IP Library › Granted Patent US 10,640,516

Granted Patent B2

US 10,640,516 · App. 15/525,779 · Granted May 5, 2020

Difluoromethyl-aminopyridines and difluoromethyl-aminopyrimidines

Inventors: Vladimir Cmiljanovic (Basel, CH); Paul Hebeisen (Basel, CH); Florent Beaufils (Bartenheim, FR); Thomas Bohnacker (Basel, CH); Denise Rageot (Saint-Louis, FR); Alexander Sele (Basel, CH); Matthias Wymann (Bern, CH); Jean-Baptiste Langlois (Sierentz, FR)

Assignees: PIQUR THERAPEUTICS AG; UNIVERSITÄT BASEL

C07D498/08 A61K31/53 A61P35/00 C07D239/48 C07D401/04 C07D401/14 C07D403/04 C07D405/14 C07D413/14 C07D417/14 C07D491/048 C07D491/056 C07D491/107 C07D491/18 C07D491/20 C07D519/00

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Quick Facts

Patent No.: US 10,640,516
App. No.: 15/525,779
Granted: May 5, 2020
Kind: B2

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Abstract

The invention relates to novel phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR) and PI3k-related kinase (PIKKs) inhibitor compounds of formula (I), wherein X 1 , X 2 and X 3 are N or CH, with the proviso that at least two of X 1 , X 2 and X 3 are N; Y is N or CH, These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

Claims (162)

1. A compound of formula (I),

wherein

X 1 , X 2 and X 3 are N;

Y is N or CH;

R 1 and R 2 are independently of each other

(i) a morpholinyl of formula (II)

wherein the arrow denotes the bond in formula (I); and

wherein R 3 and R 4 are independently of each other H, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, CN, or C(O)O—C 1 -C 2 alkyl; or

R 3 and R 4 form together a bivalent residue selected from C 1 -C 3 alkylene optionally substituted with 1 to 4 F, —CH 2 —O—CH 2 —, —CH 2 —NH—CH 2 —, or any of the structures

wherein the arrows denote the bonds in formula (II);

(ii) phenyl optionally substituted with 1 to 3 R 7 , wherein R 7 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 ) 2 ;

(iii) a 5- to 6-membered heteroaryl ring W containing one to four heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 8 , wherein R 8 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 ) 2 ;

(iv) a saturated 4- to 6-membered heterocyclic ring Z containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 9 ; wherein R 9 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, ═O, —NH 2 , NHCH 3 or N(CH 3 ) 2 ; or two R 9 substituents form together a bivalent residue —R 10 R 11 selected from C 1 -C 3 alkylene optionally substituted with 1 to 4 F, —CH 2 —O—CH 2 — or —O—CH 2 CH 2 —O—;

(v) OR 12 , wherein R 12 is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 2 alkyleneC 3 -C 6 cycloalkyl; Cycle-P or C 1 -C 2 alkyleneCycle-P, wherein Cycle-P represents a saturated 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 13 , wherein R 13 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 ); Cycle-Q or C 1 -C 2 alkyleneCycle-Q, wherein Cycle-Q represents 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 14 , wherein R 14 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 ); or

(vi) NR 15 R 16 ; wherein R 15 and R 16 are independently of each other H, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl; Cycle-P or C 1 -C 2 alkyleneCycle-P, wherein Cycle-P represents a saturated 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 13 , wherein R 13 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 ); Cycle-Q or C 1 -C 2 alkyleneCycle-Q, wherein Cycle-Q represents 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from N, O and S, optionally substituted by 1 to 3 R 14 , wherein R 14 is independently at each occurrence halogen, —OH, C 1 -C 3 alkyl optionally substituted with one or two OH, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, —NH 2 , NHCH 3 or N(CH 3 );

with the proviso that at least one of R 1 and R 2 is a morpholinyl of formula II;

or a tautomer, solvate, or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1 , wherein said R 1 and said R 2 are independently of each other (i) a morpholinyl of formula (II); (ii) said 5- to 6-membered heteroaryl ring W; (iii) said saturated 4- to 6-membered heterocyclic ring Z; (iv) said OR 12 ; or (v) said NR 15 R 16 .

3. The compound of formula (I) according to claim 1 , wherein said R 1 and said R 2 are independently of each other selected from

4. The compound of formula (I) according to claim 1 , wherein R 1 and R 2 are independently of each other selected from

5. The compound of formula (I) according to claim 1 , wherein R 1 and R 2 are independently of each other selected from

6. The compound of formula (I) according to claim 1 , wherein said compound is selected from

4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;

4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;

5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;

5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;

(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;

(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;

4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;

4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;

(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine;

(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;

4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyridin-2-amine;

4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;

5-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;

5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;

4-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]morpholin-3-one;

5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine;

5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

(4S,5R)-3-[4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(hydroxymethyl)-5-methyl-oxazolidin-2-one;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

5-[4,6-bis[(3R)-3-ethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

5-[4,6-bis(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

5-[4,6-bis[(3R)-3-isopropylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-methyl-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine;

4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-N-(2,2,2-trifluoroethyl)-1,3,5-triazin-2-amine;

4-[6-amino-4-(difluoromethyl)-3-pyridyl]-N-(cyclopropylmethyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]pyridin-2-amine;

5-[4-(2,2-difluoroethoxy)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

5-[4-[(3aR,6aS)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

5-[4-[(4aS,7aR)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

4-(difluoromethyl)-5-[4-(4,4-difluoro-1-piperidyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

[(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]morpholin-3-yl]methanol;

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

5-[4-(4-cyclopropylpiperazin-1-yl)-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

[(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]morpholin-3-yl]methanol;

4-(difluoromethyl)-5-[4-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-morpholino-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

5-[4,6-bis(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

5-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(4-morpholino-1-piperidyl)-1,3,5-triazin-2-yl]pyridin-2-amine;

5-[4-(4-cyclopropylpiperazin-1-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

5-[4-(4-cyclopropylpiperazin-1-yl)-6-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

4-(difluoromethyl)-5-[4-[4-(2-methoxyethyl)piperazin-1-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-(4-morpholino-1-piperidyl)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-(1,1-dioxo-1,4-thiazinan-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-tetrahydropyran-4-yloxy-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3S)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3S,5R)-3,5-dimethylmorpholin-4-yl]-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

3-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]oxazolidin-2-one;

5-(4-((1R,2R,4S,5S)-7-oxa-9-azatricyclo[3.3.1.0 2,4 ]nonan-9-yl)-6-((2R,4S)-7-oxa-9-azatricyclo[3.3.1.0 2,4 ]nonan-9-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;

5-[4,6-bis(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

5-[4,6-bis(6,7-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

5-[4-(6-amino-3-pyridyl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine;

4-(difluoromethyl)-5-[4-[4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-pyridyl)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-pyrazin-2-yl-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-pyrazol-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-pyrazol-4-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1,2,4-triazol-1-yl)-1,3,5-triazin-2-yl]pyridin-2-amine;

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(1H-1,2,4-triazol-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; and

4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2H-tetrazol-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine.

7. The compound of formula (I) according to claim 1 , wherein said compound is selected from the group consisting of

4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;

5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine;

(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;

4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine;

4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine; and

(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;

or a tautomer, solvate, or a pharmaceutically acceptable salt thereof.

8. The compound of formula (I) according to claim 1 , wherein said compound is selected from,

4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine;

5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; and

(S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine;

or a tautomer, solvate, or a pharmaceutically acceptable salt thereof.

9. The compound of formula (I) according to claim 1 , wherein said compound is selected from