. After cooling to RT, the mixture was diluted with EtOAc (100ml) and washed with hydrated HCl (1M, 100ml). The aqueous phase was back extracted with EtOAc (100ml) and the combined organic phases were washed with brine (100ml), dried (MgSO4) and concentrated in vacuo to give the product as an orange solid. The material can be used crude or recrystallized from isohexane-EtOAc (10: 1). LC-MS Rt = 1.0 min [M + H] + 237 (Method 2 min LC_v003)

NMR ¹H (400 MHz, DMSO-d6) δ 8.5 (NH2, b), 7.70 (1H, s), 3.89 (3H, s).

Indirect DA

3- (2,5-Imethyl-1H-pyrrol-1-yl) -6- (pyrrolidin-1-yl) -5 (trifluoromethyl) picolinic acid [0217]

<img file="PL2547656T3_D0059.tif" />

[0218] Step 1: 6-Bromo-3- (2,5-dimethyl-1H-pyrrol-1-yl) -5- (trifluoromethyl) picolinic acid. 6-bromo-3- (2,5-dimethylpyrrol-1-yl) -5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.9 g, 5.04 mmol) and 2M NaOH (2.52 mL, 5.04 mmol ) in THF (10 mL) was stirred at RT for 1 hour. The reaction mixture was poured into water (50ml) and the pH was adjusted to 4 by the addition of 1 M HCl. The mixture was extracted with EtOAc (2 x 50ml) and the organic portion was washed with brine (30 mL), dried over MgSO 4 (5g), filtered and concentrated to give the title compound as a crystalline orange solid; LC_MS Rt = 1.21 min [M + H] + 363.1 (Method 2 min LC_v003).

[0219] Step 2: 3- (2,5-Dimethyl-1H-pyrrol-1-yl) -6- (pyrrolidin-1-yl) -5 (trifluoromethyl) picolinic acid. To a mixed solution of 6-bromo-3- (2,5-dimethyl-1H-pyrrol-1-yl) -5- (trifluoromethyl) picolinic acid (300 mg, 0.826 mmol) in THF (1 mL), pyrrolidine (0.136 mL, 1.652 mmol). The orange solution was stirred at RT overnight. The reaction mixture was partitioned between 0.5 M HCl (30ml) and EtOAc (30ml) and shaken. The organic portion was separated and washed with brine (30ml), dried over

MgSO4, filtered and concentrated under reduced pressure to give a red oil. The crude product was purified on silica eluting with 0-40% EtOAc in isohexane to give the title product;

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

DB intermediate

3- (2,5-Dimethyl-1H-pyrrol-1-yl) -6-ethoxy-5- (trifluoromethyl) picolinic acid [0220]

<img file="PL2547656T3_D0060.tif" />

[0221] Step 1: Methyl 3- (2,5-Dimethyl-1H-pyrrol-1-yl) -6-methoxy-5- (trifluoromethyl) picolinate. 3- (2,5-Dimethyl-pyrrol-1-yl) -6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (intermediate D2) (500 mg, 1.591 mmol) in methanol (15.91 mL) was treated with H2SO4 (0 , 0424 ml, 0.795 mmol) and the solution was refluxed overnight.

[0222] The solvent was removed under reduced pressure and the brown oil obtained was neutralized to pH 7 using saturated sodium bicarbonate. The mixture was extracted with EtOAc (20 mL) and the combined organic extracts washed with water (20 mL), brine (20 mL), passed through a phase separator and concentrated under reduced pressure. Purification of the crude product by silica chromatography eluting with isohexane: EtOAc (gradient from 0 to 10% EtOAc) to give the title compound as an off-white powder.

NMR ¹H (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).

[0223] Step 2: Methyl 3- (2,5-Dimethyl-1H-pyrrol-1-yl) -6-hydroxy-5- (trifluoromethyl) picolinate. Methyl 3- (2,5-Dimethyl-1H-pyrrol-1-yl) -6-methoxy-5- (trifluoromethyl) picolinate (100 mg, 0.305 mmol) in acetonitrile (3.05 mL) was treated with KI (202 mg, 1.218 mmol) and TMS chloride (0.156 mL, 1.221 mmol) and heated to reflux for 6 hours. The solvent was removed under reduced pressure and the crude product was dissolved in EtOAc (20 mL) and washed with water (2x 10 mL) and brine (10 mL), dried over phase separator and concentrated under reduced pressure. Purification of the crude product by silica chromatography eluting with isohexane: EtOAc (gradient from 0 to 30% EtOAc) to give the title compound as a yellow powder. LC-MS Rt = 1.11 min [M + H] + 315.4 (Method 2 min LC_v003).

[0224] Step 3: Methyl 3- (2,5-Dimethyl-1H-pyrrol-1-yl) -6-ethoxy-5- (trifluoromethyl) picolinate. Methyl 3- (2,5-Dimethyl-1H-pyrrol-1-yl) -6-hydroxy-5- (trifluoromethyl) picolinate (62 mg, 0.168 mmol) in 1,4-dioxane (1.5 ml) (dry ) was treated with EtOH (0.020 mL, 0.335 mmol) and triphenylphosphine (88 mg, 0.335 mmol) and the solution was stirred. DEAD (0.053 mL, 0.335 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and purification of the crude product by silica chromatography, eluting with isohexane: EtOAc (gradient from 0 to 10% EtOAc) to give the title compound;

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

Step_4: 3- (2,5-Dimethyl-1H-pyrrol-1-yl) -6-ethoxy-5- (trifluoromethyl) picolinic acid. Methyl 3- (2,5-Dimethyl-1H-pyrrol-1-yl) -6-ethoxy-5- (trifluoromethyl) picolinate (140 mg, 0.409 mmol) was dissolved in THF (2.045 mL). NaOH (0.613 mL, 1.226 mmol) was added and heated to reflux for 6 hours. The solvent was removed under reduced pressure and the resulting mixture was diluted with EtOAc (25 mL) acidified to pH 1 with HCl (5M). The organic portion was washed with brine, dried using a phase separator and concentrated in vacuo to give the title compound as a yellow oil. LC-MS Rt = 1.26 min [M + H] + 329.2 Method 2 min LC_v003.

Intermediate compound E

3-amino-5-trifluoromethylpyridine-2-carboxylic acid [0226]

<img file="PL2547656T3_D0061.tif" />

[0227] To a mixed solution of 3-amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (intermediate A3) (1 g, 4.54 mmol) in MeOH (20 mL) was added 2M NaOH (0.182 g, 4.54 mmol) . The orange solution was stirred at RT for 1 minute and added to water (10 mL). The solution was acidified to pH 1 by the addition of 1 M HCl and the product was extracted with EtOAc (150 mL). The organics were combined, washed with brine (50 mL), dried over MgSO 4 and concentrated in vacuo to give the title compound as an orange solid; LC-MS Rt = 0.82 min [M + H] + 207.1 (Method 2 min LC_v002); NMR 1H (400MHz, DMSO-d6) δ 13.9 (1H, wide hump), 8.11 (1H, s), 7.59 (1H, s), 7.08 (2H, wide hump) (trace of presence EtOAc but correlates with the proposed structure).

Intermediate G

3-Amino-6- (4-fluoro-phenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid [0228]

<img file="PL2547656T3_D0062.tif" />

[0229] A mixture containing 3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (intermediate A) (1 g, 3.51 mmol), 4-fluorophenyl boronic acid (0.736 g, 5.26 mmol) and dichloride 1 , 1'bis (diphenylphosphotio) ferrocenopalladium (0.286 g, 0.351 mmol) and 1.0 M Cs2CO3 (3.3ml) in THF (10ml) was heated to reflux for 10 hours. After cooling to RT, the mixture was partitioned between DCM (100ml) and 1M NaOH (2 x 100ml). The aqueous phase was acidified with 5M HCl and the resulting milky solution was extracted into DCM (2 x 100ml). The organic portion was separated, dried (MgSO4) and concentrated in vacuo to give the product as a crude oil. The crude material was purified by flash chromatography on a silica cartridge, eluting with a DCM: MeOH gradient from 0% to 10% MeOH to give the title product as a pale yellow solid;

NMR ¹H (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).

Intermediate GA

3-Amino-6-cyclopropyl-5- (trifluoromethyl) picolinic acid [0230]

<img file="PL2547656T3_D0063.tif" />

Step 1: 3-Amino-6-cyclopropyl-5- (trifluoromethyl) picolinic acid [0231] The microwave tube was charged with amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (intermediate A4) (0.5 g, 1.754 mmol), cyclopropylboronic acid (0.753 g, 8.77 mmol) and 1,1'bis (diphenylphosphosphino) ferrocenopalladium dichloride (0.143 g, 0.175 mmol). The mixture was dissolved as a solution in THF (6 mL) and flushed with N2, sealed and heated using microwave irradiation at 150 ° C for 20 minutes. The reaction mixture was filtered through Celite® (filter material) and washed with EtOAc (20ml). The filtrate was partitioned between EtOAc (30ml) and water (50ml). The phases were separated and the organic portion was washed with brine (30ml), dried over MgSO4, filtered and concentrated under reduced pressure.

[0232] The crude material was dissolved in EtOAc (20ml) and dry loaded onto silica (2-3g). The material was then purified on Combiflash Rf Teledyne ISCO System 100% Isohexane to 60% EtOAc: Isohexane, to give a semi-pure material that was used without further purification.

