NOVEL HETEROCYCLIC COMPOUNDS AS ANTIMALARIAL AGENTS The invention relates to novel heterocyclic compounds of the Formula I. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the Formula I and especially their use as medicaments to treat or prevent malaria infections or to treat or prevent other protozoal diseases like sleeping sickness, Chagas disease, amebiasis, giardiasis, trichomoniasis, toxoplasmosis, and leishmaniasis.

Numerous serious diseases affecting humans as well as domestic and livestock animal are caused by protozoal organisms such as kinetoplastida, apicomplexa, anaerobic protozoa, microsporidia and Plasmodium, for example. The clinically most relevant of these diseases is malaria.

Malaria is one of the most serious and complex health problems affecting humanity in the 21 ^st century. The disease affects about 300 million people worldwide, killing 1 to 1 .5 million people every year. Malaria is an infectious disease caused by four species of the protozoan parasite Plasmodium, P. falciparum being the most severe of the four. All attempts to develop vaccines against P. falciparum have failed so far. Therefore, therapies and preventive measures against malaria are confined to drugs. Various classes of antimalarial drugs exist. The most widely used are the quinoline antimalarials, e.g. chloroquine which has been an especially effective drug for both prophylaxis and therapy. However, resistance to many of the currently available antimalarial drugs is spreading rapidly, threatening people in areas where malaria is endemic. Reports of multi-drug resistant strains of malaria parasites render the search for new antimalarial agents especially urgent.

P. falciparum enters the human body by way of bites of the female anophelino mosquito (it may also be transmitted by blood transfusion from asymptotic donors; almost all infected blood components including red cells, platelet concentrates, white cells, cryoprecipitates and fresh plasma can transmit malaria). The Plasmodium parasite initially populates the liver, and during later stages of the infectious cycle reproduces in red blood cells. During this stage, the parasite degrades hemoglobin and uses the degradation products as nutrients for growth. The limitations of the current antiprotozoal chemotherapeutic arsenal underscore the need for new drugs in this therapeutic area. The present invention relates to the identification of novel heterocyclic compounds of Formula I which are useful in the treatment and/or prevention of protozoal infections, especially in the treatment and/or prevention of malaria, in particular Plasmodium falciparum malaria.

1) A first embodiment of the present invention relates to a compound of the Formula I:

Formula I

wherein

A represents 1 ,4-phenylene, 1 ,3-phenylene, pyridin-2,6-diyl, or the following group:

wherein the asterisk indicates the bond that is attached to the group X-R ¹ ; or, in case X is absent, A may also represent piperidin-1 ,4-diyl, wherein R ¹ is attached to the nitrogen atom of the piperidin-1 ,4-diyl;

• X represents -NR ³ - wherein R ³ represents hydrogen or (C ₁ _ ₃ )alkyl (such as especially hydrogen, methyl or ethyl, preferably hydrogen or methyl), and

R ¹ represents a 6-membered heteroaryl ring (especially pyridinyl, pyrimidinyl or pyrazinyl), wherein said heteroaryl ring is optionally mono- or di-substituted (if substituted preferably mono-substituted) wherein the substituents are independently selected from the group consisting of (C _1-3 )alkyl, (C^alkoxy, halogen, (C^fluoroalkyl, (C^fluoroalkoxy, and pyrrolidinyl; or quinolinyl (especially quinolin-4-yl) optionally mono- or di-substituted wherein the substituents are independently selected from the group consisting of (C _1-3 )alkyl, (C^alkoxy, halogen, (C^fluoroalkyl, and (C^fluoroalkoxy; or

• X is absent, and

R ¹ respresents pyridinyl optionally mono-substituted with (C ₁ _ ₃ )alkyl or, in case A is not piperidin-1 ,4-diyl, R ¹ may also represent piperazinyl (especially piperazin-1 -yl) mono- subsituted (preferably at a nitrogen atom) with (C _1-3 )alkyl, such as especially 4-methyl- piperazin-1 -yl; R ² represents piperidinyl (especially piperidin-4-yl or piperidin-3-yl, preferably piperidin-4- yl), pyrrolidinyl (especially pyrrolidin-3-yl), or (3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl, all optionally mono-substituted (preferably at the nitrogen atom) wherein the subsituent is selected from the group consisting of (C _1-5 )alkyl; (C ₃ . ₆ )cycloalkyl (especially cyclopentyl); (C^fluoroalkyl; (C^alkyl (such as especially methyl) mono-substituted with (C ₃ . ₆ )cycloalkyl (especially cyclopropyl), phenyl, imidazolyl (especially 3H-imidazol-4-yl), isoxazolyl (especially isoxazol-4-yl), or imidazo[1 ,2-a]pyridinyl (especially imidazo[1 ,2- a]pyridin-7-yl), wherein the phenyl is optionally mono- or di-substituted wherein the substituents are independently selected from the group consisting of (C _1-3 )alkyl, (C^alkoxy, (C^fluoroalkyl, (C^fluoroalkoxy, halogen, hydroxy and -(CH ₂ ) _n -NR'R", wherein n is 0 or 1 and R' and R" independently represent (C _1-3 )alkyl, and wherein imidazolyl, isoxazolyl, and imidazo[1 ,2-a]pyridinyl are optionally mono- or di-substituted with (Ci _-3 )alkyl; and piperidinyl (especially piperidin-4-yl) or pyrrodinyl (especially pyrrolidin-3-yl), both optionally mono-substituted (preferably at the nitrogen atom) with (C _1-3 )alkyl or (C _1-3 )alkyl-CO; or R ² represents R ⁴ R ⁵ N-(C ₂ . ₄ )alkyl, wherein R ⁴ and R ⁵ independently represent hydrogen or (C _1-3 )alkyl, with the exception that not both R ⁴ and R ⁵ represent hydrogen (preferably both represent methyl), or wherein R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a piperazine ring which is optionally mono- substituted (preferably at the nitrogen atom at position 4) with (C ₁ _ ₃ )alkyl (especially methyl); and

Het represents pyridinyl, pyrimidinyl (especially pyrimidin-2-yl), or pyrazinyl (especially pyrazin-2-yl), all optionally mono- or di-substituted (preferably mono-substituted) wherein the substituents are independently selected from the group consisting of (C ₁ _ ₃ )alkyl; (C _1-3 )alkoxy (especially methoxy) optionally mono-substituted with phenyl; (C _1-3 )fluoroalkyl; phenyl or pyridinyl, both optionally mono-substituted with (C _1-4 )alkyl, (C _1-3 )alkoxy, halogen, (Ci _-3 )fluoroalkyl, (C^fluoroalkoxy, cyano, or methylsulfonyl; and -NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ independently represent (C _1-5 )alkyl or wherein R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperazine ring wherein the piperazine ring is optionally mono-substituted (preferably at the nitrogen atom at position 4) with (C _1-3 )alkyl (especially methyl); or Het represents benzooxazolyl (especially benzooxazol-2-yl), benzothiazolyl (especially benzothiazol-2-yl), quinolinyl (especially quinolin-4-yl), quinoxalinyl (especially quinoxalin-2-yl), or quinazolinyl (especially quinazolin-2-yl or quinazolin-4-yl), all optionally mono-substituted with (C ₁ _ ₄ )alkyl, (C _1-3 )alkoxy, halogen or (C _1-3 )fluoroalkyl; or oxadiazolyl (especially 1 ,2,4-oxadiazol-5-yl or 1 ,3,4-oxadiazol-2-yl) or thiazolyl (especially thiazol-2-yl), both optionally mono-substituted with phenyl or pyridinyl, wherein phenyl or pyridinyl is optionally mono-substituted with (C _1-4 )alkyl, (C^alkoxy, halogen, (C^fluoroalkyl, (C^fluoroalkoxy, cyano, or methylsulfonyl;

with the exception of:

N-(1 -isopropylpiperidin-4-yl)-N-(3-(methyl(pyridin-2-yl)amino)be nzyl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine, and

N-(1 -isopropylpiperidin-4-yl)-N-((6-(methyl(pyridin-3-yl)amino)p yridin-2-yl)methyl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine.

The following definitions are intended to apply uniformly to the compounds of Formula I according to embodiment 1) and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term as defined herein below or anywhere else in the description or the claims defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.

The term "halogen" refers to fluorine, chlorine, or bromine, preferably fluorine or chlorine.

The term "(C _x . _y )alkyl" (x and y each being an integer), used alone or in combination, refers to a saturated straight or branched chain alkyl group containing x to y carbon atoms. For example a (C ₁ _ ₅ )alkyl group contains from one to five carbon atoms.

The term "(Ci _-3 )alkoxy" refers to a (Ci _-3 )alkyl-0- group wherein the (C ₁ _ ₃ )alkyl group is as defined before containing one to three carbon atoms and thus refers to methoxy, ethoxy, n- propoxy, and isopropoxy, preferably methoxy.

The term "(C^fluoroalkyl" refers to a (C ₁ _ ₃ )alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. A preferred (C^fluoroalkyl is trifluoromethyl. If R ² represents piperidin-4-yl mono-substituted at the nitrogen atom with (C^fluoroalkyl, then (C^ ₃ )fluoroalkyl preferably represents 3-fluoro-propyl, 3,3,3-trifluoro-propyl or 2-fluoro-1 - (fluoromethyl)-ethyl.

The term "(C^fluoroalkoxy" refers to a (C^alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. A preferred (C _! ^fluoroalkoxy group is trifluoromethoxy. The term "(C ₃ . ₆ )cycloalkyl" refers to a saturated cyclic alkyl group containing three to 6 carbon atoms and thus refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "6-membered heteroaryl ring" refers to pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl.

2) Another embodiment of the invention relates to a compound according to embodiment 1), wherein A represents 1 ,4-phenylene.

3) Another embodiment of the invention relates to a compound according to embodiment 1), wherein A represents the following group:

wherein the asterisk indicates the bond that is attached to the group X-R ¹ .

4) Another embodiment of the invention relates to a compound according to any one of embodiments 1) to 3), wherein

• X represents -NR ³ - wherein R ³ represents hydrogen or (C ₁ _ ₃ )alkyl (such as especially hydrogen, methyl or ethyl, preferably hydrogen or methyl), and

R ¹ represents pyridinyl (especially pyridin-4-yl) optionally mono- or di-substituted (if substituted preferably mono-substituted) wherein the substituents are independently selected from the group consisting of (C _1-3 )alkyl, (C^alkoxy, halogen, (C^fluoroalkyl, (C^fluoroalkoxy, and pyrrolidinyl; pyridmidinyl optionally mono-substituted with (Ci _-3 )alkyl; pyrazinyl (especially pyrazin-2-yl); or quinolinyl (especially quinolin-4-yl) optionally mono- or di-substituted wherein the substituents are independently selected from the group consisting of (C _1-3 )alkyl, (C _1-3 )alkoxy, halogen, (C _1-3 )fluoroalkyl, and (C^fluoroalkoxy.

5) Another embodiment of the invention relates to a compound according to any one of embodiments 1) to 3), wherein

• X represents -NR ³ - wherein R ³ represents hydrogen or (C ₁ _ ₃ )alkyl (such as especially hydrogen, methyl or ethyl, preferably hydrogen or methyl), and

R ¹ represents pyridinyl (especially pyridin-4-yl) which is optionally mono- or di- substituted (if substituted preferably mono-substituted) wherein the substituents are independently selected from the group consisting of (C _1-3 )alkyl, (C^alkoxy, halogen, (C^fluoroalkyl, (C^fluoroalkoxy, and pyrrolidinyl.

6) Another embodiment of the invention relates to a compound according to any one of embodiments 1) to 3), wherein

• X represents -NR ³ - wherein R ³ represents hydrogen or (C^alkyl (such as especially hydrogen, methyl or ethyl, preferably hydrogen or methyl), and

R ¹ represents pyridin-4-yl optionally mono-substituted with methyl (if substituted with methyl, especially 2-methyl-pyridin-4-yl) or pyrimidin-4-yl optionally mono-substituted with methyl (especially pyrimidin-4-yl or 2-methyl-pyrimidin-4-yl, preferably pyrimidin-4- yi).

7) Another embodiment of the invention relates to a compound according to any one of embodiments 1) to 3), wherein

· X represents -NR ³ - wherein R ³ represents hydrogen or methyl, and

R ¹ represents pyridin-4-yl or 2-methyl-pyridin-4-yl.

8) Another embodiment of the invention relates to a compound according to any one of embodiments 1) to 3), wherein

· X represents -NR ³ - wherein R ³ represents hydrogen or methyl, and

R ¹ represents quinolinyl (especially quinolin-4-yl) optionally mono- or di-substituted wherein the substituents are independently selected from the group consisting of (C _1-3 )alkyl, (C^alkoxy, halogen, (C^fluoroalkyl, and (C^fluoroalkoxy. 9) Another embodiment of the invention relates to a compound according to any one of embodiments 1) to 8), wherein R ² represents piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl, all optionally mono-substituted (preferably at the nitrogen atom) wherein the subsituent is selected from the group consisting of (C ₁ _ ₅ )alkyl; (C ₃ . ₆ )cycloalkyl (especially cyclopentyl); (C^fluoroalkyl; (C^alkyl (such as especially methyl) mono-substituted with (C ₃ . ₆ )cycloalkyl (especially cyclopropyl), phenyl, imidazolyl (especially 3H-imidazol-4-yl), isoxazolyl (especially isoxazol-4-yl), or imidazo[1 ,2-a]pyridinyl (especially imidazo[1 ,2- a]pyridin-7-yl), wherein the phenyl is optionally mono- or di-substituted wherein the substituents are independently selected from the group consisting of (C _1-3 )alkyl, (Ci- ₃ )alkoxy, (Ci _-3 )fluoroalkyl, (Ci _-3 )fluoroalkoxy, halogen, hydroxy and -(CH ₂ ) _n -NR'R", wherein n is 0 or 1 and R' and R" independently represent (C _1-3 )alkyl, and wherein imidazolyl, isoxazolyl, and imidazo[1 ,2-a]pyridinyl are optionally mono- or di-substituted with (C _1-3 )alkyl; and piperidinyl (especially piperidin-4-yl) or pyrrodinyl (especially pyrrolidin-3-yl), both optionally mono-substituted (preferably at the nitrogen atom) with (C ₁ _ ₃ )alkyl or (Chalky I-CO-. 10) Another embodiment of the invention relates to a compound according to embodiment

9) , wherein R ² represents piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl, all optionally mono- substituted at the nitrogen atom wherein the subsituent is selected from the group consisting of (C _1-5 )alkyl; (C ₃ . ₆ )cycloalkyl (especially cyclopentyl); methyl mono-substituted with (C ₃ . ₆ )cycloalkyl (especially cyclopropyl), phenyl, imidazolyl (especially 3H-imidazol-4- yl), isoxazolyl (especially isoxazol-4-yl), or imidazo[1 ,2-a]pyridinyl (especially imidazo[1 ,2- a]pyridin-7-yl), wherein the phenyl is optionally mono-substituted with (C _1-3 )alkyl, (C^alkoxy, (C^fluoroalkyl, (C^fluoroalkoxy, or halogen, and wherein imidazolyl, isoxazolyl, and imidazo[1 ,2-a]pyridinyl are optionally mono- or di-substituted with (C _ ₃ )alkyl; and piperidinyl (especially piperidin-4-yl) or pyrrodinyl (especially pyrrolidin-3-yl), both optionally mono-substituted at the nitrogen atom with (C ₁ _ ₃ )alkyl or (C^alkyl-CO-.

1 1 ) Another embodiment of the invention relates to a compound according to embodiment

10) , wherein R ² represents piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl, all mono- substituted at the nitrogen atom with isopropyl, cyclopentyl, or 1 -methyl-piperidin-4-yl.

12) Another embodiment of the invention relates to a compound according to embodiment

1 1 ) , wherein R ² represents piperidin-4-yl or piperidin-3-yl, both mono-substituted at the nitrogen atom with isopropyl, cyclopentyl, or 1 -methyl-piperidin-4-yl. 13) Another embodiment of the invention relates to a compound according to any one of embodiments 1 ) to 8), wherein R ² represents R ⁴ R ⁵ N-(C ₂ -4)alkyl, wherein R ⁴ and R ⁵ independently represent hydrogen or (C _1-3 )alkyl, with the exception that not both R ⁴ and R ⁵ represent hydrogen (preferably both represent methyl), or wherein R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a piperazine ring which is optionally mono-substituted (preferably at the nitrogen atom at position 4) with (C _1-3 )alkyl (especially methyl).

14) Another embodiment of the invention relates to a compound according to embodiment

13) , wherein R ² represents R ⁴ R ⁵ N-(C ₂ - ₄ )alkyl, wherein R ⁴ and R ⁵ both represent methyl, or wherein R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a piperazine ring which is mono-substituted at the nitrogen atom at position 4 with methyl. 15) Another embodiment of the invention relates to a compound according to any one of embodiments 1 ) to 14), wherein Het represents mono-subsituted pyrimidinyl (especially mono-subsituted pyrimidin-2-yl) wherein the substituent is selected from the group consisting of (C _1-3 )alkyl; (C^alkoxy (especially methoxy) optionally mono-substituted with phenyl; (C^fluoroalkyl; phenyl or pyridinyl, both optionally mono-substituted with (C ₁ _ ₄ )alkyl, (C^^alkoxy, halogen, (Ci _-3 )fluoroalkyl, (C^fluoroalkoxy, cyano, or methylsulfonyl; and -NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ independently represent (C ₁ _ ₅ )alkyl or wherein R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperazine ring wherein the piperazine ring is optionally mono- substituted (preferably at the nitrogen atom at position 4) with (C ₁ _ ₃ )alkyl (especially methyl).

16) Another embodiment of the invention relates to a compound according to embodiment 15), wherein Het represents pyrimidin-2-yl mono-substituted at position 4 wherein the substituent is selected from the group consisting of (C _1-3 )alkyl; (C^alkoxy (especially methoxy) optionally mono-substituted with phenyl; (C^fluoroalkyl; phenyl or pyridinyl, both optionally mono-substituted with (Ci_ ₄ )alkyl, (C^alkoxy, halogen, (C^fluoroalkyl, (C^fluoroalkoxy, cyano, or methylsulfonyl; and -NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ independently represent (Ci_ ₅ )alkyl or wherein R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperazine ring wherein the piperazine ring is optionally mono-substituted (preferably at the nitrogen atom at position 4) with (C ₁ _ ₃ )alkyl (especially methyl).

17) Another embodiment of the invention relates to a compound according to embodiment 16), wherein Het represents pyrimidin-2-yl mono-substituted at position 4 with phenyl or pyridinyl, wherein phenyl or pyridinyl are optionally mono-substituted (preferably mono- substituted) with (C _1-4 )alkyl, (C^alkoxy, halogen, (C^fluoroalkyl, (C^fluoroalkoxy, cyano, or methylsulfonyl. 18) Another embodiment of the invention relates to a compound according to embodiment 17), wherein Het represents pyrimidin-2-yl mono-substituted at position 4 with 4- (trifluoromethyl)-phenyl or 6-(trifluoromethyl)-pyridin-3-yl.

19) Another embodiment of the invention relates to a compound according to any one of embodiments 1) to 14), wherein Het represents quinolinyl (especially quinolin-4-yl) optionally mono-substituted with (C _1-4 )alkyl or halogen. 20) Another embodiment of the invention relates to a compound according to embodiment 19), wherein Het represents quinolin-4-yl. 21 ) Another embodiment of the invention relates to a compound according to embodiment 1), wherein

A represents 1 ,4-phenylene, 1 ,3-phenylene, pyridin-2,6-diyl, or the following group:

wherein the asterisk indicates the bond that is attached to the group X-R ¹ ; or, in case X is absent, A may also represent piperidin-1 ,4-diyl, wherein R ¹ is attached to the nitrogen atom of the piperidin-1 ,4-diyl;

• X represents -NR ³ - wherein R ³ represents hydrogen, methyl, or ethyl, and

R ¹ represents pyridin-4-yl, 2-methyl-pyridin-4-yl, 2-methoxy-pyridin-4-yl, 2-fluoro-pyridin- 4-yl, 3-methyl-pyridin-4-yl, 3-fluoro-pyridin-4-yl, 2-(pyrrolidin-1 -yl)-pyridin-4-yl, 3- trifluoromethyl-pyridin-4-yl, 2,6-dimethyl-pyridin-4-yl, pyridin-3-yl, 2-fluoro-pyridin-3-yl, 5- fluoro-pyridin-3-yl, 6-methyl-pyridin-3-yl, pyridin-2-yl, pyrimidin-4-yl, 2-methyl-pyrimidin- 4-yl, 6-methyl-pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, or 6-methoxy-2-methyl- quinolin-4-yl; or

• X is absent and R ¹ represents pyridin-4-yl, pyridin-3-yl or pyridin-2-yl, or, in case A is not piperidin-1 ,4-diyl, R ¹ may also represent 4-methyl-piperazin-1 -yl;

R ² represents piperidin-4-yl, piperidin-3-yl, 1 -cyclopentyl-piperidin-4-yl, 1 -(1 -methyl- piperidin-4-yl)-piperidin-4-yl, 1 -isopropyl-piperidin-4-yl, 1 -(cyclopropylmethyl)-piperidin-4-yl, 1 -isopentyl-piperidin-4-yl, 1 -((4-methyl-phenyl)-methyl)-piperidin-4-yl, 1 -((4-dimethylamino- phenyl)-methyl)-piperidin-4-yl, 1 -((4-hydroxy-3-(dimethylaminomethyl)-phenyl)-methyl)- piperidin-4-yl, 1 -(imidazo[1 ,2-a]pyridin-7-ylmethyl)-piperidin-4-yl, 1 -(3,5-dimethyl-isoxazol-4- ylmethyl)-piperidin-4-yl, 1 -(3-methyl-3H-imidazol-4-ylmethyl)-piperidin-4-yl, 1 -isobutyl- piperidin-4-yl, 1 -cyclopentyl-piperidin-3-yl, 1 -(2-fluoro-1 -(fluoromethyl)-ethyl)-piperidin-4-yl, 1 -(3,3,3-trifluoro-propyl)-piperidin-4-yl, 1 -(1 -methylcarbonyl-piperidin-4-yl)-piperidin-4-yl, 1 - ethyl-piperidin-4-yl, 1 -(1 -methyl-piperidin-4-yl)-piperidin-3-yl, 1 -cyclopentyl-piperidin-3-yl, 1 - isopentyl-piperidin-3-yl, 1 -isopropyl-piperidin-3-yl, 1 -ethyl-piperidin-3-yl, 1 -(1 -methyl- pyrrolidin-3-yl)-piperidin-4-yl, 1 -(3-fluoro-propyl)-piperidin-4-yl, 1 -methyl-piperidin-4-yl, 1 - benzyl-piperidin-4-yl, 1 -(1 -methyl-piperidin-4-yl)-pyrrolidin-3-yl, 1 -((4-hydroxy-3- (dimethylaminomethyl)-phenyl)-methyl)-pyrrolidin-3-yl, 1 -isopropyl-pyrrolidin-3-yl, 1 - isopentyl-pyrrolidin-3-yl, 1 -cyclopentyl-pyrrolidin-3-yl, 2-(dimethylamino)-ethyl, 1 -methyl-2- (dimethylamino)-ethyl, 3-(dimethylamino)-propyl, 2-(4-methyl-piperazin-1-yl)-ethyl, 3-(4- methyl-piperazin-1 -yl)-propyl, 1 -methyl-3-(dimethylamino)-propyl, (3aR,6aS)-2-(1 -methyl- piperidin-4-yl)-octahydrocyclopenta[c]pyrrol-5-yl, (3aR,6aS)-2-isopentyl- octahydrocyclopenta[c]pyrrol-5-yl, or (3aR,6aS)-2-cyclopentyl-octahydrocyclopenta[c]pyrrol- 5-yl; and

Het represents pyrimidin-2-yl optionally substituted at position 4 by a radical selected from the group consisting of isopropyl, trifluoromethyl, methoxy, pyrrolidin-1-yl, 4-methyl- piperazin-1-yl, phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl, 4- chloro-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 4-methoxy-phenyl, 4-methylsulfonyl- phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 4- methyl-phenyl, 4-tert-butyl-phenyl, 4-(trifluoro-methoxy)-phenyl, pyridin-4-yl, 6- trifluoromethyl-pyridin-3-yl, and phenylmethoxy; 5-phenyl-pyrimidin-2-yl; 5-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl; quinolin-4-yl; benzooxazol-2-yl; benzothiazol-2-yl; quinoxalin-2-yl; 3-(4-(trifluoromethyl)phenyl)-1 ,2,4-oxadiazol-5-yl; 5-(4- (trifluoromethyl)phenyl)-1 ,3,4-oxadiazol-2-yl; 7-chloro-quinazolin-4-yl; 7-isobutyl-quinazolin- 4-yl; 6-fluoro-quinazolin-2-yl; 6-(4-trifluoromethyl-phenyl)-pyridin-2-yl; 4-(4-trifluoromethyl- phenyl)-thiazol-2-yl; 2-phenyl-pyrimidin-4-yl; 6-(4-trifluoromethyl-phenyl)-pyrazin-2-yl; 4-(4- trifluoromethyl-phenyl)-pyridin-2-yl; 2-(4-trifluoromethyl-phenyl)-pyridin-4-yl; 4,6-dimethyl- pyrimidin-2-yl; or 6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl.

