Chemical Compounds

Patent metadata

Field	Value
Publication number	US-2016176906-A1
Application number	US-201514969775-A
Country	US
Kind code	A1
Filing date	Dec 15, 2015
Priority date	Aug 6, 2010
Publication date	Jun 23, 2016
Grant date	—

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

1 - 15 . (canceled)

16 . A process for preparing a compound of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from —CN, —OR 1a , 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)(O) 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,
or a pharmaceutically acceptable salt thereof, wherein said process comprises:
(i) providing a carboxylic acid compound of formula (1-f):

(ii) providing a sulfonamide compound of formula (1-g):

and
(iii) coupling the carboxylic acid compound of formula (1-f) with the sulfonamide compound of formula (1-g).

17 . A process for preparing a compound of formula (2-g) and (2-h), said process comprising:

performing enantioselective reduction to a compound of formula (3-c).

18 . A process for preparing a compound of formula (5-f), said process comprising:

selectively deprotecting a compound of formula (5-e).

19 . A process for preparing a compound of formula (M), said process comprising:

(i) converting a compound of formula (J) to a compound of formula (K);
(ii) reducing a compound of formula (K) to form a compound of formula (L);
(iii) performing a substitution reaction on a compound of formula (L) to form a corresponding thioether;
(iv) performing a deprotection on the thioether to form a corresponding amine; and
(v) performing an aromatic substitution reaction on the corresponding amine to form a compound of formula (M).

Assignees

• Astrazeneca Ab

Inventors

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

Classifications

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/451 Primary

  having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title