Step 2: 3-Amino-6-cyclopropyl-5- (trifluoromethyl) picolinic acid [0233] To a mixed solution of 3-amino-6-cyclopropyl-5- (trifluoromethyl) picolinic acid (472 mg, 1.814 mmol) in THF (10 mL ), 2 M NaOH (10 mL, 20.00 mmol) was added. The orange solution was stirred at RT for 2 days. The reaction mixture was poured into water (30 mL) and the pH was adjusted to pH 6 by adding 1 M HCl. The product was extracted with EtOAc (50 mL) and the organic portion dried over MgSO 4, filtered and concentrated under reduced pressure to give the title compound as a red / orange oil. LC-MS Rt = 1.10 min [M + H] + 247.1 (Method 2 min LC_v003);

Intermediate H

3-Amino-6- (2,4-dichlorophenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid [0234]

<img file="PL2547656T3_D0064.tif" />

Intermediate H1: 3-Amino-6- (2,4-dichlorophenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester [0235] 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (intermediate A4) (3 g, 10.03 mmol), 2,4-dichlorophenyl boronic acid (2.297 g, 12.04 mmol), potassium phosphate (4.26 g, 20.06 mmol) and Fibrecat® 1034A (Johnson Matthey, palladium complex polymer support) (500 mg, 10.03 mmol) was suspended in toluene (50 ml) and water (15 ml). The reaction mixture was heated to 110 ° C with vigorous stirring for 3 hours. The mixture was allowed to cool to RT and EtOAc (100 mL) was added. The organic layer was separated and washed with brine (15 ml). MP-TMT (macroporous trimesteraptotriazine bound to polystyrene, 3 g, Polymern laboratories) was added and mixed for 1 hour at RT. MgSO4 was added and the suspension was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (C18130g column) eluting with water / MeOH to give the title compound as a white solid; LS-MS Rt = 1.55 min [M + H] + 365 (Method 2 min LC_v002).

Intermediate H: 3-Amino-6- (2,4-dichlorophenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid [0236] 3-Amino-6- (2,4-dichlorophenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester ( 0.9 g, 2.465 mmol) was suspended in MeOH (15 mL) and 2M NaOH (2.465 mL, 4.93 mmol) was added with stirring. 1,4-dioxane (15.00 ml) was added and the solution was left at RT overnight. The solvent was removed under reduced pressure and the resulting residue was dissolved in water (10 mL) and carefully acidified to pH 4 by slowly adding 2M HCl (2 mL) with stirring. The mixture was extracted with EtOAc (20 mL) and the organic portion was washed with brine and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (C18130g column) eluting with water / MeOH to give the title compound; LS-MS Rt = 1.57 min [M + H] +351.0 (Method 2 min LC_v002).

Indirect relationship

3-Amino-6- (4-chloro-2-methylphenyl) -5-trifluoromethylpyridine-2-carboxylic acid methyl ester [0237]

<img file="PL2547656T3_D0065.tif" />

[0238] This compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (intermediate A4) and 4-chloro-2-methylphenylboronic acid in analogy with intermediate H; LC-MS Rt = 1.53 min, [M + H] + 331 (Method 2 min LC_v002).

Intermediate J

2-Aminomethyl-1,1,1,3,3,3-hexafluoropropan-2-ol [0239] To a mixed mixture of 35% ammonia (1 ml) and diethyl ether (1 ml), 3,3,3- oxide was added dropwise. trifluoro-2- (trifluoromethyl) -1,2-propene (500 mg, 2.78 mmol) and the reaction mixture was allowed to stir at RT for 3 hours. The reaction mixture was separated and the aqueous layer extracted with diethyl ether (2 x 3 mL). The combined organics were dried (MgSO 4) and concentrated in vacuo to give a white crystalline solid; NMR¹H (400 MHz, DMSO-d6) δ 4.20 (wide), 3.30 (wide), 3.15 (s), 3.02 (s), 2.50 (s, DMSO). NMR¹⁹F (400 MHz, DMSO-d6) δ -85 (CF3), -84.5 (CF3).

Intermediate relationship K

5-Amino-6'-methyl-3- (trifluoromethyl) -2,3'-bipyridine-6-carboxylic acid [0240]

<img file="PL2547656T3_D0066.tif" />

Intermediate K1: 5-Amino-6'-methyl-3-trifluoromethyl- [2,3 '] bipyridinyl-6-carboxylic acid methyl ester [0241] This compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-methyl acid ester -carboxylic acid (intermediate A4) and 2-methylpyridine-5-boric acid analogously to 3-amino-6- (4-fluorophenyl) -5-trifluoromethylpyridine-2-carboxylic acid (intermediate G); LC-MS Rt 0.96 min [M + H] + 312 (Method 2 min LC_v002); NMR¹H (400 MHz, DMSO-d6) δ 8.41 (1H, s), 7.79 (1H, s), 7.69 (1H, dd), 7.32 (1H, d), 7.10 ( 2H, s), 3.82 (3H, s), 2.52 (3H, s).

Intermediate K: 5-Amino-6'-methyl-3- (trifluoromethyl) -2,3'-bipyridine-6-carboxylic acid [0242] This compound was prepared from: 5-amino-6'-methyl-3-trifluoromethyl acid methyl ester - [2,3 '] bipyridinyl-6-carboxylic acid analogous to 3-amino-6- (4-chloro-2-methylphenyl) -5-trifluoromethylpyridine-2-carboxylic acid methyl ester (intermediate I); LC-MS Rt 0.90 min; [M + H] + 298 (Method 2 min LC_v002); NMR¹H (400 MHz, DMSO-d6) δ 12.90 (1H, broad), 8.45 (1H, s), 7.72 (2H), 7.32 (1H, d), 7.12 (2H, broad), 2.51 (3H).

Intermediate relationship KA

5-amino-3- (trifluoromethyl) -2,4'-bipyridine-6-carboxylic acid [0243]

<img file="PL2547656T3_D0067.tif" />

[0244] The title compound was prepared in analogy to intermediate K, using the appropriate boric acid in step 1; NMR¹H (400 MHz, DMSO-d6) δ 13.00 (1H, broad), 8.65 (2H, d), 7.65 (1H, s), 7.43 (2H, d), 7.18 ( 2H, wide).

Intermediate relationship M.

3- (2,5-Dimethyl-pyrrol-1-yl) -5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid [0245]

<img file="PL2547656T3_D0068.tif" />

Intermediate M1: 3- (2,5-Dimethyl-pyrrol-1-yl) -5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid methyl ester [0246] Mixed KF mixture (2.12 g, 5.62 mmol) and Cul (0.490 g, 8.43 mmol) was heated in a sealed 10.0-20.0 mL vial for the microwave under reduced pressure until a slight greenish color appeared. The vial was then placed under a nitrogen atmosphere to cool. A solution of 6-bromo-3- (2,5-dimethylpyrrol-1-yl) -5-trifluoromethylpyridine-2-carboxylic acid methyl ester (intermediate D) (2.64 mL, 16.86 mmol) in dry DMF / dry was then added NMP 1: 1 (14 ml) followed by TMS-CF3 (2.64 ml, 16.86 mmol). A new stopper was then used to seal the vial and the reaction mixture was heated under microwave stirring at 100 ° C for 3 hours and allowed to cool. The mixture was added to a 5M NH3 solution (50 mL) and then extracted with diethyl ether (4 x 50 mL). The combined organic extracts were washed with 5M NH3 (3 x 20 mL), 1M HCl (50 mL), sat. sodium bicarbonate solution (2 x 50 mL), brine (50 mL), dried (MgSO 4) and concentrated in vacuo to give a brown oil. The crude material was purified by silica chromatography eluting with isohexane / EtOAc, 0-10% to give the title compound as an orange solid; LC-MS Rt 1.37 min; MS m / z 367.1 [M + H] +; Method 2 min LC_v003.

Intermediate M: 3- (2,5-Dimethyl-pyrrol-1-yl) -5,6-bistrifluoromethyl-pyridine-2-carboxylic acid [0247] To a mixed solution of 3- (2,5-dimethylpyrrole-1- methyl acid ester yl) -5,6-bis-trifluoromethyl-pyridine-2-carboxyl (1.28 g, 3.49 mmol) in methanol (25 mL) 1 M NaOH (7 mL, 6.99 mmol) was added and the reaction mixture was allowed to stir at RT for 30 min The solvent was removed under reduced pressure and water (20 ml) was added to the residue. The pH was adjusted to pH 4/5 by adding 1 M HCl. The mixture was extracted with EtOAc (3 x 20 mL) and the combined organic extracts were washed with brine (30 mL), dried (MgSO 4) and concentrated in vacuo and dried in a vacuum oven (50 ° C) overnight to give the crude title product as an orange a solid that was used without further purification; LC-MS: Rt 1.23 min; MS m / z 353.1 [M + H] +; Method 2 min LC_v003.

Intermediate N

3,3,3-trifluoro-N2- (4-methoxybenzyl) -2-methylpropane-1,2-diamine [0248]

<img file="PL2547656T3_D0069.tif" />

Step 1: 1- (4-methoxyphenyl) -N- (1,1,1-trifluoropropan-2-ylidene) methanamine [0249] To a stirred solution of trifluoroacetone (7.75 g, 69.2 mmol) in diethyl ether (60 ml) at -40 ° C 4-methoxybenzylamine (9.49 g, 69.2 mmol) and triethylamine (14 g, 138 mmol) in diethyl ether (40 ml) were added. A cooled (0 ° C) mixture of TiCl4 (6.56 g, 34.6 mmol) in hexane (40 ml) was added dropwise over 10 minutes and the resulting mixture was allowed to warm to ambient temperature for 20 min 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 under reduced pressure to give a yellow oil. Purification of the crude product by silica chromatography, eluting with 0% to 25% EtOAc in isohexane, gave the title product.