22) The invention, thus, relates to compounds of the Formula I as defined in embodiment

1) , or to such compounds further limited by the characteristics of any one of embodiments

2) to 21), under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to such compounds or pharmaceutically acceptable salts thereof for use as medicaments especially for the treatment and/or prevention of protozoal infections, especially malaria. Especially the following embodiments relating to the compounds of Formula I are thus possible and intended and herewith specifically disclosed in individualized form:

1, 2+1, 3+1, 4+1, 4+2+1, 4+3+1, 5+1, 5+2+1, 5+3+1, 6+1, 6+2+1, 6+3+1, 7+1, 7+2+1, 7+3+1, 8+1, 8+2+1, 8+3+1, 9+1, 9+2+1, 9+3+1, 9+4+1, 9+4+2+1, 9+4+3+1, 9+5+1, 9+5+2+1, 9+5+3+1, 9+6+1, 9+6+2+1, 9+6+3+1, 9+7+1, 9+7+2+1, 9+7+3+1, 9+8+1, 9+8+2+1, 9+8+3+1, 10+9+1, 10+9+2+1, 10+9+3+1, 10+9+4+1, 10+9+4+2+1, 10+9+4+3+1, 10+9+5+1, 10+9+5+2+1, 10+9+5+3+1, 10+9+6+1, 10+9+6+2+1, 10+9+6+3+1, 10+9+7+1, 10+9+7+2+1, 10+9+7+3+1, 10+9+8+1, 10+9+8+2+1, 10+9+8+3+1, 11+10+9+1, 11+10+9+2+1, 11+10+9+3+1, 11+10+9+4+1, 11+10+9+4+2+1, 11+10+9+4+3+1, 11+10+9+5+1, 11+10+9+5+2+1, 11+10+9+5+3+1, 11+10+9+6+1, 11+10+9+6+2+1, 11+10+9+6+3+1, 11+10+9+7+1, 11+10+9+7+2+1, 11+10+9+7+3+1, 11+10+9+8+1, 11+10+9+8+2+1, 11+10+9+8+3+1, 12+11+10+9+1, 12+11+10+9+2+1, 12+11+10+9+3+1, 12+11+10+9+4+1, 12+11+10+9+4+2+1, 12+11+10+9+4+3+1, 12+11+10+9+5+' 12+11+10+9+5+2+1, 12+11+10+9+5+3+1, 12+11+10+9+6+1, 12+11+10+9+6+2+1, 12+11+10+9+6+3+ ^' 12+11+10+9+7+1, 12+11+10+9+7+2+1, 12+11+10+9+7+3+1, 12+11+10+9+8+1, 12+11+10+9+8+2+' 12+11+10+9+8+3+1, 13+1, 13+2+1, 13+3+1, 13+4+1, 13+4+2+1, 13+4+3+1, 13+5+1, 13+5+2+1, 13+5+3+' 13+6+1, 13+6+2+1, 13+6+3+1, 13+7+1, 13+7+2+1, 13+7+3+1, 13+8+1, 13+8+2+1, 13+8+3+1, 14+13+' 14+13+2+1, 14+13+3+1, 14+13+4+1, 14+13+4+2+1, 14+13+4+3+1, 14+13+5+1, 14+13+5+2+1, 14+13+5+3+' 14+13+6+1, 14+13+6+2+1, 14+13+6+3+1, 14+13+7+1, 14+13+7+2+1, 14+13+7+3+1, 14+13+8+' 14+13+8+2+1, 14+13+8+3+1, 15+1, 15+2+1, 15+3+1, 15+4+1, 15+4+2+1, 15+4+3+1, 15+5+1, 15+5+2+' 15+5+3+1, 15+6+1, 15+6+2+1, 15+6+3+1, 15+7+1, 15+7+2+1, 15+7+3+1, 15+8+1, 15+8+2+1, 15+8+3+' 15+9+1 , 15+9+2+1 , 15+9+3+1 , 15+9+4+1 , 15+9+4+2+1 , 15+9+4+3+1 , 15+9+5+1 , 15+9+5+2+1 , 15+9+5+3+ 15+9+6+1, 15+9+6+2+1, 15+9+6+3+1, 15+9+7+1, 15+9+7+2+1, 15+9+7+3+1, 15+9+8+1, 15+9+8+2+' 15+9+8+3+1, 15+10+9+1, 15+10+9+2+1, 15+10+9+3+1, 15+10+9+4+1, 15+10+9+4+2+1, 15+10+9+4+3+' 15+10+9+5+1, 15+10+9+5+2+1, 15+10+9+5+3+1, 15+10+9+6+1, 15+10+9+6+2+1, 15+10+9+6+3+' 15+10+9+7+1, 15+10+9+7+2+1, 15+10+9+7+3+1, 15+10+9+8+1, 15+10+9+8+2+1, 15+10+9+8+3+' 15+11+10+9+1, 15+11+10+9+2+1, 15+11+10+9+3+1, 15+11+10+9+4+1, 15+11+10+9+4+2+' 15+11+10+9+4+3+1, 15+11+10+9+5+1, 15+11+10+9+5+2+1, 15+11+10+9+5+3+1, 15+11+10+9+6+' 15+11+10+9+6+2+1, 15+11+10+9+6+3+1, 15+11+10+9+7+1, 15+11+10+9+7+2+1, 15+11+10+9+7+3+ ^' 15+11+10+9+8+1, 15+11+10+9+8+2+1, 15+11+10+9+8+3+1, 15+12+11+10+9+1, 15+12+11+10+9+2+' 15+12+11+10+9+3+1, 15+12+11+10+9+4+1, 15+12+11+10+9+4+2+1, 15+12+11+10+9+4+3+' 15+12+11+10+9+5+1, 15+12+11+10+9+5+2+1, 15+12+11+10+9+5+3+1, 15+12+11+10+9+6+' 15+12+11+10+9+6+2+1, 15+12+11+10+9+6+3+1, 15+12+11+10+9+7+1, 15+12+11+10+9+7+2+ ^' 15+12+11+10+9+7+3+1, 15+12+11+10+9+8+1, 15+12+11+10+9+8+2+1, 15+12+11+10+9+8+3+1, 15+13+' 15+13+2+1, 15+13+3+1, 15+13+4+1, 15+13+4+2+1, 15+13+4+3+1, 15+13+5+1, 15+13+5+2+1, 15+13+5+3+' 15+13+6+1, 15+13+6+2+1, 15+13+6+3+1, 15+13+7+1, 15+13+7+2+1, 15+13+7+3+1, 15+13+8+' 15+13+8+2+1, 15+13+8+3+1, 15+14+13+1, 15+14+13+2+1, 15+14+13+3+1, 15+14+13+4+ 15+14+13+4+2+1, 15+14+13+4+3+1, 15+14+13+5+1, 15+14+13+5+2+1, 15+14+13+5+3+1, 15+14+13+6+' 15+14+13+6+2+1, 15+14+13+6+3+1, 15+14+13+7+1, 15+14+13+7+2+1, 15+14+13+7+3+1, 15+14+13+8+' 15+14+13+8+2+1, 15+14+13+8+3+1, 16+15+1, 16+15+2+1, 16+15+3+1, 16+15+4+1, 16+15+4+2+' 16+15+4+3+1, 16+15+5+1, 16+15+5+2+1, 16+15+5+3+1, 16+15+6+1, 16+15+6+2+1, 16+15+6+3+ ^' 16+15+7+1, 16+15+7+2+1, 16+15+7+3+1, 16+15+8+1, 16+15+8+2+1, 16+15+8+3+1, 16+15+9+' 16+15+9+2+1, 16+15+9+3+1, 16+15+9+4+1, 16+15+9+4+2+1, 16+15+9+4+3+1, 16+15+9+5+ 16+15+9+5+2+1, 16+15+9+5+3+1, 16+15+9+6+1, 16+15+9+6+2+1, 16+15+9+6+3+1, 16+15+9+7+ 16+15+9+7+2+1, 16+15+9+7+3+1, 16+15+9+8+1, 16+15+9+8+2+1, 16+15+9+8+3+1, 16+15+10+9+' 16+15+10+9+2+1, 16+15+10+9+3+1, 16+15+10+9+4+1, 16+15+10+9+4+2+1, 16+15+10+9+4+3+' 16+15+10+9+5+1, 16+15+10+9+5+2+1, 16+15+10+9+5+3+1, 16+15+10+9+6+1, 16+15+10+9+6+2+' 16+15+10+9+6+3+1, 16+15+10+9+7+1, 16+15+10+9+7+2+1, 16+15+10+9+7+3+1, 16+15+10+9+8+' 16+' 5+10+9+8+2+1, 16+15+10+9+8+3+1, 16+15+11+10+9+1, 16+15+11+10+9+2+1, 16+15+11+10+9+3+

16+' 5+11+10+9+4+1, 16+15+11+10+9+4+2+1, 16+15+11+10+9+4+3+1, 16+15+11+10+9+5+

16+' 5+11+10+9+5+2+1, 16+15+11+10+9+5+3+1, 16+15+11+10+9+6+1, 16+15+11+10+9+6+2+

16+' 5+11+10+9+6+3+1, 16+15+11+10+9+7+1, 16+15+11+10+9+7+2+1, 16+15+11+10+9+7+3+

16+' 5+11+10+9+8+1, 16+15+11+10+9+8+2+1, 16+15+11+10+9+8+3+1, 16+15+12+11+10+9+

16+' 5+12+11+10+9+2+1, 16+15+12+11+10+9+3+1, 16+15+12+11+10+9+4+1, 16+15+12+11+10+9+4+2+

16+' 5+12+11+10+9+4+3+1, 16+15+12+11+10+9+5+1, 16+15+12+11+10+9+5+2+

16+' 5+1 2+11+10+9+5+3+1, 16+15+12+11+10+9+6+1, 16+15+12+11+10+9+6+2+

16+' 5+1 2+11+10+9+6+3+1, 16+15+12+11+10+9+7+1, 16+15+12+11+10+9+7+2+

16+' 5+1 2+11+10+9+7+3+1, 16+15+12+11+10+9+8+1, 16+15+12+11+10+9+8+2+

16+' 5+1 2+11+10+9+8+3+1, 16+15+13+1, 16+15+13+2+1, 16+15+13+3+1, 16+15+13+4+1, 16+15+13+4+2+

16+' 5+13+4+3+1, 16+15+13+5+1, 16+15+13+5+2+1, 16+15+13+5+3+1, 16+15+13+6+1, 16+15+13+6+2+

16+' 5+13+6+3+1, 16+15+13+7+1, 16+15+13+7+2+1, 16+15+13+7+3+1, 16+15+13+8+1, 16+15+13+8+2+

16+' 5+13+8+3+1, 16+15+14+13+1, 16+15+14+13+2+1, 16+15+14+13+3+1, 16+15+14+13+4+

16+' 5+14+13+4+2+1, 16+15+14+13+4+3+1, 16+15+14+13+5+1, 16+15+14+13+5+2+1, 16+15+14+13+5+3+

16+' 5+14+13+6+1, 16+15+14+13+6+2+1, 16+15+14+13+6+3+1, 16+15+14+13+7+1, 16+15+14+13+7+2+

16+' 5+14+13+7+3+1, 16+15+14+13+8+1, 16+15+14+13+8+2+1, 16+15+14+13+8+3+1, 17+16+15+

17+' 6+15+2+1, 17+16+15+3+1, 17+16+15+4+1, 17+16+15+4+2+1, 17+16+15+4+3+1, 17+16+15+5+

17+' 6+15+5+2+1, 17+16+15+5+3+1, 17+16+15+6+1, 17+16+15+6+2+1, 17+16+15+6+3+1, 17+16+15+7+

17+' 6+15+7+2+1, 17+16+15+7+3+1, 17+16+15+8+1, 17+16+15+8+2+1, 17+16+15+8+3+1, 17+16+15+9+

17+' 6+15+9+2+1, 17+16+15+9+3+1, 17+16+15+9+4+1, 17+16+15+9+4+2+1, 17+16+15+9+4+3+

17+' 6+15+9+5+1, 17+16+15+9+5+2+1, 17+16+15+9+5+3+1, 17+16+15+9+6+1, 17+16+15+9+6+2+

17+' 6+15+9+6+3+1, 17+16+15+9+7+1, 17+16+15+9+7+2+1, 17+16+15+9+7+3+1, 17+16+15+9+8+

17+' 6+15+9+8+2+1, 17+16+15+9+8+3+1, 17+16+15+10+9+1, 17+16+15+10+9+2+1, 17+16+15+10+9+3+

17+' 6+15+10+9+4+1, 17+16+15+10+9+4+2+1, 17+16+15+10+9+4+3+1, 17+16+15+10+9+5+

17+' 6+15+10+9+5+2+1, 17+16+15+10+9+5+3+1, 17+16+15+10+9+6+1, 17+16+15+10+9+6+2+

17+' 6+15+10+9+6+3+1, 17+16+15+10+9+7+1, 17+16+15+10+9+7+2+1, 17+16+15+10+9+7+3+

17+' 6+15+10+9+8+1, 17+16+15+10+9+3+2+1, 17+16+15+10+9+8+3+1, 17+16+15+11+10+9+

17+' 6+15+11+10+9+2+1, 17+16+15+11+10+9+3+1, 17+16+15+11+10+9+4+1, 17+16+15+11+10+9+4+2+

17+' 6+1 5+11+10+9+4+3+1, 17+16+15+11+10+9+5+1, 17+16+15+11+10+9+5+2+

17+' 6+1 5+11+10+9+5+3+1, 17+16+15+11+10+9+6+1, 17+16+15+11+10+9+6+2+

17+' 6+1 5+11+10+9+6+3+1, 17+16+15+11+10+9+7+1, 17+16+15+11+10+9+7+2+

17+' 6+1 5+11+10+9+7+3+1, 17+16+15+11+10+9+8+1, 17+16+15+11+10+9+8+2+

17+' 6+1 5+11+10+9+8+3+1, 17+16+15+12+11+10+9+1, 17+16+15+12+11+10+9+2+

17+' 6+1 5+12+11+10+9+3+1, 17+16+15+12+11+10+9+4+1, 17+16+15+12+11+10+9+4+2+

17+' 6+1 5+12+11+10+9+4+3+1, 17+16+15+12+11+10+9+5+1, 17+16+15+12+11+10+9+5+2+ 17+ 6+' 5+' 2+11+10+9+5+3+1, 17+16+15+12+11+10+9+6+1, 17+16+15+12+11+10+9+6+2+1

17+ 6+' 5+' 2+11+10+9+6+3+1, 17+16+15+12+11+10+9+7+1, 17+16+15+12+11+10+9+7+2+1

17+ 6+' 5+' 2+11+10+9+7+3+1, 17+16+15+12+11+10+9+8+1, 17+16+15+12+11+10+9+8+2+1

17+ 6+' 5+' 2+11+10+9+8+3+1, 17+16+15+13+1, 17+16+15+13+2+1, 17+16+15+13+3+1, 17+16+15+13+4+1

17+ 6+' 5+' 3+4+2+1, 17+16+15+13+4+3+1, 17+16+15+13+5+1, 17+16+15+13+5+2+1, 17+16+15+13+5+3+1

17+ 6+' 5+' 3+6+1, 17+16+15+13+6+2+1, 17+16+15+13+6+3+1, 17+16+15+13+7+1, 17+16+15+13+7+2+1

17+ 6+' 5+' 3+7+3+1, 17+16+15+13+8+1, 17+16+15+13+8+2+1, 17+16+15+13+8+3+1, 17+16+15+14+13+1

17+ 6+' 5+' 4+13+2+1, 17+16+15+14+13+3+1, 17+16+15+14+13+4+1, 17+16+15+14+13+4+2+1

17+ 6+' 5+' 4+13+4+3+1, 17+16+15+14+13+5+1, 17+16+15+14+13+5+2+1, 17+16+15+14+13+5+3+1

17+ 6+' 5+' 4+13+6+1, 17+16+15+14+13+6+2+1, 17+16+15+14+13+6+3+1, 17+16+15+14+13+7+1

17+ 6+' 5+' 4+13+7+2+1, 17+16+15+14+13+7+3+1, 17+16+15+14+13+8+1, 17+16+15+14+13+8+2+1

17+ 6+' 5+' 4+13+8+3+1, 18+17+16+15+1, 18+17+16+15+2+1, 18+17+16+15+3+1, 18+17+16+15+4+1

18+ 7+' 6+' 5+4+2+1, 18+17+16+15+4+3+1, 18+17+16+15+5+1, 18+17+16+15+5+2+1, 18+17+16+15+5+3+1

18+ 7+' 6+' 5+6+1, 18+17+16+15+6+2+1, 18+17+16+15+6+3+1, 18+17+16+15+7+1, 18+17+16+15+7+2+1

18+ 7+' 6+' 5+7+3+1, 18+17+16+15+8+1, 18+17+16+15+8+2+1, 18+17+16+15+8+3+1, 18+17+16+15+9+1

18+ iv 6+' 5+9+2+1, 18+17+16+15+9+3+1, 18+17+16+15+9+4+1, 18+17+16+15+9+4+2+1

18+ iv 6+' 5+9+4+3+1, 18+17+16+15+9+5+1, 18+17+16+15+9+5+2+1, 18+17+16+15+9+5+3+1

18+ iv 6+' 5+9+6+1, 18+17+16+15+9+6+2+1, 18+17+16+15+9+6+3+1, 18+17+16+15+9+7+1

18+ iv 6+' 5+9+7+2+1, 18+17+16+15+9+7+3+1, 18+17+16+15+9+8+1, 18+17+16+15+9+8+2+1

18+ iv 6+' 5+9+8+3+1, 18+17+16+15+10+9+1, 18+17+16+15+10+9+2+1, 18+17+16+15+10+9+3+1

18+ iv 6+' 5+10+9+4+1, 18+17+16+15+10+9+4+2+1, 18+17+16+15+10+9+4+3+1

18+ iv 6+' 5+10+9+5+1, 18+17+16+15+10+9+5+2+1, 18+17+16+15+10+9+5+3+1

18+ iv 6+' 5+10+9+6+1, 18+17+16+15+10+9+6+2+1, 18+17+16+15+10+9+6+3+1

18+ iv 6+' 5+10+9+7+1, 18+17+16+15+10+9+7+2+1, 18+17+16+15+10+9+7+3+1

18+ iv 6+' 5+10+9+8+1, 18+17+16+15+10+9+8+2+1, 18+17+16+15+10+9+8+3+1

18+ iv 6+' 5+11+10+9+1, 18+17+16+15+11+10+9+2+1, 18+17+16+15+11+10+9+3+1

18+ iv 6+' 5+11+10+9+4+1, 18+17+16+15+11+10+9+4+2+1, 18+17+16+15+11+10+9+4+3+1

18+ iv 6+' 5+11+10+9+5+1, 18+17+16+15+11+10+9+5+2+1, 18+17+16+15+11+10+9+5+3+1

18+ iv 6+' 5+11+10+9+6+1, 18+17+16+15+11+10+9+6+2+1, 18+17+16+15+11+10+9+6+3+1

18+ iv 6+' 5+11+10+9+7+1, 18+17+16+15+11+10+9+7+2+1, 18+17+16+15+11+10+9+7+3+1

18+ iv 6+' 5+11+10+9+8+1, 18+17+16+15+11+10+9+8+2+1, 18+17+16+15+11+10+9+8+3+1

18+ iv 6+' 5+12+11+10+9+1, 18+17+16+15+12+11+10+9+2+1, 18+17+16+15+12+11+10+9+3+1

18+ iv 6+' 5+12+11+10+9+4+1 18+17+16+15+12+11+10+9+4+2+1 , 18+17+16+15+12+11+10+9+4+3+1

18+ iv 6+' 5+12+11+10+9+5+1 18+17+16+15+12+11+10+9+5+2+1 , 18+17+16+15+12+11+10+9+5+3+1

18+ iv 6+' 5+12+11+10+9+6+1 18+17+16+15+12+11+10+9+6+2+1 , 18+17+16+15+12+11+10+9+6+3+1

18+ iv 6+' 5+12+11+10+9+7+1 18+17+16+15+12+11+10+9+7+2+1 , 18+17+16+15+12+11+10+9+7+3+1 18+17+16+15+12+11+10+9+8+1 , 18+17+16+15+12+11+10+9+8+2+1 , 18+17+16+15+12+11+10+9+8+3+' 18+17+16+15+13+1, 18+17+16+15+13+2+1, 18+17+16+15+13+3+1, 18+17+16+15+13+4+' 18+17+16+15+13+4+2+1, 18+17+16+15+13+4+3+1, 18+17+16+15+13+5+1, 18+17+16+15+13+5+2+' 18+17+16+15+13+5+3+1, 18+17+16+15+13+6+1, 18+17+16+15+13+6+2+1, 18+17+16+15+13+6+3+' 18+17+16+15+13+7+1, 18+17+16+15+13+7+2+1, 18+17+16+15+13+7+3+1, 18+17+16+15+13+8+' 18+17+16+15+13+8+2+1, 18+17+16+15+13+8+3+1, 18+17+16+15+14+13+1, 18+17+16+15+14+13+2+' 18+17+16+15+14+13+3+1 , 18+17+16+15+14+13+4+1 , 18+17+16+15+14+13+4+2+'

18+17+16+15+14+13+4+3+1 , 18+17+16+15+14+13+5+1 , 18+17+16+15+14+13+5+2+'

18+17+16+15+14+13+5+3+1 , 18+17+16+15+14+13+6+1 , 18+17+16+15+14+13+6+2+' 18+17+16+15+14+13+6+3+1, 18+17+16+15+14+13+7+1, 18+17+16+15+14+13+7+2+'

18+17+16+15+14+13+7+3+1 , 18+17+16+15+14+13+8+1 , 18+17+16+15+14+13+8+2+'

18+17+16+15+14+13+8+3+1, 19+1, 19+2+1, 19+3+1, 19+4+1, 19+4+2+1, 19+4+3+1, 19+5+1, 19+5+2+' 19+5+3+1, 19+6+1, 19+6+2+1, 19+6+3+1, 19+7+1, 19+7+2+1, 19+7+3+1, 19+8+1, 19+8+2+1, 19+8+3+' 19+9+1, 19+9+2+1, 19+9+3+1, 19+9+4+1, 19+9+4+2+1, 19+9+4+3+1, 19+9+5+1, 19+9+5+2+1, 19+9+5+3+' 19+9+6+1, 19+9+6+2+1, 19+9+6+3+1, 19+9+7+1, 19+9+7+2+1, 19+9+7+3+1, 19+9+8+1, 19+9+8+2+' 19+9+8+3+1, 19+10+9+1, 19+10+9+2+1, 19+10+9+3+1, 19+10+9+4+1, 19+10+9+4+2+1, 19+10+9+4+3+' 19+10+9+5+1, 19+10+9+5+2+1, 19+10+9+5+3+1, 19+10+9+6+1, 19+10+9+6+2+1, 19+10+9+6+3+' 19+10+9+7+1, 19+10+9+7+2+1, 19+10+9+7+3+1, 19+10+9+8+1, 19+10+9+8+2+1, 19+10+9+8+3+' 19+11+10+9+1, 19+11+10+9+2+1, 19+11+10+9+3+1, 19+11+10+9+4+1, 19+11+10+9+4+2+' 19+11+10+9+4+3+1, 19+11+10+9+5+1, 19+11+10+9+5+2+1, 19+11+10+9+5+3+1, 19+11+10+9+6+' 19+11+10+9+6+2+1, 19+11+10+9+6+3+1, 19+11+10+9+7+1, 19+11+10+9+7+2+1, 19+11+10+9+7+3+ ^' 19+11+10+9+8+1, 19+11+10+9+8+2+1, 19+11+10+9+8+3+1, 19+12+11+10+9+1, 19+12+11+10+9+2+' 19+12+11+10+9+3+1, 19+12+11+10+9+4+1, 19+12+11+10+9+4+2+1, 19+12+11+10+9+4+3+' 19+12+11+10+9+5+1, 19+12+11+10+9+5+2+1, 19+12+11+10+9+5+3+1, 19+12+11+10+9+6+' 19+12+11+10+9+6+2+1, 19+12+11+10+9+6+3+1, 19+12+11+10+9+7+1, 19+12+11+10+9+7+2+' 19+12+11+10+9+7+3+1, 19+12+11+10+9+8+1, 19+12+11+10+9+8+2+1, 19+12+11+10+9+8+3+1, 19+13+' 19+13+2+1, 19+13+3+1, 19+13+4+1, 19+13+4+2+1, 19+13+4+3+1, 19+13+5+1, 19+13+5+2+1, 19+13+5+3+' 19+13+6+1, 19+13+6+2+1, 19+13+6+3+1, 19+13+7+1, 19+13+7+2+1, 19+13+7+3+1, 19+13+8+' 19+13+8+2+1, 19+13+8+3+1, 19+14+13+1, 19+14+13+2+1, 19+14+13+3+1, 19+14+13+4+ ^' 19+14+13+4+2+1, 19+14+13+4+3+1, 19+14+13+5+1, 19+14+13+5+2+1, 19+14+13+5+3+1, 19+14+13+6+' 19+14+13+6+2+1, 19+14+13+6+3+1, 19+14+13+7+1, 19+14+13+7+2+1, 19+14+13+7+3+1, 19+14+13+8+' 19+14+13+8+2+1, 19+14+13+8+3+1, 20+19+1, 20+19+2+1, 20+19+3+1, 20+19+4+1, 20+19+4+2+' 20+19+4+3+1, 20+19+5+1, 20+19+5+2+1, 20+19+5+3+1, 20+19+6+1, 20+19+6+2+1, 20+19+6+3+ 20+19+7+1, 20+19+7+2+1, 20+19+7+3+1, 20+19+8+1, 20+19+8+2+1, 20+19+8+3+1, 20+19+9+' 20+19+9+2+1, 20+19+9+3+1, 20+19+9+4+1, 20+19+9+4+2+1, 20+19+9+4+3+1, 20+19+9+5+' 20+19+9+5+2+1, 20+19+9+5+3+1, 20+19+9+6+1, 20+19+9+6+2+1, 20+19+9+6+3+1, 20+19+9+7+ 20+19+9+7+2+1, 20+19+9+7+3+1, 20+19+9+8+1, 20+19+9+8+2+1, 20+19+9+8+3+1, 20+19+10+9+ 20+19+10+9+2+1, 20+19+10+9+3+1, 20+19+10+9+4+1, 20+19+10+9+4+2+1, 20+19+10+9+4+3+ 20+19+10+9+5+1, 20+19+10+9+5+2+1, 20+19+10+9+5+3+1, 20+19+10+9+6+1, 20+19+10+9+6+2+ 20+19+10+9+6+3+1, 20+19+10+9+7+1, 20+19+10+9+7+2+1, 20+19+10+9+7+3+1, 20+19+10+9+8+ 20+19+10+9+8+2+1, 20+19+10+9+8+3+1, 20+19+11+10+9+1, 20+19+11+10+9+2+1, 20+19+11+10+9+3+ 20+19+11+10+9+4+1, 20+19+11+10+9+4+2+1, 20+19+11+10+9+4+3+1, 20+19+11+10+9+5+ 20+19+11+10+9+5+2+1, 20+19+11+10+9+5+3+1, 20+19+11+10+9+6+1, 20+19+11+10+9+6+2+ 20+19+11+10+9+6+3+1, 20+19+11+10+9+7+1, 20+19+11+10+9+7+2+1, 20+19+11+10+9+7+3+ 20+19+11+10+9+8+1, 20+19+11+10+9+8+2+1, 20+19+11+10+9+8+3+1, 20+19+12+11+10+9+ 20+19+12+11+10+9+2+1, 20+19+12+11+10+9+3+1, 20+19+12+11+10+9+4+1, 20+19+12+11+10+9+4+2+ 20+19+12+11 +10+9+4+3+1 , 20+19+12+11 +10+9+5+1 , 20+19+12+11 +10+9+5+2+

20+19+12+11 +10+9+5+3+1 , 20+19+12+11 +10+9+6+1 , 20+19+12+11 +10+9+6+2+

20+19+12+11 +10+9+6+3+1 , 20+19+12+11 +10+9+7+1 , 20+19+12+11 +10+9+7+2+

20+19+12+11 +10+9+7+3+1 , 20+19+12+11 +10+9+8+1 , 20+19+12+11 +10+9+8+2+

20+19+12+11+10+9+8+3+1, 20+19+13+1, 20+19+13+2+1, 20+19+13+3+1, 20+19+13+4+1, 20+19+13+4+2+ 20+19+13+4+3+1, 20+19+13+5+1, 20+19+13+5+2+1, 20+19+13+5+3+1, 20+19+13+6+1, 20+19+13+6+2+ 20+19+13+6+3+1, 20+19+13+7+1, 20+19+13+7+2+1, 20+19+13+7+3+1, 20+19+13+8+1, 20+19+13+8+2+ 20+19+13+8+3+1, 20+19+14+13+1, 20+19+14+13+2+1, 20+19+14+13+3+1, 20+19+14+13+4+ 20+19+14+13+4+2+1, 20+19+14+13+4+3+1, 20+19+14+13+5+1, 20+19+14+13+5+2+1, 20+19+14+13+5+3+ 20+19+14+13+6+1, 20+19+14+13+6+2+1, 20+19+14+13+6+3+1, 20+19+14+13+7+1, 20+19+14+13+7+2+ 20+19+14+13+7+3+1, 20+19+14+13+8+1, 20+19+14+13+8+2+1, 20+19+14+13+8+3+1, and 21+1.

