DIFLUOROMETHYL-AMINOPYRIDINES AND DIFLUOROMETHYL-AMINOPYRIMIDINES
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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 X1, X2 and X3 are N or CH, with the proviso that at least two of X1, X2 and X3 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.
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27 Claims
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1. A compound of formula (I),
- View Dependent Claims (2, 3, 4, 6, 7, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 26, 27)
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2. The compound of formula (I) according to claim 1, wherein X1, X2 and X3 are N;
- and tautomers, solvates and pharmaceutically acceptable salts thereof
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3. The compound of formula (I) according to claim 1, wherein said R1 and said R2 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 OR12;
or (v) said NR15R16.
- (ii) said 5- to 6-membered heteroaryl ring W;
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4. The compound of formula (I) according to claim 1, wherein said R1 and said R2 are independently of each other selected from
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6. The compound of formula (I) according to claim 1, wherein R1 and R2 are independently of each other selected from
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7. The compound of formula (I) according to claim 1, wherein R1 and R2 are independently of each other selected from
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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)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-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine; 4′
-(difluoromethyl)-2,6-dimorpholino-[4,5′
-bipyrimidin]-2′
-amine;4-(difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine; 4′
-(difluoromethyl)-4,6-dimorpholino-[2,5′
-bipyrimidin]-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-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine; 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4′
-(difluoromethyl)-6-morpholino-[4,5′
-bipyrimidin]-2′
-amine;5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine; 4′
-(difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5′
-bipyrimidin]-2′
-amine;(S)-4-(difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine; (S)-4′
-(difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5′
-bipyrimidin]-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; (S)-4-(difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine; (S)-4′
-(difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5′
-bipyrimidin]-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; (4S,5R)-3-[6-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-2-morpholino-pyrimidin-4-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[3.3.1.02,4]nonan-9-yl)-6-((2R,4S)-7-oxa-9-azatricyclo[3.3.1.02,4]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; 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(2H-tetrazol-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine.
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11. 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; and tautomers, solvates and pharmaceutically acceptable salts thereof.
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12. 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; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine; and tautomers, solvates and pharmaceutically acceptable salts thereof
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13. The compound of formula (I) according to claim 1, wherein said compound is selected from,
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;
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14. The compound of formula (I) according to claim 1, wherein R1 and R2 are independently of each other a morpholinyl of formula (II).
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15. The compound of formula (I) according to claim 14, wherein R1 is equal to R2.
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16. The compound of formula (I) according to claim 14, wherein le is not equal to R2.
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17. The compound of formula (I) according to claim 1, wherein R1 and R2 are independently of each other a morpholinyl of formula (II) and said 5- to 6-membered heteroaryl ring W.
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18. The compound of formula (I) according to claim 1, wherein R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 4- to 6-membered heterocyclic ring Z.
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19. The compound of formula (I) according to claim 1, wherein R1 and R2 are independently of each other a morpholinyl of formula (II) and said OR12.
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20. The compound of formula (I) according to claim 1, wherein R1 and R2 are independently of each other a morpholinyl of formula (II) and said NR15R16.
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21. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.
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26. A method of preventing or treating a disease or disorder modulated by PI3Ks and/or mTOR and/or PIKKs comprising administering to a mammal in need of such prevention or treatment an effective amount of a compound of formula (I) according to claim 1.
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27. The method according to claim 26, wherein said disease or disorder is a hyperproliferative disorder.
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2. The compound of formula (I) according to claim 1, wherein X1, X2 and X3 are N;
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5. (canceled)
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9. (canceled)
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10. (canceled)
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22-25. -25. (canceled)
Specification
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Current AssigneeTorqur AG, University of Basel
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Original AssigneePIQUR Therapeutics AG, University of Basel
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InventorsCMILJANOVIC, Vladimir, HEBEISEN, Paul, BEAUFILS, Florent, BOHNACKER, Thomas, RAGEOT, Denise, SELE, Alexander, WYMANN, Matthias, LANGLOIS, Jean-Baptiste
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current
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CPC Class CodesA61K 31/53 having six-membered rings w...A61P 35/00 Antineoplastic agentsC07D 239/48 Two nitrogen atomsC07D 401/04 directly linked by a ring-m...C07D 401/14 containing three or more he...C07D 403/04 directly linked by a ring-m...C07D 405/14 containing three or more he...C07D 413/14 containing three or more he...C07D 417/14 containing three or more he...C07D 491/048 the oxygen-containing ring ...C07D 491/056 with two or more oxygen ato...C07D 491/107 with only one oxygen atom a...C07D 491/18 Bridged systemsC07D 491/20 Spiro-condensed systemsC07D 498/08 Bridged systemsC07D 519/00 Heterocyclic compounds cont...