Step 2: 3,3,3-trifluoro-2- (4-methoxybenzylamino) -2-methyl propanenitrile [0250] To a cooled (0 ° C) solution of 1- (4-methoxyphenyl) -N- (1,1,1 -trifluoropropan-2-ylidene) methanamine (4.41 g, 19.07 mmol) in DCM (100 mL), cyanotrimethylsilane (2.84 g, 28.6 mmol) and magnesium bromide were added. The mixture was stirred at RT for 90 h and then diluted with saturated NaHCO3 (200 mL). After stirring at RT for 1 h, the organic phase was separated, washed with an additional portion of sat. NaHCO3 (100 mL), dried over MgSO4 and concentrated under reduced pressure to give the title compound. Step 3: 3,3,3-trifluoro-N2- (4-methoxybenzyl) -2-methylpropane-1,2-diamine To a cooled (0 ° C) solution of 3,3,3-trifluoro-2- (4- methoxybenzylamino) -2-methylpropanenitrile (1.5 g, 5.81 mmol) in dry diethyl ether (50 mL) LiAlH4 (11.62 mL of a 2M solution in THF) was added and the resulting mixture was stirred at RT overnight. The reaction mixture was hydrolysed by the successive addition of aqueous 15% KOH and water. The resulting precipitate was filtered on Celite® (filter material) and the organic portion was washed with water, dried over MgSO 4 and concentrated in vacuo to give the title product; NMR¹H (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 min; MS m / z 412.3 [M + H] +; Method 10 min LC_v003.

Indirect relationship

Benzo [d] isoxazol-3-ylmethanamine [0252]

<img file="PL2547656T3_D0070.tif" />

ΝΗ₂ [0253] The title compound was prepared according to the procedure of Pigini, Maria; Giannella, Mario;

Gualtieri, Fulvio; Melchiorre, Carlo; Bolle, Paola; Angelucci, Luciano. Analogs with 1,2benzisoxazole nucleus of biologically active indole derivatives. III. Tryptamine and gramine isosteres. European Journal of Medicinal Chemistry (1975), 10 (1), 29-32 (compound 11 pages 31-32).

Indirect relationship P

Methyl 3-amino-6- (oxazol-2-yl) -5- (trifluoromethyl) picolinate [0254] Solution of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (intermediate A4) (500 mg, 1.672 mmol), 2- (tributylstannyl) oxazole (0.704 mL, 3.34 mmol) and tetrakis (triphenylphosphine) palladium (0) (193 mg, 0.167 mmol) in dioxane (10 mL) was heated to reflux for 13 hours. After cooling to room temperature over 8 hours, the solvent was evaporated and the resulting residue was triturated with hot methanol to remove yellow solid impurities. The remaining crude material was used without further purification. LC-MS: Rt 0.95 min; MS m / z 288 [M + H] +; Method 2 min LC_v003.

Indirect PA

3-amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid [0255]

OH

Step 1: 3-Amino-6-furan-2-yl-5-trifluoromethylpyrazine-2-carboxylic acid [0256] The title compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester (intermediate C1) and tributyltin-2-furylstannane analogously to methyl 3-amino-6- (oxazol-2-yl) -5- (trifluoromethyl) picolinate (intermediate P)

Step 2: 3-Amino-6-furan-2-yl-5-trifluoromethylpyrazine-2-carboxylic acid [0257] The title compound was prepared from 3-amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid and 6M NaOH analogous to 3-amino6-bromo-5-trifluoromethylpyrazine-2-carboxylic acid (intermediate C, final step).

Intermediate Q

2-Hydroxyl-3-methyl-2- (trifluoromethyl) butane-1-ammonium chloride [0258]

<img file="PL2547656T3_D0071.tif" />

Step 1: 1,1,1-trifluoro-3-methyl-2- (nitromethyl) butan-2-ol. Cooled (0 ° C) solution of lithium hydroxide (0.048 g, 2.015 mmol) in water (20 ml) mixed and treated with nitromethane (1.23 g, 20.15 mmol), 1,1,1-trifluoro-3-methylbutan-2-one (3.11 g, 22.17 mmol), cetyltrimethylammonium chloride (0.871 g, 2.72 mmol) and MgSO4 (0.485 g, 4.03 mmol). The white suspension was stirred at 0 ° C for 1 hour, then at RT for 2 days. The resulting biphasic mixture was separated and the denser layer was collected and dissolved in diethyl ether (30ml). The mixture was dried over MgSO4, filtered and concentrated under reduced pressure to give a pale yellow oil. The oil was dissolved in diethyl ether (10 mL) and passed through a pre-packed SCX-2 cartridge, eluting with 100% diethyl ether. The filtrate was concentrated under reduced pressure to give the title compound as a colorless oil. NMR¹H (400MHz, CDCl3): δ 4.74 (1H, d), 4.59 (1H, d), 4.29 (1H, s), 2.29 (1H, m), 1.1 (6H, two sets of unbroken doublets)

Step 2: 2-Hydroxy-3-methyl-2- (trifluoromethyl) butane-1-ammonium chloride To solution of 1,1,1-trifluoro-3-methyl-2- (nitromethyl) butan-2-ol ( 753 mg, 3.74 mmol) in EtOH (10 mL) in a 25ml glass vessel for hydrogenation under medium pressure under N 2 nitrogen, 10% Pd on carbon (39.8 mg, 0.374 mmol) was added. The vessel was flushed with N2, then H2 (22.64 mg, 11.23 mmol) at 5 bar and stirred at RT for 6 days. The mixture was filtered through Celite® and washed thoroughly with EtOH (30 mL) followed by DCM (10 mL). The filtrate was concentrated under reduced pressure to give a colorless oil. The crude product was dissolved in methanol (20 mL) and treated with 1.25M HCl in methanol solution. The resulting colorless solution was stirred at RT for 1 hour and concentrated under reduced pressure to give the title compound;

NMR 1H (400MHz, DMSO-d6) δ 8.04 (3H, broad peak), 6.74 (1H, s), 3.58 (wide peak), 3.6 (2H, m), 2.12 ( 1H, m), 0.99 (6H).

Intermediate R

3-Amino-1,1,1-trifluoro-2-metloplopan-2-ol hydrochloride [0261]

<img file="PL2547656T3_D0072.tif" />

Step 1: 1,1,1-trifluoro-2-methyl-3-nitropropan-2-ol [0262] To LiOH (0.193 g, 8.06 mmol) in a 3-neck circle bottom flask was added water (25 mL) , nitromethane (3.76 mL, 81 mmol) and trifluoroacetone (7.95 mL, 89 mmol). Cetyltrimethylammonium chloride (3.8 g, 10.88 mmol) and MgSO4 (1.9 g, 16.12 mmol) were added and the resulting yellow solution was stirred at 20-25 ° C for 2 days. The reaction mixture was poured into diethyl ether (120 ml) and washed with water (3x 200 ml) and brine (1x 100 ml). The organic portion was dried over MgSO 4 and concentrated in vacuo to give the title compound as a yellow liquid. NMR¹H (CDCl3, 400 MHz): δ 4.7 (1H d), δ 4.5 (1H, d), δ 3.7 (1H, broad), δ 1.6 (3H, s). Step 2: 3-Amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride [0263] Pd / C (1 g) was added to a 200 ml glass vessel. Ethanol (50 ml, dry) was added carefully under a CO2 atmosphere. 1,1,1-Trifluoro-2-methyl-3-nitropropan-2-ol (10 g, 57.8 mmol) was dissolved in ethanol (50 ml, dry) and added to a glass vessel. The reaction mixture was placed under a positive atmosphere of hydrogen (5 bar) at room temperature and hydrogenated for 2 days. The reaction mixture was filtered through Celite® (filter material) and washed with excess ethanol. The solvent was removed under reduced pressure to give a colorless oil. The oil was dissolved in MeOH (50 mL) and treated dropwise with HCl (1 M) in MeOH (30 mL). The solution was allowed to stir for 30 minutes and concentrated in vacuo to azeotrope with MeCN to give the title compound as a waxy white solid; NMR 1H (DMSO-d6, 400MHz) δ 8.3 (3H, broad s), 6.9 (1H, wide), 3.0 (2H, q), 1.4 (3H, s).

Indirect RA

(S) -3-Amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride [0264]

<img file="PL2547656T3_D0073.tif" />

Step 1: Benzvlu 3,3,3-Trifluoro-2-hydroxy-2-methylpropylcarbamimane [0265] To a mixed suspension of amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (intermediate R) (1 , 5 g, 8.35 mmol) in DCM (50 mL) TEA 93.54 g, 35.0 mmol) was added followed by benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.983 g, 7.96 mmol). The mixture was stirred at RT for 6 hours and then diluted with water. The organic portion was separated using a phase separator and concentrated under reduced pressure. Purification by silica chromatography eluting with 0-70% EtOAc in isohexane gave the title product; NMR¹H (400 MHz, DMSO-d6) δ 7.34 (6H, m), 5.98 (1H, s), 5.05 (2H, s), 3.31 (1H, m), 3.18 ( 1H, m), 1.21 (3H. S) LC-MS: Rt 1.05 min; MS m / z 278.1 [M + H] +; Method 2 min LC_v003.

