1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile derivatives
View Patent ↗The invention relates to 1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile derived Cathepsin S inhibitors of Formula (I), wherein R 1 is H or (C 1-3 )alkyl; R 2 is halogen or (C 1-4 )alkyl, optionally substituted with one or more halogens; n is 1-3; X is O or CH 2 ; U, V and W are CH; or one of U, V and W is N; Y is a group capable of interacting with the S n . . . S 2 substites of the active site of Cathepsin S; or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions comprising the same as well as to the use of these derivatives for the preparation of a medicament for the treatment of cathepsin S related diseases such as atherosclerosis, obesity, inflammation and immune disorders, such as rheumatoid arthritis, psoriasis, cancer, and chronic pain, such as neuropathic pain.
1. A 1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile derived Cathepsin S inhibitor of Formula I
wherein
R 1 is H or (C 1-3 )alkyl;
R 2 is halogen or (C 1-4 )alkyl, optionally substituted with one or more halogens;
n is 1-3;
X is O or CH 2 ;
U, V and W are CH; or one of U, V and W is N;
wherein Y is selected from
OH;
(C 1-4 )alkyloxy;
(C 1-4 )alkyloxy(C 1-4 )alkyloxy;
NR 3 R 4 ;
NR 4 SO 2 R 5 ;
pyridyl or N-oxy-pyridyl;
Het;
or a pharmaceutically acceptable salt thereof.
2. The 1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile derived Cathepsin S inhibitor of Formula I of claim 1 , wherein
R 1 is H or (C 1-3 )alkyl;
R 2 is halogen or (C 1-4 )alkyl, optionally substituted with one or more halogens;
n is 1-3;
X is O or CH 2 ;
U, V and W are CH; or one of U, V and W is N;
and
wherein Y is selected from
OH;
(C 1-4 )alkyloxy;
(C 1-4 )alkyloxy(C 1-4 )alkyloxy;
NR 3 R 4 ;
NR 4 SO 2 R 5 ;
pyridyl or N-oxy-pyridyl;
Het;
R 3 is H, (C 1-3 )alkyl, (C 1-6 )alkylCO, NR 10 R 11 CR 12 R 13 CO or NR 10 R 11 CO(CH 2 ) m ;
R 4 is H, (C 1-3 )alkyl or (C 3-5 )cycloalkyl; or
R 3 and R 4 together with the nitrogen to which they are bonded form a saturated 6-membered heterocyclic ring containing a further heteroatom selected from O, S and SO 2 ;
R 5 is (C 1-6 )alkyl;
R 6 is selected from
H;
(C 1-4 )alkyl, optionally substituted with 1 or 2 substituents selected from OH;
halogen, CF 3 or (C 1-4 alkylsulfonyl;
(C 1-4 )alkylsulfonyl;
(C 1-6 )alkylcarbonyl;
Het;
Het-CH 2 ;
pyridyl, optionally fused to a benzo ring and optionally substituted with (C 1-4 )alkyl, halogen or cyano;
NR 10 R 11 CO(CH 2 ) m ; and
NR 10 R 11 CR 12 R 13 CO;
R 7 is selected from
H;
(C 1-4 )alkyl, optionally substituted with 1 or 2 substituents selected from OH;
halogen, CF 3 or (C 1-4 )alkylsulfonyl;
(C 1-6 )alkylcarbonyl;
(C 1-4 )alkylsulfonyl;
pyridyl, optionally substituted with (C 1-3 )alkyl, halogen or CF 3 ; and
NR 10 R 11 CO(CH 2 ) m ;
R 8 is H, (C 1-4 )alkyl or OH;
R 9 is H, (C 1-4 )alkyl or NR 10 R 11 CO(CH 2 ) m ;
R 10 and R 11 are independently H or (C 1-6 )alkyl; or
R 10 and R 11 form together with the N to which they are bonded a 5-7 membered saturated heterocyclic ring, optionally comprising a further heteroatom selected form O and S;
R 12 and R 13 are independently H or (C 1-4 ) alkyl; or
R 12 and R 13 form together with the carbon atom to which they are bonded a (C 3-5 )cycloalkyl ring;
R 14 is H, CF 3 or oxo;
Het is a 5-membered heteroaryl ring comprising 1-3 heteroatoms selected from O, S and N, optionally substituted with (C 1-4 )alkyl, halogen or cyano;
p and q are independently 0, 1 or 2;
r is 1 or 2;
m is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
3. The 1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile derived Cathepsin S inhibitor of claim 2 , wherein U, V and W are CH; or V is N.
