Indoline compounds as aldosterone synthase inhibitors

Patent metadata

Field	Value
Publication number	US-9745282-B2
Application number	US-201615197957-A
Country	US
Kind code	B2
Filing date	Jun 30, 2016
Priority date	Oct 5, 2012
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

This invention relates to indoline compounds of the structural formula:

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.

First claim

We claim:

1. A compound of the formula

or a pharmaceutically acceptable salt thereof

wherein:
R 1 is —C(O)R 7 ; —C(O)N(R 11 )(R 12 ); —C(S)R 7 ; —S(O) 2 R 7 ; cycloalkyl, which is optionally substituted one or more times by halogen, alkyl or haloalkyl; 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 , —SO 2 N(R 8 )(R 9 ), —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ; arylalkyl, wherein the aryl ring is 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 ; 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 ; or arylalkylcarbonyl, wherein the aryl ring is 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 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 and R 14 form a 5-7 membered carbocyclic or heterocyclic ring that is

Assignees

• Merck Sharp & Dohme
• Elexopharm Gmbh
• Merck Sharp & Dohme

Inventors

• Ali Amjad
• Lo Michael Man-Chu
• Metzger Edward
• Yin Lina
• Hartmann Rolf
• Hu Qingzhong
• Heim Ralf
• Zimmer Christina

Classifications

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title