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US 2017/0247388 A1Published application
Inhibitors of irak4 activity
AssigneeMerck Sharp & Dohme Corp.
InventorsMICHAEL D. ALTMAN, JASON D. BRUBAKER, MATTHEW L. CHILDERS, ANTHONY DONOFRIO, THIERRY FISCHMANN, CRAIG R. GIBEAU, SOLOMON D. KATTAR, CHARLES A. LESBURG, JONGWON LIM, JOHN K.F. MACLEAN, UMAR F. MANSOOR, ALAN B. NORTHRUP, JOHN M. SANDERS, GRAHAM F. SMITH
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Abstract
The present invention relates to inhibitors of IRAK4 of Formula I and provides compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.
Claims10
A compound according to Formula I:
- wherein:
- X is NH or O;
- b is 0 or 1;
- n is 0, 1, 2, 3 or 4;
- R1 and R2 are independently H, (C1-C4)alkyl and heterocyclyl, or R1 and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic (fused, bridged or spirocyclic) heterocycle containing 3-8 carbon atoms optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said alkyl and heterocycle are optionally substituted with one or more substituents selected from Ra;
- R3 is (C1-C4)alkyl wherein two adjacent alkyl groups can join together and form a bridged moiety of 3-6 carbon atoms;
- R4 is absent, halo or Ob(C1-C4)alkyl;
- R5 is selected from C1-C4 alkyl and C2-C4 alkenyl which are optionally substituted with one or more substituents selected from Rb;
- R6 is absent, halo, or O(C1-C4)alkyl;
- Ra is halo, oxo, OH, Ob(C1-C4)alkyl, CF3, SO2(C1-C4)alkyl, or heterocyclyl, said heterocyclyl optionally substituted with one or more substituents independently selected from F, and (C1-C4)alkyl;
- and
- Rb is independently selected from OH, halo, Ob(C1-C4)alkyl, and CN;
- or a pharmaceutically acceptable salt or a stereoisomer thereof.
10 more elements
A compound which is selected from:
- (trans)-N1-(6,7-dimethylquinazolin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diamine;
- trans-N,N-dimethyl-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine;
- 6-methyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine;
- N-(trans-4-morpholin-4-ylcyclohexyl)-6-(trifluoromethyl)quinazolin-4-amine;
- 7-fluoro-6-methyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine;
- trans-N,N-dimethyl-N′-[6-(trifluoromethyl)quinazolin-4-yl]cyclohexane-1,4-diamine;
- 4-((trans)-4-((6-methylquinazolin-4-yl)oxy)cyclohexyl)morpholine;
- 6-methyl-N-((1R,4R)-4-(3-(methylsulfonyl)azetidin-1-yl)cyclohexyl)quinazolin-4-amine;
- N-[cis-4-(3-fluoroazetidin-1-yl)cyclohexyl]-6-methylquinazolin-4-amine;
- N-[trans-4-(3-fluoroazetidin-1-yl)cyclohexyl]-6-methylquinazolin-4-amine;
- 4-{cis-4-[(6-methylquinazolin-4-yl)amino]cyclohexyl}piperazin-2-one;
- 4-{trans-4-[(6-methylquinazolin-4-yl)amino]cyclohexyl}piperazin-2-one;
- 1-{trans-4-[(6-methylquinazolin-4-yl)amino]cyclohexyl}azetidin-3-ol;
- 1-{cis-4-[(6-methylquinazolin-4-yl)amino]cyclohexyl}azetidin-3-ol;
- N-[trans-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]-6-methylquinazolin-4-amine;
- 6-methyl-N-[trans-4-(2-oxa-6-azaspiro[3.4]oct-6-yl)cyclohexyl]quinazolin-4-amine;
- 6-methyl-N-{cis-4-[3-(methylsulfonyl)azetidin-1-yl]cyclohexyl}quinazolin-4-amine;
- 6-methyl-N-{4-[4-(trifluoromethyl)piperidin-1-yl]cyclohexyl}quinazolin-4-amine;
- 6-methyl-N-{4-[4-(trifluoromethyl)piperidin-1-yl]cyclohexyl}quinazolin-4-amine;
