Phthalazines as potassium ion channel inhibitors

Patent metadata

Field	Value
Publication number	US-9242966-B2
Application number	US-201414200063-A
Country	US
Kind code	B2
Filing date	Mar 7, 2014
Priority date	Mar 11, 2013
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

A compound of formula (I)

wherein A, R 1 , R 3 , and R 24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, I Kur -associated disorders, and other disorders mediated by ion channel function.

First claim

What is claimed is:

1. A compound of formula I

or an enantiomer, diastereomer, tautomer, or salt thereof wherein:
A is —(CH 2 ) m —R 2 , —CH(R 26 )—R 2 , —(CH 2 ) n-1 —O—R 2 , —(CH 2 ) n-1 —NR 25 —R 2 , —CH(R 26 )—CO 2 —R 2 , or —(CH 2 ) n−1 —NR 25 —CO 2 —R 2 ;
R 1 is C 1-10 alkyl substituted with 1-2 —OH, haloC 1-10 alkyl, C 2-12 alkenyl, C 3-10 cycloalkyl, wherein the cycloalkyl may be substituted with 0-2 R 13 ; or
R 1 is

 any of which may be substituted with 0-2 R 13 ;
R 2 is phenyl, cyclopentyl, cyclohexyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl, pyridinone, pyrrolidinyl, tetrahydropyrans, or thiazolyl, any of which are substituted with 0-2 R 2a ;
R 2a , at each occurrence, is independently H, —OH, F, Cl, Br, I, C 1-10 alkyl, C 1-10 alkoxy, haloC 1-10 alkyl, C 3-10 cycloalkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-10 aryl, a 4- to12-membered heteroaryl, a 4- to 12-membered heterocyclyl, a 4- to 12-membered heteroaryl-C 1-10 alkyl, —CN, —NO 2 , —(CH 2 ) m —SO 2 R 14 , —NR 14 SO 2 R 14 , ═O, —CONR 14 R 14 , —(CH 2 ) m —SO 2 NR 14 R 14 , —(CH 2 ) m —NR 14 SO 2 R 14 , —(CH 2 ) n —NR 14 SO 2 NR 14 R 14 , —NR 14 SO 2 NR 14 R 1 4 , —CO 2 NR 14 R 14 , —NR 14 CO 2 NR 14 R 14 , —NR 14 COR 14 , —SO 2 NR 14 COR 14 , —SO 2 NR 14 CONR 14 R 14 , —NR 14 CO 2 R 14 , —CO 2 R 14 , —NR 14 R 14 , NR 14 CONR 14 R 14 , —C(═NOR 14 )NR 14 R 14 , —CONR 14 OR 14 or —NCOR 14 , wherein the alkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclyl may be substituted with 0-2 R 14a , and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
R 3 is phenyl, pyridinyl, pyrimidinyl, or dihydropyran, tetrahydropyran any of which may be substituted with 0-1 R 3a ;
R 3a is halo, CN, NH 2 , —O—C 1-3 alkyl, or morpholinyl;
R 13 , at each occurrence, is independently H, —OH, F, Cl, Br, I, CN, C 1-10 alkyl, C 1-10 alkoxy, haloC 1-10 alkyl, C 3-10 cycloalkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-10 aryl, a 4- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, a 4- to 12-membered heteroaryl-C 1-10 alkyl, —CN, —NO 2 , —(CH 2 ) m —SO 2 R 14 , —NR 14 SO 2 R 14 , ═O, —CONR 14 R 14 , —(CH 2 ) m —SO 2 NR 14 R 14 , —(CH 2 ) m —NR 14 SO 2 R 14 , —(CH 2 ) n —NR 14 SO 2 NR 14 R 14 , —NR 14 SO 2 NR 14 R 14 , —CO 2 NR 14 R 14 , —NR 14 CO 2 NR 14 R 14 , —NR 14 COR 14 , —SO 2 NR 14 COR 14 , —SO 2 NR 14 CONR 14 R 14 , —NR 14 CO 2 R 14 , —CO 2 R 14 , —NR 14 R 14 , NR 14 CONR 14 R 14 , —C(═NOR 14 )NR 14 R 14 , —CONR 14 OR 14 or —NCOR 14 , OR 14 , wherein the alkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclyl may be substituted with 0-2 R 14a , and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
R 14 , at each occurrence, is independently selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, a 4- to 12-membered heteroaryl or a 4- to 12-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may be substituted with 0-3 R 14a and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O; or
alternatively, two R 14 's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring may be substituted with 0-1 R 14a and optionally contain 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
R 14a , at each occurrence, is independently selected from F, Cl, Br, I, C 1-10 alkyl, haloC 1-10 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, a 4- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, F, Cl, Br, I, —CN, —NO 2 , —CO 2 R 26 , —CO 2 NR 24 R 24 , —OCF 3 , —OR 25 , ═O, —CONR 24 R 24 , —COR 24 , —SO 2 R 24 , —NR 24 R 24 , —NR 24 CO 2 R 24 , —SO 2 NR 24 R 24 , or C 6-10 arylC 1-10 alkyl, wherein the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
R 24 , at each occurrence, is independently selected from hydrogen, C 1-10 alkyl, C 3-6 cycloalkyl, or phenyl; or
R 25 , at each occurrence, is independently selected from hydrogen, C 1-10 alkyl, C 3-6 cycloalkyl, or phenyl;
R 26 , at each occurrence, is independently selected from hydrogen, C 1-10 alkyl, C 3-6 cycloalkyl, or phenyl;
m is 0 to 4;
n is 0 to 4; or
n−1 is 2 to 4.

