Substituted sulfonamides useful as antiapoptotic Bcl inhibitors

Patent metadata

Field	Value
Publication number	US-9346795-B2
Application number	US-201214122173-A
Country	US
Kind code	B2
Filing date	May 23, 2012
Priority date	May 25, 2011
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

Disclosed are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: W and Q and G are defined herein. Also disclosed are methods of using such compounds as inhibitors of Bcl-2 family antiapoptotic proteins for the treatment of cancer; and pharmaceutical compositions comprising such compounds.

First claim

What is claimed is:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
W is:

Q is:
(a) naphthalenyl or isoquinolinyl, each substituted with zero to 3 substituents independently selected from —OH, —CN, halo, —NO 2 , —C(O)OH, —C(O)O(C 1-4 alkyl), —S(O) 2 (C 1-4 alkyl), —S(CH 2 ) 1-3 C(O)OH, —S(CH 2 ) 1-3 NH 2 , C 1-4 alkoxy, —OCH(CH 3 )CH 2 N(C 1-4 alkyl) 2 , —O(CH 2 ) 1-3 R x , —O(CH 2 ) 3 N(CH 3 ) 2 , —O(CH 2 ) 1-4 OH, —O(CH 2 ) 1-4 O(C 1-4 alkyl), —O(CH 2 ) 1-4 O(phenyl), —N(C 1-4 alkyl) 2 , —C(O)N(C 1-4 alkyl) 2 , —C(O)R x , and/or —NHC(O)R x ;
(b)

 each substituted with zero to 3 substituents independently selected from halo, C 1-4 alkyl, C(O)(C 1-4 alkyl), —C(O)R x , —C(O)(CH 2 ) 1-3 R x , —C(O)O(C 1-4 alkyl), —(CH 2 ) 1-3 R x , —C(O)(CH 2 ) 1-3 S(phenyl), —(CH 2 ) 1-3 S(phenyl), C 2-4 alkenyl, and/or morpholinyl; or
(c) C 1-6 alkyl or —(CH 2 ) 1-3 (trimethylsilyl), provided that W is

 each R x is independently C 3-6 cycloalkyl, phenyl, chlorophenyl, difluorophenyl, dichlorophenyl, benzoic acid, methyl benzoate, methylsulfonylphenyl, pyridinyl, chloropyridinyl, furanyl, pyrrolidinyl, piperidinyl, morpholinyl, (morpholinoethoxy)pyridinyl, N-methylpyrrolidinyl, N-methylpiperazinyl, N-methyl-1H-imidazolyl, 1-methyl-1H-indolyl, or N-(2-hydroxyethyl)piperazinyl;
G is:
(a) —N(C 1-4 alkyl) 2 ; or
(b) a bicyclic heterocyclyl selected from:

 wherein said bicyclic heterocyclyl is substituted with zero to 3 substituents independently selected from: halo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, —(CH 2 ) 0-3 C(O)OH, —(CH 2 ) 1-3 NH 2 , —(CH 2 ) 1-3 N 3 , —(CH 2 ) 1-3 N(CH 3 )(C 1-4 hydroxyalkyl), —(CH 2 ) 1-3 N(CH 3 )((CH 2 ) 1-3 OCH 3 ), —(CH 2 ) 1-3 O(CH 2 ) 1-3 N(C 1-4 alkyl) 2 , —(CH 2 ) 1-3 O(CH 2 ) 1-3 OH, —(CH 2 ) 1-3 O(CH 2 ) 1-3 (C 1-4 alkyl), —(CH 2 ) 1-3 O(CH 2 ) 1-3 O(phenyl), —(CH 2 ) 1-3 O(CH 2 ) 1-3 CH 3 , —(CH 2 ) 1-3 R x , —(CH 2 ) 0-3 N(CH 3 ) 2 , —N(CH 3 )((CH 2 ) 1-3 O(C 1-4 alkyl),