In the list above, the numbers refer to the embodiments according to their numbering provided hereinabove whereas "+" indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, "9+6+1" for example refers to embodiment 9) depending on embodiment 6) depending on embodiment 1), i.e. embodiment "9+6+1" corresponds to the compounds of embodiment 1) further limited by the features of the embodiments 6) and 9). The compounds of Formula I may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. The compounds of Formula I may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art. Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like. Any reference hereinbefore or hereinafter to a compound of Formula I is to be understood as referring also to salts, especially pharmaceutically acceptable salts, of a compound of Formula I, as appropriate and expedient.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example 'Handbook of Pharmaceutical Salts. Properties, Selection and Use.', P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008 and 'Pharmaceutical Salts and Co-crystals', Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.

The present invention also includes isotopically labelled, especially ² H (deuterium) labelled compounds of Formula I, which compounds are identical to the compounds of Formula I except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially ² H (deuterium) labelled compounds of Formula I and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope ² H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of Formula I are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of Formula I are not isotopically labelled at all. Isotopically labelled compounds of Formula I may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.

23) Particular compounds of Formula I are selected from the group consisting of:

[4-(Methyl-pyridin-4-yl-amino)-benzyl]-piperidin-4-yl-[4- (4-trifluoromethyl-phenyl)-pyrimidin- 2-yl]-amine,

[4-(Methyl-pyridin-4-yl-amino)-benzyl]-(S)-piperidin-3-yl-[4 -(4-trifluoromethyl-phenyl)- pyrimidin-2-yl]-amine,

[6-(2-Methyl-pyridin-4-ylamino)-pyridin-3-ylmethyl]-piperidi n-4-yl-quinolin-4-yl-amine,

[4-(Methyl-pyridin-4-yl-amino)-benzyl]-piperidin-4-yl-qui nolin-4-yl-amine,

[4-(2-Methyl-pyridin-4-ylamino)-benzyl]-(S)-piperidin-3-yl-q uinolin-4-yl-amine, (1 -Cyclopentyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-amino)-be nzyl]-[4-(4-trffl

phenyl)-pyrimidin-2-yl]-amine,

(1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[4-(methyl-pyridin-4-yl-amino)-benzy l]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-amino)-benz yl]-[4-(4-trifluorom phenyl)-pyrimidin-2-yl]-amine,

(1 -Cyclopropylmethyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-ami no)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[1 -(3-Methyl-butyl)^iperidin-4-yl]-[4-(methyl^yridin-4-yl-amin o)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[1 -(4-Methyl-benzyl)^iperidin-4-yl]-[4-(methyl^yridin-4-yl-ami no)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[1 -(4-Dimethylamino-benzyl)^iperidin-4-yl]-[4-(m

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

2-Dimethylaminomethyl-4-(4-{[4-(methyl^yridin-4-yl-amino) -benzyl]-[4-(4-triflu

phenyl)^yrimidin-2-yl]-amino}-piperidin-1 -ylmethyl)-phenol,

(1 -lmidazo[1 ,2-a]pyridin-7-ylmethyl^iperidin-4-yl)-[4-(methyl^yridin-4-y l-amino)-benzyl]-[4- (4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[1 -(3,5-Dimethyl-isoxazol-4-ylmethyl)^iperidin-4-yl]-[4-(methy l^yridin-4-yl-amino)

[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[1 -(3-Methyl-3H-imidazol-4-ylmethyl)^iperidin-4-yl]-[4-(methyl ^yridin-4-yl-am

[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[1 -(3-Methy butyl)^iperidin-4-yl]-[6-(methyl^y

4-yl-amine,

(1 -Cyclopropylmethyl^iperidin-4-yl)-[6-(methy^

quinolin-4-yl-amine,

[1 -(3-Methyl-3H-imidazol-4-ylmethyl)^iperidin-4-yl]-[6-(methyl ^yridin-4-yl-am

ylmethyl]-quinolin-4-yl-amine,

(1 -lsobutyl^iperidin-4-yl)-[6-(methyl^yridin-4-yl-amino)^yridi n-3-ylmethyl]-quin amine,

((S)-1 -Cyclopentyl^iperidin-3-yl)-[4-(2-methyl^yridin-4-ylamino)-b enzyl]-quinolin-4 amine,

Benzooxazol-2-yl-(1 '-methyl-[1 ,4']bipiperidinyl-4-yl)-[4-(methyl-pyridin-4-yl-amino)-benzy l]- amine,

4-(4-{Benzooxazol-2-yl-[4-(methyl-pyridin-4-yl-amino)-ben zyl]-amino}-piperidin-1 -ylmethyl)- 2-dimethylaminomethyl-phenol, Benzooxazol-2-yl-(1 -isopropyl-piperidin-4-yl)-[4-(met^

Benzooxazol-2-yl-[1 -(3-methyl-butyl)-piperidin-4-yl]-[4-(^

amine,

(1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[4-(methyl^yridin-4-yl-amino)-benzyl ]-quinoxalin-2-yl- amine,

2-Dimethylaminomethyl-4-(4-{[4-(methyl-pyridin-4-yl-amino)-b enzyl]-quinoxalin-2-yl-amino}- piperidin-1 -ylmethyl)-phenol,

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-be nzyl]-quinoxalin-2-yl-amine, [1 -(3-Methyl-butyl)-piperidin-4-yl]-[4-(methyl-pyridin-4-yl-am ino)-benzyl]-quinoxalin-2-yl- amine,

(1 -Cyclopentyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)- benzyl]-quinoxalin-2-yl-amine, Benzooxazol-2-yl-[1 -(3-methyl-3H-imidazol-4-ylmethyl)-piperidin-4-yl]-[4-(methy l-pyridin-4- yl-amino)-benzyl]-amine,

[1 -(3-Methyl-3H-imidazol-4-ylmethyl)^iperidin-4-yl]-[4-(methyl -pyridin-4-yl-amino)-benzyl]- quinoxalin-2-yl-amine,

Benzooxazol-2-yl-(1 -cyclopentyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)- benzyl]- amine,

[1 -(2-Fluoro-1 -fluoromethyl-ethyl)-piperidin-4-yl]-[4-(methyl-pyridin-4-yl -amino)-benzyl]-[4- (4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[4-(Methyl-pyridin-4-yl-amino)-benzyl]-[4-(4-trifluoromet hyl-phenyl)-pyrimidin-2-yl]-[1 -(3,3,3- trifluoro-propyl)-piperidin-4-yl]-amine,

1 -(4-{[4-(Methyl-pyridin-4-yl-amino)-benzyl]-[4-(4-trifluorom ethyl-phenyl)-pyrimidin-2-yl]- amino}-[1 ,4']bipiperidinyl-1 '-yl)-ethanone,

(1 -Ethyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-benzyl ]-[4-(4-trifluoromethyl-phenyl)- pyrimidin-2-yl]-amine,

(1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[4-(methyl-pyridin-4-yl-amino)-benzy l]-quinolin-4-yl-amine, Benzothiazol-2-yl-(1 '-methyl-[1 ,4']bipiperidinyl-4-yl)-[4-(methyl-pyridin-4-yl-amino)-benzy l]- amine,

Benzothiazol-2-yl-(1 -cyclopentyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)- benzyl]- amine,

Benzothiazol-2-yl-[1 -(3-methyl-butyl)-piperidin-4-yl]-[4-(methyl-pyridin-4-yl-am ino)-benzyl]- amine,

Benzothiazol-2-yl-[1 -(3-methyl-3H-imidazol-4-ylmethyl)-piperidin-4-yl]-[4-(methy l-pyridin-4- yl-amino)-benzyl]-amine,

(S)-1 '-methyl-N-(4-(methyl(pyridin-4-yl)amino)benzyl)-N-(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'-bipiperidin]-3-amine, (S)-N-(1-cyclopentylpiperidin-3-yl)-N-(4-(methyl(pyridin-4-y l)amino)benzyl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine,

(S)-N-(1 -isopentylpiperidin-3-yl)-N-(4-(methyl(pyridin-4-yl)amino)be nzyl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine,

(3aR,6aS)-N-(4-(methyl(pyridin-4-yl)amino)benzyl)-2-(1 -methylpiperidin-4-yl)-N-(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)octahydrocyclopenta[c ]pyrrol-5-amine,

(3aR,6aS)-2-isopentyl-N-(4-(methyl(pyridin-4-yl)amino)ben zyl)-N-(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)octahydrocyclopenta[c ]pyrrol-5-amine,

(3aR,6aS)-2-cyclopentyl-N-(4-(methyl(pyridin-4-yl)amino)b enzyl)-N-(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)octahydrocyclopenta[c ]pyrrol-5-amine,

(S)-N-(4-(Ethyl(pyridin-4-yl)amino)benzyl)-1 '-methyl-N-(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'-bipiperidin]-3-amine,

((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-[4-(methyl^yridin-3-yl-amino)-benzyl ]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-{4-[methyl-(2-methyl^yridin-4-yl)-am ino]-benzyl}-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

((S)-1-lsopropyl^iperidin-3-yl)-[4-(methyl^yridin-4-yl-amino )-benzyl]-[4-(4-trifluorom phenyl)-pyrimidin-2-yl]-amine,

((S)-1-Ethyl^iperidin-3-yl)-[4-(methyl^yridin-4-yl-amino)-be nzyl]-[4-(4-trifluorom phenyl)-pyrimidin-2-yl]-amine,

N-(4-(Methyl(pyridin-4-yl)amino)benzyl)-N-(1 '-methyl-[1 ,4'-bipiperidin]-4-yl)-3-(4- (trifluoromethyl)phenyl)-1 ,2,4-oxadiazol-5-amine,

N-(4-(Methyl(pyridin-4-yl)amino)benzyl)-N-(1 '-methyl-[1 ,4'-bipiperidin]-4-yl)-5-(4- (trifluoromethyl)phenyl)-1 ,3,4-oxadiazol-2-amine,

[(S)-1 -(1-Methyl^iperidin-4-yl)^yrrolidin-3-yl^

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

2-Dimethylaminomethyl-4-((S)-3-{[4-(methyl-pyridin-4-yl-amin o)-benzyl]-[4-(4- trifluoromethyl^henyl)^yrimidin-2-yl]-amino}^yrrolidin-1-ylm ethyl)-phenol,

((S)-1-lsopropyl^yrrolidin-3-yl)-[4-(methyl^yridin-4-yl-a mino)-benzyl]-[4-(4-trifluorom phenyl)-pyrimidin-2-yl]-amine,

[(R)-1-(1-Methyl^iperidin-4-yl)^yrrolidin-3-y^^

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

2-Dimethylaminomethyl-4-((R)-3-{[4-(methyl^yridin-4-yl-amino )-benzyl]-[4-(4- trifluoromethyl^henyl)^yrimidin-2-yl]-amino}^yrrolidin-1-ylm ethyl)-phenol,

[(S)-1-(3-Methyl-butyl)^yrrolidin-3-yl]-[4-(methyl^yridin -4-yl-amino)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine, ((S)-1 -Cyclopentyl^yrrolidin-3-yl)-[4-(methyl^yridin-4-yl-amino)-b enzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

((R)-1 -lsopropyl^yrrolidin-3-yl)-[4-(methyl^yridin-4-yl-amino)-ben zyl]-[4-(4-trifluorom phenyl)-pyrimidin-2-yl]-amine,

[(R)-1 -(3-Methyl-butyl)^yrrolidin-3-yl]-[4-(methyl^yridin-4-yl-ami no)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

((R)-1 -Cyclopentyl^yrrolidin-3-yl)-[4-(methyl-pyridin-4-yl-amino)- benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[4-(Methyl^yridin-4-yl-amino)-benzyl]-[1 -(1 -methyl^yrrolidin-3-yl)^iperidin-4-yl]^ trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[1 -(3-Fluoro^ropyl)^iperidin-4-yl]-[4-(methyl-pyridin-4-yl-ami no)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -Methyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-amino)-benzyl] -[4-(4-trifluorometh pyrimidin-2-yl]-amine,

(1 -Benzy piperidin-4-yl)-[4-(2-methyl^yridin-4-ylamm^

amine,

(1 -Benzyl^iperidin-4-yl)-[4-(3 1uoro^henyl)^yrim^

benzyl]-amine,

(1 -Benzyl^iperidin-4-yl)-[4-(2-methyl^yridin-4-ylamino)-benzyl ]-[5-(4-trifluorom

phenyl)-pyrimidin-2-yl]-amine,

(1 -Benzyl^iperidin-4-yl)-(7-chloro-quinazolin-4-yl)-[4-(2-meth yl^yridin-4-ylamino)-be amine,

(1 -Benzyl-piperidin-4-yl)-(6-fluoro-quinazolin-2-yl)-[4-(2-met hyl-pyridin-4-ylamino)-benzyl]- amine,

(1 -Benzyl-piperidin-4-yl)-[4-(2-methyl-pyridin-4-ylamino)-benz yl]-[4-(4-trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-{6-[methyl-(2-methyl^yridin-4-yl)- amino]-pyridin-3-ylmethyl}-[4- (4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl-piperidin-4-yl)-[6-(2-methyl-pyridin-4-ylamino)-p yridin-3-ylmethyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl-piperidin-4-yl)-[6-(3-methyl-pyridin-4-ylamino)-p yridin-3-ylmethyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[6-(3-Fluoro-pyridin-4-ylamino)-pyridin-3-ylmethyl]-(1 -isopropyl-piperidin-4-yl)-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[6-(pyrimidin-4-ylamino)^yridin-3- ylmethyl]-[4-(4-trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine, (1 -lsopropy piperidin-4-yl)-[4-(methyl-pyridin^^

phenyl)-pyridin-2-yl]-amine,

(1 -lsopropy piperidin-4-yl)-[6-(methyl-pyridm^

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropy piperidin-4-yl)-[3-(methyl-pyridm^

phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropy piperidin-4-yl)-[3-(methyl-pyridm^

phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-{3-[methyl-(2-methyl^yridin-4-yl)- amino]-benzyl}-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[3-(2-methyl^yridin-4-ylamino)-ben zyl]-[4-(4-trifluorom phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl-piperidin-4-yl)-[3-(3-methyl-pyridm^

phenyl)-pyrimidin-2-yl]-amine,

[3-(3-Fluoro-pyridin-4-ylamino)-benzyl]-(1 -isopro

phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropy piperidin-4-yl)-[3-(pyrimidin-4-ylamm^

pyrimidin-2-yl]-amine,

[4-(4-Fluoro-phenyl)-pyrimidin-2-yl]-(1 -isopropy pi^^

amino)-benzyl]-amine,

N,N-Dimethyl-N'-[4-(methyl^yridin-4-yl-amino)-benzyl]-N'-[4- (4-trifluoromethyl^he pyrimidin-2-yl]-ethane-1 ,2-diamine,

N1 ,N1 -Dimethyl-N2-[4-(methyl-pyridin-4-yl-ami^

pyrimidin-2-yl]-propane-1 ,2-diamine,

N,N-Dimethyl-N'-[4-(methyl-pyridin-4-yL

pyrimidin-2-yl]-propane-1 ,3-diamine,

[2-(4-Methyl-piperazin-1 -yl)-ethyl]-[4-(methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[2-(4-Methyl-piperazin-1 -yl)-ethyl]-[4-(2-methyl-pyridin-4-ylamino)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[3-(4-Methyl-piperazin-1 -yl)-propyl]-[4-(methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[3-(4-Methyl-piperazin-1 -yl)-propyl]-[4-(2-methyl-pyridin-4-ylamino)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[3-(4-Methyl-piperazin-1 -yl)-propyl]-[4-(3-methyl-pyridin-4-ylamino)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine, [4-({(1 -Benzyl^iperidin-4-yl)-[4-(4-trifluorome

phenyl]-(2-methyl-pyridin-4-yl)-amine,

(1 -lsopropy piperidin-4-yl)-[4-(methyl^yridin-4^

amine,

(1 -lsopropy piperidin-4-yl)-[4-(2-methy pyridin-4-ylam

amine,

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-be nzyl]-[6-(4-trifluoromethyl- phenyl)-pyrazin-2-yl]-amine,

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-be nzyl]-quinolin-4-yl-amine, (4-Benzyloxy-pyrimidin-2-yl)-(1 -isopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)- benzyl]-amine,

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-be nzyl]-[4-(4-trifluoromethyl- phenyl)-pyridin-2-yl]-amine,

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-be nzyl]-[2-(4-trifluoromethyl- phenyl)-pyridin-4-yl]-amine,

(4,6-Dimethyl^yrimidin-2-yl)-(1 -isopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)- benzyl]-amine,

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-be nzyl]-[6-(4-trifluoromethyl- phenyl)-pyrimidin-4-yl]-amine,

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-be nzyl]-pyrimidin-2-yl-amine, (1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-be nzyl]-[5-(4-trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-be nzyl]-(4-trifluoromethyl- pyrimidin-2-yl)-amine,

N1 ,N1 -Dimethyl-N3-[4-(methyl-pyridin-4-yl-amino)-benzyl]-N3-[4-(4 -trifluoromethyl-phenyl)- pyrimidin-2-yl]-butane-1 ,3-diamine,

((S)-1 -lsopropyl^iperidin-3-yl)-[6-(2-methyl-pyridin-4-ylamino)-py ridin-3-ylmethyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[6-(2-methyl-pyridin-4-ylamino)-pyri din-3-ylmethyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[6-(methyl-pyridin-4-yl-amino)-pyrid in-3-ylmethyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl-piperidin-4-yl)-(4-methoxy-pyrimidin-2-yl)-[4-(me thyl-pyridin-4-yl-amino)- benzyl]-amine,

1 '-Methyl-N-(4-((2-methylpyridin-4-yl)amino)benzyl)-N-(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'-bipiperidin]-4-amine, N-(4-((2,6-Dimethylpyridin-4-yl)amino)benzyl)-1 '-methyl-N-(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'-bipiperidin]-4-amine,

1 '-Methyl-N-(4-(methyl(pyridin-3-yl)amino)benzyl)-N-(4-(4-(tr ifluoromethyl)phenyl)pyn 2-yl)-[1 ,4'-bipiperidin]-4-amine,

1 '-Methyl-N-(4-(methyl(pyridin-2-yl)amino)benzyl)-N-(4-(4-(tr ifluoromethyl)phenyl)pyn 2-yl)-[1 ,4'-bipiperidin]-4-amine,

1 '-Methyl-N-(4-(methyl(2-methylpyridin-4-yl)amino)benzyl)-N-( 4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'-bipiperidin]-4-amine,

1 '-Methyl-N-(4-(pyridin-4-ylamino)benzyl)-N-(4-(4-(trifluorom ethyl)phenyl)pyrimidin [1 ,4'-bipiperidin]-4-amine,

1 '-Methyl-N-(4-(pyrimidin-4-ylamino)benzyl)-N-(4-(4-(trifluor omethyl)phenyl)pyrimi^ [1 ,4'-bipiperidin]-4-amine,

N-(4-((2-Methoxypyridin-4-yl)amino)benzyl)-1 '-methyl-N-(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'-bipiperidin]-4-amine,

N-(4-((2-Fluoropyridin-4-yl)amino)benzyl)-1 '-methyl-N-(4-(4-

(trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'-bipiperidin]-4-amine,

6-Methoxy-2-methyl-N-(4-(((1 '-methyl-[1 ,4'-bipiperidin]-4-yl)(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)amino)methyl)phenyl)q uinolin-4-amine, N-(4-(Ethyl(pyridin-4-yl)amino)benzyl)-1 '-methyl-N-(4-(4-(trifluoromethyl)phenyl)pyrim yl)-[1 ,4'-bipiperidin]-4-amine,

N-(4-((3-Fluoropyridin-4-yl)amino)benzyl)-1 '-methyl-N-(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'-bipiperidin]-4-amine,

1 '-Methyl-N-(4-((3-methylpyridin-4-yl)amino)benzyl)-N-(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'-bipiperidin]-4-amine,

1 '-Methyl-N-(4-(4-methylpiperazin-1-yl)benzyl)-N-(4-(4-(trifl uoromethyl)phenyl)pyrimid^ yl)-[1 ,4'-bipiperidin]-4-amine,

N-(1 -lsopropylpiperidin-4-yl)-N-(4-((2-methylpyridin-4-yl)amino) benzyl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine,

N-(1 -lsopropylpiperidin-4-yl)-N-(4-((3-methylpyridin-4-yl)amino) benzyl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine,

N-(4-((3-Fluoropyridin-4-yl)amino)benzyl)-N-(1 -isopropylpiperidin-4-yl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine,

N-(1-lsopropylpiperidin-4-yl)-4-(4-(trifluoromethyl)phenyl)- N-(4-((3-(trifluoromethyl)pyri yl)amino)benzyl)pyrimidin-2-amine,

N-(4-((5-Fluoropyridin-3-yl)amino)benzyl)-N-(1 -isopropylpiperidin-4-yl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine, N-(1-lsopropylpiperidin-4-yl)-N-(4-(pyridin-3-ylamino)benzyl )-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine,

N-(1-lsopropylpiperidin-4-yl)-N-(4-((2-(pyrrolidin-1-yl)pyri din-4-yl)amino)benzyl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine,

N-(1-lsopropylpiperidin-4-yl)-N-(4-((2-methylpyrimidin-4- yl)amino)benzyl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine,

N-(1 -lsopropylpiperidin-4-yl)-N-(4-(methyl(2-methylpyrimidin-4-y l)amino)benzyl)-4-(4^ (trifluoromethyl)phenyl)pyrimidin-2-amine,

(1-lsopropyl^iperidin-4-yl)-[4-(pyrimidin-4-ylamino^

pyrimidin-2-yl]-amine,

N-(1-lsopropylpiperidin-4-yl)-N-(4-((6-methylpyrimidin-4-yl) amino)benzyl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine,

N-(1 -lsopropylpiperidin-4-yl)-N-(4-(methyl(6-methylpyrimidin-4-y l)amino)benzyl)-4-(4 (trifluoromethyl)phenyl)pyrimidin-2-amine,

(1-lsopropyl^iperidin-4-yl)-[4-(pyrimidin-2-ylamino^

pyrimidin-2-yl]-amine,

(1-lsopropyl^iperidin-4-yl)-[4-(6-methyl^yridin-3-ylamino)-b enzyl]-[4-(4-trifluorom phenyl)-pyrimidin-2-yl]-amine,

(1-lsopropyl^iperidin-4-yl)-[4-(pyrazin-2-ylamino)-benzyl]-[ 4-(4-trifluoromethyl^henyl)- pyrimidin-2-yl]-amine,

(1-lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-3-yl-amino)-be nzyl]-[4-(4-trifluorom phenyl)-pyrimidin-2-yl]-amine,

[4-(2-Fluoro^yridin-3-ylamino)-benzyl]-(1 -isopro

phenyl)-pyrimidin-2-yl]-amine,

[2-(4-Methyl^iperazin-1-yl)-ethyl]-[4-(3-methyl^yridin-4- ylamino)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

{4-[Methyl-(2-methyl^yridin-4-yl)-amino]-benzy^

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

{4-[Methyl-(2-methyl^yridin-4-yl)-amino]-benzyl}-^^

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1-lsopropyl^iperidin-4-yl)-{4-[methyl-(3-methyl^yridin-4-yl )-amino]-benzyl}-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1-lsopropyl^iperidin-4-yl)-[6-(methyl^yridin^^

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1-lsopropyl^iperidin-4-yl)-{6-[methyl-(2-met^

(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine, (1 -lsopropyl^iperidin-4-yl)-[6-(2-methyl^yridin-4-ylamino)^yri din-2-ylmeth trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[6-(3-methyl^yridin^^

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

[6-(3-Fluoro^yridin-4-ylamino)^yridin-2-ylmethyl]-(1 -isopropyl^iperidin-4-yl)-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[6-(pyrimidin-4-yla^

phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[6-(methyl^yr^

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[4-(4-methyl^iperazi^

yl-amino)-benzyl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-amino)-benz yl]-(4-pyrrolidin-1 -yl- pyrimidin-2-yl)-amine,

(1 -lsopropyl-piperidin-4-yl)-(3,4,5,6-tetrahydro-2H-[1 ,4']bipyridinyl-4-ylmethyl)-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl-piperidin-4-yl)-(3,4,5,6-tetrahydro-2H-[1 ,3']bipyridinyl-4-ylmethyl)-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl-piperidin-4-yl)-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-ylmethyl)-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(7-lsobutyl-quinazolin-4-yl)-(1 -isopropyl^iperidin-4-yl)-[4-(2-methyl^yridin-4-ylamino benzyl]-amine,

[4-(4-Chloro^henyl)^yrimidin-2-yl]-(1 -isopropy

amino)-benzyl]-amine,

[4-(4-tert-Butyl^henyl)^yrimidin-2-yl]-(1 -isopro

amino)-benzyl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridm^

yl)-amine,

(1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-amino)-benz yl]-[4-(4-trifluorome^ phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridm^

amine,

[4-(2-Fluoro^henyl)^yrimidin-2-yl]-(1 -isopro

amino)-benzyl]-amine,

4-(2-{(1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-amino)-benz yl]-amino}^yrim yl)-benzonitrile, (1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-a

phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-amino)-benz yl]-[4-(2-trifluorom phenyl)-pyrimidin-2-yl]-amine,

4-(2-{((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-[4-(methyl-pyridin-4-yl-amino)-benzy l]-amino}- pyrimidin-4-yl)-benzonitrile,

((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-[4-(methyl-pyridin-4-yl-amino)-benzy l]-[4-(6- trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-amine,

[4-(4-Fluoro-phenyl)-pyrimidin-2-yl]-((S)-1 '-methyl-[1 ,4']bipiperidinyl-3-yl)-[4-(methyl-pyridin- 4-yl-amino)-benzyl]-amine,

[4-(4-Methanesulfonyl-phenyl)-pyrimidin-2-yl]-((S)-1 '-methyl-[1 ,4']bipiperidinyl-3-yl)-[4- (methyl-pyridin-4-yl-amino)-benzyl]-amine,

[4-(4-Chloro-phenyl)-pyrimidin-2-yl]-((S)-1 '-methyl-[1 ,4']bipiperidinyl-3-yl)-[4-(methyl-pyridin- 4-yl-amino)-benzyl]-amine,

[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-((S)-1 '-methyl-[1 ,4']bipiperidinyl-3-yl)-[4-(methyl-pyridin- 4-yl-amino)-benzyl]-amine,

3-(2-{((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-[4-(methyl-pyridin-4-yl-amino)-benzy l]-amino}- pyrimidin-4-yl)-benzonitrile,

(1 -lsopropyl^iperidin-4-yl)-[4-(4-methoxy^henyl)^yrimidin-2-yl ]-[4-(methyl^yridin amino)-benzyl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-4-yL^

amine,

(1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-amino)-benz yl]-[4-(6-trifluorom pyridin-3-yl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-(4^yridin-3-yl-benzyl)-[4-(4-^

yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-(4^yridin-4-yl-benzyl)-[4-(4-trifl uoromethyl^henyl)^yrim yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-(4^yridin-2-yl-benzyl)-[4-(4-trifl uoromethyl^henyl)^yrim yl]-amine, and

(1 -lsopropyl^iperidin-4-yl)-(4-isopropyl^yrimidin-2-yl)-[4-(me thyl^yridin-4-yl-amino)- benzyl]-amine.

