Indoline compounds as aldosterone synthase inhibitors
View Patent ↗This invention relates to indo line compounds of the structural formula I, or their pharmaceutically acceptable salts, wherein the variables 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.
1. A compound of the formula
or a pharmaceutically acceptable salt thereof
wherein:
R 1 is —C(O)R 7 ; —C(O)OR 7 ; —C(S)R 7 ;
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 ); —N(R 10 )C(O)—R 7 ; —C(O)OR 7 ; —OC(O)R 7 ; —SO 2 N(R 11 )(R 12 ); —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;
R 3 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 ); —N(R 10 )C(O)—R 7 ; —C(O)OR 7 ; —OC(O)R 7 ; —SO 2 N(R 11 )(R 12 ); —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;
R 4 is H; halogen; —CN; alkyl optionally substituted one or more times by halogen or cycloalkyl optionally substituted once or twice by alkyl or halogen; or cycloalkyl optionally substituted once or twice by alkyl or halogen;
R 5 is H; halogen; —CN; alkyl optionally substituted one or more times by halogen or cycloalkyl optionally substituted once or twice by alkyl or halogen; or cycloalkyl optionally substituted once or twice by alkyl or halogen;
R 6 is H; halogen; —CN; alkyl optionally substituted one or more times by halogen or cycloalkyl optionally substituted once or twice by alkyl or halogen; or cycloalkyl optionally substituted once or twice by alkyl or halogen;
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)R 10 , —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, —OR 10 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 10 , —C(O)N(R 8 )(R 9 ), —C(O)R 10 , —C(O)OR 10 —OC(O)R 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)R 10 , —C(O)OR 10 —OC(O)R 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 form a saturated 5- to 7-membered heterocyclic ring;
R 10 is independently H, alkyl or haloalkyl;
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)R 7 , —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)R 7 , —C(O)OR 7 , —OC(O)R 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)R 7 , —C(O)OR 7 , —OC(O)R 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)R 7 , —C(O)OR 7 , —OC(O)R 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)R 7 , —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)R 7 , —C(O)OR 7 , —OC(O)R 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)R 7 , —C(O)OR 7 , —OC(O)R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 or —S(O) m —R 7 ;
or R 11 and R 12 are joined together with the nitrogen to which they are attached form a saturated 5- to 7-membered heterocyclic ring;
R 13 is H; halogen; —CN; —OR 7 ; —NR 11 R 12 ; —N(R 10 )C(O)R 7 ; —C(O)N(R 11 )(R 12 ); —C(O)R 7 ; —C(O)OR 7 ; —OC(O)R 7 ; —SO 2 N(R 11 )(R 12 ); —N(R 10 )SO 2 —R 7 ; —S(O) m —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 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ; or monocyclic 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;
R 14 is H; halogen; —CN; —OR 7 ; —NR 11 R 12 ; —N(R 10 )C(O)R 7 ; —C(O)N(R 11 )(R 12 ); —C(O)R 7 ; —C(O)OR 7 ; —OC(O)R 7 ; —SO 2 N(R 11 )(R 12 ); —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ; aryl optionally substituted one or more times (e.g., 1 to 4 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ; or monocyclic 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;
R 15 is independently H; halogen; —CN; —OR 7 ; —C(O)N(R 8 )(R 9 ); —C(O)R 7 ; —C(O)OR 7 ; —OC(O)R 7 ; —SO 2 N(R 8 )(R 9 ); —N(R 10 )SO 2 —R 7 ; —S(O) m —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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )S(O) 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;
is a single or double bond; and
m is 0, 1 or 2;
provided that when R 1 is benzyl or —C(O)alkyl, R 5 , R 6 R 13 and R 14 cannot all be hydrogen at the same time
and further provided that monocyclic heteroaryl cannot be a tetrazole ring.
2. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —C(O)R 7 , —C(O)OR 7 , —C(S)—R 7 or benzoyl, which is optionally substituted once or twice by alkyl, halogen, alkoxy or haloalkyl;
R 2 is H;
R 3 is H;
R 4 is H;
R 5 is H or halogen;
R 6 is H or halogen;
R 7 is H, alkyl, haloalkyl, cycloalkyl or phenyl optionally substituted once or twice by halogen, —OH, alkoxy or haloalkoxy, or heteroaryl;
R 11 is H;
R 12 is alkyl, phenyl or phenyl substituted one or twice by halogen, OH, alkoxy or haloalkoxy;
R 13 is
i) H, halogen, —CN, alkyl, —OR 7 , haloalkyl, hydroxyl-substituted alkyl, —C(O)R 7 or phenyl optionally substituted by halogen or haloalkyl; or
ii) a group of the formula:
where:
R a is H, OH, or —C 1 -C 3 -alkyl optionally substituted with 1 to 3 —F;
R b is H, —OH, or —C 1 -C 3 -alkyl optionally substituted with 1 to 3 —F;
R c is —C 1 -C 3 -alkyl optionally substituted with 1 to 3 —F; and
R 14 is H, alkyl or haloalkyl.
3. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula
wherein:
R 1 is —C(O)R 7 ;
R 6 is halogen
R 7 is alkyl, haloalkyl, phenyl or phenyl substituted one or twice by halogen, —OH, alkoxy or haloalkoxy;
R 13 is
i) H, halogen, —CN, alkyl, —OR 7 , haloalkyl or phenyl optionally substituted by halogen or haloalkyl; or
ii) a group of the formula:
where:
R a is H, OH, or —C 1 -C 3 -alkyl optionally substituted with 1 to 3 —F;
R b is H, —OH, or —C 1 -C 3 -alkyl optionally substituted with 1 to 3 —F;
R c is —C 1 -C 3 -alkyl optionally substituted with 1 to 3 —F; and
R 14 is H, alkyl or haloalkyl.
4. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula
wherein:
R 1 is —C(O)R 7 ;
R 5 is halogen
R 7 is alkyl, haloalkyl, phenyl or phenyl substituted one or twice by halogen, —OH, alkoxy or haloalkoxy;
R 13 is
i) H, halogen, —CN, alkyl, —OR 7 , haloalkyl or phenyl optionally substituted by halogen or haloalkyl; or
ii) a group of the formula:
where:
R a is H, OH, or —C 1 -C 3 -alkyl optionally substituted with 1 to 3 —F;
R b is H, —OH, or —C 1 -C 3 -alkyl optionally substituted with 1 to 3 —F;
R c is —C 1 -C 3 -alkyl optionally substituted with 1 to 3 —F; and
R 14 is H, alkyl or haloalkyl.
5. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula
wherein:
R 1 is —C(O)OR 7 , wherein R 7 , R 11 or R 12 ;
R 7 is alkyl, phenyl or phenyl substituted one or twice by halogen, —OH, alkoxy or haloalkoxy;
R 11 is H or haloalkyl;
R 12 is alkyl, haloalkyl, phenyl or phenyl substituted one or twice by halogen, OH alkoxy or haloalkoxy
R 13 is H, halogen, —CN, alkyl, —OH, —OR 7 , haloalkyl or phenyl optionally substituted by halogen or haloalkyl;
R 14 is H or alkyl.
6. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula
wherein
R 1 is —C(O)R 7 or —C(S)R 7 or benzoyl, which is optionally substituted once or twice by alkyl, halogen, alkoxy or haloalkyl;
R 7 is alkyl, haloalkyl, cycloalkyl, phenyl, phenyl substituted once or twice by halogen or alkoxy, or heteroaryl;
R 13 is H, —CN, alkoxy, halogen, hydroxy-substituted alkyl, phenyl or —C(O)-alkyl; and
R 14 is H, alkyl or halogen.
7. A compound selected from the group consisting of:
1-propanoyl-5-pyridin-3-yl-2,3-dihydro-1H-indole;
1-(3-chloropropanoyl)-5-pyridin-3-yl-2,3-dihydro-1H-indole;
1-(cyclopropylcarbonyl)-5-pyridin-3-yl-2,3-dihydro-1H-indole;
1-[(4-fluorophenyl)carbonyl]-5-pyridin-3-yl-2,3-dihydro-1H-indolel-[(4-fluorophenyl)carbonyl]-5-pyridin-3-yl-2,3-dihydro-1H-indole;
1-[(4-methoxyphenyl)carbonyl]-5-pyridin-3-yl-2,3-dihydro-1H-indole;
1-(phenylacetyl)-5-pyridin-3-yl-2,3-dihydro-1H-indole;
5-pyridin-3-yl-1-(thiophen-2-ylcarbonyl)-2,3-dihydro-1H-indole;
1-(5-(pyridin-3-yl)indolin-1-yl)ethanethione;
1-acetyl-5-pyridin-3-yl-1H-indole;
1-acetyl-5-(5-fluoropyridin-3-yl)-2,3-dihydro-1H-indole;
5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)pyridine-3-carbonitrile;
1-acetyl-5-(5-methoxypyridin-3-yl)-2,3-dihydro-1H-indole;
1-[5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)pyridin-3-yl]ethanone;
1-[5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)pyridin-3-yl]ethanol;
1-acetyl-5-(5-phenylpyridin-3-yl)-2,3-dihydro-1H-indole;
1-acetyl-5-(4-methylpyridin-3-yl)-2,3-dihydro-1H-indole;
or a pharmaceutically acceptable salt thereof.