Step 2: Separation of benzyl 3,3,3-trifluoro-2-hydroxy-2-methylpropylcarbamate benzyl 3,3,3-Trifluoro-2-hydroxy-2-methylpropylcarbamate benzyl (1.7 g) was dissolved in 2-propanol ( 10 ml) and purified using the following chromatographic conditions:

<td>Mobile phase:</td><td>10% 2-propanol / 90% CO2</td>

<td>Column:</td><td>2 x Chiralcel OJ-H, 250 x 10 mm id, 5 μm (coupled columns w number)</td>

<td>Detection:</td><td>UV @ 220nm</td>

<td>Speed flow</td><td>10 ml / min</td>

<td>Sample Concentration:</td><td>1.7 g in 10 ml 2-propanol</td>

<td>Injection Volume:</td><td>75 pl</td>

[0267] First eluted peak: Rt = 6.94 minutes (R) -benzyl-3,3,3-trifluoro-2-hydroxy-215 methylpropylcarbamate [0268] Second eluted peak: Rt = 8.04 minutes (S) - benzyl-3,3,3-trifluoro-2-hydroxy-2-methylpropylcarbamate (stereochemistry confirmed by analysis of the final compound prepared by subsequent steps)

Step 3: (S) -3-Amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride [0269] A mixture containing (S) -benzyl-3,3,3-trifluoro-2-hydroxy- 2-methylpropylcarbamate in EtOH (165 mL) was pumped through H-Cube (hydrogenation reactor, 1-2 mL / min, pressure 1 bar, RT) for 8 hours using a 10% cartridge with a palladium-carbon catalyst. To the mixture, 1.25 M HCl in methanol (130 ml) was added, stirred for 30 min. The solvent was removed under reduced pressure to azeotrope with MeCN to give the title product as a white powder; NMR¹H (400 MHz, DMSO-d6) δ 8.3 (3H, broad), 6.8 (1H, s), 3.0 (2H, s), 1.5 (3H, s).

[0270] Alternatively, racemic 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol can be separated into separate enantiomers by recrystallization with either (S) mandelic acid or L-tartaric acid in isopropanol or ethanol.

Intermediate

2-Aminomethyl-1,1,1,3,3,3-hexafluoro-propan-2-ol [0271] 3,3,3-trifluoro-2- (trifluoromethyl) -1,2-propene oxide (1 g, 5.55 mmol) was added to a mixed solution of an aqueous solution of ammonia (0.88 g / ml, 3 ml) and diethyl ether (3 ml). The resulting colorless solution was stirred at room temperature for 3 hours. The biphasic mixture was separated and the aqueous portion was further extracted with diethyl ether (2 x 5 mL). The combined organic layers were dried over MgSO 4 and concentrated in vacuo (without heating) to give the title compound as a white crystalline solid which was used without further purification; NMR¹H (400 MHz, DMSO-d6) unassigned signals δ 4.20 (wide), 3.15 (s).

Intermediate relationship T.

3,3,3-trifluoro-2-methoxy-2-methylpropan-1-amine [0272]

<img file="PL2547656T3_D0074.tif" />

Step 1: 2- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) isoindoline-1,3-dione [0273] A mixture containing 3,3,3-trifluoro-2-hydroxy-2-methyl- propylammonium (0.9 g), phthalic anhydride (1.039 g) and DIPEA (2.188 ml) in chloroform (30 ml) was heated at 70 ° C for 5 hours. After cooling to RT, the mixture was washed with water and passed through a phase separator. The organic phase was reduced to dryness. The crude product was purified by silica chromatography, eluting in 0% to 30% isohexane: EtOAc, removed to give the title product; NMR¹H (400 MHz, Methanol-d4) δ 7.92 (2H, m), 7.85 (2H, m), 3.95 (2H, m), 1.36 (3H, s).

Step 2: 2- (3,3,3-trifluoro-2-methoxy-2-methylpropyl) isoindoline-1,3-dione [0274] To a mixed solution of 2- (3,3,3-trifluoro-2-hydroxy- 2-methylpropyl) isoindoline-1,3-dione (250 mg, 0.915 mmol)) at 0 ° C in THF (8 mL), NaH (80 mg, 2 mmol) was added. After 30 minutes, methyl iodide (1.299, 9.15 mmol) was added. The reaction mixture was allowed to stir in an ice bath and allowed to warm to 25 ° C for 3.5 hours. The reaction was quenched with saturated NH 4 Cl and the mixture was extracted with DCM. The organic extract was separated using a phase separator and purified by silica chromatography, eluting in 0% to 30% isohexane: EtOAc, to give the title product; NMR¹H (400 MHz, Methanol-d4) δ 7.91 (2H, m), 7.85 (2H, m), 3.97 (2H, m), 3.44 (3H, s), 1.42 ( 3H, s); LC-MS: Rt 1.17 min; MS m / z 288.10 [M + H] +; Method 2 min LC_v003.

Step 3: 3,3,3-trifluoro-2-methoxy-2-methylpropane-1-amine A mixture containing 2- (3,3,3-trifluoro-2-methoxy-2-methylpropyl) isoindoline 1,3- dione (272 mg, 0.95 mmol) and hydrazine (0.033 mL, 1.045 mmol) were stirred at 75 ° C for 4 hours. After cooling to RT, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title product which was used without further purification (no characteristic data available).

[0276] From the above, it should be understood that, although specific embodiments of the invention have been described herein for illustrative purposes, various modifications may be made without departing from the spirit and scope of the invention. In this regard, the invention is not limited except for the appended claims. Embodiments / Presentation of the invention [0277]

Performance 1: Compound of formula I:

<img file="PL2547656T3_D0075.tif" />

or a pharmaceutically acceptable salt thereof, where:

A is N or CR^4a;

R¹ is H; C1-C8 alkyl optionally substituted with one or more halogen; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; -C1-C4 alkylC3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted with one or more halogen; halogen; 2 NR⁸R⁹; SO 2 R¹⁰; S-C1-C8 alkyl optionally substituted with one or more halogen; S-C6-C14 aryl; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; A 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) -, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; CN; NO¹¹R¹²; CONR¹³R¹⁴; NO¹³SO 2 R¹⁵; NO¹³C (O) R¹⁵ and CO2R¹⁵wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted with one or more Z substituents;

R² is C1-C4 haloalkyl;

R³, R⁴ and R^4a are independently H or C1-C8 alkyl optionally substituted with one or more halogen;

R⁵ and R⁶ are each independently H; C1-C8 alkyl optionally substituted with one or more halogen; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5C10 cycloalkenyl; -C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted with one or more halogen; OH; CN; halogen; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; 3 to a 14 membered heterocyclic group with - (C 0 -C 4 alkyl) -, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or - (C 0 -C 4 alkyl) CO2R¹⁵wherein the cycloalkyl, cycloalkenyl, - (C 0 -C 4 alkyl) -C 6 -C 14 aryl and a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) - are each optionally substituted with one or more Z substituents; or

R⁵ and R⁶ are independently of each other and a group of formula:

- (CH2) m-NR¹⁷R¹⁸;

or

R⁵ and R⁶ independently represent a group of formula:

- (CH2) m-OR⁴;

or

R⁴ and R⁵ together with the carbon atom to which they are attached form a 3 to 8-membered carbocyclic ring system; or

R⁵ and R⁶ together with the carbon atom to which they are attached form a 5 to 8-membered carbocyclic ring system or a 5 to 8-membered heterocyclic ring system containing one or more heteroatom selected from N, O and S, wherein the ring system is optionally substituted with one or more than one Z substituent;

R⁴, R⁵ and R⁶ cannot be the same;

m is 0, 1, 2 or 3;

R⁸, R¹¹, R¹³ and R¹⁷ are independently H, $ C1-C8 alkyl optionally substituted with one or more halogen, $ C3-C10 cycloalkyl, or - (C1C4 alkyl) -C3-C8 cycloalkyl;

R⁹, R¹⁰, R¹², R¹⁴, R¹⁵, R¹⁶ and R¹⁸ are each independently H; C₁-C₈ alkyl optionally substituted with one or more halogen; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; -C1-C4 alkyl-C3-C8 cycloalkyl; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) -, where the heterocyclic group contains at least one heteroatom selected from N, O and S, where the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted with one or more than one Z substituent; or

R⁸ and R⁹, R¹¹ and R¹², R¹³ and R¹⁴, and R¹⁷ and R¹⁸ together with the nitrogen atom to which they are attached may form a 4 to 14-membered heterocyclic group optionally substituted with one or more Z substituents;

Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted with one or more OH or NH2 group, $ C1-C6 alkyl optionally substituted with one or more halogen, $ C1-C6 alkoxy optionally substituted with one or more OH or C1-C4 alkoxy, NR¹⁸(SO2) R²¹, (SO₂) NR¹⁹R²¹, (SO₂) R²¹, NO¹⁸C (O) R²¹, C (O) NR¹⁹R²¹, NO¹⁸C (O) NR¹⁹R²¹, NO¹⁸C (O) OR¹⁹,

NO¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, SR¹⁹, OR¹⁹, oxo, CN, NO₂, a halogen $ or 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;

R¹⁹ and R²¹ are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4 alkoxyC1-C4 alkyl; (C 0 -C 4 alkyl) -aryl optionally substituted with one or more than one group selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; A 3- to 14-membered heterocyclic group with - (C 0 -C 4 alkyl) -, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S, optionally substituted with one or more than one group selected from halogen, oxo , C1-C6 alkyl and C (O) C1-C6 alkyl; (C 0 -C 4 alkyl) -O-aryl optionally substituted by one or more than one group selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; and a 3- to 14-membered heterocyclic group with - (C 0 -C 4 alkyl) -O-, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S, optionally substituted with one or more group selected from halogen, C1-C6 alkyl or C (O) C1-C6 alkyl; wherein the alkyl groups are optionally substituted with one or more halogen, C1-C4 alkoxy, C (O) NH2, C (O) NHC1-C6 alkyl or C (O) N (C1-C6 alkyl) 2; or R¹⁹ and R²¹ together with the nitrogen atom to which they are attached form a 5- to 10-membered heterocyclic group, the heterocyclic group includes one or more additional heteroatom selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more than one substituent selected from OH; chlorowica; aryl; A 5- to 10-membered heterocyclic group, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S; S (O) 2-aryl; S (O) 2-C 1 -C 6 alkyl; C1-C6 alkyl optionally substituted with one or more halogen; C1-C6 alkoxy optionally substituted with one or more OH or C1-C4 alkoxy; and C (O) OC1-C6 alkyl, where the aryl and heterocyclic substituent groups are themselves optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