24) Preferred compounds of Formula I are selected from the group consisting of:

(1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[4-(methyl-pyridin-4-yl-amino)-benzy l]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine, (1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-am

phenyl)-pyrimidin-2-yl]-amine,

(1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[4-(methyl^yridin-4-yl-am

(S)-1 '-methyl-N-(4-(methyl(pyridin-4-yl)amino)benzyl)-N-(4-(4- (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'-bipiperidin]-3-amine,

(3aR,6aS)-N-(4-(methyl(pyridin-4-yl)amino)benzyl)-2-(1 -methylpiperidin-4-yl)-^

(trifluoromethyl)phenyl)pyrimidin-2-yl)octahydrocyclopent a[c]pyrrol-5-amin

((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-{4-[methyl-(2-m

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[6-(2-methyl^yridin-4-ylamm^

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[3-(2-methyl^yridin-4-ylamino)-ben zyl]-[4-(4-trffl

phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-am

(1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[6-(methyl^yridin-4-yl-am

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-[4-(methyl^yridin-4-yl-amino)-benzyl ]-[4-(6- trifluoromethyl^yridin-3-yl)^yrimidin-2-yl]-amine, and

(1 -lsopropyl^iperidin-4-yl)-[4-(methyl^yridin-4-yl-amino)-benz yl]-[4-(6-trifluoromethy^ pyridin-3-yl)-pyrimidin-2-yl]-amine.

25) Particularly preferred compounds of Formula I are selected from the group consisting of:

(1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[4-(methyl-pyridin-4-yl-amino)-benzy l]-quinolin-4-yl-amine, (1 -lsopropyl-piperidin-4-yl)-[6-(2-methyl-pyridin-4-ylamino)-p yridin-3-ylmethyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine,

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-be nzyl]-quinolin-4-yl-amine, and

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)-be nzyl]-[4-(6-trifluoromethyl- pyridin-3-yl)-pyrimidin-2-yl]-amine.

The compounds of Formula I according to any one of embodiments 1) to 25) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral (including topical application or inhalation) administration, and are suitable for the treatment and/or prevention of the diseases mentioned herein, such as malaria infections, or other protozoal diseases like sleeping sickness, Chagas disease, amebiasis, giardiasis, trichomoniasis, toxoplasmosis, and leishmaniasis; especially malaria.

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by bringing the described compounds of Formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

In one embodiment, the invention relates to a method for the treatment or prevention of the diseases mentioned herein, such as especially malaria, said method comprising administering to a subject a pharmaceutically active amount of a compound of Formula I.

In a preferred embodiment of the invention, the administered amount of a compound according to any one of embodiments 1) to 25) is comprised between 1 mg and 2000 mg per day, particularly between 50 mg and 1500 mg per day, more particularly between 100 mg and 1000 mg per day, especially between 250 mg and 1000 mg per day.

For the avoidance of any doubt, if compounds are described as useful for the prevention or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention or treatment of the diseases mentioned herein, such as especially malaria.

The compounds of Formula I according to any one of embodiments 1) to 25), or the above- mentioned pharmaceutical compositions, may also be used in combination with one or more other therapeutically useful substances e.g. with other antimalarials like quinolines (e.g. quinine, chloroquine, amodiaquine, mefloquine, primaquine, and tafenoquine), peroxide antimalarials (e.g. artemisinin, artemether, and artesunate), pyrimethamine- sulfadoxine antimalarials (e.g. Fansidar®), hydroxynaphtoquinones (e.g. atovaquone), acroline-type antimalarials (e.g. pyronaridine), and other antiprotozoal agents like ethylstibamine, hydroxystilbamidine, pentamidine, stilbamidine, quinapyramine, puromycine, propamidine, nifurtimox, melarsoprol, nimorazole, nifuroxime, aminitrozole and the like. The present invention also relates to the use of a compound of Formula I according to any one of embodiments 1 ) to 25), or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition, optionally for use in combination with one or more other therapeutically useful substances such as those mentioned in the preceding paragraph, for the prevention and/or treatment of the diseases mentioned herein, such as especially malaria.

Preparation of compounds of Formula I

Compounds of Formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimization procedures. Compounds of Formula I of the present invention can be prepared according to the general sequence of reactions outlined below wherein, if not explicitly stated otherwise, R ¹ to R ⁷ , Het, X, and A are as defined for Formula I.

Compounds of Formula I can be prepared following one of the synthetic sequence described in Schemes 1 to 7. Compounds of Formula l-A (wherein X represents -NR ³ -) are synthesized following the synthetic pathway depicted in Scheme 1 . A primary amine 2 can be used in a Buchwald-Hartwig cross-coupling with a heterocycle 3 (wherein R ^A represents bromo, chloro, or triflate) in the presence of a palladium catalyst like Pd ₂ (dba) ₃ , a ligand like X-Phos, a base like NaOfBu and a solvent like dioxane to afford a secondary amine 4. Alternatively, a nucleophilic aromatic substitution between a primary amine 2 and an appropriate heterocycle 3 (wherein R ^A represents bromo or chloro) in the presence of a base like NEt ₃ or DIPEA in a solvent like EtOH or / ^' PrOH can yield a secondary amine 4. An amine 4 can be alkylated with an electrophile 5 (wherein R ^B represents chloro or bromo and ring B represents phenylene or pyridin-diyl) in the presence of a base like NaH to give a bromide of Structure 6. A compound of Formula l-A (wherein X represents -NR ³ -) is obtained by a Buchwald-Hartwig cross-coupling between a bromide of Structure 6 and an amine 7 in the presence of a palladium catalyst like Pd ₂ (dba) ₃ , a ligand like X-phos, a base like NaOiBu and a solvent like dioxane.

Formula l-A

Scheme 1 . Synthesis of a compound of Formula l-A.

In a further aspect, a bromide of Structure 6 can be engaged in a Suzuki cross-coupling with an appropriate boronic acid or a boronic ester derivative 8 (wherein R ^c represents hydrogen or pinacole, and R ^D represents an optionally mono-substituted pyridinyl) in the presence of a base like Na ₂ C0 ₃ or K ₃ P0 ₄ , and a palladium catalyst like Pd(PPh ₃ ) ₄ , or Pd(OAc) ₂ and S-Phos to give a compound of Formula l-B (wherein X is absent) (Scheme 2).

Formula l-B

Scheme 2. Synthesis of a compound of Formula l-B.

In a further aspect, a bromide of Structure 6 can undergo a Buc wald-Hartwig cross- coupling with a compound 9 (wherein R ^E -H represents mono-substituted piperazinyl) in the presence of palladium catalyst like Pd ₂ (dba) ₃ , a ligand like X-phos, a base like NaOfBu and a solvent like dioxane to afford a compound of Formula l-C (wherein X is absent) (Scheme 3).

Structure 6 9

Formula l-C

Scheme 3. Synthesis of a compound of Formula l-C. In another aspect, a secondary amine 4 can be alkylated with an electrophile 10 in the presence of a base like NaH to give a tertiary amine 11. An intermediate of Structure 12 is obtained after removal of a protecting group (PG) from a tertiary amine 11 , applying reaction conditions known to a skilled person. Preferably, PG is a group such as tert- butoxycarbonyl. A fe/ -butoxycarbonyl group is cleaved under acidic conditions. A compound of Formula l-D is obtained by a Buchwald-Hartwig cross-coupling between an intermediate of Structure 12 and a bromide 13 in the presence of palladium catalyst like Pd ₂ (dba) ₃ , a ligand like X-phos, a base like NaOiBu and a solvent like dioxane (Scheme 4).

Scheme 4. Synthesis of a compound of Formula l-D.

In another aspect, heating an amine 2 in the presence of an electrophile 14 and base like DIPEA in solvent like EtOH or / ^' PrOH gives an amine 15. In analogy to Schemes 1 -4, an amine 15 can be converted into an intermediate 16. Removal of the benzyl protecting group under an H ₂ -atmosphere in the presence of Pd/C and in a solvent like EtOH affords an alcohol 17. An intermediate 17 can be converted into a triflate 18 upon treatment with triflic anhydride in the presence of a base like NEt ₃ in a solvent like DCM. A triflate 18 can be engaged in a Suzuki cross-coupling with an appropriate boronic acid or a boronic ester derivative 19 (wherein R ^F represents optionally mono-substituted phenyl or pyridinyl) in the presence of a base like Na ₂ C0 ₃ or K ₃ P0 ₄ , and a palladium catalyst like Pd(PPh ₃ ) ₄ , or Pd(OAc) ₂ and S-Phos to give a compound of Formula l-E (wherein X is absent) (Scheme 5).

19 Formu

Scheme 5. Synthesis of a compound of Formula l-E.

In a further aspect, a triflate 18 can undergo a Buchwald-Hartwig cross-coupling with an amine 20 in the presence of palladium catalyst like Pd ₂ (dba) ₃ , a ligand like X-phos, a base like NaOfBu and a solvent like dioxane to afford a compound of Formula l-F (Scheme 6).

18 20 Formula l-F

Scheme 6. Synthesis of a compound of Formula l-F.

In a different aspect, a cyclic amine 21 (wherein ring C represents piperidinyl, pyrrolidinyl, or (3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl) is converted to an intermediate 22 according to Schemes 1 -4. An intermediate of Structure 23 is obtained after removal of a protecting group (PG) from an intermediate 22, applying reaction conditions known to a skilled person. Preferably, PG is a group such as fe/f-butoxycarbonyl. A fe/f-butoxycarbonyl group is cleaved under acidic conditions. An cyclic amine of Structure 23 undergoes a reductive amination with an appropriate aldehyde or ketone 24 (wherein R ^G and R ^H together with the carbon atom to which they are attached form a ring C substituent possible according to the present invention) in the presence of a reducing agent like NaHB(OAc) ₃ to give a compound of Formula l-G (Scheme 7). If 24 is a ketone, activation with a Lewis acid or AcOH may be required.

Formula l-G

Scheme 7. Synthesis of a compound of Formula l-G. The following examples illustrate the present invention. All solvents and reagents are used as obtained from commercial sources unless otherwise stated. All temperatures are indicated in degrees Celsius and pressures in mbar. Unless mentioned otherwise, the reactions take place at room temperature (r.t.). In mixtures, relations of parts of solvent or eluent or reagent mixtures in liquid form are given as volume relations (v/v), unless indicated otherwise.

Whenever the compounds of Formula I are obtained in the form of mixtures of stereoisomers such as especially enantiomers, the stereoisomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Daicel ChiralPak AD-H (5 μηι) column, a Daicel ChiralCel OD-H (5 μηι) column, a Daicel ChiralCel OD (10 μηι) column, a Daicel ChiralPak IA (5 μηι) column, a Daicel ChiralPak IB (5 μηι) column, a Daicel ChiralPak IC (5 μηι) column, or a (R,R)-Whelk-01 (5 μηι) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of a base like triethylamine and/or diethylamine or of an acid like TFA) and eluent B (heptane). Experimental part

General conditions:

Analytical HPLC conditions:

LC-MS 1TFA:

LC-MS-conditions: Analytical. Pump: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector. Column: Acquity UPLC BEH C18 1 .7 um 2.1 x50 mm from Waters, thermostated in the Acquity UPLC Column Manager at 60°C. Eluents: A: H ₂ 0 + 0.05% TFA; B: MeCN + 0.045% TFA. Method: Gradient: 2% B 98% B over 2.0 min. Flow: 1 .0 mL/min. Detection: UV 214 nm and MS, t _R is given in min.

LC-MS 2 to LC-MS 4:

HPLC/MS analyses are performed on an Ultimate 3000RS Dionex HPLC instrument, equipped with a Dionex Ultimate 3000 RS Photodiode Array Detector, a Dionex Ultimate 3000RS pump and a Dionex MSQ ⁺ mass spectrometer.

The LC retention times are obtained using the following elution conditions:

- LC-MS 2: Analytical HPLC on a Waters X-Bridge C18 column (4.6x30 mm, 2.5 μηι, Waters); Linear gradient of water/ 0.04% TFA (A) and MeCN (B) from 5% to 95% B over 1 .5 min; flow rate 4.5 mL/min, detection at 215 nm.

- LC-MS 3: Analytical HPLC on a Waters X-Bridge C18 column (4.6x30 mm, 2.5 μηι, Waters); Linear concentrated NH ₃ in water (1 .0 mL/L) (A) and MeCN (B) from 5% to 95% B over 1 .5 min; flow rate 4.5 mL/min, detection at 215 nm.

- LC-MS 4: Analytical HPLC on a Zorbax ^® SB-AQ column (4.6x50 mm, 3.5 μηι, Agilent); Linear gradient of water/ 0.04% TFA (A) and MeCN (B) from 5% to 95% B over 1 .5 min; flow rate 4.5 mL/min, detection at 215 nm.

Preparative HPLC conditions:

Preparative HPLC/MS purifications are performed on a Gilson HPLC system, equipped with a Gilson 215 autosampler, Gilson 333/334 pumps, Finnigan AQA MS detector system, and a Dionex UV detector, using a Waters Xbridge C18 or an Waters Atlantis T3 column, with a linear gradient of water/formic acid 0.02% (A) and MeCN (B) (acidic conditions) or water/ammonia 0.02% (A) and MeCN (B) (basic conditions).

Flash chromatography:

Flash chromatography purifications are performed using Si0 ₂ 60 (230-400 mesh, particle size 40-63 μηι) from Fluka.

Flashmaster purifications are performed using a Biichi system (Biichi Fraction Collector C- 660, Biichi Pump Manager C-615, Biichi Pump Module C-605).

Abbreviations (as used herein below and in the description above):

Ac acetyl

AcOEt ethyl acetate

AcOH acetic acid

aq. aqueous

Ar argon

Bn benzyl

Boc tert-butyloxycarbonyl

BrettPhos 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl -1 ,1 '-biphenyl

CC column chromatography on silica gel

comb. combined

DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane

DIPEA Λ/,/V-diisopropylethylamine

DMAP 4-(dimethylamino)-pyridine

DMF N,N-dimethylformamide

eq. equivalent(s)

Et ₂ 0 diethyl ether

EtOH ethanol

FC flash chromatography

Hept heptane

HPLC high performance liquid chromatography

/ ^' PrOH isopropanol

LC-MS liquid chromatography - mass spectroscopy

M molarity [mol L ^"1 ]

mCPBA 3-chloroperbenzoic acid

Me methyl MeCN acetonitrile

MeOH methanol

min minute(s)

MS mass spectroscopy

N normality of solution

NaOiBu sodium tert-butoxide

NEt ₃ triethylamine

NMP 1 -methyl-2-pyrrolidone

org. organic

Pd/C palladium on carbon

Pd ₂ (dba) ₃ tris(dibenzylideneacetone)dipalladium(0)

Pd(dppf)CI ₂ CH ₂ CI ₂ [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with DCM

Pd(PPh ₃ ) ₄ tetrakis(triphenylphosphine)palladium(0)

prep. preparative

r.t. room temperature

sat. saturated

soln. solution

S-Phos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl

Tf trifluoromethyl-sulfonyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

t _R retention time

UV ultraviolet

w% weight percent

X-Phos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

General methods and examples

The following examples illustrate the preparation of compounds of the invention. First the synthesis of compounds of Formula I is described, followed by the description of the synthesis of intermediates and starting materials. Whenever used in the experimental part, generic Structures 1 , 2, 3 etc. refer to the respective structures described in the preceeding general description of the preparation of compounds of Formula I. Compounds denotated with (+) are prepared as racemic mixtures. General method for the preparation of compounds of Formula I:

Boc deprotection:

Method A: To an ice-cooled solution of 4-{[4-(methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amino}-piperidine-1 -carboxylic acid tert-butyl ester (2.10 g, 3.39 mmol, 1 eq.) in DCM (50 mL), 4M hydrogen chloride in dioxane (12 mL) was added. The reaction mixture was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between 1 M aq. NaOH (100 mL) and DCM (100 mL). The layers were separated. The aq. phase was extracted with DCM (2 x 50 mL). The comb. org. phases were washed with water (2 x 100 mL), sat. aq. NaCI soln. (1 x 100 mL), dried over MgS0 ₄ and concentrated in vacuo to give the desired product as a pale yellow foam. The product was used without further purification.

Listed in Table 1 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding Boc-protected amine 22 as starting material.

Table 1

Example Compound of Formula I *R [min] MS-data

LC-MS m/z Method [M+H] ⁺

1 [4-(Methyl-pyridin-4-yl-amino)-benzyl]-piperidin-4- 0.79 519.4 yl-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]- LC-MS

amine 1 TFA

2 [4-(Methyl-pyridin-4-yl-amino)-benzyl]-(S)-piperidin- 0.79 519.4 3-yl-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]- LC-MS

amine 1 TFA

Method B: To an ice-cooled solution of tert-butyl 4-(((6-((2-methylpyridin-4-yl)amino)pyridin- 3-yl)methyl)(quinolin-4-yl)amino)piperidine-1 -carboxylate (1 .18 g, 2.25 mmol, 1 eq.) in DCM (15 ml_) under N ₂ , TFA (1 .72 ml_, 22.5 mmol, 10 eq.) was added. The reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between 1 M aq. NaOH and DCM. The layers were separated. The aq. phase was extracted with DCM. The comb. org. phases were washed with water, sat. aq. NaCI soln., dried over MgS0 ₄ and concentrated in vacuo to give the desired product as an orange solid. The product was used without further purification.

Listed in Table 2 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding Boc-protected amine 22 as starting material. Table 2

Reductive amination:

Method A: To a solution of cyclopentanone (8.4 mg, 0.10 mmol, 1 .3 eq.) and [4-(methyl- pyridin-4-yl-amino)-benzyl]-piperidin-4-yl-[4-(4-trifluorome thyl-phenyl)-pyrimidin-2-yl]-amine (46 mg, 0.08 mmol, 1 .0 eq.) in MeOH (1 mL), AcOH (6 μΐ, 0.09 mmol, 1 .1 eq.) was added. The mixture was stirred at 45 °C for 30 min. The mixture was allowed to cool to r.t. and sodium triacetoxyborohydride (16 mg, 0.08 mmol, 1 .0 eq.) was added. The mixture was stirred at r.t. for 4 hours. The mixture was partitioned between DCM (3 mL) and sat. aq. NaHC0 ₃ soln. (2 mL). The layers were separated and the aq. phase was extracted with DCM (3 x 2 mL). The comb. org. phases were concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-bridge, 30x75 mm, 10 μηι, UV/MS, basic conditions), and concentrated in vacuo. Listed in Table 3 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding amine of Structure 23 and the corresponding aldehyde or ketone 24 as starting materials.

Table 3

Example Compound of Formula I i _R [min] MS-data

LC-MS m/z Method [M+H] ⁺

6 (1 -Cyclopentyl-piperidin-4-yl)-[4-(methyl-pyridin-4- 0.86 587.4 yl-amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine 1 TFA

7 (1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[4-(methyl-pyridin- 0.60 616.4 4-yl-amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS 4

pyrimidin-2-yl]-amine

8 (1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.83 561 .4 amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine 1 TFA

9 (1 -Cyclopropylmethyl-piperidin-4-yl)-[4-(methyl- 0.85 573.4 pyridin-4-yl-amino)-benzyl]-[4-(4-trifluoromethyl- LC-MS phenyl)-pyrimidin-2-yl]-amine 1 TFA

10 [1 -(3-Methyl-butyl)-piperidin-4-yl]-[4-(methyl-pyridin- 0.90 589.4 4-yl-amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine 1 TFA

1 1 [1 -(4-Methyl-benzyl)-piperidin-4-yl]-[4-(methyl- 0.92 623.5 pyridin-4-yl-amino)-benzyl]-[4-(4-trifluoromethyl- LC-MS phenyl)-pyrimidin-2-yl]-amine 1 TFA

12 [1 -(4-Dimethylamino-benzyl)-piperidin-4-yl]-[4- 0.89 652.5

(methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- LC-MS trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine 1 TFA

13 2-Dimethylaminomethyl-4-(4-{[4-(methyl-pyridin-4- 0.73 682.4 yl-amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS pyrimidin-2-yl]-amino}-piperidin-1 -ylmethyl)-phenol 1 TFA 14 (1 -lmidazo[1 ,2-a]pyridin-7-ylmethyl-piperidin-4-yl)- 0.72 649.3 [4-(methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- LC-MS trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine UFA

15 [1 -(3,5-Dimethyl-isoxazol-4-ylmethyl)-piperidin-4- 0.84 628.4 yl]-[4-(methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- LC-MS trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine UFA

16 [1 -(3-Methyl-3H-imidazol-4-ylmethyl)-piperidin-4-yl]- 0.72 613.4

[4-(methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- LC-MS trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine UFA

17 [1 -(3-Methyl-butyl)-piperidin-4-yl]-[6-(methyl-pyridin- 0.47 495.4 4-yl-amino)-pyridin-3-ylmethyl]-quinolin-4-yl-amine LC-MS

UFA

18 (1 -Cyclopropylmethyl-piperidin-4-yl)-[6-(methyl- 0.41 479.4 pyridin-4-yl-amino)-pyridin-3-ylmethyl]-quinolin-4-yl- LC-MS

amine UFA

19 [1 -(3-Methyl-3H-imidazol-4-ylmethyl)-piperidin-4-yl]- 0.37 519.4

[6-(methyl-pyridin-4-yl-amino)-pyridin-3-ylmethyl]- LC-MS

quinolin-4-yl-amine UFA

20 (1 -lsobutyl-piperidin-4-yl)-[6-(methyl-pyridin-4-yl- 0.43 481 .4 amino)-pyridin-3-ylmethyl]-quinolin-4-yl-amine LC-MS

UFA

21 ((S)-1 -Cyclopentyl-piperidin-3-yl)-[4-(2-methyl- 0.45 492.4 pyridin-4-ylamino)-benzyl]-quinolin-4-yl-amine LC-MS

UFA

Method B: To a solution of benzooxazol-2-yl-[4-(methyl-pyridin-4-yl-amino)-benzyl]- piperidin-4-yl-amine (41 mg, 0.1 mmol, 1 eq.) and 1 -methyl-4-piperidone (34 mg, 0.3 mmol, 3 eq.) in MeCN (2 mL), sodium triacetoxyborohydride (64 mg, 0.3 mmol, 3 eq.) was added. The mixture was stirred at 45 °C for 18 hours. The solution was allowed to cool to r.t. and purified by prep. HPLC (column: Waters X-Bridge, 18x50 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo.