R 1a is H, halo, C 1-6 alkyl, —CF 3 , C 1-4 hydroxyalkyl, —(CH 2 ) 1-3 O(C 1-4 alkyl), —(CH 2 ) 1-3 O(C 1-4 hydroxyalkyl), —(CH 2 ) 0-3 C(O)OH, —(CH 2 ) 0-3 N(C 1-4 alkyl) 2 , —(CH 2 ) 0-3 C(O)NH(C 1-4 alkyl), —(CH 2 ) 1-3 R x , —(CH 2 ) 0-3 OC(O)NH 2 , —(CH 2 ) 0-3 C(O)NHS(O) 2 (C 3-6 cycloalkyl), —(CH 2 ) 1-3 OC(O)R x , or —(CH 2 ) 0-3 OC(O)NH(CH 2 ) 1-3 R x ;
R 1b is H, C 1-6 alkyl, —CF 3 , C 1-4 hydroxyalkyl, —(CH 2 ) 1-3 O(C 1-4 alkyl), —(CH 2 ) 1-3 O(C 1-4 hydroxyalkyl), —(CH 2 ) 0-3 C(O)OH, —(CH 2 ) 0-3 N(C 1-4 alkyl) 2 , —(CH 2 ) 0-3 C(O)NH(C 1-4 alkyl), —(CH 2 ) 1-3 R x , —(CH 2 ) 0-3 OC(O)NH 2 , —(CH 2 ) 0-3 C(O)NHS(O) 2 (C 3-6 cycloalkyl), —(CH 2 ) 1-3 OC(O)R x , or —(CH 2 ) 0-3 OC(O)NH(CH 2 ) 1-3 R x ;
R 2 is:
(a) H, Cl, Br, C 1-3 hydroxyalkyl, —(CH 2 ) 0-3 C(O)OH, or —(CH 2 ) 0-3 N(CH 3 ) 2 ; or
(b) phenyl substituted with zero to 2 substituents independently selected from C 1-4 alkyl, —(CH 2 ) 0-3 OH, —O(CH 3 ) 0-3 CH 3 , —O(CH 2 ) 1-3 OH, —O(CH 2 ) 1-2 CH(OH)(CH 2 ) 1-2 OH, —O(C 2-4 alkenyl), —OR x , —C(O)O(C 1-4 alkyl), and/or phenyl;

R 2a is:
(a) H, C 1-3 hydroxyalkyl, —(CH 2 ) 0-3 C(O)OH, or —(CH 2 ) 0-3 N(CH 3 ) 2 ; or
(b) phenyl substituted with zero to 2 substituents independently selected from C 1-4 alkyl, —(CH 2 ) 0-3 OH, —O(CH 3 ) 0-3 CH 3 , —O(CH 2 ) 1-3 OH, —O(CH 2 ) 1-2 CH(OH)(CH 2 ) 1-2 OH, —O(C 2-4 alkenyl), —OR x , —C(O)O(C 1-4 alkyl), and/or phenyl;

one of R 2b and R 2c is H and the other of R 2b and R 2c is R 2 ;
R 3 is —(CH 2 ) 1-3 OH, —C(O)OH, —C(O)O(C 1-4 alkyl), —C(O)NR a R b , or —NR a R b ;
R a is H, C 1-6 alkyl, or C 1-4 fluoroalkyl; and
R b is
(a) C 1-6 alkyl, C 1-4 fluoroalkyl, —(CH 2 ) 1-3 C(O)OH, —(CH 2 ) 1-3 C(O)O(C 1-4 alkyl), —(CH 2 ) 1-3 (C 3-6 cycloalkyl), —CH 2 (naphthalenyl), —(CH 2 ) 1-3 C(O)NHCH(C 1-4 hydroxyalkyl) 2 , —(CH 2 ) 1-3 C(O)NHCH(C 1-4 hydroxyalkyl) 3 , or —(CH 2 ) 1-3 C(O)NH(CH 2 ) 1-3 R x ;
(b) —(CH 2 ) 0-2 (phenyl) wherein said phenyl is substituted with zero to 2 substituents independently selected from Cl, I, C 1-4 alkyl, C 1-4 alkoxy, —(CH 2 ) 0-3 C(O)OH, —C(O)O(C 1-4 alkyl), —(CH 2 ) 1-3 C(O)O(C 1-4 alkyl), phenyl, halophenyl, halophenoxy, phenyl acetic acid, and/or —(CH 2 ) 1-3 C(O)R x ; or
(c)

or R a and R b , together with the nitrogen atom to which they are attached, form a pyrrolidinyl ring substituted with zero to 1 substituent selected from C 1-4 alkyl or —(CH 2 ) 1-3 (phenyl).