8. A compound selected from the group consisting of:
1-(7-chloro-5-(5-fluoropyridin-3-yl)indolin-1-yl)-2,2,2-trifluoroethanone;
2,2,2-trifluoro-1-(7-fluoro-5-(5-fluoropyridin-3-yl)indolin-1-yl)ethanone;
or a pharmaceutically acceptable salt thereof.
9. A compound selected from the group consisting of:
1-(7-fluoro-5-(4-methylpyridin-3-ypindolin-1-ypethanone; or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of at least one additional therapeutic agent and a pharmaceutically acceptable carrier.
12. A method for the treatment or amelioration of one or more conditions associated with inhibiting CYP11B2comprising hypertension, heart failure, hypokalemia, and post-myocardial infarction, which comprises administering a therapeutically effective amount at least one compound of Formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.
13. The method according to claim 12 wherein the condition of heart failure is congestive heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, and systolic dysfunction.
14. A method for inhibiting CYP11B2 in a mammal in need thereof, which comprises administering an effective amount of a compound of the formula
or a pharmaceutically acceptable salt thereof
wherein:
R 1 is —C(O)R 7 ; —C(O)OR 7 ; —C(S)R 7 ;
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 ); —N(R 10 )C(O)—R 7 ; —C(O)OR 7 ; —OC(O)R 7 ; —SO 2 N(R 11 )(R 12 ); —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;
R 3 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 ); —N(R 10 )C(O)—R 7 ; —C(O)OR 7 ; —OC(O)R 7 ; —SO 2 N(R 11 )(R 12 ); —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;
R 4 is H; halogen; —CN; alkyl optionally substituted one or more times by halogen or cycloalkyl optionally substituted once or twice by alkyl or halogen; or cycloalkyl optionally substituted once or twice by alkyl or halogen;
R 5 is H; halogen; —CN; alkyl optionally substituted one or more times by halogen or cycloalkyl optionally substituted once or twice by alkyl or halogen; or cycloalkyl optionally substituted once or twice by alkyl or halogen;
R 6 is H; halogen; —CN; alkyl optionally substituted one or more times by halogen or cycloalkyl optionally substituted once or twice by alkyl or halogen; or cycloalkyl optionally substituted once or twice by alkyl or halogen;
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)R 10 , —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, —OR 10 , —NR 8 R 9 , —CN, —N(R 10 )C(O)R 10 , —C(O)N(R 8 )(R 9 ), —C(O)R 10 , —C(O)OR 10 —OC(O)R 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)R 10 , —C(O)OR 10 —OC(O)R 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 form a saturated 5- to 7-membered heterocyclic ring;
R 10 is independently H, alkyl or haloalkyl;
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)R 7 , —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)R 7 , —C(O)OR 7 , —OC(O)R 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)R 7 , —C(O)OR 7 , —OC(O)R 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)R 7 , —C(O)OR 7 , —OC(O)R 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)R 7 , —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)R 7 , —C(O)OR 7 , —OC(O)R 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)R 7 , —C(O)OR 7 , —OC(O)R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 or —S(O) m —R 7 ;
or R 11 and R 12 are joined together with the nitrogen to which they are attached form a saturated 5- to 7-membered heterocyclic ring;
R 13 is H; halogen; —CN; —OR 7 ; —NR 11 R 12 ; —N(R 10 )C(O)R 7 ; —C(O)N(R 11 )(R 12 ); —C(O)R 7 ; —C(O)OR 7 ; —OC(O)R 7 ; —SO 2 N(R 11 )(R 12 ); —N(R 10 )SO 2 —R 7 ; —S(O) m —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 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ; or monocyclic 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;
R 14 is H; halogen; —CN; —OR 7 ; —NR 11 R 12 ; —N(R 10 )C(O)R 7 ; —C(O)N(R 11 )(R 12 ); —C(O)R 7 ; —C(O)OR 7 ; —OC(O)R 7 ; —SO 2 N(R 11 )(R 12 ); —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ; aryl optionally substituted one or more times (e.g., 1 to 4 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ; or monocyclic 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;
R 15 is independently H; halogen; —CN; —OR 7 ; —C(O)N(R 8 )(R 9 ); —C(O)R 7 ; —C(O)OR 7 ; —OC(O)R 7 ; —SO 2 N(R 8 )(R 9 ); —N(R 19 )SO 2 —R 7 ; —S(O) m —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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )S(O) 2 —R 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 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)R 7 , —C(O)OR 7 , —OC(O)R 7 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;
is a single or double bond; and
m is 0, 1 or 2;
provided that when R 1 is —C(O)alkyl, R 5 , R 6 R 13 and R 14 cannot all be hydrogen at the same time
and further provided that monocyclic heteroaryl cannot be a tetrazole ring.