Listed in Table 4 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding amine of Structure 23 and the corresponding aldehyde or ketone 24 as starting materials. Table 4

Example Compound of Formula I i _R [min] MS-data

LC-MS m/z Method [M+H] ⁺

22 Benzooxazol-2-yl-(1 '-methyl-[1 ,4']bipiperidinyl-4-yl)- 0.50 511 .4

[4-(methyl-pyridin-4-yl-amino)-benzyl]-amine LC-MS 4

23 4-(4-{Benzooxazol-2-yl-[4-(methyl-pyridin-4-yl- 0.57 577.4 amino)-benzyl]-amino}-piperidin-1-ylmethyl)-2- LC-MS dimethylaminomethyl-phenol UFA

24 Benzooxazol-2-yl-(1 -isopropyl-piperidin-4-yl)-[4- 0.62 456.4

(methyl-pyridin-4-yl-amino)-benzyl]-amine LC-MS

UFA

25 Benzooxazol-2-yl-[1-(3-methyl-butyl)-piperidin-4-yl]- 0.70 484.4

[4-(methyl-pyridin-4-yl-amino)-benzyl]-amine LC-MS

UFA

26 (1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[4-(methyl-pyridin- 0.55 522.4

4-yl-amino)-benzyl]-quinoxalin-2-yl-amine LC-MS

UFA

27 2-Dimethylaminomethyl-4-(4-{[4-(methyl-pyridin-4- 0.56 588.4 yl-amino)-benzyl]-quinoxalin-2-yl-amino}-piperidin- LC-MS

1 -ylmethyl)-phenol UFA

28 (1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.63 467.4 amino)-benzyl]-quinoxalin-2-yl-amine LC-MS

UFA

29 [1-(3-Methyl-butyl)-piperidin-4-yl]-[4-(methyl-pyridin- 0.71 495.5

4-yl-amino)-benzyl]-quinoxalin-2-yl-amine LC-MS

UFA

30 (1 -Cyclopentyl-piperidin-4-yl)-[4-(methyl-pyridin-4- 0.67 493.5 yl-amino)-benzyl]-quinoxalin-2-yl-amine LC-MS

UFA

31 Benzooxazol-2-yl-[1-(3-methyl-3H-imidazol-4- 0.55 508.4 ylmethyl)-piperidin-4-yl]-[4-(methyl-pyridin-4-yl- LC-MS

amino)-benzyl]-amine UFA

32 [1-(3-Methyl-3H-imidazol-4-ylmethyl)-piperidin-4-yl]- 0.55 519.4

[4-(methyl-pyridin-4-yl-amino)-benzyl]-quinoxalin-2- LC-MS

yl-amine UFA Benzooxazol-2-yl-(1 -cyclopentyl-piperidin-4-yl)-[4- 0.65 482.4 (methyl-pyridin-4-yl-amino)-benzyl]-amine LC-MS

UFA

[1 -(2-Fluoro-l -fluoromethyl-ethyl)-piperidin-4-yl]-[4- 0.83 597.4 (methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- LC-MS trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine UFA

[4-(Methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- 0.86 615.4 trifluoromethyl-phenyl)-pyrimidin-2-yl]-[1 -(3,3,3- LC-MS

trifluoro-propyl)-piperidin-4-yl]-amine UFA

1 -(4-{[4-(Methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- 0.79 644.5 trifluoromethyl-phenyl)-pyrimidin-2-yl]-amino}- LC-MS

[1 ,4']bipiperidinyl-1 '-yl)-ethanone UFA

(1 -Ethyl-pipe ridin-4-yl)-[4-(methyl-pyridin-4-yl- 0.81 547.4 amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

(1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[4-(methyl-pyridin- 0.38 521 .4 4-yl-amino)-benzyl]-quinolin-4-yl-amine LC-MS

UFA

Benzothiazol-2-yl-(1 '-methyl-[1 ,4']bipiperidinyl-4-yl)- 0.57 527.5

[4-(methyl-pyridin-4-yl-amino)-benzyl]-amine LC-MS

UFA

Method C: To a solution of benzothiazol-2-yl-[4-(methyl-pyridin-4-yl-amino)-benzyl]- piperidin-4-yl-amine (30 mg, 0.070 mmol, 1 .0 eq.) in MeOH (3.5 ml_), cyclopentanone (6 mg, 0.070 mmol, 1 .0 eq.) and acetic acid (4 μΙ_, 0.077 mmol, 1 .1 eq.) were added in sequence. The mixture was stirred at 45 °C, then cooled to r.t. Sodium triacetoxyborohydride (15 mg, 0.070 mmol, 1 .0 eq.) was added. The mixture was stirred at r.t. for 18 hours. Cyclopentanone (12 mg, 0.140 mmol, 2.0 eq.) and sodium triacetoxyborohydride (30 mg, 0.140 mmol, 2.0 eq.) were added. The mixture was stirred at 45 °C for 24 hours. The mixture was allowed to cool to r.t. and partitioned between sat. aq. NaHC0 ₃ soln. and DCM. The layers were separated and the aq. phase was extracted with DCM. The comb. org. phases were concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 18x50 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo. Listed in Table 5 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding amine of Structure 23 and the corresponding aldehyde or ketone 24 as starting materials.

Table 5

Method D: To a solution of [4-(methyl-pyridin-4-yl-amino)-benzyl]-(S)-piperidin-3-yl-[4 -(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine (25 mg, 0.05 mmol, 1 .0 eq.) in MeCN (1 mL), N-methyl-4-piperidone (6 μί, 0.05 mmol, 1 .0 eq.) was added. The reaction mixture was stirred at r.t. for 2 hours. Sodium triacetoxyborohydride (15 mg, 0.07 mmol, 1 .5 eq.) was added and the reaction mixture was stirred at r.t. for 18 hours. The mixture was filtered through isolute H-MN and purified by prep. HPLC (column: Waters Xbridge C18, 10 μηι, 30x75mm, acidic conditions) and concentrated in vacuo. Listed in Table 6 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding amine of Structure 23 and the corresponding aldehyde or ketone 24 as starting materials.

Table 6

Example Compound of Formula 1 *R [min] MS-data

LC-MS m/z Method [M+H] ⁺

43 (S)-1 '-methyl-N-(4-(methyl(pyridin-4- 0.69 616.4 yl)amino)benzyl)-N-(4-(4- LC-MS

(trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'- 1 TFA

bipiperidin]-3-amine

44 (S)-N-(1 -cyclopentylpiperidin-3-yl)-N-(4- 0.86 587.5

(methyl(pyridin-4-yl)amino)benzyl)-4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-amine 1 TFA

45 (S)-N-(1 -isopentylpiperidin-3-yl)-N-(4- 0.90 589.5

(methyl(pyridin-4-yl)amino)benzyl)-4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-amine 1 TFA

46 (3aR,6aS)-N-(4-(methyl(pyridin-4-yl)amino)benzyl)- 0.74 642.5

2-(1 -methylpiperidin-4-yl)-N-(4-(4- LC-MS

(trifluoromethyl)phenyl)pyrimidin-2- 1 TFA

yl)octahydrocyclopenta[c]pyrrol-5-amine (mixture of

stereoisomers)

47 (3aR,6aS)-2-isopentyl-N-(4-(methyl(pyridin-4- 0.92 615.5 yl)amino)benzyl)-N-(4-(4- LC-MS

(trifluoromethyl)phenyl)pyrimidin-2- 1 TFA

yl)octahydrocyclopenta[c]pyrrol-5-amine (mixture of

stereoisomers) (3aR,6aS)-2-cyclopentyl-N-(4-(methyl(pyridin-4- 0.88 613.4 yl)amino)benzyl)-N-(4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2- UFA

yl)octahydrocyclopenta[c]pyrrol-5-amine (mixture of

stereoisomers)

(S)-N-(4-(Ethyl(pyridin-4-yl)amino)benzyl)-r- 0.71 630.5 methyl-N-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2- LC-MS

yl)-[1 ,4'-bipiperidin]-3-amine UFA

((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-[4-(methyl- 0.70 616.5 pyridin-3-yl-amino)-benzyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-{4-[methyl-(2- 0.71 630.3 methyl-pyridin-4-yl)-amino]-benzyl}-[4-(4- LC-MS trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine UFA

((S)-1-lsopropyl-piperidin-3-yl)-[4-(methyl-pyridin-4- 0.83 561 .4 yl-amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

((S)-1-Ethyl-piperidin-3-yl)-[4-(methyl-pyridin-4-yl- 0.81 547.4 amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

N-(4-(Methyl(pyridin-4-yl)amino)benzyl)-N-(1 '- 0.69 606.5 methyl-[1 ,4'-bipiperidin]-4-yl)-3-(4- LC-MS

(trifluoromethyl)phenyl)-1 ,2,4-oxadiazol-5-amine UFA

N-(4-(Methyl(pyridin-4-yl)amino)benzyl)-N-(1 '- 0.63 606.4 methyl-[1 ,4'-bipiperidin]-4-yl)-5-(4- LC-MS

(trifluoromethyl)phenyl)-1 ,3,4-oxadiazol-2-amine UFA

Method E: To a solution of [4-(methyl-pyridin-4-yl-amino)-benzyl]-(S)-pyrrolidin-3-yl-[ 4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine (180 mg, 0.36 mmol, 1 eq.) and 1 -methyl-4- piperidone (0.12 mL, 1 .07 mmol, 3 eq.) in acetonitrile (4 mL), sodium triacetoxyborohydride (227 mg, 1 .07 mmol, 3 eq.) was added. The mixture was stirred at 45 °C for 18 hours. The reaction mixture was quenched with sat. aq. Na ₂ C0 ₃ soln. The mixture was extracted with DCM. The comb. org. phases were washed with water, sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 18x50 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo.

Listed in Table 7 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding amine of Structure 23 and the corresponding aldehyde or ketone 24 as starting materials. Table 7

Example Compound of Formula I *R [min] MS-data

LC-MS m/z Method [M+H] ⁺

56 [(S)-1 -(1 -Methyl-piperidin-4-yl)-pyrrolidin-3-yl]-[4- 0.70 602.5

(methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- LC-MS

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine 1 TFA

57 2-Dimethylaminomethyl-4-((S)-3-{[4-(methyl- 0.71 668.6 pyridin-4-yl-amino)-benzyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amino}-pyrrolidin-1 - 1 TFA

ylmethyl)-phenol

58 ((S)-1 -lsopropyl-pyrrolidin-3-yl)-[4-(methyl-pyridin- 0.83 547.4

4-yl-amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine 1 TFA

59 [(R)-1 -(1 -Methyl-pipe ridin-4-yl)-pyrrolidin-3-yl]-[4- 0.69 602.5

(methyl-pyridin-4-yl-amino)-benzyl]-[4-(4- LC-MS

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine 1 TFA

60 2-Dimethylaminomethyl-4-((R)-3-{[4-(methyl- 0.71 668.5 pyridin-4-yl-amino)-benzyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amino}-pyrrolidin-1 - 1 TFA

ylmethyl)-phenol [(S)-1-(3-Methyl-butyl)-pyrrolidin-3-yl]-[4-(methyl- 0.91 575.5 pyridin-4-yl-amino)-benzyl]-[4-(4-trifluoromethyl- LC-MS phenyl)-pyrimidin-2-yl]-amine UFA

((S)-1-Cyclopentyl-pyrrolidin-3-yl)-[4-(methyl- 0.87 573.4 pyridin-4-yl-amino)-benzyl]-[4-(4-trifluoromethyl- LC-MS phenyl)-pyrimidin-2-yl]-amine UFA

((R)-1-lsopropyl-pyrrolidin-3-yl)-[4-(methyl-pyridin- 0.83 547.3

4-yl-amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS pyrimidin-2-yl]-amine UFA

[(R)-1 -(3-Methyl-butyl)-pyrrolidin-3-yl]-[4-(methyl- 0.91 575.5 pyridin-4-yl-amino)-benzyl]-[4-(4-trifluoromethyl- LC-MS phenyl)-pyrimidin-2-yl]-amine UFA

((R)-1-Cyclopentyl-pyrrolidin-3-yl)-[4-(methyl- 0.86 573.4 pyridin-4-yl-amino)-benzyl]-[4-(4-trifluoromethyl- LC-MS phenyl)-pyrimidin-2-yl]-amine UFA

Example 66: (±)-[4-(Methyl-pyridin-4-yl-amino)-benzyl]-[ 1-( 1 -methyl-pyrrolidin-3-yl)- piperidin-4-yl]-[4-(4-trifluoromethyl^henyl)^yrimidin-2-yl]- ^

To a solution of [4-(methyl^yridin-4-yl-amino)-benzyl]^iperidin-4-yl-[4-(4-tr ifluoromethyl- phenyl)-pyrimidin-2-yl]-amine (38 mg, 0.073 mmol, 1 eq.) in acetonitrile (5 mL), 1 -methyl-3- pyrrolidinone (35 μΙ_, 0.363 mmol, 5 eq.) and sodium triacetoxy borohydride (77 mg, 0.363 mmol, 5 eq.) were added in sequence. The resulting suspension was stirred at 50 °C for 18 hours. The residue was purified by prep. HPLC (column: Waters X-Bridge, 30x75 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo to give the title compound as a white solid.

LC-MS 1 TFA: t _R = 0.72 min; [M+H] ⁺ = 602.6

Example 67: [1-{3-Fluoro-propyl)-piperidin -yl]-[4-{methyl-pyndin-4-yl-am

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine

To a mixture of [4-(methyl-pyridin-4-yl-amino)-benzyl]-piperidin-4-yl-[4-(4- trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine (18 mg, 0.035 mmol, 1 eq.) and Cs ₂ C0 ₃ (1 1 mg, 0.035 mmol, 1 eq.) in DMF (2 mL), 3-fluoro-1 -iodopropane (4 μί, 0.035 mmol, 1 eq.) was added. The mixture was stirred at r.t. for 18 hours. The reaction mixture was purified by prep. HPLC (column: Waters X-Bridge, 30x75 mm, 10 μηι, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a white solid.

LC-MS 1 TFA: t _R = 0.82 min; [M+H] ⁺ = 579.4

Example 68: ( 1-Methyl^iperidin-4-yl)-[4-(methyl-pyridin-4-yl-am

trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine

To a solution of [4-(methyl-pyridin-4-yl-amino)-benzyl]-piperidin-4-yl-[4-(4- trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine (75 mg, 0.15 mmol, 1 .0 eq.) in formic acid (0.55 mL, 14.5 mmol, 100 eq.), 37 w% aq. formaldehyde solution (12 μί, 0.16 mmol, 1 .1 eq.) was added.

The mixture was stirred at 90 °C for 3 hours. The mixture was allowed to cool down to r.t. and partitioned between sat. aq. NaHC0 ₃ soln. and DCM. The layers were separated. The aq. phase was extracted with DCM. The comb. org. phases were dried over MgS0 ₄ and concentrated in vcacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge,

18x50 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo to give the title compound as a white solid.

LC-MS 1 TFA: t _R = 0.79 min; [M+H] ⁺ = 533.4

Buchwald cross-coupling: Method A: A solution of (1 -benzyl-piperidin-4-yl)-(4-bromo-benzyl)-(5-phenyl-pyrimidin -2-yl)- amine (189 mg, 0.37 mmol, 1 .00 eq.), sodium tert-butoxide (44 mg, 0.46 mmol, 1 .25 eq.) and 4-amino-2-picoline (40 mg, 0.37 mmol, 1 .00 eq.) in dioxane (2 mL) was degased with N ₂ for 15 min before the addition of X-Phos (18 mg, 0.04 mmol, 0.10 eq.) and tris(dibenzylideneacetone)dipalladium(0) (17 mg, 0.02 mmol, 0.05 eq.). The reaction mixture was degased again with N ₂ for 15 min and then heated at 105 °C for 18 hours. The reaction was allowed to cool down to r.t. and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 30x75 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo.

Listed in Table 8 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding amine 7 and the corresponding bromide of Structure 6 as starting materials. Table 8

Example Compound of Formula I *R [min] MS-data

LC-MS m/z Method [M+H] ⁺

69 (1 -Benzyl-piperidin-4-yl)-[4-(2-methyl-pyridin-4- 0.80 541 .5 ylamino)-benzyl]-(5-phenyl-pyrimidin-2-yl)-amine LC-MS

1 TFA

70 (1 -Benzyl-piperidin-4-yl)-[4-(3-fluoro-phenyl)- 0.81 559.4 pyrimidin-2-yl]-[4-(2-methyl-pyridin-4-ylamino)- LC-MS

benzyl]-amine 1 TFA

71 (1 -Benzyl-piperidin-4-yl)-[4-(2-methyl-pyridin-4- 0.89 609.5 ylamino)-benzyl]-[5-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine 1 TFA

72 (1 -Benzyl-pipe ridin-4-yl)-(7-chloro-quinazolin-4-yl)- 0.51 549.2

[4-(2-methyl-pyridin-4-ylamino)-benzyl]-amine LC-MS

1 TFA

73 (1 -Benzyl-piperidin-4-yl)-(6-fluoro-quinazolin-2-yl)- 0.75 533.4

[4-(2-methyl-pyridin-4-ylamino)-benzyl]-amine LC-MS

1 TFA

74 (1 -Benzyl-piperidin-4-yl)-[4-(2-methyl-pyridin-4- 0.88 609.5 ylamino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine 1 TFA (1-lsopropyl-piperidin-4-yl)-{6-[methyl-(2-methyl- 0.79 576.4 pyridin-4-yl)-amino]-pyridin-3-ylmethyl}-[4-(4- LC-MS trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine UFA

(1-lsopropyl-piperidin-4-yl)-[6-(2-methyl-pyridin-4- 0.81 562.4 ylamino)-pyridin-3-ylmethyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

(1-lsopropyl-piperidin-4-yl)-[6-(3-methyl-pyridin-4- 0.79 562.4 ylamino)-pyridin-3-ylmethyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

[6-(3-Fluoro-pyridin-4-ylamino)-pyridin-3-ylmethyl]- 0.79 566.4 (1-isopropyl-piperidin-4-yl)-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

(1-lsopropyl-piperidin-4-yl)-[6-(pyrimidin-4-ylamino)- 0.77 549.4 pyridin-3-ylmethyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.88 560.4 amino)-benzyl]-[6-(4-trifluoromethyl-phenyl)-pyridin- LC-MS

2-yl]-amine UFA

(1 -lsopropyl-piperidin-4-yl)-[6-(methyl-pyridin-3-yl- 0.78 562.5 amino)-pyridin-3-ylmethyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

(1 -lsopropyl-piperidin-4-yl)-[3-(methyl-pyridin-4-yl- 0.82 561 .4 amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

(1 -lsopropyl-piperidin-4-yl)-[3-(methyl-pyridin-3-yl- 0.83 561 .4 amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

(1-lsopropyl-piperidin-4-yl)-{3-[methyl-(2-methyl- 0.83 575.5 pyridin-4-yl)-amino]-benzyl}-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

(1-lsopropyl-piperidin-4-yl)-[3-(2-methyl-pyridin-4- 0.82 561 .5 ylamino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

(1-lsopropyl-piperidin-4-yl)-[3-(3-methyl-pyridin-4- 0.81 561 .4 ylamino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA [3-(3-Fluoro-pyridin-4-ylamino)-benzyl]-(1- 0.80 565.4 isopropyl-piperidin-4-yl)-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

(1-lsopropyl-piperidin-4-yl)-[3-(pyrimidin-4-ylamino)- 0.80 548.4 benzyl]-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]- LC-MS

amine UFA

[4-(4-Fluoro-phenyl)-pyrimidin-2-yl]-(1-isopropyl- 0.74 511 .4 piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)- LC-MS

benzyl]-amine UFA

N,N-Dimethyl-N'-[4-(methyl-pyridin-4-yl-amino)- 0.78 507.3 benzyl]-N'-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2- LC-MS

yl]-ethane-1 ,2-diamine UFA

(+)-N1 ,N1-Dimethyl-N2-[4-(methyl-pyridin-4-yl- 0.78 521 .4 amino)-benzyl]-N2-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-propane-1 ,2-diamine UFA

N,N-Dimethyl-N'-[4-(methyl-pyridin-4-yl-amino)- 0.79 521 .4 benzyl]-N'-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2- LC-MS

yl]-propane-1 ,3-diamine UFA

[2-(4-Methyl-piperazin-1 -yl)-ethyl]-[4-(methyl- 0.74 562.4 pyridin-4-yl-amino)-benzyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

[2-(4-Methyl-piperazin-1 -yl)-ethyl]-[4-(2-methyl- 0.74 562.4 pyridin-4-ylamino)-benzyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

[3-(4-Methyl-piperazin-1-yl)-propyl]-[4-(methyl- 0.73 576.5 pyridin-4-yl-amino)-benzyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

[3-(4-Methyl-piperazin-1-yl)-propyl]-[4-(2-methyl- 0.72 576.3 pyridin-4-ylamino)-benzyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

[3-(4-Methyl-piperazin-1-yl)-propyl]-[4-(3-methyl- 0.72 576.5 pyridin-4-ylamino)-benzyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

[4-({(1-Benzyl-piperidin-4-yl)-[4-(4-trifluoromethyl- 0.91 614.4 phenyl)-thiazol-2-yl]-amino}-methyl)-phenyl]-(2- LC-MS

methyl-pyridin-4-yl)-amine UFA (1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.72 493.4 amino)-benzyl]-(2-phenyl-pyrimidin-4-yl)-amine LC-MS

UFA

(1-lsopropyl-piperidin-4-yl)-[4-(2-methyl-pyridin-4- 0.72 493.4 ylamino)-benzyl]-(2-phenyl-pyrimidin-4-yl)-amine LC-MS

UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.79 561 .4 amino)-benzyl]-[6-(4-trifluoromethyl-phenyl)- LC-MS

pyrazin-2-yl]-amine UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.42 466.4 amino)-benzyl]-quinolin-4-yl-amine LC-MS

UFA

(4-Benzyloxy-pyrimidin-2-yl)-(1 -isopropyl-piperidin- 0.69 523.4 4-yl)-[4-(methyl-pyridin-4-yl-amino)-benzyl]-amine LC-MS

UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.62 560.3 amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)-pyridin- LC-MS 4

2-yl]-amine

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.57 560.3 amino)-benzyl]-[2-(4-trifluoromethyl-phenyl)-pyridin- LC-MS

4-yl]-amine UFA

(4,6-Dimethyl-pyrimidin-2-yl)-(1-isopropyl-piperidin- 0.60 445.4 4-yl)-[4-(methyl-pyridin-4-yl-amino)-benzyl]-amine LC-MS

UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.66 561 .5 amino)-benzyl]-[6-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-4-yl]-amine UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.53 417.4 amino)-benzyl]-pyrimidin-2-yl-amine LC-MS

UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.84 561 .4 amino)-benzyl]-[5-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.69 485.4 amino)-benzyl]-(4-trifluoromethyl-pyrimidin-2-yl)- LC-MS

amine UFA 1 1 1 (+)-N1 ,N1 -Dimethyl-N3-[4-(methyl-pyridin-4-yl- 0.80 535.4 amino)-benzyl]-N3-[4-(4-trifluoromethyl-phenyl)- LC-MS pyrimidin-2-yl]-butane-1 ,3-diamine UFA

1 12 ((S)-1 -lsopropyl-piperidin-3-yl)-[6-(2-methyl-pyridin- 0.80 562.4 4-ylamino)-pyridin-3-ylmethyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

1 13 (1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[6-(2-methyl- 0.69 617.6 pyridin-4-ylamino)-pyridin-3-ylmethyl]-[4-(4- LC-MS trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine UFA

1 14 (1 '-Methyl-[1 ,4']bipiperidinyl-4-yl)-[6-(methyl-pyridin- 0.67 617.5 4-yl-amino)-pyridin-3-ylmethyl]-[4-(4-trifluoromethyl- LC-MS

phenyl)-pyrimidin-2-yl]-amine UFA

1 15 (1 -lsopropyl-piperidin-4-yl)-(4-methoxy-pyrimidin-2- 0.52 447.4 yl)-[4-(methyl-pyridin-4-yl-amino)-benzyl]-amine LC-MS

UFA

Method B: To a solution under Ar of (4-bromo-benzyl)-(1 '-methyl-[1 ,4']bipiperidinyl-4-yl)-[4- (4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine (59 mg, 0.10 mmol, 1 .00 eq.), 4-amino-2- picoline (13 mg, 0.12 mmol, 1 .20 eq.), and sodium tert-butoxide (14 mg, 0.14 mmol, 1 .4 eq.) in dioxane (1 mL), X-Phos (5 mg, 0.01 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.005 mmol, 0.05 eq.) were added. The reaction mixture was stirred at 105 °C for 1 hour. The mixture was allowed to cool down to r.t. and filtered through alumina. The alumina was rinsed with MeOH and the filtrate concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 30x75 mm, 10 μηι, UV/MS, acidic conditions) and concentrated in vacuo.

Listed in Table 9 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding amine 7 and the corresponding bromide of Structure 6 as starting materials.

Table 9

Example Compound of Formula I *R [min] MS-data

LC-MS m/z

Method [M+H] ⁺ 1 '-Methyl-N-(4-((2-methylpyridin-4- 0.71 616.5 yl)amino)benzyl)-N-(4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'- UFA

bipiperidin]-4-amine

N-(4-((2,6-Dimethylpyridin-4-yl)amino)benzyl)-1 '- 0.72 630.4 methyl-N-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2- LC-MS

yl)-[1 ,4'-bipiperidin]-4-amine UFA

1 '-Methyl-N-(4-(methyl(pyridin-3-yl)amino)benzyl)- 0.72 616.5 N-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'- LC-MS

bipiperidin]-4-amine UFA

1 '-Methyl-N-(4-(methyl(pyridin-2-yl)amino)benzyl)- 0.71 616.4 N-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'- LC-MS

bipiperidin]-4-amine UFA

1 '-Methyl-N-(4-(methyl(2-methylpyridin-4- 0.72 630.6 yl)amino)benzyl)-N-(4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'- UFA

bipiperidin]-4-amine

1 '-Methyl-N-(4-(pyridin-4-ylamino)benzyl)-N-(4-(4- 0.69 602.5 (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'- LC-MS

bipiperidin]-4-amine UFA

1 '-Methyl-N-(4-(pyrimidin-4-ylamino)benzyl)-N-(4- 0.68 603.5 (4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'- LC-MS

bipiperidin]-4-amine UFA

N-(4-((2-Methoxypyridin-4-yl)amino)benzyl)-1 '- 0.71 632.4 methyl-N-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2- LC-MS

yl)-[1 ,4'-bipiperidin]-4-amine UFA

N-(4-((2-Fluoropyridin-4-yl)amino)benzyl)-1 '- 0.85 620.5 methyl-N-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2- LC-MS

yl)-[1 ,4'-bipiperidin]-4-amine UFA

6-Methoxy-2-methyl-N-(4-(((1 '-methyl-[1 ,4'- 0.79 696.5 bipiperidin]-4-yl)(4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2- UFA

yl)amino)methyl)phenyl)quinolin-4-amine

N-(4-(Ethyl(pyridin-4-yl)amino)benzyl)-1 '-methyl-N- 0.74 630.5 (4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'- LC-MS

bipiperidin]-4-amine UFA N-(4-((3-Fluoropyridin-4-yl)amino)benzyl)-1 '- 0.69 620.5 methyl-N-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2- LC-MS

yl)-[1 ,4'-bipiperidin]-4-amine UFA

1 '-Methyl-N-(4-((3-methylpyridin-4- 0.70 616.5 yl)amino)benzyl)-N-(4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'- UFA

bipiperidin]-4-amine

1 '-Methyl-N-(4-(4-methylpiperazin-1 -yl)benzyl)-N- 0.68 608.5 (4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)-[1 ,4'- LC-MS

bipiperidin]-4-amine UFA

N-(1 -lsopropylpiperidin-4-yl)-N-(4-((2-methylpyridin- 0.82 561 .4

4-yl)amino)benzyl)-4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-amine UFA

N-(1 -lsopropylpiperidin-4-yl)-N-(4-((3-methylpyridin- 0.82 561 .4

4-yl)amino)benzyl)-4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-amine UFA

N-(4-((3-Fluoropyridin-4-yl)amino)benzyl)-N-(1- 0.81 565.5 isopropylpiperidin-4-yl)-4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-amine UFA

N-(1-lsopropylpiperidin-4-yl)-4-(4- 0.84 615.5 (trifluoromethyl)phenyl)-N-(4-((3- LC-MS

(trifluoromethyl)pyridin-4-yl)amino)benzyl)pyrimidin- UFA

2-amine

N-(4-((5-Fluoropyridin-3-yl)amino)benzyl)-N-(1- 0.95 565.4 isopropylpiperidin-4-yl)-4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-amine UFA

N-(1-lsopropylpiperidin-4-yl)-N-(4-(pyridin-3- 0.81 547.4 ylamino)benzyl)-4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-amine UFA

N-(1 -lsopropylpiperidin-4-yl)-N-(4-((2-(pyrrolidin-1- 0.88 616.5 yl)pyridin-4-yl)amino)benzyl)-4-(4- LC-MS

(trifluoromethyl)phenyl)pyrimidin-2-amine UFA

N-(1-lsopropylpiperidin-4-yl)-N-(4-((2- 0.81 562.4 methylpyrimidin-4-yl)amino)benzyl)-4-(4- LC-MS

(trifluoromethyl)phenyl)pyrimidin-2-amine UFA 138 N-(1 -lsopropylpiperidin-4-yl)-N-(4-(methyl(2- 0.84 576.4 methylpyrimidin-4-yl)amino)benzyl)-4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-amine UFA

139 (1-lsopropyl-piperidin-4-yl)-[4-(pyrimidin-4-ylamino)- 0.79 548.5 benzyl]-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]- LC-MS

amine UFA

140 N-(1-lsopropylpiperidin-4-yl)-N-(4-((6- 0.81 562.5 methylpyrimidin-4-yl)amino)benzyl)-4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-amine UFA

141 N-(1 -lsopropylpiperidin-4-yl)-N-(4-(methyl(6- 0.83 576.4 methylpyrimidin-4-yl)amino)benzyl)-4-(4- LC-MS (trifluoromethyl)phenyl)pyrimidin-2-amine UFA

142 (1-lsopropyl-piperidin-4-yl)-[4-(pyrimidin-2-ylamino)- 0.99 548.4 benzyl]-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]- LC-MS

amine UFA

143 (1-lsopropyl-piperidin-4-yl)-[4-(6-methyl-pyridin-3- 0.83 561 .4 ylamino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

144 (1 -lsopropyl-piperidin-4-yl)-[4-(pyrazin-2-ylamino)- 0.99 548.4 benzyl]-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]- LC-MS

amine UFA

145 (1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-3-yl- 0.84 561 .5 amino)-benzyl]-[4-(4-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

146 [4-(2-Fluoro-pyridin-3-ylamino)-benzyl]-(1- 1 .06 565.4 isopropyl-piperidin-4-yl)-[4-(4-trifluoromethyl- LC-MS phenyl)-pyrimidin-2-yl]-amine UFA

Method C: A solution of N-(4-bromobenzyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine (75 mg, 0.14 mmol, 1.00 eq.), sodium tert- butoxide (17 mg, 0.18 mmol, 1.25 eq.) and 4-amino-3-methylpyridine (15 mg, 0.14 mmol, 1.00 eq.) in dioxane (3 mL) was degased with N ₂ before the addition of X-Phos (7 mg, 0.01 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium(0) (6 mg, 0.007 mmol, 0.05 eq.). The reaction mixture was degased again with N ₂ and then heated at 100 °C for 18 hours. The reaction was allowed to cool down to r.t. and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 18x50 mm, 10 μηι, UV/MS, acid conditions) and concentrated in vacuo.

