Chemical compounds
The present invention relates to compounds of Formula (I): and to their salts, pharmaceutical compositions, methods of use, and methods for their preparation. These compounds inhibit Bcl-2 and/or Bcl-X L activities and may be used for the treatment of cancer.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from —CN, —OR la , and —N(R 1a ) 2 ;
R 1a in each occurrence is independently selected from H, C 1-4 alkyl, —C(O)CH 2 NH 2 , —C(O)CH 2 NHCH 3 , and when R 1 is —OR 1a , then R 1a is additionally selected from —P(═O)(OH)(OCH 3 ), —P(═O)(OCH 2 CH 3 ) 2 , —CH 2 OP(═O)(OH)[OC(CH 3 ) 3 ] and —CH 2 OP(═O)[OC(CH 3 ) 3 ] 2 ;
R 2 is selected from —N(O) 2 and —S(O) 2 CF 3 ;
R 3 is selected from H and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with one or more R 40 ;
R 4 is selected from H and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with one or more R 40 ;
or R 3 and R 4 together with the nitrogen to which they are attached form a 5-or 6-membered heterocyclic ring, wherein
i) said 5-or 6-membered heterocyclic ring is optionally substituted on carbon with one or more R 40 ; and
ii) if said 5-or 6-membered heterocyclic ring contains a nitrogen, that nitrogen is optionally substituted with R 40* to form a tertiary amine;
R 40* is selected from C 1-4 alkyl and —(CH 2 ) 2 OP(═O)(OH) 2 , wherein said C 1-4 alkyl is optionally substituted with one or more R a ;
R 40 in each occurrence is selected from —OR 40a , —N(R 40a ) 2 , —CH 2 OR 5a , —CH 2 N(R 5a ) 2 , —OP(═O)(OH) 2 , and —OP(═O)[OC(CH 3 ) 3 ] 2 ;
R 5a in each occurrence is selected from H and C 1-3 alkyl;
R 40a in each occurrence is independently selected from H and C 1-4 alkyl; and
R a is selected from halo, —OR m , and —N(R m ) 2 ; and
R m in each occurrence is independently selected from H and C 1-4 alkyl.
2. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein,
R 1 is —OH;
R 2 is —S(O) 2 CF 3 ;
R 3 is C 1-2 alkyl, wherein said C 1-2 alkyl is optionally substituted with one or more R 40 ;
R 4 is C 1-2 alkyl, wherein said C 1-2 alkyl is optionally substituted with one or more R 40 ;
R 40 in each occurrence is selected from —OR 40a and —OP(═O)(OH) 2 ; and
R 40a is H.
3. The compound of claim 1 wherein the compound has the following stereochemistry:
4. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 3 , wherein the compound is 4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)-N-(4-((R)-4-((2-hydroxyethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide.
5. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 3 , wherein the compound is 2-(((R)-3-(4-(N-(4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)(methyl)amino)ethyl dihydrogen phosphate.
6. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 3 , wherein the compound is 4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)-N-(4-((R)-4-(ethyl(2-hydroxyethyl)amino)-1 -(phenylthio)butan-2-ylamino)-3 -(trifluoromethylsulfonyl)phenylsulfonyl)benzamide.
7. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 3 , wherein the compound is 2-(((R)-3-(4-(N-(4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1 -yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)(ethyl)amino)ethyl dihydrogen phosphate.
8. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , and at least one pharmaceutically acceptable carrier, diluent, or excipient.