- 6-methyl-N-{4-[3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}quinazolin-4-amine;
- 6-methyl-N-{4-[2-(trifluoromethyl)piperidin-1-yl]cyclohexyl}quinazolin-4-amine;
- 6-methyl-N-{4-[2-(trifluoromethyl)piperidin-1-yl]cyclohexyl}quinazolin-4-amine;
- 6-methyl-N-{4-[3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}quinazolin-4-amine;
- (trans)-N1-(6-methylquinazolin-4-yl)-N4-(tetrahydro-2H-pyran-4-yl)cyclohexane-1,4-diamine;
- trans-N-(6-methylquinazolin-4-yl)-N′-(tetrahydro-2H-pyran-4-ylmethyl)cyclohexane-1,4-diamine;
- trans-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine;
- trans-N-(6-methylquinazolin-4-yl)-N′-(thiophen-2-ylmethyl)cyclohexane-1,4-diamine;
- trans-N-[(1S)-1-cyclopropylethyl]-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine;
- trans-N-(6-methylquinazolin-4-yl)-N-[(1S)-3,3,3-trifluoro-1-methylpropyl]cyclohexane-1,4-diamine;
- (3 S)-2-methyl-3-({trans-4-[(6-methylquinazolin-4-yl)amino]cyclohexyl}amino)butan-2-ol;
- trans-N-(1-methylethyl)-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine;
- trans-N-(cyclopropylmethyl)-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine;
- trans-N-[(1-methyl-1H-pyrazol-5-yl)methyl]-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine;
- trans-N-[(3-methyloxetan-3-yl)methyl]-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine;
- trans-N-(6-methylquinazolin-4-yl)-N′-(3,3,3-trifluoropropyl)cyclohexane-1,4-diamine;
- trans-N-(2,2-dimethylpropyl)-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine;
- trans-N-[(1S)-2,2-difluoro-1-methylethyl]-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine;
- trans-N-[(1S)-1-methyl-2-(methylsulfonyl)ethyl]-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine;
- (trans)-N1-(6-((E)-2-cyclopropylvinyl)quinazolin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diamine;
- N′-(6-ethenylquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine;
- trans-N′-{6-[(1E)-3-methoxyprop-1-en-1-yl]quinazolin-4-yl}-N,N-dimethylcyclohexane-1,4-diamine;
- 6-ethyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine;
- 4-(4-(((trans)-4-morpholinocyclohexyl)amino)quinazolin-6-yl)butanenitrile;
- (trans)-N1-(6-ethylquinazolin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diamine;
- N,N-dimethyl-N′-[6-(1-methylethyl)quinazolin-4-yl]cyclohexane-1,4-diamine;
- 6-butyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine;
- N-(trans-4-morpholin-4-ylcyclohexyl)-6-propylquinazolin-4-amine;
- 2-(4-(((trans)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)ethan-1-ol;
- 3-{4-[(trans-4-morpholin-4-ylcyclohexyl)amino]quinazolin-6-yl}propan-1-ol;
- 4-{4-[(trans-4-morpholin-4-ylcyclohexyl)amino]quinazolin-6-yl}butan-1-ol;
- 1-(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)ethanol;
- 4-((trans)-4-((6-methylquinazolin-4-yl)amino)cyclohexyl)thiomorpholine-1,1-dioxide;
- N-((trans)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-6-methylquinazolin-4-amine;
- 4-(4-(((trans)-4-Morpholinocyclohexyl)amino)quinazolin-6-yl)butan-2-ol);
- and
- (4-(((trans)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)methanol;
- or a pharmaceutically acceptable salt or stereoisomer thereof.
54 more elements
Dependencies are inferred from the claim text.