Listed in Table 10 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding amine 7 and the corresponding bromide of Structure 6 as starting materials.

Table 10

Method D: A solution of N-((6-bromopyridin-2-yl)methyl)-N-(1 -isopropylpiperidin-4-yl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine (50 mg, 94 μηιοΙ, 1 .00 eq.), sodium tert-butoxide (1 1 mg, 1 17 μηιοΙ, 1 .25 eq.) and 4-(methylamino)pyridine (10 mg, 94 μηιοΙ, 1 .00 eq.) in dioxane (2 mL) was degased with N ₂ before the addition of X-Phos (4.5 mg, 9 μηιοΙ, 0.10 eq.) and tris(dibenzylideneacetone)dipalladium(0) (4.3 mg, 5 μηιοΙ, 0.05 eq.). The reaction mixture was degased again with N ₂ and then stirred at 100 °C for 18 hours. The mixture was allowed to cool to r.t. and 4-(methylamino)pyridine (10 mg, 94 μηιοΙ, 1 .00 eq.), X-Phos (4.5 mg, 9 μηιοΙ, 0.10 eq.) and tris(dibenzylideneacetone)dipalladium(0) (4.3 mg, 5 μηιοΙ, 0.05 eq.) were added. The reaction mixture was degased again with N ₂ and then stirred at 100 °C for 18 hours. The reaction was allowed to cool down to r.t. and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 18x50 mm, 10 μηι, UV/MS, acidic conditions) and concentrated in vacuo.

Listed in Table 1 1 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding amine 7 and the corresponding bromide of Structure 6 as starting materials.

Table 11

Method E: To an ice-cooled solution of 2-{(1 -isopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- amino)-benzyl]-amino}-pyrimidin-4-ol (50 mg, 0.12 mmol, 1 .00 eq.) in DCM (1 mL), triethylamine (48 μί, 0.35 mmol, 3.00 eq.) and trifluoromethanesulfonic anhydride (30 μL·, 0.17 mmol, 1 .50 eq.) were added in sequence. The reaction mixture was stirred at 0 °C for 30 min and further at r.t. for 45 min. The mixture was concentrated in vacuo. To a mixture of the resulting triflate in dioxane (2 ml_), sodium tert-butoxide (14 mg, 0.14 mmol, 1 .25 eq.) and 1 -methylpiperazine (13 μΙ_, 0.12 mmol, 1 .00 eq.) were added. The resulting mixture was degased with N ₂ before the addition of X-Phos (5.5 mg, 0.01 mmol, 0.10 eq.) and tris(dibenzylideneacetone)dipalladium (0) (5.3 mg, 6 μηιοΙ, 0.05 eq.). The reaction mixture was degased again with N ₂ and then stirred at 100 °C for 18 hours. The reaction was allowed to cool down to r.t. and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 18x50 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo.

Listed in Table 12 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding amine 20 and the corresponding phenol of Structure 17 as starting materials.

Table 12

Example Compound of Formula I *R [min] MS-data

LC-MS m/z Method [M+H] ⁺

158 (1 -lsopropyl-piperidin-4-yl)-[4-(4-methyl-piperazin- 0.37 515.3 1 -yl)-pyrimidin-2-yl]-[4-(methyl-pyridin-4-yl-amino)- LC-MS 4

benzyl]-amine

159 (1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.49 486.4 amino)-benzyl]-(4-pyrrolidin-1 -yl-pyrimidin-2-yl)- LC-MS

amine 1 TFA

Method F: A solution of N-(1 -isopropylpiperidin-4-yl)-N-(piperidin-4-ylmethyl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine (63 mg, 0.14 mmol, 1 .00 eq.), sodium tert- butoxide (16 mg, 0.17 mmol, 1 .25 eq.) and 4 bromopyridine (22 mg, 0.14 mmol, 1 .00 eq.) in dioxane (2 ml_) was degased with N ₂ before the addition of X-Phos (6.5 mg, 0.01 mmol, 0.10 eq.) and tris(dibenzylideneacetone)dipalladium (0) (6.2 mg, 7 μηιοΙ, 0.05 eq.). The reaction mixture was degased again with N ₂ and then stirred at 100 °C for 18 hours. The reaction was allowed to cool down to r.t. and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 18x50 mm, 10 μηι, UV/MS, acid conditions) and concentrated in vacuo.

Listed in Table 13 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding bromide 13 as starting material and the corresponding amine of Structure 12.

Table 13

Example 163: (7-lsobutyl-quinazolin-4-yl)-(1-isopropyl^iperidin-4-yl)-[4- (2-m

ylamino)-benzyl]-amine

To a solution under Ar of (4-bromo-benzyl)-(7-isobutyl-quinazolin-4-yl)-(1 -isopropyl- piperidin-4-yl)-amine (50 mg, 0.10 mmol, 1 .00 eq.), 4-amino-2-methylpyridine (15 mg, 0.14 mmol, 1 .38 eq.), and NaOtBu (12 mg, 0.12 mmol, 1 .24 eq.) in toluene (1 mL), X-Phos (5 mg, 0.01 mmol, 0.10 eq.) and Pd ₂ (dba) ₃ (5 mg, 5 μηιοΙ, 0.05 eq.) were added. The mixture was stirred at 85 °C for 2 hours. The mixture was allowed to cool to r.t. and 4-amino-2- methylpyridine (33 mg, 0.30 mmol, 3.00 eq.), NaOtBu (12 mg, 0.12 mmol, 1 .24 eq.), X- Phos (5 mg, 0.01 mmol, 0.10 eq.) and Pd ₂ (dba) ₃ (5 mg, 5 μηιοΙ, 0.05 eq.) were added. The mixture was stirred under Ar at 85 °C for 18 hours. The mixture was allowed to cool to r.t. and diluted with AcOEt. The mixture was washed with water (2 x). The org. layer was dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by prep. TLC on Si0 ₂ (0.5 mm, DCM/MeOH/NH ₄ OH 90:10:1 ) to give the title compound as a yellow solid.

LC-MS 1 TFA: t _R = 0.56 min; [M+H] ⁺ = 523.5 Suzuki cross-coupling:

Method A: To an ice-cooled solution of 2-{(1 -isopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- amino)-benzyl]-amino}-pyrimidin-4-ol (50 mg, 0.12 mmol, 1 .00 eq.) in DCM (1 ml_), triethylamine (48 μΙ_, 0.35 mmol, 3.00 eq.) and trifluoromethanesulfonic anhydride (30 μΙ_, 0.17 mmol, 1 .50 eq.) were added in sequence. The reaction mixture was stirred at 0 °C for 30 min and further at r.t. for 45 min. The mixture was concentrated in vacuo. To a mixture under N ₂ of the resulting triflate, 4-chlorophenylboronic acid (18 mg, 0.12 mmol, 1 .00 eq.), and sodium carbonate (49 mg, 0.46 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (2 ml_), tetrakis(triphenylphosphine)palladium (0) (7 mg, 6 μηιοΙ, 0.05 eq.) was added. The mixture was stirred at 100 °C for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt and water. The layers were separated. The org. phase was washed with sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 18x50 mm, 10 μηι, UV/MS, acid conditions) and concentrated in vacuo. Listed in Table 14 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding boronic acid or boronic ester 19 and the corresponding phenol of Structure 17 as starting materials.

Table 14

Example Compound of Formula I *R [min] MS-data

LC-MS m/z Method [M+H] ⁺

164 [4-(4-Chloro-phenyl)-pyrimidin-2-yl]-(1 -isopropyl- 0.79 527.4 piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)- LC-MS

benzyl]-amine 1 TFA [4-(4-tert-Butyl-phenyl)-pyrimidin-2-yl]-(1 -isopropyl- 0.90 549.5 piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)- LC-MS

benzyl]-amine UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.48 494.4 amino)-benzyl]-(4-pyridin-4-yl-pyrimidin-2-yl)-amine LC-MS

UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.85 577.5 amino)-benzyl]-[4-(4-trifluoromethoxy-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.77 507.5 amino)-benzyl]-(4-p-tolyl-pyrimidin-2-yl)-amine LC-MS

UFA

[4-(2-Fluoro-phenyl)-pyrimidin-2-yl]-(1-isopropyl- 0.75 511 .4 piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)- LC-MS

benzyl]-amine UFA

4-(2-{(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin- 0.69 518.4 4-yl-amino)-benzyl]-amino}-pyrimidin-4-yl)- LC-MS

benzonitrile UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.80 561 .4 amino)-benzyl]-[4-(3-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

(1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.78 561 .4 amino)-benzyl]-[4-(2-trifluoromethyl-phenyl)- LC-MS

pyrimidin-2-yl]-amine UFA

4-(2-{((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-[4- 0.58 573.4 (methyl-pyridin-4-yl-amino)-benzyl]-amino}- LC-MS

pyrimidin-4-yl)-benzonitrile UFA

((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-[4-(methyl- 0.61 617.5 pyridin-4-yl-amino)-benzyl]-[4-(6-trifluoromethyl- LC-MS

pyridin-3-yl)-pyrimidin-2-yl]-amine UFA

[4-(4-Fluoro-phenyl)-pyrimidin-2-yl]-((S)-1 '-methyl- 0.61 566.2

[1 ,4']bipiperidinyl-3-yl)-[4-(methyl-pyridin-4-yl- LC-MS

amino)-benzyl]-amine UFA

[4-(4-Methanesulfonyl-phenyl)-pyrimidin-2-yl]-((S)- 0.53 626.6 1 '-methyl-[1 ,4']bipiperidinyl-3-yl)-[4-(methyl-pyridin- LC-MS

4-yl-amino)-benzyl]-amine UFA 177 [4-(4-Chloro-phenyl)-pyrimidin-2-yl]-((S)-1 '-methyl- 0.65 582.4 [1 ,4']bipiperidinyl-3-yl)-[4-(methyl-pyridin-4-yl- LC-MS

amino)-benzyl]-amine UFA

178 [4-(3-Chloro-phenyl)-pyrimidin-2-yl]-((S)-1 '-methyl- 0.64 582.5

[1 ,4']bipiperidinyl-3-yl)-[4-(methyl-pyridin-4-yl- LC-MS

amino)-benzyl]-amine UFA

179 3-(2-{((S)-1 '-Methyl-[1 ,4']bipiperidinyl-3-yl)-[4- 0.57 573.5

(methyl-pyridin-4-yl-amino)-benzyl]-amino}- LC-MS pyrimidin-4-yl)-benzonitrile UFA

180 (1 -lsopropyl-piperidin-4-yl)-[4-(4-methoxy-phenyl)- 0.71 523.5 pyrimidin-2-yl]-[4-(methyl-pyridin-4-yl-amino)- LC-MS

benzyl]-amine UFA

181 (1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.72 493.4 amino)-benzyl]-(4-phenyl-pyrimidin-2-yl)-amine LC-MS

UFA

182 (1 -lsopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl- 0.73 562.4 amino)-benzyl]-[4-(6-trifluoromethyl-pyridin-3-yl)- LC-MS

pyrimidin-2-yl]-amine UFA

Method B: A mixture under N ₂ of (4-bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-[4-(4- trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine (50 mg, 94 μηιοΙ, 1 .00 eq.), 3-pyridineboronic acid (1 1 .5 mg, 94 μηιοΙ, 1 .00 eq.), bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(ll) (3.3 mg, 5 μηιοΙ, 0.05 eq.) and K ₂ C0 ₃ (39 mg, 0.28 mmol, 3.00 eq.) in acetonitrile (3 mL) was stirred at 100 °C for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (20 mL) and water (20 mL). The layers were separated. The org. phase was washed with sat. aq. NaCI soln. (1 x 10 mL), dried over MgS0 ₄ , and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 18x50 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo.

Listed in Table 15 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding boronic acid or boronic ester 19 and the corresponding bromide of Structure 17 as starting materials. Table 15

Example 185: (1-lsopropyl^iperidin -yl)-(4-pyridin-2-yl-benzyl)-[4-(4-trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine

To a mixture under N ₂ of (4-bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-[4-(4-trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine (50 mg, 94 μηιοΙ, 1 .00 eq.), 2-pyridineboronic acid N- phenyldiethanolamine ester (38 mg, 141 μηιοΙ, 1 .50 eq.) and (XPhos) palladium(ll) phenethylamine chloride (3.5 mg, 5 μηιοΙ, 0.05 eq.) in DMF (5 mL), diethanolamine (96 μL·, 1 .00 mmol, 10.69 eq.), potassium phosphate tribasic (99.5 mg, 0.47 mmol, 5.00 eq.) and copper(ll) acetate (8.5 mg, 47 μηιοΙ, 0.50 eq.) were added. The mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to r.t. 2N aq. HCI soln. (5 mL), then 2N aq. NaOH soln. (5 mL) were added in sequence. The mixture was extracted with Et ₂ 0. The comb. org. phases were washed with sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 18x50 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo to give the title compound as a white solid.

LC-MS 1 TFA: t _R = 0.87 min; [M+H] ⁺ = 532.4 Example 186: ( 1-lsopropyl-plperl0lnA-yl)-{4-lsopropyl-pyrlml&

amino)-benzyl]-amine

To an ice-cooled solution of 2-{(1 -isopropyl-piperidin-4-yl)-[4-(methyl-pyridin-4-yl-amino)- benzyl]-amino}-pyrimidin-4-ol (200 mg, 0.46 mmol, 1 .00 eq.) in DCM (2 mL), triethylamine (0.19 mL, 1 .39 mmol, 3.00 eq.) and trifluoromethanesulfonic anhydride (0.12 mL, 0.69 mmol, 1 .50 eq.) were added in sequence. The reaction mixture was stirred at 0 °C for 30 min and further at r.t. for 45 min. The mixture was concentrated in vacuo. To a solution of the resulting triflate in THF/NMP 5/0.4 (5.4 mL), iron(lll)-acetylacetonate (3.4 mg, 9 μηιοΙ, 0.02 eq.) was added and the mixture was cooled to 0 °C. 2.9M isopropylmagnesium bromide solution in 2-methyltetrahydrofuran (0.32 mL, 0.93 mmol, 2.00 eq.) was added dropwise. The mixture was stirred at 0 °C for 30 min. A second portion of 2.9M isopropylmagnesium bromide solution in 2-methyltetrahydrofuran (0.32 mL, 0.93 mmol, 2.00 eq.) was added dropwise. The mixture was stirred at 0 °C for 30 min. The reaction was quenched with sat. aq. NH ₄ CI soln. and extracted with Et ₂ 0. The comb. org. phases were dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 18x50 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo to give the title compound as a brown solid.

LC-MS 1 TFA: t _R = 0.68 min; [M+H] ⁺ = 459.5

General methods for the synthesis of precursors and intermediates:

General method for the synthesis of a bromide of Structure 6

Method A: To an ice-cooled solution of (1 -isopropyl-piperidin-4-yl)-[4-(4-trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine (3.64 g, 10 mmol, 1 .0 eq.) in DMF (40 mL), sodium hydride 60% dispersion in mineral oil (520 mg, 13 mmol, 1 .3 eq.) was added. The resulting orange mixture was stirred at r.t. for 2 hours. Then a solution of 4-bromobenzyl bromide (2.75 g, 1 1 mmol, 1 .1 eq.) in DMF (20 mL) was added dropwise and the mixture was stirred at r.t. for 18 hours. The reaction mixture was quenched with sat. aq. Na ₂ C0 ₃ soln. (200 mL). The mixture was extracted with DCM (3 x 150 mL). The comb. org. phases were washed with water (1 x 150 mL), sat. aq. NaCI soln. (1 x 150 mL), dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 340 g, flow: 90 mL/min, 90 fractions of 45 mL, Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 95:5 to Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 1 :1) to give the desired product as a yellow foam.

Listed in Table 16 below are bromides of Structure 6, prepared according to the above- mentioned method with the corresponding amine 4 as starting material. Table 16

Bromide of Structure 6 *R [min] MS-data

LC-MS Method m/z [M+H] ⁺

(4-Bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-[4-(4- 0.87 533.2 trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine LC-MS 4

(1 -Benzyl-piperidin-4-yl)-(4-bromo-benzyl)-[4-(4- 1 .35 585.6 trifluoromethyl-phenyl)-thiazol-2-yl]-amine LC-MS 3 4-[(4-Bromo-benzyl)-quinoxalin-2-yl-amino]-piperidine- 1 .10 497.1 1 -carboxylic acid tert-butyl ester LC-MS 2

(4-Bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-(2-phenyl- 0.83 464.9 pyrimidin-4-yl)-amine LC-MS 4

(R)-3-{(4-Bromo-benzyl)-[4-(4-trifluoromethyl-phenyl)- 1 .14 577.0 pyrimidin-2-yl]-amino}-pyrrolidine-1 -carboxylic acid tert- LC-MS 4

butyl ester

(S)-3-{(4-Bromo-benzyl)-[4-(4-trifluoromethyl-phenyl)- 1 .14 577.0 pyrimidin-2-yl]-amino}-pyrrolidine-1 -carboxylic acid tert- LC-MS 4

butyl ester

(4-Bromo-benzyl)-[4-(4-fluoro-phenyl)-pyrimidin-2-yl]-(1 - 0.82 483.3 isopropyl-piperidin-4-yl)-amine LC-MS 4

N-(4-Bromo-benzyl)-N',N'-dimethyl-N-[4-(4- 0.84 479.3 trifluoromethyl-phenyl)-pyrimidin-2-yl]-ethane-1 ,2- LC-MS 4

diamine

(+)-N2-(4-Bromo-benzyl)-N1 ,N1 -dimethyl-N2-[4-(4- 0.86 493.3 trifluoromethyl-phenyl)-pyrimidin-2-yl]-propane-1 ,2- LC-MS 4

diamine

N-(4-Bromo-benzyl)-N',N'-dimethyl-N-[4-(4- 0.84 493.3 trifluoromethyl-phenyl)-pyrimidin-2-yl]-propane-1 ,3- LC-MS 4

diamine

(4-Bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-quinolin-4- 0.56 438.3 yl-amine LC-MS 4

(+)-N3-(4-Bromo-benzyl)-N1 ,N1 -dimethyl-N3-[4-(4- 0.86 507.1 trifluoromethyl-phenyl)-pyrimidin-2-yl]-butane-1 ,3- LC-MS 4

diamine

4-{(4-Bromo-benzyl)-[3-(4-trifluoromethyl-phenyl)- 1 .12 581 .0 [1 ,2,4]oxadiazol-5-yl]-amino}-piperidine-1 -carboxylic LC-MS 4

acid tert-butyl ester

4-{(4-Bromo-benzyl)-[5-(4-trifluoromethyl-phenyl)- 1 .07 580.8 [1 ,3,4]oxadiazol-2-yl]-amino}-piperidine-1 -carboxylic LC-MS 4

acid tert-butyl ester

4-[Benzooxazol-2-yl-(4-bromo-benzyl)-amino]- 1 .01 486.3 piperidine-1 -carboxylic acid tert-butyl ester LC-MS 4

(4-Bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-(4- 0.65 419.0 methoxy-pyrimidin-2-yl)-amine LC-MS 4 4-[Benzothiazol-2-yl-(4-bromo-benzyl)-amino]- 1 .03 502.3 piperidine-1 -carboxylic acid tert-butyl ester LC-MS 4

Method B: To an ice-cooled solution of 4-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-ylamino]- piperidine-1 -carboxylic acid tert-butyl ester (2.59 g, 6.13 mmol, 1 .0 eq.) in DMF (30 mL), 95% sodium hydride (201 mg, 7.97 mmol, 1 .3 eq.) was added. The resulting red mixture was stirred at r.t. for 45 min. Then a solution of 4-bromobenzyl bromide (1 .69 g, 6.74 mmol, 1 .1 eq.) in DMF (10 mL) was added dropwise and the orange mixture was stirred at r.t. for 18 hours. The reaction mixture was quenched with sat. aq. Na ₂ C0 ₃ soln. The mixture was extracted with DCM. The comb. org. phases were washed with water, sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 45 fractions of 45 mL, Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 9:1 to Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 4:6) to give the desired product as a pale yellow solid.

Listed in Table 17 below are bromides of Structure 6, prepared according to the above- mentioned method with the corresponding amine 4 as starting material.

Table 17

Bromide of Structure 6 *R [min] MS-data

LC-MS Method m/z [M+H] ⁺

4-{(4-Bromo-benzyl)-[4-(4-trifluoromethyl-phenyl)- 1 .15 591 .1 pyrimidin-2-yl]-amino}-piperidine-1 -carboxylic acid tert- LC-MS 4

butyl ester

(S)-3-{(4-Bromo-benzyl)-[4-(4-trifluoromethyl-phenyl)- 1 .16 590.7 pyrimidin-2-yl]-amino}-piperidine-1 -carboxylic acid tert- LC-MS 4

butyl ester

(3aR,6aS)-tert-butyl 5-((4-bromobenzyl)(4-(4- 1 .17 616.6

(trifluoromethyl)phenyl)pyrimidin-2- LC-MS 4

yl)amino)hexahydrocyclopenta[c]pyrrole-2(1 H)- carboxylate (mixture of stereoisomers)

(S)-3-[(4-Benzyloxy-pyrimidin-2-yl)-(4-bromo-benzyl)- 1 .02 553.1 amino]-piperidine-1 -carboxylic acid tert-butyl ester LC-MS 4

4-[(4-Bromo-benzyl)-quinolin-4-yl-amino]-piperidine-1 - 0.80 496.3 carboxylic acid tert-butyl ester LC-MS 4 (S)-3-[(4-Bromo-benzyl)-quinolin-4-yl-amino]-piperidine- 0.82 496.3

1 -carboxylic acid tert-butyl ester LC-MS 4

Method C: To an ice-cooled solution of (4,6-dimethyl-pyrimidin-2-yl)-(1 -isopropyl-piperidin- 4-yl)-amine (417 mg, 1 .68 mmol, 1 .0 eq.) in DMF (8 mL), sodium hydride 60% dispersion in mineral oil (87 mg, 2.18 mmol, 1 .3 eq.) was added. The resulting orange mixture was stirred at r.t. for 2 hours. Then a solution of 4-bromobenzyl bromide (462 mg, 1 .85 mmol, 1 .1 eq.) in DMF (2 mL) was added dropwise and the mixture was stirred at 60 °C for 18 hours. The reaction mixture was quenched with sat. aq. Na ₂ C0 ₃ soln. The mixture was extracted with DCM. The comb. org. phases were washed with water, sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 25 fractions of 30 mL, Hept 100% to Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 8:2) to afford the desired product as a pale yellow solid.

Listed in Table 18 below are bromides of Structure 6, prepared according to the above- mentioned method with the corresponding amine 4 as starting material.