2. The compound of claim 1 , wherein:
one of R 1 or R 1a is C 1-10 alkyl substituted with 1-2 —OH, haloC 1-10 alkyl, C 3-10 cycloalkyl, wherein the cycloalkyl may be substituted with 0-2 R 13 ; or

 any of which may be substituted with 0-2 R 13 .

3. The compound, of claim 2 , wherein:
R 13 , at each occurrence, is independently H, —OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, C 3-6 cycloalkyl, phenyl, a 4- to 12-membered heteroaryl, wherein the heteroaryl is selected from tetrazolyl, —CN, —NO 2 , —(CH 2 ) m —SO 2 R 14 , —NR 14 SO 2 R 14 , —CONR 14 R 14 , —(CH 2 ) m —SO 2 NR 14 R 14 , —NR 14 CO 2 NR 14 R 14 , —NR 14 CO 2 NR 14b R 14b , —NR 14 COR 14 , —NR 14 CO 2 R 14 , —CO 2 R 14 , or —NR 14 R 14 , wherein the alkyl, cycloalkyl, phenyl, and heteroaryl may be substituted with 0-2 R 14a , and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;
R 14 , at each occurrence, is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, wherein the alkyl, cycloalkyl, and phenyl, may be substituted with 0-3 R 14a ; or
alternatively, two R 14b 's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring is morpholinyl, piperidinyl, or piperazinyl, and may be substituted with 0-1 C 1-6 alkyl;
R 14a , at each occurrence, is independently selected from F, Cl, Br, I, C 1-6 alkyl, haloC 1-6 alkyl, phenyl, C 3-6 cycloalkyl.

4. The compound of claim 3 , wherein:
A is —(CH 2 ) m —R 2 , —CH(R 26 )—R 2 , —(CH 2 ) n−1 —O—R 2 , —(CH 2 ) n−1 —NR 25 —R 2 , —CH(R 26 )—CO 2 —R 2 , or —(CH 2 ) n−1 —NR 25 —CO 2 —R 2 ;
R 2 is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, or pyridinone, any of which are substituted with 0-2 R 2a ; or
R 2a , at each occurrence, is independently H, —OH, F, C 1-6 alkyl, C 1-6 alkoxy, 6-SO 2 NR 14 R 14 .

5. The compound of claim 4 , wherein:
R 1 is C 1-10 alkyl substituted with 1-2 —OH, haloC 1-10 alkyl, C 3-10 cycloalkyl, wherein the cycloalkyl may be substituted with 0-1 R 13 ; or
R 1 is

 any of which may be substituted with 0-2 R 13 .

6. The compound of claim 5 , wherein:
R 13 , at each occurrence, is independently H, C 1-6 alkyl, a 4- to 12-membered heteroaryl, wherein the heteroaryl is selected from tetrazolyl, —CN, —NR 14 SO 2 R 14 , —CONR 14 R 14 , —SO 2 NR 14 R 14 , —NR 14 CO 2 NR 14 R 14 , —NR 14 CO 2 NR 14b R 14b , —NR 14 COR 14 . —CO 2 R 14 , or —NR 14 R 14 , wherein the alkyl, and heteroaryl may be substituted with 0-2 R 14a ;
R 14 , at each occurrence, is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, wherein the alk

Assignees

• Bristol Myers Squibb Co

Inventors

• Finlay Heather
• Adisechan Ashok Kumar
• Gunaga Prashantha
• Lloyd John
• Srinivasu Pothukanuri

Classifications

• A61K31/502

  ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title