4. The 1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile derived Cathepsin S inhibitor of claim 3 , wherein X is O and U, V and W are CH.
5. The 1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile derived Cathepsin S inhibitor of claim 4 , wherein R 1 is methyl and R 2 is CF 3 .
6. The 1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile derived Cathepsin S inhibitor of claim 1 which is selected from
1-methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-(1-(2-dimethylamino-2-oxoethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(2-(1-(2-methylamino-2-oxoethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-(1-(2-amino-2-oxoethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(2-(1-(pyridin-2-yl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(2-(1-(6-methylpyridin-2-yl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-(1-(3-cyanopyridin-2-yl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(2-(1-(methylsulfonyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-(1-acetylpiperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
4-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N-methylpiperidine-1-carboxamide;
1-methyl-6-(4-(2-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(pyridin-2-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(1-N-oxy-pyridin-2-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-Methyl-6-(6-(2-(piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(6-(2-(1-(2-Dimethylamino-2-oxo-ethyl)piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-Methyl-6-(6-(2-(1-(2-methylamino-2-oxo-ethyl)piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(6-(2-(1-(2-Amino-2-oxo-ethyl)piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-Methyl-6-(6-(2-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-Methyl-6-(6-(2-(1-(2-morpholino-2-oxoethyl)piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-(1-(1-aminocyclopropanecarbonyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-(azetidin-3-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-(1-(2-dimethylamino-2-oxoethyl)azetidin-3-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-methoxyethoxyl)methoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
N-(3-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)propyl)acetamide;
6-(4-(3-(dimethylamino)propoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(3-(4-hydroxy-4-methylpiperidin-1-yl)propoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-(3-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)propyl)piperidine-4-carboxamide;
1-methyl-6-(3-(trifluoromethyl)-4-(3-(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propoxy)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(3-(4-(3-methylpyridin-2-yl)piperazin-1-yl)propoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(3-(4-(5-chloropyridin-2-yl)piperazin-1-yl)propoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(3-(4-(3-chloropyridin-2-yl)piperazin-1-yl)propoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-(1-(1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-(1-(1,2,4-oxadiazol-3-yl)methyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(2-(1-(oxazol-2-ylmethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(pyridin-3-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(2-(1-(6-methylpyridin-2-yl)azetidin-3-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(2-(1-(pyridin-2-yl)azetidin-3-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile hydrochloride;
methyl-6-(4-(1-N-oxy-pyridin-3-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
1-methyl-6-(4-(pyridin-4-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
methyl-6-(4-(1-N-oxy-pyridin-4-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(6-(2-(1-(2-Hydroxy-2-methylpropyl)piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(6-(2-(1-(2-Hydroxyethyl)piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
6-(4-(2-(1-(2-dimethylamino-2-oxoethyl)azetidin-3-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile hydrochloride;
6-(4-(3-(dimethylamino)propoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile;
2-(4-(3-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)propyl)piperazin-1-yl)-N,N-dimethylacetamide;
6-(4-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile dihydrochloride;
2-(4-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)piperazin-1-yl)-N,N-dimethylacetamide; dihydrochloride;
6-(4-(2-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile dihydrochloride;
2-((1S,4S)-5-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N,N-dimethylacetamide;
N-(3-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenyl)propyl)-2-(dimethylamino)-N-methylacetamide;
methyl-6-(4-(3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)propyl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile hydrochloride;
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a 1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile derived Cathepsin S inhibitor of claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable auxiliaries.