Table 18

Bromide of Structure 6 *R [min] MS-data

LC-MS Method m/z [M+H] ⁺

(4-Bromo-benzyl)-(4,6-dimethyl-pyrimidin-2-yl)-(1 - 0.74 417.2 isopropyl-piperidin-4-yl)-amine LC-MS 4

(4-Bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-(4- 0.79 457.2 trifluoromethyl-pyrimidin-2-yl)-amine LC-MS 4

(4-Bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-[6-(4- 0.75 533.2 trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine LC-MS 4

(4-Bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-[5-(4- 0.87 533.2 trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine LC-MS 4

(4-Bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-[6-(4- 0.91 532.2 trifluoromethyl-phenyl)-pyridin-2-yl]-amine LC-MS 4

(4-Benzyloxy-pyrimidin-2-yl)-(4-bromo-benzyl)-(1 - 0.78 495.2 isopropyl-piperidin-4-yl)-amine LC-MS 4

(4-Bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-[4-(4- 0.78 532.2 trifluoromethyl-phenyl)-pyridin-2-yl]-amine LC-MS 4 (4-Bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-[2-(4- 0.66 532.2 trifluoromethyl-phenyl)-pyridin-4-yl]-amine LC-MS 4

N-(4-bromobenzyl)-N-(1 -isopropylpiperidin-4- 0.69 389.3 yl)pyrimidin-2-amine LC-MS 4

N-(4-bromobenzyl)-N-(3-(4-methylpiperazin-1 - 0.76 548.2 yl)propyl)-4-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine LC-MS 4

Method D: To an ice-cooled solution of (1 -benzyl-piperidin-4-yl)-(5-phenyl-pyrimidin-2-yl)- amine (206 mg, 0.60 mmol, 1 .0 eq.) in DMF (3.5 mL), sodium hydride 60% dispersion in mineral oil (93 mg, 2.32 mmol, 3.9 eq.) was added. The reaction mixture was stirred at r.t. for 2 hours. Then 4-bromobenzyl bromide (164 mg, 0.66 mmol, 1 .1 eq.) was added and the mixture was stirred at r.t. for 18 hours. The mixture was cooled to 0 °C and sodium hydride 60% dispersion in mineral oil (43 mg, 1 .07 mmol, 1 .8 eq.) was added. The mixture was stirred at r.t. for 30 min. 4-Bromobenzyl bromide (268 mg, 1 .07 mmol, 1 .8 eq.) was added. The reaction mixture was stirred at 70 °C for 18 hours. The mixture was allowed to cool to r.t. and purified by prep. HPLC (column: Waters X-Bridge, 30x75 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo to give the desired product.

Listed in Table 19 below are bromides of Structure 6, prepared according to the above- mentioned method with the corresponding amine 4 as starting material.

Table 19

Bromide of Structure 6 *R [min] MS-data

LC-MS Method m/z [M+H] ⁺

(1 -Benzyl-pipe ridin-4-yl)-(4-bromo-benzyl)-(5-phenyl- 1 .29 513.0 pyrimidin-2-yl)-amine LC-MS 3

(1 -Benzyl-piperidin-4-yl)-(4-bromo-benzyl)-[4-(3-fluoro- 1 .31 531 .0 phenyl)-pyrimidin-2-yl]-amine LC-MS 3

(1 -Benzyl-piperidin-4-yl)-(4-bromo-benzyl)-[5-(4- 1 .32 580.9 trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine LC-MS 3

(1 -Benzyl-piperidin-4-yl)-(4-bromo-benzyl)-(7-chloro- 1 .20 520.8 quinazolin-4-yl)-amine LC-MS 3

(1 -Benzyl-piperidin-4-yl)-(4-bromo-benzyl)-(6-fluoro- 1 .27 505.0 quinazolin-2-yl)-amine LC-MS 3 (1 -Benzyl-piperidin-4-yl)-(4-bromo-benzyl)-[4-(4- 1 .38 581 .0 trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine LC-MS 3

Method E: To an ice-cooled solution of ((S)-1 -isopropyl-piperidin-3-yl)-[4-(4-trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine (303 mg, 0.82 mmol, 1 .0 eq.) in DMF (4 mL), sodium hydride 95% (25 mg, 1 .06 mmol, 1 .3 eq.) was added. The resulting mixture was stirred at r.t. for 45 min. Then a solution of 2-bromo-5-(bromomethyl)pyridine (234 mg, 0.90 mmol, 1 .1 eq.) in DMF (4 mL) was added dropwise and the mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo and the residue taken up in sat. aq. Na ₂ C0 ₃ soln. (10 mL). The mixture was extracted with DCM (3 x 6 mL). The comb. org. phases were washed with water (1 x 6 mL), sat. aq. NaCI soln. (1 x 6 mL), dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 30x75 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo to give the desired product.

Listed in Table 20 below are bromides of Structure 6, prepared according to the above- mentioned method with the corresponding amine 4 as starting material.

Table 20

Synthesis of ( 6-Bromo-pyridin-3-ylmethyl)-( 1-isopropyl-piperidin-4-yl)-[4-(4-trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine

To an ice-cooled solution of (1 -isopropyl-piperidin-4-yl)-[4-(4-trifluoromethyl-phenyl)- pyrimidin-2-yl]-amine (1 .09 g, 3.0 mmol, 1 .0 eq.) in DMF (15 mL), sodium hydride 60% dispersion in mineral oil (94 mg, 3.9 mmol, 1 .3 eq.) was added. The resulting orange mixture was stirred at r.t. for 2 hours. Then a solution of 2-bromo-5-(bromomethyl)pyridine (828 mg, 3.3 mmol, 1 .1 eq.) in DMF (5 mL) was added dropwise and the mixture was stirred at 60 °C for 18 hours. The reaction mixture was quenched with sat. aq. Na ₂ C0 ₃ soln. (200 mL). The mixture was extracted with DCM (3 x 150 mL). The comb. org. phases were washed with water (1 x 150 mL), sat. aq. NaCI soln. (1 x 150 mL), dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 35 fractions of 45 mL, Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 95:5 to Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 1 :1 ) to give the title compound as a yellow solid.

LC-MS 4: t _R = 0.81 min; [M+H] ⁺ = 534.2

Synthesis of N-((6-Bromopyridin-2-yl)methyl)-N-( 1-isopropylpiperidin-4-yl)-4-(4- (trifluoromethyl)phenyl)pyrimidin-2-amine

To an ice-cooled solution of (1 -isopropyl-piperidin-4-yl)-[4-(4-trifluoromethyl-phenyl)- pyrimidin-2-yl]-amine (1 .00 g, 2.74 mmol, 1 .0 eq.) in DMF (15 mL), sodium hydride 60% dispersion in mineral oil (154 mg, 3.84 mmol, 1 .4 eq.) was added. The resulting orange mixture was stirred at r.t. for 2 hours. Then a solution of 2-bromo-6-(bromomethyl)pyridine (757 mg, 3.02 mmol, 1 .1 eq.) in DMF (5 mL) was added dropwise and the mixture was stirred at 60 °C for 18 hours. The mixture was cooled to 0 °C and sodium hydride 60% dispersion in mineral oil (77 mg, 1 .92 mmol, 0.7 eq.) was added. The resulting orange mixture was stirred at r.t. for 2 hours. Then a solution of 2-bromo-6-(bromomethyl)pyridine (378 mg, 1 .51 mmol, 0.55 eq.) in DMF (2 mL) was added dropwise and the mixture was stirred at 60 °C 4 hours. The reaction mixture was quenched with sat. aq. Na ₂ C0 ₃ solution. The mixture was extracted with DCM. The comb. org. phases were washed with water, sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 35 fractions of 45 mL, Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 95:5 to Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 1 :1) to afford the title compound as an orange oil.

LC-MS 4: t _R = 0.82 min; [M+H] ⁺ = 534.2

Synthesis of (3-Bromo-benzyl)-( 1 '-methyl-[ 1, 4]' bipiperidinyl-4-yl)-[4-(4-trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine

To an ice-cooled solution of (1 -isopropyl-piperidin-4-yl)-[4-(4-trifluoromethyl-phenyl)- pyrimidin-2-yl]-amine (1 .00 g, 2.75 mmol, 1 .0 eq.) in DMF (15 mL), sodium hydride 60% dispersion in mineral oil (86 mg, 3.57 mmol, 1 .3 eq) was added. The resulting orange mixture was stirred at r.t. for 2 hours. Then a solution of 3-bromobenzyl bromide (756 mg, 3.02 mmol, 1 .1 eq.) in DMF (5 mL) was added dropwise and the mixture was stirred at 60 °C for 18 hours. The reaction mixture was quenched with sat. aq. Na ₂ C0 ₃ solution. The mixture was extracted with DCM. The comb. org. phases were washed with water, sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 35 fractions of 45 mL, Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 95:5 to Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 1 :1) to afford the title compound as a yellow solid.

LC-MS 4: t _R = 0.86 min; [M+H] ⁺ = 533.1 Synthesis of (4-Bromo-benzyl)^iperidin-4-yl-[4-(4-trifluo

amine

To an ice-cooled solution of 4-{(4-bromo-benzyl)-[4-(4-trifluoromethyl-phenyl)-pyrimidin- 2- yl]-amino}-piperidine-1 -carboxylic acid tert-butyl ester (2.50 g, 4.23 mmol, 1 eq.) in DCM (50 mL), 4M HCI in dioxane (12 mL) was added. The reaction mixture was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between 1 M aq. NaOH soln. (100 mL) and DCM (100 mL). The layers were separated. The aq. phase was extracted with DCM (2 x 50 mL). The comb. org. phases were washed with water (2 x 100 mL), sat. aq. NaCI soln. (1 x 100 mL), dried over MgS0 ₄ , and concentrated in vacuo to give the title compound as a pale yellow foam. The product was used without further purification.

LC-MS 4: t _R = 0.81 min; [M+H] ⁺ = 491 .2

Synthesis of (4-Bromo-benzyl)-( 1 '-methyl-[ 1, 4]' bipiperidinyl-4-yl)-[4-(4-trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine

To a solution of (4-bromo-benzyl)-piperidin-4-yl-[4-(4-trifluoromethyl-phenyl )-pyrimidin-2-yl]- amine (2.20 g, 4.48 mmol, 1 eq.) in acetonitrile (50 mL), 1 -methyl-4-piperidone (1 .03 mL, 8.95 mmol, 2 eq.) and sodium triacetoxy borohydride (2.85 g, 13.4 mmol, 3 eq.) were added in sequence. The resulting suspension was stirred at 50 °C for 18 hours. The reaction mixture was poured in water (150 mL). The mixture was extracted with DCM (2x 200 mL). The comb. org. phases were dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, from AcOEt-NEt ₃ (10% NEt ₃ ) to AcOEt-NEt ₃ (10% NEt ₃ )/MeOH 8:2) to yield the title compound as a white solid.

LC-MS 4: t _R = 0.71 min; [M+H] ⁺ = 588.2

Synthesis of {4-Bromo-benzyi)-{7-isobutyi-quinazoiin -yi)-{1-isopropyi-pipen

Step 1 : To a suspension under Ar of 7-bromo-3H-quinazolin-4-one (500 mg, 2.22 mmol, 1 .00 eq.) and Pd(dppf)CI ₂ CH ₂ CI ₂ (181 mg, 0.22 mmol, 0.10 eq.) in THF (1 mL), 0.5N isobutylzinc bromide in THF (9 mL, 4.5 mmol, 2.03 eq.) was added. The purple solution was stirred at r.t. for 18 hours. 0.5N isobutylzinc bromide in THF (4.5 mL, 2.25 mmol, 1 .01 eq.) was added and the mixture was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between AcOEt and 1 N aq. HCI soln. The layers were separated. The org. phase was washed with sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by CC (Si0 ₂ , DCM to DCM/MeOH 100:5) to give 7-isobutyl-3H-quinazolin-4-one as a brown solid.

LC-MS 4: t _R = 0.73 min; [M+H] ⁺ = 203.3

Step 2: A mixture of 7-isobutyl-3H-quinazolin-4-one (173 mg, 0.86 mmol, 1 .0 eq.), N,N- dimethylaniline (0.3 mL, 2.37 mmol, 2.8 eq.), and POCI ₃ (0.8 mL, 8.58 mmol, 10.0 eq.) was stirred at 1 15 °C for 1 hour. Toluene (5 mL) was added and the mixture was concentrated in vacuo. The residue was dissolved in DCM (30 mL) and heptane was added. The DCM was removed in vacuo. The resulting suspension was filtered. The filtrate was concentrated in vacuo to give 4-chloro-7-isobutyl-quinazoline as a yellow oil. The product was used withtout further purification.

LC-MS 4: t _R = 0.96 min; [M+H] ⁺ = 221 .2

Step 3: To a solution of 4-amino-1 -isopropylpiperidine (5.0 g, 35.2 mmol, 1 .00 eq.) in MeOH (80 mL), 4-bromobenzaldehyde (6.8 g, 36.8 mmol, 1 .05 eq.) and NEt ₃ (5.2 mL, 37.0 mmol, 1 .05 eq.) were added. The mixture was refluxed for 2 hours. The solution was allowed to cool down to r.t. and NaBH ₄ (1 .33 g, 35.2 mmol, 1 .00 eq.) was added portionwise. The mixture was stirred at r.t. for 18 hours. The reaction mixture was quenched with sat. aq. NaHC0 ₃ soln. and the org. solvent was removed in vacuo. The residue was diluted with AcOEt. The layers were separated. The org. phase was washed with sat. NaHC0 ₃ soln., dried over MgS0 ₄ and concentrated in vacuo to give (4-bromo-benzyl)-(1 -isopropyl- piperidin-4-yl)-amine as a colorless oil that solidified upon standing. The product was used without further purification.

LC-MS 4: t _R = 0.44 min; [M+H] ⁺ = 31 1 .2

Step 4: To a suspension of 4-chloro-7-isobutyl-quinazoline (130 mg, 0.59 mmol, 1 .0 eq.) and (4-bromo-benzyl)-(1 -isopropyl-piperidin-4-yl)-amine (557 mg, 1 .79 mmol, 3.0 eq.) in te/ -butanol (1 mL), DIPEA (0.2 mL, 1 .19 mmol, 2.0 eq.) was added. The mixture was stirred at 125 °C for 4.5 hours. The mixture was concentrated in vacuo. The residue was purified by CC (Si0 ₂ , DCM/MeOH (with 1 % of NH ₄ OH) 99:1 to 90:10) to give the title compound as a pale yellow solid.

LC-MS 4: t _R = 0.44 min; [M+H] ⁺ = 31 1 .2

General method for the synthesis of a phenol of Structure 17 To a solution under N ₂ of (4-benzyloxy-pyrimidin-2-yl)-(1 -isopropyl-piperidin-4-yl)-[4- (methyl-pyridin-4-yl-amino)-benzyl]-amine (2.33 g, 4.46 mmol, 1 eq.) in EtOH (150 ml_), palladium on activated carbon (10 w%, 237 mg) was added. The flask was carefully evacuated and backfilled with H ₂ (3x). The black suspension was stirred at 40 °C under an H ₂ -atmosphere for 18 hours. The black suspension was filtered through Celite and the filter cake was rinsed with EtOH. The filtrate was concentrated in vacuo to give the desired phenol. The product was used without further purification.

Listed in Table 21 below are phenol of Structure 17, prepared according to the above- mentioned method with the corresponding benzyl protected phenol 16 as starting material.

Table 21

Synthesis of (S)-3-{(4-Benzyloxy^yrimidin-2-yl)-[4-(methyl^yridin-4-yl-am ino)-benzyl]- amino}-piperidine-1-carboxylic acid tert-butyl ester

A solution of (S)-3-[(4-benzyloxy-pyrimidin-2-yl)-(4-bromo-benzyl)-amino]- piperidine-1 - carboxylic acid tert-butyl ester (2.36 g, 4.26 mmol, 1 .00 eq.), sodium tert-butoxide (512 mg, 5.33 mmol, 1 .25 eq.) and 4-(methylamino)pyridine (461 mg, 4.26 mmol, 1 .00 eq.) in dioxane (60 mL) was degased with N ₂ for 15 min before the addition of X-Phos (203 mg, 0.43 mmol, 0.10 eq.) and tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (221 mg, 0.21 mmol, 0.05 eq.). The reaction mixture was degased again with N ₂ for 15 min and then heated at 105 °C for 24 hours. The reaction was allowed to cool to r.t. and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (snap 100 g, from Hept/AcOEt-10%Et ₃ N 5:5 to Hept/AcOEt-10%Et ₃ N 3:7) to give the title compound as a pale yellow foam.

LC-MS 4: t _R = 0.81 min; [M+H] ⁺ = 581 .2

Synthesis of (4-Benzyloxy^yrimidin-2-yl)-[4-(methyl^yridin-4-yl-amino)-be nzyl]-(S)- piperidin-3-yl-amine To an ice-cooled solution of (S)-3-{(4-benzyloxy-pyrimidin-2-yl)-[4-(methyl-pyridin-4-yl- amino)-benzyl]-amino}-piperidine-1 -carboxylic acid tert-butyl ester (2.00 g, 3.44 mmol, 1 eq.) in DCM (12 mL), 4N HCI in dioxane (12 mL) was added dropwise. The resulting mixture was stirred at r.t. for 30 min. The mixture was concentrated in vacuo. Sat. aq. NaHC0 ₃ was added and the mixture was extracted with DCM. The comb. org. phases were dried over MgS0 ₄ and concentrated in vacuo to give the title compound as a pale orange foam.

LC-MS 4: t _R = 0.60 min; [M+H] ⁺ = 481 .1 Synthesis of (S)-N-(4-(benzyloxy)pyrimidin-2-yl)-1'-methyl-N-(4-(methyl(p yridin-4- yl)amino)benzyl)-[ 1 ,4'-bipiperidin]-3-amine

To a solution of (4-benzyloxy-pyrimidin-2-yl)-[4-(methyl-pyridin-4-yl-amino)- benzyl]-(S)- piperidin-3-yl-amine (1 .64 g, 3.34 mmol, 1 .0 eq.) in MeCN (15 mL), N-methyl-4-piperidone (0.40 mL, 3.34 mmol, 1 .0 eq.) was added. The mixture was stirred at r.t. for 2 hours. Sodium triacetoxyborohydride (1 .06 g, 5.02 mmol, 1 .5 eq.) was added. The mixture was stirred at r.t. for 1 hour. Sat. aq. NaHC0 ₃ was added and the mixture was extracted with DCM (3x). The comb. org. layers were dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 30x75 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo to give the title compound as an off-white foam.

LC-MS 4: t _R = 0.56 min; [M+H] ⁺ = 577.9

General method for the synthesis of an amine of Structure 23

To an ice-cooled solution of 4-{[4-(methyl-pyridin-4-yl-amino)-benzyl]-quinoxalin-2-yl- amino}-piperidine-1 -carboxylic acid tert-butyl ester (566 mg, 1 .08 mmol, 1 eq.) in DCM (15 mL), 4M HCI in dioxane (6 mL) was added. The reaction mixture was stirred at r.t. for 17 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between 1 M aq. NaOH (50 mL) and DCM (50 mL). The layers were separated. The aq. phase was extracted with DCM (2 x 50 mL). The comb. org. phases were washed with water (2 x 50 mL), sat. aq. NaCI soln. (1 x 50 mL), dried over MgS0 ₄ and concentrated in vacuo to give the desired amine. The product was used without further purification.

Listed in Table 22 below are amine of Structure 23, prepared according to the above- mentioned method with the corresponding Boc-protected amine 22 as starting material.

Table 22 Amine of Structure 23 i _R [min] MS-data

LC-MS Method m/z [M+H] ⁺

[4-(Methyl-pyridin-4-yl-amino)-benzyl]-piperidin-4-yl- 0.81 425.1 quinoxalin-2-yl-amine LC-MS 3

Benzooxazol-2-yl-[4-(methyl-pyridin-4-yl-amino)- 0.53 414.2 benzyl]-piperidin-4-yl-amine LC-MS 4

Benzothiazol-2-yl-[4-(methyl-pyridin-4-yl-amino)- 0.55 430.2 benzyl]-piperidin-4-yl-amine LC-MS 4

Methyl-[4-({piperidin-4-yl-[3-(4-trifluoromethyl-phenyl)- 0.65 508.9 [1 ,2,4]oxadiazol-5-yl]-amino}-methyl)-phenyl]-pyridin-4- LC-MS 4

yl-amine

[4-(Ethyl-pyridin-4-yl-amino)-benzyl]-(S)-piperidin-3-yl- 0.69 533.3

[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine LC-MS 4

[4-(Methyl-pyridin-3-yl-amino)-benzyl]-(S)-piperidin-3-yl- 0.68 518.9

[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine LC-MS 4

{4-[Methyl-(2-methyl-pyridin-4-yl)-amino]-benzyl}-(S)- 0.68 533.2 piperidin-3-yl-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2- LC-MS 4

yl]-amine

Methyl-[4-({piperidin-4-yl-[5-(4-trifluoromethyl-phenyl)- 0.61 509.4 [1 ,3,4]oxadiazol-2-yl]-amino}-methyl)-phenyl]-pyridin-4- LC-MS 4

yl-amine

Synthesis of [4-(2-Methyl^yridin -ylamino)-benzyl]-(S)^iperidin-3-yl-quinolin -yl-amine To an ice-cooled solution under N ₂ of (S)-tert-butyl 3-((4-((2-methylpyridin-4- yl)amino)benzyl)(quinolin-4-yl)amino)piperidine-1 -carboxylate (886 mg, 1 .69 mmol, 1 eq.) in DCM (10 mL), TFA (1 .3 mL, 16.9 mmol, 10 eq.) was added. The reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between 1 M aq. NaOH and DCM. The layers were separated. The aq. phase was extracted with DCM. The comb. org. phases were washed with water, sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by prep. HPLC (column: Water X-Bridge, 18x50 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo to yield the title compound as a white solid.

LC-MS 4: t _R = 0.42 min; [M+H] ⁺ = 424.4

General method for the synthesis of an amine 4 Method A: A mixture of 4-amino-1 -benzylpiperidine (0.1 1 mL, 0.53 mmol, 1 .0 eq.), 2-chloro- 5-phenyl-pyrimidine (150 mg, 0.79 mmol, 1 .5 eq.), and DIPEA (0.37 mL, 2.10 mmol, 4.0 eq.) in MeCN (2.0 mL) was stirred at 190 °C under microvawe irradiations for 1 hour. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 45 mL/min, 20 fractions of 45 mL, Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 9:1 to Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 3:7) to yield the desired product as a yellow solid.

Listed in Table 23 below are amine 4, prepared according to the above-mentioned method with the corresponding amine 2 and the corresponding compound 3 as starting materials.

Table 23

Method B: To a suspension under N ₂ of 2-methanesulfonyl-4-(4-trifluoromethyl-phenyl)- pyrimidine (907 mg, 3.0 mmol, 1 .0 eq.) in 2-propanol (6.0 mL), 1 -N-Boc-4-aminopiperidine (601 mg, 3.0 mmol, 1 .0 eq.) and triethylamine (0.42 mL, 3.0 mmol, 1 .0 eq.) were added. The suspension was stirred at 90 °C for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. Sat. aq. NaHC0 ₃ soln. was added and the mixture was extracted with AcOEt. The comb. org. phases were washed with sat. aq. NaCI soln., dried over MgS0 ₄ , filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 36 fractions of 45 mL, from Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 8:2 to Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 2:8) to yield the desired product as a yellow foam.

Listed in Table 24 below are amine 4, prepared according to the above-mentioned method with the corresponding amine 2 and the corresponding compound 3 as starting materials.

Table 24

Amine 4 i _R [min] MS-data

LC-MS Method m/z [M+H] ⁺

4-[4-(4-Trifluoromethyl-phenyl)-pyrimidin-2-ylamino]- 1 .05 423.1 piperidine-1 -carboxylic acid tert-butyl ester LC-MS 3

(1 -Benzyl-pipe ridin-4-yl)-(4-methoxy-pyrimidin-2-yl)- 0.88 298.9 amine LC-MS 3

(1 -lsopropyl-piperidin-4-yl)-(4-methoxy-pyrimidin-2-yl)- 0.36 251 .2 amine LC-MS 4

(1 -lsopropyl-piperidin-4-yl)-[4-(4-trifluoromethyl-phenyl)- 0.68 365.2 pyrimidin-2-yl]-amine LC-MS 4

4-(Benzooxazol-2-ylamino)-piperidine-1 -carboxylic acid 0.87 318.2 tert-butyl ester LC-MS 3

4-(Benzothiazol-2-ylamino)-piperidine-1 -carboxylic acid 0.92 334.2 tert-butyl ester LC-MS 3

4-(Quinoxalin-2-ylamino)-piperidine-1 -carboxylic acid 0.90 329.1 tert-butyl ester LC-MS 3

(R)-3-[4-(4-Trifluoromethyl-phenyl)-pyrimidin-2- 0.95 409.2 ylamino]-pyrrolidine-1 -carboxylic acid tert-butyl ester LC-MS 4

(S)-3-[4-(4-Trifluoromethyl-phenyl)-pyrimidin-2-ylamino]- 0.95 409.2 pyrrolidine-1 -carboxylic acid tert-butyl ester LC-MS 4

N,N-Dimethyl-N'-[4-(4-trifluoromethyl-phenyl)-pyrimidin- 0.64 31 1 .1

2-yl]-ethane-1 ,2-diamine LC-MS 4

(+)-N1 ,N1 -Dimethyl-N2-[4-(4-trifluoromethyl-phenyl)- 0.67 325.1 pyrimidin-2-yl]-propane-1 ,2-diamine LC-MS 4

N,N-Dimethyl-N'-[4-(4-trifluoromethyl-phenyl)-pyrimidin- 0.63 325.2

2-yl]-propane-1 ,3-diamine LC-MS 4

(+)-N1 ,N1 -Dimethyl-N3-[4-(4-trifluoromethyl-phenyl)- 0.65 339.1 pyrimidin-2-yl]-butane-1 ,3-diamine LC-MS 4 (4-Benzyloxy-pyrimidin-2-yl)-(1 -isopropyl-piperidin-4-yl)- 0.53 327.3 amine LC-MS 4

(S)-3-[4-(4-Trifluoromethyl^henyl)^yrimidin-2-ylamino]- 0.96 423.1 piperidine-1 -carboxylic acid tert-butyl ester LC-MS 4

(3aR,6aS)-tert-butyl 5-((4-(4- 0.95 449.1 (trifluoromethyl)phenyl)pyrimidin-2- LC-MS 4

yl)amino)hexahydrocyclopenta[c]pyrrole-2(1 H)- carboxylate (mixture of stereoisomers)

(4,6-Dimethyl-pyrimidin-2-yl)-(1 -isopropyl-piperidin-4- 0.39 249.3 yl)-amine LC-MS 4

(1 -lsopropyl-piperidin-4-yl)-pyrimidin-2-yl-amine 0.37 221 .4

LC-MS 4

(1 -lsopropyl-piperidin-4-yl)-[5-(4-trifluoromethyl-phenyl)- 0.69 365.1 pyrimidin-2-yl]-amine LC-MS 4

(1 -lsopropyl-piperidin-4-yl)-[6-(4-trifluoromethyl-phenyl)- 0.55 365.4 pyrimidin-4-yl]-amine LC-MS 4

(S)-3-(4-Benzyloxy-pyrimidin-2-ylamino)-piperidine-1 - 0.76 385.0 carboxylic acid tert-butyl ester LC-MS 4

((S)-1 -lsopropyl-piperidin-3-yl)-[4-(4-trifluoromethyl- 0.71 365.2 phenyl)-pyrimidin-2-yl]-amine LC-MS 4

[3-(4-Methyl-piperazin-1 -yl)-propyl]-[4-(4-trifluoromethyl- 0.58 380.3 phenyl)-pyrimidin-2-yl]-amine LC-MS 4

Benzooxazol-2-yl-(1 -isopropyl-piperidin-4-yl)-amine 0.51 260.4

LC-MS 4

Method C: A solution of 4-amino-1 -isopropylpiperidine (0.16 mL, 1 .00 mmol, 1 .00 eq.), sodium tert-butoxide (120 mg, 1 .25 mmol, 1 .25 eq.) and 4-bromoquinoline (208 mg, 1 .00 mmol, 1 .00 eq.) in dioxane (4 mL) was degased with N ₂ for 15 min before the addition of X- Phos (48 mg, 0.10 mmol, 0.10 eq.) and tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol, 0.05 eq.). The reaction mixture was degased again with N ₂ for 15 min and then stirred at 105 °C for 18 hours. The reaction was allowed to cool down to r.t. and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 10 g, flow: 15 mL/min, 40 fractions of 20 mL, from Hept/AcOEt + 10% Et ₃ N 6:4 to Hept/AcOEt + 10% Et ₃ N 3:7) to afford the desired product as a yellow solid. Listed in Table 25 below are amine 4, prepared according to the above-mentioned method with the corresponding amine 2 and the corresponding compound 3 as starting materials.