Embodiment 2: Compound of formula I

<img file="PL2547656T3_D0076.tif" />

or a pharmaceutically acceptable salt thereof, where:

A is N or CR^4a;

R¹ is H; C1-C8 alkyl optionally substituted with one or more halogen; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; -C1-C4 alkylC3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted with one or more halogen; halogen; 2 NR⁸R⁹; SO 2 R¹⁰; S-C1-C8alkyl optionally substituted with one or more halogen; S-C6-C14 aryl groups; CN; NO¹¹R¹²; C (O) NR¹³R¹⁴; NO¹³SO 2 R¹⁵; NO¹³C (O) R¹⁵, CO2R¹⁵, - (C.₀-C₄ alkyl) -C₆-C₁₄ aryl; or a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) -, 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 with one or more Z substituents;

R² is C1-C4 haloalkyl;

R³ and R^4a are independently H or C1-C8 alkyl optionally substituted with one or more halogen;

R⁴ is H, or C1-C8 alkyl optionally substituted with one or more halogen;

R⁵ means - (CH2) m-NR¹⁷R¹⁸, - (CH2) m-OR '; C1-C8 alkoxy optionally substituted with one or more halogen; - (C 0 -C 4 alkyl) -CO 2 R¹⁵; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein - (C 0 -C 4 alkyl) -C 6 -C 14 aryl and a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) - each, are optionally substituted with one or more Z substituents;

R⁶ is C1-C8 alkyl optionally substituted with one or more halogen; C3-C10 cycloalkyl; -C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted with one or more halogen; OH; CN; halogen; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) -, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, - (C 0 -C 4 alkyl) -C 6 -C 14 aryl and a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) - are each optionally substituted with one or more Z substituents; or

R⁶ is H and R⁵ means - (CH2) m-NR¹⁷R¹⁸, - (CH2) m-OR ', C1-C8 alkoxy optionally substituted with one or more halogen; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; A 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) -, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or - (C 0 -C 4 alkyl) CO2R¹⁵wherein - (C 0 -C 4 alkyl) -C 6 -C 14 aryl and a 3 to 14 membered heterocyclic group with (C 0 -C 4 alkyl) - each, are optionally substituted with one or more Z substituents; or

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

R⁴ and R⁵ together they form an oxo group (C = O) and R⁶ is C1-C4 alkyl optionally substituted with one or more halogen; C1-C4 alkoxy optionally substituted with one or more halogen; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) -, where the heterocyclic group contains at least one heteroatom selected from N, O and S, where each aryl and heterocyclyl groups are optionally substituted with one or more Z substituents ; or

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

R is H, or C1-C8 alkyl optionally substituted with one or more halogen; m is 0, 1, 2 or 3;

R⁸, R¹¹, R¹³ and R¹⁷ are independently H, C1-C8 alkyl optionally substituted with one or more halogen, C3-C10 cycloalkyl or - (C1-C4 alkyl) -C3-C8 cycloalkyl;

R⁹, R¹⁰, R¹², R¹⁴, R¹⁵, R¹⁶ and R¹⁸ are each independently H; C₁-C₈ alkyl optionally substituted with one or more halogen; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; -C1-C4 alkyl-C3-C8 cycloalkyl; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) -, where the heterocyclic group contains at least one heteroatom selected from N, O and S, where the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted with one or more than one Z substituent; or

R⁸ and R⁹, R¹¹ and R¹², R¹³ and R¹⁴, and R¹⁷ and R¹⁸ together with the nitrogen atom to which they are attached may form a 4 to 14-membered heterocyclic group optionally substituted with one or more Z substituents;

Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted with one or more OH or NH2 group, $ C1-C6 alkyl optionally substituted with one or more halogen, $ C1-C6 alkoxy optionally substituted with one or more OH or C1-C4 alkoxy, NR¹⁸(SO2) R²¹, (SO2) NR¹⁹R²¹, (SO2) R²¹, NO¹⁸C (O) R²¹, C (O) NR¹⁹R²¹, NO¹⁸C (O) NR¹⁹R²¹, NO¹⁸C (O) OR¹⁹, NO¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, SR¹⁹, OR¹⁹, oxo, CN, NO₂, a halogen $ or 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;

R¹⁹ and R²¹ are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4 alkoxyC1-C4 alkyl; (C 0 -C 4 alkyl) -aryl optionally substituted with one or more than one group selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; A 3- to 14-membered heterocyclic group with - (C 0 -C 4 alkyl) -, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S, optionally substituted with one or more than one group selected from halogen, oxo , C1-C6 alkyl and C (O) C1-C6 alkyl; (C 0 -C 4 alkyl) -O-aryl optionally substituted by one or more than one group selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; and a 3- to 14-membered heterocyclic group with - (C 0 -C 4 alkyl) -O-, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S, optionally substituted with one or more group selected from halogen, C1-C6 alkyl or C (O) C1-C6 alkyl; wherein the alkyl groups are optionally substituted with one or more halogen, C1-C4 alkoxy, C (O) NH2, C (O) NHC1-C6 alkyl or C (O) N (C1-C6 alkyl) 2; or

R¹⁹ and R²¹ together with the nitrogen atom to which they are attached form a 5- to 10-membered heterocyclic group, the heterocyclic group includes one or more additional heteroatom selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more than one substituent selected from OH; halogen; aryl; A 5- to 10-membered heterocyclic group, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S; S (O) 2-aryl; S (O) 2-C 1 -C 6 alkyl; C1-C6 alkyl optionally substituted with one or more halogen; C1-C6 alkoxy optionally substituted with one or more OH or C1-C4 alkoxy; and C (O) OC1-C6 alkyl, where the aryl and heterocyclic substituent groups are themselves optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

Embodiment 3: The compound of embodiment 1 or 2, where

100

R¹ is H; C1-C4 alkyl optionally substituted with one or more halogen; C1-C4 alkoxy optionally substituted with one or more halogen; halogen; C6-C14 aryl; A 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) where 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 with one or more Z substituents.

Embodiment 4: The compound of embodiment 1 to 3, where

R¹ is C1-C4 alkyl optionally substituted with one or more halogen.

Embodiment 5: The compound of embodiment 1 to 4, wherein

R¹ means -CH3 or CF3.

Embodiment 6: The compound of embodiment 1, 2 or 3, where

R¹ is C1-C4 alkoxy optionally substituted with one or more halogen.

Embodiment 7: The compound of embodiment 1, 2, 3 or 6, wherein

R¹ means -OCH3, -OCH2CH3 or -OCF3.

Embodiment 8: The compound of embodiment 1, 2 or 3, wherein R¹ is aryl, where aryl is phenyl optionally substituted with one or more Z substituents, Embodiment 9: The compound of embodiment 1, 2, 3 or 8, wherein R¹ means 4-fluorophenyl, 4-chloro-2-methylphenyl, or 2,4-dichlorophenyl.

Embodiment 10: The compound of embodiment 1, 2 or 3, wherein R¹ is pyridyl, oxazole, pyrrolidine or pyrazole and is optionally substituted with one or more Z substituents.

Embodiment 11: The compound of embodiment 1, 2, 3 or 10, wherein R¹ is 1-methyl-4-pyridyl, oxazol-2-yl, 1-methyl-1H-pyrazol-4-yl or pyrrolidin-1-yl.

Embodiment 12: The compound of embodiments 1 to 11, wherein R¹ means Br, -CH3, -CF3, -OCH3, -OCH2CH3, -OCF3, 4-fluorophenyl, 4-chloro-2-methylphenyl, 2,4-dichlorophenyl, 1-methyl-4-pyridyl, 1-methyl-1H-pyrazol- 4-yl, oxazol-2-yl, or pyrrolidin-1-yl.

Embodiment 13: The compound of embodiments 1 to 12, wherein R⁵ provides a heteroatom two carbides from amide nitrogen, where the heteroatom is oxygen or nitrogen.

Embodiment 14: The compound of embodiment 1 to 13, wherein

R⁴ is H or C1-C4 alkyl optionally substituted with one or more halogen;

R⁵ is C1-C4 alkoxy optionally substituted with one or more halogen; - (CH2) m-NR¹⁷R¹⁸; - (CH2) m-OR 'or OH;

R is H, or C1-C4 alkyl optionally substituted with one or more halogen;

101 m is 0, 1 or 2;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen; C1-C4 alkoxy optionally substituted with one or more halogen; OH; CN; halogen; - (C 0 -C 4 alkyl) -C 6 aryl; or a 5 to 6 membered heterocyclic group with - (C 0 -C 4 alkyl) -, where the heterocyclic group contains at least one heteroatom selected from N, O and S, where aryl and heterocyclyl groups are each optionally substituted with one or more Z substituents ; or R⁴ and R⁶ together with the carbon atom to which they are attached form a 3 to 8-membered carbocyclic ring system; or

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

R¹⁷ and R¹⁸ are each independently H; or C1-C4 alkyl optionally substituted with one or more halogen.

Embodiment 15: A compound according to any one of the preceding embodiments, wherein R³ is H;

R⁴ is H or Me;

R^4a is H;

R⁵ means - (CH2) m-NR¹⁷R¹⁸; - (CH2) m-OR '; or OH;

m is 0 or 1;

R 'is H;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen; or

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

R¹⁷ and R¹⁸ are each independently H; or C1-C4 alkyl optionally substituted with one or more halogen.

Embodiment 16: A compound according to any one of the preceding embodiments, wherein R³ is H;

R⁴ is H or Me;

R^4a is H;

R⁵ means -NR¹⁷R¹⁸; or OH;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen; or

102

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

R¹⁷ and R¹⁸ are each independently H; or C1-C4 alkyl optionally substituted with one or more halogen.