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Q is:
(a) naphthalenyl substituted with zero to 3 substituents independently selected from —OH, —CN, Cl, Br, I, —NO 2 , —N(CH 3 ) 2 , —C(O)OH, —C(O)OCH 2 CH 3 , —S(O) 2 CH 2 CH 3 , C 1-3 alkoxy, —OCH(CH 3 )CH 2 N(CH 3 ) 2 , —O(CH 2 ) 3 N(CH 3 ) 2 , —OCH 2 (phenyl), —OCH 2 (dichlorophenyl), —OCH 2 (benzoic acid), —OCH 2 (methyl benzoate), —OCH 2 (methylsulfonylphenyl), —OCH 2 (furanyl), —OCH 2 (N-methyl-1H-imidazolyl), —O(CH 2 ) 2 (N-methylpyrrolidinyl), —O(CH 2 ) 2-3 (morpholinyl), —O(CH 2 ) 3 (pyrrolidinyl), —O(CH 2 ) 3 (piperidinyl), O(CH 2 ) 3 (N-methylpiperazinyl), —O(CH 2 ) 3 (pyridinyl), —OCH 2 CH 2 OH, —OCH 2 CH 2 O(C 1-2 alkyl), —OCH 2 CH 2 O(phenyl), —C(O)N(CH 3 ) 2 , —C(O)(N-methylpiperazinyl), —C(O)(morpholinyl), and/or —NHC(O)(dichlorophenyl);
(b) isoquinolinyl substituted with —OCH 2 CH 2 (morpholinyl), —SCH 2 CH 2 NH 2 , or —SCH 2 C(O)OH;
(c)

 each substituted with zero to 3 substituents independently selected from Cl, Br, I, —CH 2 CH 3 , —CH 2 (cyclohexyl), —CH 2 (phenyl), —CH 2 (difluorophenyl), —(CH 2 ) 1-2 (dichlorophenyl), —CH 2 (chloropyridinyl), —CH 2 (1-methyl-1H-indolyl), —(CH 2 ) 1-3 (morpholinyl), —C(O)(cyclohexyl), —C(O)(dichlorophenyl), —C(O)(morpholinyl), —C(O)((morpholinoethoxy)pyridinyl), —C(O)OCH 3 , —C(O)CH 2 (dichlorophenyl), —C(O)(CH 2 ) 1-3 (morpholinyl), —C(O)CH 2 S(phenyl), —CH 2 CH 2 S(phenyl), —CH═CHCH 3 , —CH═CHCH 2 CH 3 , and/or morpholinyl; or
(d) ethyl, pentyl, or —CH 2 CH 2 (trimethylsilyl)), provided that W is

G is:
(a) —N(CH 3 ) 2 ; or
(b) a bicyclic heterocyclyl selected from:

 wherein said bicyclic heterocyclyl is substituted with zero to 2 substituents independently selected from: Br, —CH 3 , —CF 3 , —CH 2 OH, —CH 2 NH 2 , —CH 2 N 3 , —CH 2 N(CH 3 )(CH 2 CH 2 OH), —CH 2 N(CH 3 )(CH 2 CH 2 OCH 3 ), —CH 2 OCH 2 CH 2 N(CH 3 ) 2 , —CH 2 OCH 2 CH 2 OH, —CH 2 OCH 2 CH 2 O(phenyl), —CH 2 OCH 2 CH 2 CH 2 OCH 3 , —CH 2 (pyrrolidinyl), —CH 2 (N-methyl piperazinyl), —CH 2 (N-(2-hydroxyethyl)piperazinyl), —CH 2 (morpholinyl), —OCH 3 , —C(O)OH, —(CH 2 ) 0-1 N(CH 3 ) 2 , —N(CH 3 )(CH 2 CH 2 OCH 3 ),

Assignees

• Borzilleri Robert M
• Cai Zhen-Wei
• Tebben Andrew J
• Perez Heidi L
• Zhang Liping
• Schroeder Gretchen M
• Wei Donna D
• Bristol Myers Squibb Co

Inventors

• Borzilleri Robert M
• Cai Zhen-Wei
• Tebben Andrew J
• Perez Heidi L
• Zhang Liping
• Schroeder Gretchen M
• Wei Donna D

Classifications

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title