Table 25

Synthesis of (1-lsopropyl^iperidin-4-yl)-[6-(4-trifluorom

A solution of 4-amino-1 -isopropylpiperidine (142 mg, 1 .00 mmol, 1 .00 eq.), sodium tert- butoxide (120 mg, 1 .25 mmol, 1 .25 eq.) and 2-chloro-6-(4-trifluoromethyl-phenyl)-pyrazine (259 mg, 1 .00 mmol, 1 .00 eq.) in dioxane (4 mL) was degased with N ₂ for 15 min before the addition of BrettPhos (54 mg, 0.10 mmol, 0.10 eq.) and tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol, 0.05 eq.). The reaction mixture was degased again with N ₂ for 15 min and then stirred at 105 °C for 18 hours. The reaction was allowed to cool down to r.t. and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 10 g, flow: 15 mL/min, 40 fractions of 20 mL, from Hept/AcOEt + Et ₃ N 6:4 to Hept/AcOEt + Et ₃ N 10% 3:7 to afford the title compound as an orange oil.

LC-MS 4: t _R = 0.71 min; [M+H] ⁺ = 365.3

Synthesis of (1-Benzyl^iperidin -yl)-[4-(4-trifluoromethyl^henyl)-thiazol-2-yl]-amine Step 1 : A solution of 4-amino-1 -benzylpiperidine (0.32 mL, 1 .58 mmol, 1 .0 eq.) and 1 ,1 '- thiocarbonyldiimidazol (355 mg, 1 .89 mmol, 1 .2 eq.) in DCM (16 mL) was stirred at r.t. for 2 hours. 2M ammonia in EtOH (3.3 mL) was added and the mixture was stirred at r.t. for 48 hours. 2M ammonia in EtOH (3.3 mL) was added and the mixture was stirred at 40 °C for 18 hours. The mixture was concentrated in vacuo to yield 1 -(1 -benzylpiperidin-4-yl)thiourea as an orange oil. The product was used crude with no further purification.

LC-MS 3: t _R = 0.71 min; [M+H] ⁺ = 250.2

Step 2: A mixture of 1 -(1 -benzylpiperidin-4-yl)thiourea (860 mg, 1 .72 mmol, 1 .00 eq.) and 2- bromo-4'-(trifluoromethyl)acetophenone (498 mg, 1 .81 mmol, 1 .05 eq.) in ethanol (50 mL) was heated at 100 °C for 1 hour. The reaction mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 45 mL/min, 20 fractions of 45 mL, Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 9:1 to Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 4:6) to yield the title compound as an off-white powder.

LC-MS 3: t _R = 1 .09 min; [M+H] ⁺ = 418.0

Synthesis of [4-(4-Fluoro-phenyl)-pyrimidin-2-yl]-( 1-isopropyl-piperidin-4-yl)-amine

Step 1 : To a solution 4-amino-1 -isopropylpiperidine (1 .42 g, 10 mmol, 1 .0 eq.) and N,N'-bis- Boc-1 -guanylpyrazol (3.10 g, 10 mmol, 1 .0 eq.) in MeCN (50 mL), triethylamine (4.18 mL, 30 mmol, 3.0 eq.) and DMAP (122 mg, 1 mmol, 0.1 eq.) were added in sequence. The mixture was stirred at 40 °C for 72 hours. The mixture was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 50 fractions of 45 mL, from Heptane to Hept/AcOEt-NEt ₃ (10% NEt ₃ ) 75:25) to yield carbamic acid [[1 -isopropyl- piperidin-4-amino][[(1 ,1 -dimethylethoxy)carbonyl]amino]methylene]-, 1 ,1 -dimethylethyl ester (9CI) as a white solid.

LC-MS 3: t _R = 1 .08 min; [M+H] ⁺ = 385.2 Step 2: To an ice-cooled solution of carbamic acid [[1 -isopropyl-piperidin-4-amino][[(1 ,1 - dimethylethoxy)carbonyl]amino]methylene]-, 1 ,1 -dimethylethyl ester (9CI) (1 .50 g, 3.9 mmol, 1 .3 eq.) in DCM (50 mL), 4M HCI in dioxane (7.5 mL, 30 mmol, 10.0 eq.) was added. The reaction mixture was stirred at r.t. for 5 hours. 4M HCI in dioxane (7.5 mL, 30 mmol, 10.0 eq.) was added and the mixture was stirred at r.t. for 72 hours. The reaction mixture was concentrated in vacuo. The resulting white solid was suspended in DBU (9 mL, 60 mmol, 20.0 eq.). 3-(Dimethylamino)-1 -(4-fluorophenyl)-2-propen-1 -one (580 mg, 3 mmol, 1 .0 eq.) was added and the mixture was stirred at 120 °C for 2 hours. The mixture was allowed to cool to r.t. and partitioned between AcOEt (100 mL) and water (100 mL). The layers were separated. The org. phase was washed with sat. aq. NaCI soln. (50 mL), dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters XBridge, 75x30 mm, 10 μηι, UV/MS, acidic conditions) to give the title compound as a pale yellow solid.

LC-MS 4: t _R = 0.57 min; [M+H] ⁺ = 315.2 Synthesis of 4-[3-(4-Trifluoromethyl^henyl)-[1,2,4]oxadiazol-5-ylamino]-p iperidine-1- carboxylic acid tert-butyl ester

Step 1 : To a solution of 4-(trifluoromethyl)benzamidoxime (1 .00 g, 4.9 mmol, 1 eq.) in toluene (17 ml_), trichloroacetic anhydride (0.9 ml_, 4.9 mmol, 1 eq.) was added. The solution was heated at 120 °C for 2.5 hours. The reaction was cooled down to r.t. and poured into water. The aq. layer was extracted with AcOEt. The comb. org. phases were washed with sat. aq. NaHC0 ₃ soln. and dried over MgS0 ₄ to yield 5-trichloromethyl-3-(4- trifluoromethyl-phenyl)-[1 ,2,4]oxadiazole as a yellow solid. The product was used without further purification.

LC-MS 3: t _R = 1 .09 min; [M+H] ⁺ = no ionization

Step 2: 5-Trichloromethyl-3-(4-trifluoromethyl-phenyl)-[1 ,2,4]oxadiazole (1 .46 g, 4.40 mmol, 1 .0 eq.), 1 -N-Boc-4-aminopiperidine (990 mg, 4.84 mmol, 1 .1 eq.), and NaHC0 ₃ (740 mg, 8.81 mmol, 2.0 eq.) in 1 -methyl-2-pyrrolidone (14.7 ml_) was heated at 120 °C under microwave irradiation for 20 min. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between sat. aq. NaCI soln. and Et ₂ 0. The layers were separated and the aq. phase was extracted with Et ₂ 0. The comb. org. phases were dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by CC (Si0 ₂ , Hept to Hept/AcOEt 1 :1) to give the title compound as a yellow powder.

LC-MS 4: t _R = 1 .30 min; [M+H] ⁺ = 413.0

Synthesis of 4-[5-(4-Trifluoromethyl^henyl)-[1,3,4]oxadiazol-2-ylamino]-p iperidine-1- carboxylic acid tert-butyl ester

Step 1 : To a solution of 4-(trifluoromethyl)benzhydrazide (1 .00 g, 4.9 mmol, 1 .0 eq.) in EtOH (17 mL), carbon disulfide (0.33 mL, 5.4 mmol, 1 .1 eq.) and a solution of KOH (275 mg, 4.9 mmol, 1 .0 eq.) in water (2.5 mL) were added in sequence. The reaction mixture was refluxed for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in excess water and acidified with 2M aq. HCI to pH 2-3. The resulting suspension was filtered. The solid was dissolved in AcOEt and the solution was dried over MgS0 ₄ and evaporated in vacuo to give 5-(4-trifluoromethyl-phenyl)-[1 ,3,4]oxadiazole-2- thiol as a white solid. The product was used without further purification.

LC-MS 4: t _R = 1 .18 min; [M+H] ⁺ = no ionization Step 2: To a mixture of 5-(4-trifluoromethyl-phenyl)-[1 ,3,4]oxadiazole-2-thiol (921 mg, 3.74 mmol, 1 eq.) and NEt ₃ (1 .0 ml_, 7.1 1 mmol, 1 .9 eq.) in EtOH (10 ml_), benzyl bromide (0.45 ml_, 3.74 mmol, 1 .0 eq.) was added. The mixture was stirred at r.t. for 2 hours. The resulting suspension was filtered and the solids were washed with EtOH and dried in vacuo to yield 2-benzylsulfanyl-5-(4-trifluoromethyl-phenyl)-[1 ,3,4]oxadiazole as a white solid.

LC-MS 4: t _R = 1 .00 min; [M+H] ⁺ = 337.0

Step 3: To an ice-cooled solution of 2-benzylsulfanyl-5-(4-trifluoromethyl-phenyl)- [1 ,3,4]oxadiazole (150 mg, 0.45 mmol, 1 .0 eq.) in DCM (5 ml_), 3-chloroperbenzoic acid (543 mg, 0.98 mmol, 2.2 eq.) was added portionwise. The reaction mixture was warmed up to r.t. and stirred at r.t. for 18 hours. 3-Chloroperbenzoic acid (247 mg, 0.45 mmol, 1 .0 eq.) was added and the mixture was stirred at r.t. for 6 hours. DCM (5 ml_) and 3- chloroperbenzoic acid (247 mg, 0.45 mmol, 1 .0 eq.) were added and the mixture was stirred at r.t. for 18 hours. The suspension was filtered and the solids washed with DCM. The filtrate was washed with a sat. aq. NaHC0 ₃ soln., dried over MgS0 ₄ , and concentrated in vacuo to give 2-phenylmethanesulfonyl-5-(4-trifluoromethyl-phenyl)-[1 ,3,4]oxadiazole as a white solid. The product was used without further purification.

LC-MS 4: t _R = 0.95 min; [M+H] ⁺ = no ionization

Step 4: 2-Phenylmethanesulfonyl-5-(4-trifluoromethyl-phenyl)-[1 ,3,4]oxadiazole (721 mg, 1 .57 mmol, 1 eq.) and 1 -N-Boc-4-aminopiperidine (320 mg, 1 .57 mmol, 1 eq.) were dissolved in dioxane (5 ml_) and the mixture was heated at 100 °C under microwave irradiations for 35 min. 1 -N-Boc-4-aminopiperidine (320 mg, 1 .57 mmol, 1 eq.) was added and the mixture was heated at 150 °C under microwave irradiations for 15 min. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was purified by CC (Si0 ₂ , Hept/AcOEt 8:2 to Hept/AcOEt 4:6) to yield the title compound as a pale yellow powder.

LC-MS 4: t _R = 0.94 min; [M+H] ⁺ = 413.0

Synthesis of 2-Methanesulfonyl -(4-trifluoromethyl^henyl)^yrimidine

Step 1 : A mixture under N ₂ of 4-(trifluoromethyl)phenylboronic acid (3.80 g, 20 mmol, 1 .00 eq.), 4-chloro-2-methylthiopyrimidine (2.4 mL, 20 mmol, 1 .00 eq.), sodium carbonate (8.48 g, 80 mmol, 4.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (1 .16 g, 1 mmol, 0.05 eq.) in toluene/EtOH/water 20:4:1 (75 mL) was stirred at 100 °C for 18 hours. The mixture was allowed to cool to r.t. and partitioned between AcOEt and water. The layers were separated. The org. phase was washed with sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 45 fractions of 45 mL, Hept to Hept/AcOEt 8:2) to yield 2-methylsulfanyl-4-(4- trifluoromethyl-phenyl)-pyrimidine as a white solid.

LC-MS 4: t _R = 0.97 min; [M+H] ⁺ = 271 .3

Step 2: To an ice-cooled solution of 2-methylsulfanyl-4-(4-trifluoromethyl-phenyl)-pyrimidine (3.35 g, 12.4 mmol, 1 .0 eq.) in DCM (85 mL), 70-75% mCPBA (6.54 g, 27.3 mmol, 2.2 eq.) was added portionwise. The reaction mixture was warmed up to r.t. and stirred for 3.5 hours. The resulting suspension was filtered and the solids rinsed with DCM. The filtrate was washed with sat. aq. NaHC0 ₃ soln. and with sat. aq. NaCI soln. The org. phase was dried over MgS0 ₄ and concentrated in vacuo to give the title compound as a white solid. The product was used without further purification.

LC-MS 4: t _R = 0.82 min; [M+H] ⁺ = 303.2

Synthesis of 2-Methanesulfonyl-4-( 6-trifluoromethyl-pyridin-3-yl)-pyrimidine

Step 1 : A mixture under N ₂ of 2-trifluoromethylpyridine-5-boronic acid (2.86 g, 15 mmol, 1 .00 eq.), 4-chloro-2-(methylthio)pyrimidine (1 .76 mL, 15 mmol, 1 .00 eq.), sodium carbonate (6.36 g, 60 mmol, 4.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (867 mg, 0.75 mmol, 0.05 eq.) in toluene/EtOH/Water 20:4:1 (50 mL) was stirred at 100 °C for 18 hours. The mixture was allowed to cool to r.t. and partitioned between AcOEt and water. The layers were separated. The org. phase was washed with sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 45 fractions of 45 mL, Hept to Hept/AcOEt 7:3) to yield 2- methylsulfanyl-4-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine as a white solid.

LC-MS 4: t _R = 0.88 min; [M+H] ⁺ = 272.1

Step 2: To an ice-cooled solution of 2-methylsulfanyl-4-(6-trifluoromethyl-pyridin-3-yl)- pyrimidine (2.99 g, 1 1 mmol, 1 eq.) in THF/MeOH 1 :1 (120 mL), a solution of Oxone (27.1 g, 44 mmol, 4 eq.) in water (80 mL) was added. After 30 min a sat. NaHC0 ₃ soln. was added and the mixture was extracted with AcOEt. The layers were separated and the org. phase was washed with sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo to give the title compound as a pale yellow solid. The residue was used without further purification.

LC-MS 4: t _R = 0.72 min; [M+H] ⁺ = 304.2 Synthesis of 4-Benzyloxy-2-methanesulfonyl-pyrimidine

Step 1 : Benzylalcohol (3 mL, 29.0 mmol, 1 .0 eq.) was added dropwise to a suspension of sodium hydride 60% dispersion in mineral oil (1 .74 g, 43.4 mmol, 1 .5 eq.) in dioxane (30 mL), and the mixture was stirred at 100 °C for 30 min. The mixture was allowed to cool to 50 °C. A solution of 4-chloro-2-(methylthio)pyrimidine (3.4 mL, 29.0 mmol, 1 .0 eq.) in dry dioxane (20 mL) was added dropwise and the mixture was stirred at 50 °C for 4.5 hours. The mixture was cooled to r.t. and acidified with glacial acetic acid, diluted with water, and extracted with DCM. The comb. org. phases were dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 35 fractions of 40 mL, from Hept/AcOEt 85:15 to Hept/AcOEt 6:4) to afford 4-benzyloxy-2- methylsulfanyl-pyrimidine as a colorless oil.

LC-MS 4: t _R = 0.89 min; [M+H] ⁺ = 233.3

Step 2: To a solution of 4-benzyloxy-2-methylsulfanyl-pyrimidine (3.90 g, 16.8 mmol, 1 eq.) in THF/MeOH 1 :1 (150 mL), a solution of Oxone (41 .28 g, 67.2 mmol, 4 eq.) in water (100 mL) was added. The mixture was stirred at r.t. for 45 min. Sat. NaHC0 ₃ soln. was added and the mixture was extracted with AcOEt. The org. phase was washed with sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 45 fractions of 45 mL, from Hept/AcOEt 9:1 to Hept/AcOEt 6:4) to afford the title compound as a white solid.

LC-MS 4: t _R = 0.77 min; [M+H] ⁺ = 265.3

Synthesis of 2-Chloro-6-(4-trifluoromethyl-phenyl)-pyrazine

To a mixture under N ₂ of 2,6-dichloropyrazine (1 .51 g, 10.0 mmol, 1 .00 eq.), sodium carbonate (2.76 g, 26.0 mmol, 2.60 eq.), and 4-(trifluoromethyl)phenylboronic acid (1 .90 g, 10.0 mmol, 1 .00 eq.) in dimethoxyethane (45 mL) and water (22.5 mL), tetrakis(triphenylphosphine) palladium (0) (231 mg, 0.2 mmol, 0.02 eq.) was added. The reaction mixture was heated at reflux for 2 days. After cooling to r.t., the reaction was diluted with water (50 mL) and extracted with DCM (2 x 75 mL). The comb. org. phases were dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 45 fractions of 45 mL, Hept to Hept/AcOEt 8:2) to yield the title compound as a pale yellow solid.

LC-MS 4: t _R = 0.95 min; [M+H] ⁺ = 259.2 Synthesis of 4-Chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine A mixture under N ₂ of 4,6-dichloropyrimidine (447 mg, 3.00 mmol, 1 .00 eq.), 4- (trifluoromethyl)phenylboronic acid (188 mg, 0.99 mmol, 0.33 eq.), Na ₂ C0 ₃ (1 .59 g, 15.00 mmol, 5.00 eq.) and tetrakis(triphenylphosphine)palladium (0) (173 mg, 0.15 mmol, 0.05 eq.) in acetonitrile (5 mL) was stirred at 80 °C for 24 hours and further at 100 °C for 18 hours. The reaction mixture was allowed to cool down to r.t. and concentrated in vacuo. The residue was partitioned between DCM and sat. aq. NaHC0 ₃ soln. The layers were separated. The aq. phase was extracted with DCM. The comb. org. phases were washed with sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 18x50 mm, 10 μηι, UV/MS, basic conditions) and concentrated in vacuo to afford the title compound as a white solid.

LC-MS 4: t _R = 0.94 min; [M+H] ⁺ = 259.3

Synthesis of 2-Chloro-6-(4-trifluoromethyl-phenyl)-pyridine

To a mixture under N ₂ of 2,6-dichloropyridine (740 mg, 5.00 mmol, 1 .00 eq.) and tetrakis(triphenylphosphine) palladium (0) (289 mg, 0.25 mmol, 0.05 eq.) in toluene/EtOH/H ₂ 0 (7:2:1) (4 mL), 4-(trifluoromethyl)phenylboronic acid (1 .04 g, 5.50 mmol, 1 .10 eq.) and sodium carbonate (2.12 g, 20.00 mmol, 4.00 eq.) were added. The mixture was stirred at 100 °C for 18 hours. After cooling to r.t., the reaction was partitioned between AcOEt and sat. aq. NaCI soln. The comb. org. layers were dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by FC (Si0 ₂ , eluent: Hept/AcOEt 99:1 to Hept/AcOEt 95:5) to give the title compound as a white solid.

LC-MS 2: t _R = 0.98 min; [M+H] ⁺ = 258.0

Synthesis of 2-Chloro-5-(4-trifluoromethyl-phenyl)-pyrimidine

To a mixture of 5-bromo-2-chloropyrimidine (967 mg, 5 mmol, 1 .00 eq.), 4- (trifluoromethyl)phenylboronic acid (997 mg, 5.25 mmol, 1 .05 eq.), and sodium carbonate (2.12 g, 20 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (25 mL), tetrakis(triphenylphosphine) palladium (0) (289 mg, 0.25 mmol, 0.05 eq.) was added. The resulting mixture was stirred at 100 °C for 19 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (40 mL) and water (20 mL). The layers were separated. The org. phase was washed with sat. aq. NaCI soln. (1 x 20 mL), dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Hept to Hept + 16% AcOEt) to yield the title compound as a white solid.

LC-MS 2: t _R = 0.83 min; [M+H] ⁺ = 259.2 Synthesis of 2-Bromo-4-(4-trifluoromethyl-phenyl)-pyridine

A mixture under N ₂ of 4-(trifluoromethyl)phenylboronic acid (950 mg, 5.00 mmol, 1 .00 eq.), 2-bromo-4-iodopyridine (1 .42 g, 5.00 mmol, 1 .00 eq.), sodium carbonate (2.12 g, 20.00 mmol, 4.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (289 mg, 0.25 mmol, 0.05 eq.) in toluene/EtOH/water 20:4:1 (17 mL) was stirred at 100 °C for 17 hours. The mixture was allowed to cool to r.t. and partitioned between AcOEt and water. The layers were separated. The org. phase was washed with sat. aq. NaCI soln., dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 45 fractions of 45 mL, Hept/AcOEt 95:5 to Hept/AcOEt 8:2) to afford the title compound as an white solid.

LC-MS 4: t _R = 0.96 min; [M+H] ⁺ = 302.1

Synthesis of 4-Chloro-2-(4-trifluoromethyl-phenyl)-pyridine

To a mixture of 2-bromo-4-chloro-pyridine (385 mg, 2 mmol, 1 .00 eq.), 4- (trifluoromethyl)phenylboronic acid (380 mg, 2 mmol, 1 .00 eq.) and sodium carbonate (848 mg, 8 mmol, 4.00 eq.) in toluene/MeOH/water 25:5:1 .5 (32 mL), tetrakis(triphenylphosphine) palladium (0) (1 16 mg, 0.1 mmol, 0.05 eq.) was added and the mixture was stirred at 100 °C for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and water (50 mL). The layers were separated. The org. phase was washed with sat. aq. NaCI soln. (1 x 25 mL), dried over MgS0 ₄ , and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 30 fractions of 45 mL, from Hept/AcOEt 9:1 to Hept/AcOEt 7:3) to yield the title compound as a viscous oil.

LC-MS 4: t _R = 0.96 min; [M+H] ⁺ = 257.9

In vitro antimalarial activity: Plasmodium falciparum in vitro assay:

In vitro activity against erythrocytic stages of P. Falciparum in human red blood cells is determined using a [ ³ H]-hypoxanthine incorporation assay. One strain sensitive to all drugs (P. Falciparum NF54) is used in this assay and all tested compounds are compared for activity with the standard drugs chloroquine (sigma C6628) and artesunate (sigma 36, 159- 3). Compounds, tested in duplicates, are serially diluted with screening medium [RPMI1640 medium, supplemented with HEPES (5.94 g/L), NaHC0 ₃ (2.1 g/L), neomycin (100 U/mL) and human serum (50% final concentration)] in 96-well microtiter plates within an appropriate concentration range. Thereafter, the parasite cultures incubated in screening medium containing washed human red blood cells at 2.5% hematocrit (0.3% parasitemia) are added to the serially diluted compounds and incubated in a humidifying atmosphere at 37°C, 4% C0 ₂ , 3% 0 ₂ and 93% N ₂ . After 48 hours, [ ³ H]-hypoxanthine (0.5 μθί) is added to each well of a plate. The plates are incubated for a further 24 hours under the same conditions then harvested with a Betaplate cell harvester (Wallac) and washed with distilled water. The dried filters are inserted into a plastic foil with 10 mL of scintillation fluid and counted in a Betaplate liquid scintillation counter. IC ₅₀ values are calculated from sigmoidal inhibition curves using Microsoft Excel.

Table 26: IC ₅₀ values (nM) for compounds of Formula I:

Compound Compound Compound

IC ₅₀ [nM] IC ₅₀ [nM] IC ₅₀ [nM] of Example of Example of Example

1 10 63 18 125 10

2 17 64 31 126 3.4

3 189 65 38 127 5.7

4 58 66 15 128 3.3

5 120 67 18 129 10

6 19 68 9.4 130 9.9

7 3.3 69 51 131 8.8

8 6.6 70 1 19 132 44

9 23 71 38 133 38

10 2.9 72 27 134 34

1 1 43 73 35 135 66

12 32 74 21 136 19

13 0.5 75 21 137 42

14 30 76 13 138 55

15 6.1 77 15 139 95

16 2.0 78 217 140 187

17 1 1 79 358 141 170

18 28 80 21 142 370

19 57 81 20 143 101

20 15 82 20 144 179

21 26 83 164 145 44

22 21 84 20 146 307

23 <7.8 85 17 147 36

24 277 86 19 148 53 76 87 43 149 38

17 88 45 150 10

<7.8 89 41 151 39

86 90 21 152 38

49 91 22 153 8.6

41 92 17 154 21

270 93 50 155 71

153 94 17 156 22

71 95 31 157 493

69 96 18 158 23

40 97 20 159 23

14 98 46 160 13

13 99 33 161 85

<7.8 100 27 162 335

82 101 22 163 23

39 102 15 164 13

66 103 328 165 41

126 104 22 166 22

<7.8 105 12 167 16

19 106 286 168 47

20 107 88 169 148

4.8 108 430 170 9.5

20 109 23 171 42

20 110 71 172 94

3.6 111 13 173 <7.8

3.7 112 30 174 <7.8

3.3 113 10 175 <7.8

13 114 3.2 176 <7.8

17 115 160 177 <7.8

20 116 4.6 178 <7.8

20 117 13 179 <7.8

6.5 118 6.3 180 76

6.8 119 46 181 42

20 120 3.6 182 <7.8

5.8 121 3.9 183 103 60 6.7 122 23 184 246

61 39 123 16 185 331

62 42 124 19 186 195

Chloroquine 6.8 Artesunate 0.8