Embodiment 17: A compound according to any one of the preceding claims wherein R³ is H;

R⁴ is H or Me;

R^4a is H;

R⁵ means -NR¹⁷R¹⁸; or OH;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen; and

R¹⁷ and R¹⁸ are each independently H; or C1-C4 alkyl optionally substituted with one or more halogen.

Embodiment 18: The compound of embodiment 1 to 13, where

R³ is H;

R^4a is H;

R⁴ and R⁵ forms an oxo group;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen; C1-C4 alkoxy optionally substituted with one or more halogen; 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 with one or more Z substituents.

Embodiment 19: The compound of embodiment 1 to 13 or 18, wherein

R³ is H;

R^4a is H;

R⁴ and R⁵ forms an oxo group;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen; or phenyl, wherein the phenyl is optionally substituted with one or more Z substituents;

Z is independently OH, C1-C4 alkyl optionally substituted with one or more OH or NH2, C1-C4 alkyl optionally substituted with one or more halogen, C1-C4 alkoxy optionally substituted with one or more OH or C1-C4 alkoxy, C (O) OR¹⁹, C (O) R¹⁹, OR¹⁹, CN or halogen;

103

R¹⁹ is H; C1-C4 alkyl; C3-C6 cycloalkyl; or C1-C4 alkoxy-C1-C4 alkyl, wherein all alkyl are optionally substituted with halogen.

Embodiment 20: The compound of embodiment 1 to 13 or 18 to 19, wherein R³ is H;

R^4a is H;

R⁴ and R⁵ forms an oxo group;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen; or phenyl, wherein the phenyl is optionally substituted with one or more Z substituents;

Z is independently, C 1 -C 4 alkyl optionally substituted with one or more halogen, C 1 -C 4 alkoxy or halogen.

Embodiment 21. The compound of embodiments 1 to 13, wherein the compound is represented by formula II, ο

<img file="PL2547656T3_D0077.tif" />

f₃cw nh₂ or a pharmaceutically acceptable salt thereof, where,

R¹⁰¹ is selected from the following:

<img file="PL2547656T3_D0078.tif" />

104

<img file="PL2547656T3_D0079.tif" />

<img file="PL2547656T3_D0080.tif" />

<img file="PL2547656T3_D0081.tif" />

<img file="PL2547656T3_D0082.tif" />

105

<img file="PL2547656T3_D0083.tif" />

<img file="PL2547656T3_D0084.tif" />

<img file="PL2547656T3_D0085.tif" />

<img file="PL2547656T3_D0086.tif" />

106

<img file="PL2547656T3_D0087.tif" />

Embodiment 22: The compound of embodiment 21, where

R³ is H;

R¹⁰¹ means

<img file="PL2547656T3_D0088.tif" />

Embodiment 23: The compound of embodiment 21, wherein R³ is H;

R¹⁰¹ means

<img file="PL2547656T3_D0089.tif" />

107

<img file="PL2547656T3_D0090.tif" />

<img file="PL2547656T3_D0091.tif" />

<img file="PL2547656T3_D0092.tif" />

Embodiment 24: The compound of embodiment 21, wherein R³ is H;

<img file="PL2547656T3_D0093.tif" />

<img file="PL2547656T3_D0094.tif" />

108

<img file="PL2547656T3_D0095.tif" />

<img file="PL2547656T3_D0096.tif" />

<img file="PL2547656T3_D0097.tif" />

109

<img file="PL2547656T3_D0098.tif" />

Embodiment 25: The compound of embodiment 21, where 5 R³ is H;

R¹⁰¹ means

<img file="PL2547656T3_D0099.tif" />

<img file="PL2547656T3_D0100.tif" />

Embodiment 26: The compound of embodiments 1 to 13, wherein R³ is H;

R¹⁰¹ is a 5 to 10 membered heterocyclic group with - (C1-C2 alkyl) -, where the heterocyclic group contains at least one heteroatom selected from N, O and S, where aryl and heterocyclyl groups are each optionally substituted with one or more Z substituents .

Embodiment 27: The compound of embodiment 21 or 26, wherein R³ is H;

110

R¹⁰¹ means

101

<img file="PL2547656T3_D0101.tif" />

ο

R Implementation 28: Compound of formula III ο

AND

<img file="PL2547656T3_D0102.tif" />

III or pharmaceutically acceptable salts thereof, where:

A is N or CR^4a;

X is NR^s or O;

R¹ is C1-C8 alkyl optionally substituted with one or more halogen; C3-C10 cycloalkyl; -C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted with one or more halogen; halogen; CN; NO¹¹R¹²; C (O) NR¹³R¹⁴; NO¹³C (O) R¹⁵, CO2R¹⁵, - (C0-C₄ alkyl) -C₆-C₁₄ aryl; or a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) -, 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 with one or more Z substituents;

R² is C1-C4 haloalkyl;

R³ and R^4a are independently H or C1-C8 alkyl optionally substituted with one or more halogen;

R⁴ is H, or C1-C8 alkyl optionally substituted with one or more halogen;

R^5a is H, C 1 -C 8 alkyl optionally substituted with one or more halogen, - (C 0 -C 4 alkyl) -C 6 -C 14 aryl or -3 to 14 membered heterocyclic group z, wherein the heterocyclic group contains at least one heteroatom selected from N , O and S; wherein - (C 0 -C 4 alkyl) -C 6 -C 14 aryl and a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) - each, are optionally substituted with one or more Z substituents; R^s is H, $ C 1 -C 8 alkyl optionally substituted with one or more halogen, $ - (C 0 -C 4 alkyl) -C 6 -C 14 aryl or -3 to 14 membered heterocyclic group, where the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein - (C 0 -C 4 alkyl) -C 6 -C 14 aryl and a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) - each, are optionally substituted with one or more Z substituents;

111

R⁶ is C1-C8 alkyl optionally substituted with one or more halogen; C3-C10 cycloalkyl; -C1-C4 alkyl-C3-C8 cycloalkyl; C1-C8 alkoxy optionally substituted with one or more halogen; OH; CN; halogen; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) -, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, - (C 0 -C 4 alkyl) -C 6 -C 14 aryl and a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) - are each optionally substituted with one or more Z substituents; or

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

R^5a and R⁶ together with the atoms to which the 5 to 8-membered heterocyclic ring system containing one or more heteroatom selected from N, O and S is bonded, wherein the ring system is optionally substituted with one or more Z substituents; or R^5a and R^s together with the atoms to which they are attached a 5 to 8 membered heterocyclic ring system containing one or more heteroatom selected from N, O and S, wherein the ring system is optionally substituted with one or more Z substituents;

R¹¹ and R¹³ are independently H, C1-C8 alkyl optionally substituted with one or more halogen, C3-C10 cycloalkyl or - (C1-C4 alkyl) -C3-C8 cycloalkyl;

R¹², R¹⁴, and R¹⁵ are each independently H; C1-C8 alkyl optionally substituted with one or more halogen; C2-C8 alkenyl; C2-C8 alkynyl; C3-C10 cycloalkyl; C5-C10 cycloalkenyl; -C1-C4 alkyl-C3-C8 cycloalkyl; - (C 0 -C 4 alkyl) -C 6 -C 14 aryl; or a 3 to 14 membered heterocyclic group with - (C 0 -C 4 alkyl) -, where the heterocyclic group contains at least one heteroatom selected from N, O and S, where the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted with one or more than one Z substituent; or R¹¹ and R¹², and R¹³and R¹⁴ together with the nitrogen atom to which they are attached may form a 4 to 14-membered heterocyclic group optionally substituted with one or more Z substituents;

Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted with one or more OH or NH2 group, $ C1-C6 alkyl optionally substituted with one or more halogen, $ C1-C6 alkoxy optionally substituted with one or more OH or C1-C4 alkoxy, NR¹⁸(SO2) R²¹, (SO2) NR¹⁹R²¹, (SO2) R²¹, NO¹⁸C (O) R²¹, C (O) NR¹⁹R²¹, NO¹⁸C (O) NR¹⁹R²¹, NO¹⁸C (O) OR¹⁹, NO¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, SR¹⁹, OR¹⁹, oxo, CN, NO₂, $ or 3- to 14-membered halogen

112 a heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;

R¹⁹ and R²¹ are each independently of one another H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4 alkoxy-C1-C4 alkyl; (C 0 -C 4 alkyl) -aryl optionally substituted with one or more than one group selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; A 3- to 14-membered heterocyclic group with - (C 0 -C 4 alkyl) -, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S, optionally substituted with one or more than one group selected from halogen, oxo , C1-C6 alkyl and C (O) C1-C6 alkyl; (C 0 -C 4 alkyl) -O-aryl optionally substituted with one or more than one group selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; and a 3- to 14-membered heterocyclic group with - (C 0 -C 4 alkyl) -O-, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S, optionally substituted with one or more group selected from halogen, C1-C6 alkyl or C (O) C1-C6 alkyl; wherein the alkyl groups are optionally substituted with one or more halogen, C1-C4 alkoxy, C (O) NH2, C (O) NHC1-C6 alkyl or C (O) N (C1C6 alkyl) 2; or

R¹⁹ and R²¹ together with the nitrogen atom to which they are attached form a 5- to 10-membered heterocyclic group, the heterocyclic group includes one or more additional heteroatom selected from N, O and S, and the heterocyclic group is optionally substituted with one or more than one a substituent selected from OH; halogen; aryl; A 5- to 10-membered heterocyclic group, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S; S (O) 2-aryl; S (O) 2-C 1 -C 6 alkyl; C1-C6 alkyl optionally substituted with one or more halogen; C1-C6 alkoxy optionally substituted with one or more OH or C1-C4 alkoxy; and C (O) OC1-C6 alkyl, where the aryl and heterocyclic substituent groups are themselves optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

