Chemical compounds

Patent metadata

Field	Value
Publication number	US-9018381-B2
Application number	US-201113198764-A
Country	US
Kind code	B2
Filing date	Aug 5, 2011
Priority date	Aug 6, 2010
Publication date	Apr 28, 2015
Grant date	Apr 28, 2015

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Diebold Robert Bruce
• Gero Thomas
• Grover Paul
• Huang Shan
• Ioannidis Stephanos
• Ogoe Claude Afona
• Saeh Jamal Carlos
• Astrazeneca Ab

Inventors

• Diebold Robert Bruce
• Gero Thomas
• Grover Paul
• Huang Shan
• Ioannidis Stephanos
• Ogoe Claude Afona
• Saeh Jamal Carlos

Classifications

• C07D211/22 Primary

  by oxygen atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D211/26

  with hydrocarbon radicals, substituted by nitrogen atoms · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07F9/650952

  having the nitrogen atoms in the positions 1 and 4 · CPC title