Imidazopyridyl compounds as aldosterone synthase inhibitors

Patent metadata

Field	Value
Publication number	US-9518055-B2
Application number	US-201514885187-A
Country	US
Kind code	B2
Filing date	Oct 16, 2015
Priority date	Sep 22, 2011
Publication date	Dec 13, 2016
Grant date	Dec 13, 2016

Abstract

This invention relates to imidazopyridyl compounds of the structural formula:

or their pharmaceutically acceptable salts, wherein the variable are defined herein. The inventive compounds selectively inhibit aldosterone synthase. This invention also provides for pharmaceutical compositions comprising the compounds of Formula I or their salts as well as potentially to methods for the treatment, amelioration or prevention of conditions that could be treated by inhibiting aldosterone synthase.

First claim

We claim:

1. A compound of the structural formula

or a pharmaceutically acceptable salt thereof

wherein:
Ring A is attached to Ring B via positions D and E and is:

D is C;
E is N;
R 1 is H or alkyl;
R 2 is H; halogen; —CN; —OR 7 ; —N(R 10 )C(O)R 7 ; —NR 11 R 12 ; —C(O)R 7 ; —C(O)N(R 11 )(R 12 ); —C(O)OR 7 ; —S(O) m —R 7 ; alkyl optionally substituted one or more times by halogen, —OR 7 , NR 8 R 9 , —CN, —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 , or —S(O) m —R 7 ; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 7 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 , or —S(O) m —R 7 ; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 , —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ;
R 3 is cycloalkyl optionally substituted once or twice by alkyl or halogen;
R 4 is H; halogen; —CN; —OR 7 ; —NR 8 R 9 ; —N(R 10 )C(O)R 7 ; —C(O)R 7 ; —C(O)N(R 8 )(R 9 ); —C(O)OR 7 ; —N(R 10 )S(O) 2 —R 7 ; —S(O) n —R 7 ; alkyl optionally substituted one or more times by halogen, —OR 7 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 , —N(R 10 )S(O) 2 —R 7 or —S(O) n R 7 ; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 7 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 , —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ;
R 5 is H; halogen; —CN; —OR 7 ; —NR 8 R 9 ; —N(R 10 )C(O)R 7 ; —C(O)N(R 8 )(R 9 ); —C(O)R 7 ; —C(O)OR 7 ; —N(R 10 )S(O) 2 —R 7 ; —S(O) n —R 7 ; alkyl optionally substituted one or more times by halogen, —OR 7 , —NR 8 R 9 , —CN, —N(R 11 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 , —N(R 10 )S(O) 2 —R 7 , or —S(O) n —R 7 ; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 7 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)(R 7 ), —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 , —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ;
or R 4 and R 5 are joined together to form a 5- to 7-membered carbocyclic or heterocyclic ring that is fused to the pyridyl ring to which R 4 and R 5 are attached, wherein the ring formed by R 4 and R 5 is optionally substituted by 1 to 3 R 6 ;

R 6 is independently H; halogen; —CN; —OR 7 ; —NR 8 R 9 ; —N(R 10 )C(O)R 7 ; —C(O)N(R 7 )(R 8 ); —C(O)N(R 8 )(R 9 ); —C(O)OR 7 ; —S(O) m —R 7 ; alkyl optionally substituted one or more times by halogen, —OR 7 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 7 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)(R 7 ), —C(O)N(R 7 )(R 8 ), —C(O)OR 7 or —S(O) m —R 7 ; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 , —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ;
R 7 is independently H; alkyl optionally substituted one or more times by halogen, —OR 10 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 10 , —C(O)N(R 8 )(R 9 ), —C(O)OR 10 or —S(O) m —R 10 ; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 10 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 10 , —C(O)N(R 8 )(R 9 ), —C(O)OR 10 or —S(O) m —R 10 ; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OH, —OR 10 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 10 , —C(O)N(R 8 )(R 9 ), —C(O)OR 10 or —S(O) m —R 10 ; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 10 , —NR 8 R 9 , —CN, —N(R 9 )C(O)R 10 , —C(O)N(R 8 )(R 9 ), —C(O)OR 10 or —S(O) m —R 10 ;
R 8 is independently H or alkyl;
R 9 is independently H or alkyl;
or R 8 and R 9 are joined together with the nitrogen to which they are attached to form a saturated 5- to 7-membered heterocyclic ring;

R 10 is independently H or alkyl;
R 11 is independently H; alkyl optionally substituted one or more times by halogen, —OR 7 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 7 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 8 or —S(O) m —R 8 ; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)(R 7 ), —C(O)N(R 7 )(R 8 ), —C(O)OR 7 or —S(O) m —R 7 ; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 , —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ;
R 12 is independently H; alkyl optionally substituted one or more times by halogen, —OR 7 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 7 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 8 or —S(O) m —R 8 ; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)(R 7 ), —C(O)N(R 7 )(R 8 ), —C(O)OR 7 or —S(O) m —R 7 ; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR 7 , —CN, —NR 8 R 9 —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR 7 , —CN, —NR 8 R 9 , —N(R 10 )C(O)R 7 , —C(O)N(R 8 )(R 9 ), —C(O)OR 7 or —S(O) m —R 7 ;
a is 0, 1, 2, 3 or 4;
n is 1 or 2; and
m is 0, 1 or 2.

2. The compound as defined in claim 1 or a pharmaceutically ac

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

• Ali Amjad
• Bennett D Jonathan
• Cai Jaiqiang
• Carswell Emma
• Cooke Andrew
• Hoyt Scott B
• Lo Michael
• London Clare
• Maclean John
• Park Min K
• Ratcliffe Paul
• Taylor Jerry Andrew
• Whitehead Brent
• Xiong Yusheng

Classifications

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title