Embodiment 29: The compound of embodiment 28, where

A is N or CR^4a;

X is NR^s or O;

R¹ is C1-C4 alkyl optionally substituted with one or more halogen; C1-C4 alkoxy optionally substituted with one or more halogen; halogen; - (C 0 -C 4 alkyl) -C 6 aryl; or a 5 to 6 membered heterocyclic group with (C 0 -C 4 alkyl) -, 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 with one or more Z substituents; R² is C1-C4 haloalkyl;

113

R³ and R^4a are H;

R⁴ is H, or C1-C4 alkyl optionally substituted with one or more halogen;

R^5a is H, C 1 -C 4 alkyl optionally substituted with one or more halogen, - (C 0 -C 4 alkyl) -C 6 aryl or a -5 to 8-membered heterocyclic group, where the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein - (C 0 -C 4 alkyl) -C 6 aryl and -5 to 8-membered heterocyclic group are each optionally substituted with one or more Z substituents;

R^s is H, C 1 -C 4 alkyl optionally substituted with one or more halogen, - (C 0 -C 4 alkyl) -C 6 aryl or a -5 to 8-membered heterocyclic group, where the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein - (C 0 -C 4 alkyl) -C 6 aryl and -5 to 8-membered heterocyclic group are each optionally substituted with one or more Z substituents;

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen; C1-C4 alkoxy optionally substituted with one or more halogen; OH; CN; - (C 0 -C 4 alkyl) -C 6 aryl; 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 -C6 aryl and the -5 to 8-membered heterocyclic group are each optionally substituted with one or more Z substituents; or R⁴ and R⁶ together with the carbon atom to which they are attached form a 3 to 8-membered carbocyclic ring system; or

R^5a and R⁶ together with the atoms to which they are attached 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 with one or more Z substituents; or R^5a and R^s together with the atoms to which they are attached form a 5 to 8 membered heterocyclic ring system containing one or more heteroatom selected from N, O and S, wherein the ring system is optionally substituted with one or more Z substituents;

Z is independently OH, aryl, O-aryl, C1-C6 alkyl optionally substituted with one or more than one OH group or NH2 group, $ C1-C6 alkyl optionally substituted with one or more halogen, $ C1-C6 alkoxy optionally substituted one or more than one OH or C group₁-C₄ alkoxy, NR¹⁸C (O) R²¹, C (O) NR¹⁹R²¹, NO¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, SR¹⁹, OR¹⁹, oxo, CN, NO₂, a halogen or 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 with halogen, C1-C4 alkyl optionally substituted with halogen, C1-C4 alkoxy or 114

CN;

R¹⁸ is H or C1-C4 alkyl;

R¹⁹ and R²¹ are each independently H; C1-C8 alkyl; C3-C8 cycloalkyl; C1-C4 alkoxy, C1-C4 alkyl; (C 0 -C 4 alkyl) -aryl optionally substituted with one or more than one group selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; A 3- to 14-membered heterocyclic group with - (C 0 -C 4 alkyl) -, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S, optionally substituted with one or more than one group selected from halogen, oxo , C1-C6 alkyl and C (O) C1-C6 alkyl; (C 0 -C 4 alkyl) -O-aryl optionally substituted with one or more than one group selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; and a 3- to 14-membered heterocyclic group with - (C 0 -C 4 alkyl) -O-, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S, optionally substituted with one or more group selected from halogen, C1-C6 alkyl or C (O) C1-C6 alkyl; wherein the alkyl groups are optionally substituted with one or more halogen, C1-C4 alkoxy, C (O) NH2, C (O) NHC1-C6 alkyl or C (O) N (C1-C6 alkyl) 2; or

R¹⁹ and R²¹ together with the nitrogen atom to which they are attached form a 5- to 10-membered heterocyclic group, the heterocyclic group includes one or more additional heteroatom selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more than one substituent selected from OH;^AND halogen;^AND aryl; A 5- to 10-membered heterocyclic group, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S; S (O) 2-aryl; S (O) 2-C 1 -C 6 alkyl; C1-C6 alkyl optionally substituted with one or more halogen; C1-C6 alkoxy optionally substituted with one or more OH or C1-C4 alkoxy; and C (O) OC1-C6 alkyl, where the aryl and heterocyclic substituent groups are themselves optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

Embodiment 30: A compound according to embodiment 28 or 29, wherein

A is N or CR^4a;

X is NR^s or O;

R¹ is C1-C4 alkyl optionally substituted with one or more halogen; C1-C4 alkoxy optionally substituted with one or more halogen; or halogen;

R² is CF3;

R³ and R^4a are H;

R⁴ is H, or C1-C4 alkyl optionally substituted with one or more halogen;

115

R^5a is H, C1-C4 alkyl optionally substituted with one or more halogen,

R^s is H, C1-C4 alkyl optionally substituted with one or more halogen,

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen; C1-C4 alkoxy optionally substituted with one or more halogen; OH; CN; or R⁴ and R⁶ together with the carbon atom to which they are attached they form a 3- to 6-membered carbocyclic ring system; or

R^5a and R⁶ together with the atoms to which they are attached 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 with one or more Z substituents; or R^5a and R^s together with the atoms to which they are attached form a 5 to 8 membered heterocyclic ring system containing one or more heteroatom selected from N, O and S, wherein the ring system is optionally substituted with one or more Z substituents;

Z is independently OH, $ C1-C6 alkyl optionally substituted with one or more OH or NH2 group, $ C1-C6 alkyl optionally substituted with one or more halogen, $ C1-C6 alkoxy optionally substituted with one or more than one OH or C group₁-C₄ alkoxy, NR¹⁹R²¹, C (O) OR¹⁹, C (O) R¹⁹, SR¹⁹, OR¹⁹, oxo, CN, NO2, or halogen;

R¹⁹ is H; C1-C8 alkyl; (C 0 -C 4 alkyl) -aryl optionally substituted with one or more than one group selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; A 3- to 14-membered heterocyclic group - (C 0 -C 4 alkyl) -, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S, optionally substituted with one or more than one group selected from halogen, oxo, C 1-4 C6 alkyl and C (O) C1-C6 alkyl; (C 0 -C 4 alkyl) -O-aryl optionally substituted by one or more than one group selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; and a 3- to 14-membered heterocyclic group with - (C 0 -C 4 alkyl) - O-, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S, optionally substituted with one or more group selected from halogen, C1-C6 alkyl or C (O) C1-C6 alkyl; wherein the alkyl groups are optionally substituted with one or more halogen, C1-C4 alkoxy, C (O) NH2, C (O) NHC1-C6 alkyl or C (O) N (C1C6 alkyl) 2; or

R¹⁹ and R²¹ together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group, the heterocyclic group includes one or more additional heteroatom selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more than one substituent selected from

116

OH;^AND halogen;^AND aryl; A 5- to 10-membered heterocyclic group, wherein the heterocyclic group includes one or more heteroatom selected from N, O and S; S (O) 2-aryl; S (O) 2-C 1 -C 6 alkyl; C1-C6 alkyl optionally substituted with one or more halogen; C1-C6 alkoxy optionally substituted with one or more OH or C1-C4 alkoxy; and C (O) OC1-C6 alkyl, where the aryl and heterocyclic substituent groups are themselves optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

Embodiment 31: The compound of embodiment 28 to 30, wherein

A is N or CR^4a;

X is NR^s or O;

R¹ is C1-C4 alkyl optionally substituted with one or more halogen; C1-C4 alkoxy optionally substituted with one or more halogen; or halogen;

R² is CF3;

R³ and R^4a are H;

R⁴ is H, or C1-C4 alkyl optionally substituted with one or more halogen;

R^5a is H, C1-C4 alkyl optionally substituted with one or more halogen,

R^s is H, C1-C4 alkyl optionally substituted with one or more halogen,

R⁶ is C1-C4 alkyl optionally substituted with one or more halogen; C1-C4 alkoxy optionally substituted with one or more halogen; OH; CN; or R^5a and R⁶ together with the atoms to which they are attached 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 with one or more Z substituents; or R^5a and R^s together with the atoms to which they are attached form a 5 to 8-membered heterocyclic ring system containing one or more heteroatom selected from N, O and S, wherein the ring system is optionally substituted with one or more Z substituents;

Z is independently OH, $ C1-C6 alkyl optionally substituted with one or more OH or NH2 group, $ C1-C6 alkyl optionally substituted with one or more halogen, $ C1-C6 alkoxy optionally substituted with one or more than one OH or C1-C4 alkoxy, oxo, CN, NO2, or halogen;

Embodiment 32: A compound according to any one of the preceding embodiments wherein A is N.

Embodiment 33: The compound of embodiments 1 to 31, wherein A is CR^4a.

Embodiment 34: The compound of embodiment 33, wherein A is CR^4a and R^4a means H.

117

Embodiment 35: A compound according to any one of the preceding embodiments, wherein R² means CF3CF2-, (CF3) 2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CH3-CCl2-, CF3CFCClH-, CBr3, CBr2HCF3CF2CHCF3 or CF3CF2CF2CF2-.

Embodiment 36: A compound according to any one of the preceding embodiments, wherein R² means CF3.

Embodiment 37: A compound according to any one of the preceding embodiments, wherein the compound is a substantially pure enantiomer with an S configuration.

Embodiment 38: The compound of embodiments 1 to 36, wherein the compound is a substantially pure enantiomer with an R configuration.

Embodiment 39: The compound of embodiment 2, 21 or 28, wherein the compound is represented by:

3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

acid

Trifluoromethylpyridine-2-carboxylic 3-amino-6-bromo-5- (3,3,3-trifluoro-2-hydroxypropyl) amide;

3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxypropyl) amide;

3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [(R) -1- (tetrahydrofuran-2-yl) methyl] amide;

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid ([1,3] dioxolan-2-ylmethyl) amide;

3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [(S) -1- (tetrahydrofuran-2-yl) methyl] amide;

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (tetrahydrofuran-2-ylmethyl) amide;

3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-methyl-2-piperidin-1-yl-propyl) -amide;

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (2-hydroxypropyl) amide;

3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methylpropyl) amide;

3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-methyltetrahydrofuran-2-ylmethyl) amide;

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (2-methoxyethyl) amide;

3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [2- (4-fluorophenyl) -2-morpholin-4-ylethyl] amide;

118 3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (2-morpholin-4-yl-2-phenylethyl) amide;

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (2-dimethylamino-2-phenylethyl) amide;

3-amino-6- (4-fluorophenyl) -5-trifluoromethylpyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

3-amino-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

3-amino-6- (4-chloro-2-methylphenyl) -5-trifluoromethylpyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxypropyl) amide; Trifluoromethylpyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropyl) amide; Trifluoromethyl- [2,3 '] bipyridinyl-6-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide; Trifluoromethylpyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide; Trifluoromethylpyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide; Trifluoromethylpyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

3-amino-6- (4-fluoro-phenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

3-amino-6- (4-fluoro-phenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

3-amino-6- (2,4-dichlorophenyl) -5-trifluoromethylpyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

acid

3-amino-6-bromo-55-amino-6'-methyl-33-amino-6-bromo-53-amino-6-bromo-53-amino-6-methoxy-53-amino-6- (4- fluorophenyl) -5 (2-hydroxy-2-methylpropyl) trifluoromethylpyridine-2-carboxylic amide; Trifluoromethylpyridine-2-carboxylic (3,3,3-trifluoro-2-hydroxypropyl) amide; Trifluoromethyl- [2,3 '] bipyridinyl-6-carboxylic (3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropyl) amide; Trifluoromethyl- [2,3 '] bipyridinyl-6-carboxylic (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide; Trifluoromethylpyridine-2-carboxylic ((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

acid

3-amino-6'-methyl-3-acid 3-amino-5,6-bis119 3-amino-6-methoxy-5-acid 5-amino-6'-methyl-3-acid 3-amino-5'-bis119 ((R) -3,3,3-trifluoro 3-amino-5,6-bistrifluoromethyl-pyridine-2-carboxylic acid -2-hydroxy-2-methylpropyl) amide;

3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide; Methyl 3- (3-amino-6-bromo-5- (trifluoromethyl) picolinamido) propanoate; 3-amino-N- (benzo [d] isoxazol-3-ylmethyl) -6-bromo-5- (trifluoromethyl) picolinamide; 3-amino-6- (oxazol-2-yl) -N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

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

3-amino-N- (2-hydroxy-3-methyl-2- (trifluoromethyl) butyl) -6-methoxy-5- (trifluoromethyl) picolinamide;

3-amino-6-cyclopropyl-N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -5- (trifluoromethyl) picolinamide;

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

5-amino-N- (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) -3- (trifluoromethyl) -2,4'-bipirydyno6-carboxamide;

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (3-methyl-2-oxobutyl) amide;

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

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

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

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

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

Embodiment 40: A compound of Embodiment 39 wherein the compound is 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [(R) -1- (tetrahydrofuran-2-yl) methyl] amide;

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid ([1,3] dioxolan-2-ylmethyl) amide;

120 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [(S) -1- (tetrahydrofuran-2-yl) methyl] amide;

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (tetrahydrofuran-2-ylmethyl) amide; or 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-methyltetrahydrofuran-2-ylmethyl) amide.

Embodiment 41: The compound of embodiment 2, 21 or 28, wherein the compound is 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (4-fluorophenyl) -2-morpholin-4-ethylethyl] amide;

3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid [2- (4-fluorophenyl) -2-morpholin-4-ylethyl] amide;

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (2-morpholin-4-yl-2-phenylethyl) amide;

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (2-dimethylamino-2-phenylethyl) amide;

3-amino-6-b romo-5-trifluoromethylpyrazine-2-carboxylic acid (3-methyl-2-morpholin-4-ylbutyl) amide ;

3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-methyl-2-morpholin-4-yl-propyl) -amide;

3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (1-morpholin-4-ylcyclohexylmethyl) amide;

3-amino-6-bromo-5-trifluoromethylpyrazine-2-carboxylic acid (2-morpholin-4-yl-2-phenylethyl) amide;

3-amino-6-bromo-5-trifluoromethylpyrazine-2-carboxylic acid (2-dimethylamino-2-phenylethyl) amide;

3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (4-methoxyphenyl) -2-pyrrolidin-1-ylethyl] amide;

3-amino-N- (2-amino-3,3,3-trifluoro-2-methylpropyl) -6-methoxy-5- (trifluoromethyl) picolinamide; or 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2-dimethylamino-2- (4-methoxyphenyl) ethyl] amide.

Embodiment 42: The compound of embodiment 2, 21 or 28, wherein the compound is 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-methyltetrahydrofuran-2-ylmethyl) amide;

3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (4-fluorophenyl) -2-morpholin-4-ylethyl] amide;

3-amino-6-bromo-5-trifluoromethylpyrazine (3-methyl-2-morpholin-4-ylbutyl) amide

2-carboxylic acid;

3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2-methyl-2-morpholin-4-yl-propyl) -amide;

3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (1-morpholin-4-ylcyclohexylmethyl) amide;

3-amino-6-bromo-5-trifluoromethylpyrazine-2-carboxylic acid (2-morpholin-4-yl-2-phenylethyl) amide;

3-amino-6-bromo-5-trifluoromethylpyrazine-2-carboxylic acid (2-dimethylamino-2-phenylethyl) amide;

3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (4-methoxyphenyl) -2-pyrrolidin-1-ylethyl] amide;

3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2-dimethylamino-2- (4-methoxyphenyl) ethyl] amide;

3-amino-6-bromo-5-trifluoromethylpyrazine-2-carboxylic acid [2- (4-fluorophenyl) -2-oxoethyl] amide;

3-amino-6-furan-2-yl-5-trifluoromethylpyrazine-2-carboxylic acid [2- (2-methoxyphenyl) ethyl] amide;

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

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

3-amino-6-bromo-N- (2-morpholinoethyl) -5- (trifluoromethyl) pyrazine-2-carboxamide; or 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid [2- (4-fluorophenyl) -2-oxoethyl] amide.

Embodiment 43: The compound of embodiment 39, wherein the compound is 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

3-amino-6-bromo-5-trifluoromethylpyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxypropyl) amide;

<td>((S) -3,3,3-trifluoro-2-hydroxypropyl) amide trifluoromethyl-pyridine-2-carboxylic acid amide;</td><td>acid</td><td>3-amino-6-bromo-5-</td>

<td>((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide trifluoromethyl-pyridine-2-carboxylic acid amide;</td><td>acid</td><td>3-amino-5,6-bis</td>

<td>((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide trifluoromethyl-pyridine-2-carboxylic acid amide;</td><td>acid</td><td>3-amino-5,6-bis</td>

<td>((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide trifluoromethyl-pyridine-2-carboxylic acid amide;</td><td>acid</td><td>3-amino-6-methoxy-5-</td>

122 3-amino-6- (4-fluoro-phenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid ((S) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

3-amino-6- (4-fluoro-phenyl) -5-trifluoromethyl-pyridine-2-carboxylic acid ((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

3-amino-6- (2,4-dichlorophenyl) -5-trifluoromethylpyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide;

3-amino-6- (4-fluorophenyl) -5-trifluoromethylpyridine-2-carboxylic acid (2-hydroxy-2-methylpropyl) amide; or 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (((R) -3,3,3-trifluoro-2-hydroxy-2-methylpropyl) amide.

Embodiment 44: Use of a compound of embodiment 1 to 43 in the manufacture of a medicament for use in the treatment of inflammatory disease or with airway spasm or mucosal hydration.

Embodiment 45: Use of the compound of embodiments 1 to 43, in the manufacture of a medicament for use in the treatment of CFTR-mediated disease.

Embodiment 46: Use of a compound of embodiment 42 in the manufacture of a medicament for use in the treatment of CFTR-mediated disease, wherein the disease is CF or COPD.

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

Embodiment 48: A pharmaceutical composition for the treatment of a disease or condition mediated by CFTR, including:

a compound of embodiments 1 to 43 and one or more pharmaceutically acceptable excipients.

Embodiment 49: The pharmaceutical composition according to embodiment 48, wherein the disease or disease is cystic fibrosis or COPD.

Embodiment 49: The pharmaceutical composition according to embodiment 49, wherein the disease or disease is cystic fibrosis.

Version 50: Pharmaceutical combination, including:

a first active substance comprising a compound of embodiments 1 to 43 and a second active substance selected from osmotic agents, ENaC blockers, anti-inflammatory agents, bronchodilators, antihistamines, anti-cough agents, antibiotics and DNase drug substances, where the first and second active substances may occur in the same or different pharmaceutical composition.

Embodiment 51: The pharmaceutical combination according to embodiment 50, wherein the second active agent is blockerEnaC.

123

Embodiment 52: A method for preparing compounds of formula (I), comprising:

<img file="PL2547656T3_D0103.tif" />

suitable amino-protecting group;

removal of protecting groups and isolation of the compound of formula I.

Embodiment 53: The method of embodiment 48, wherein the condition for coupling the peptides is HATU in an aprotic solvent.

Novartis AG, Szwajacaria Representative:

124

EP 2 547 656 B1 Z-13715/15