IP Library › Granted Patent US 9,745,282

Granted Patent B2

US 9,745,282 · App. 15/197,957 · Granted Aug 29, 2017

Indoline compounds as aldosterone synthase inhibitors

Inventors: Amjad Ali (Freehold, NJ); Michael Man-Chu Lo (Edison, NJ); Edward Metzger (Somerset, NJ); Lina Yin (Saarbrucken, DE); Rolf Hartmann (Saarbrucken, DE); Qingzhong Hu (Saarbrucken, DE); Ralf Heim (Saarbrucken, DE); Christina Zimmer (Volklingen, DE)

Assignees: Merck Sharp & Dohme Corp; ElexoPharm GmbH

C07D401/04 A61K31/4439 A61K31/4709 A61K31/4725 A61K45/06 C07D409/14

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Quick Facts

Patent No.: US 9,745,282
App. No.: 15/197,957
Granted: Aug 29, 2017
Kind: B2

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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.

Claims (78)

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 fused to the pyridyl ring to which R 13 and R 14 are attached, wherein the ring formed by R 13 and R 14 is optionally substituted by 1 to 3 R 15 ;

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 , —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.

2. The compound as defined in claim 1 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 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 and R 14 are joined together with the pyridine ring to which they are attached form

where:

R 15 is alkyl or halogen; and

a is 0, 1 or 2.

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 H or halogen;

R 7 is alkyl, haloalkyl, phenyl or phenyl substituted one or twice by halogen, —OH, alkoxy or haloalkoxy;

R 15 is alkyl or halogen; and

a is 0, 1 or 2.

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 , —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;

R 15 is alkyl or halo; and

a is 0, 1 or 2.

5. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

4-(1-acetyl-2,3-dihydro-1H-indol-5-yl)isoquinoline;

4-(1-propanoyl-2,3-dihydro-1H-indol-5-yl)isoquinoline;

4-[1-(2-methylpropanoyl)-2,3-dihydro-1H-indol-5-yl]isoquinoline;

4-[1-(cyclopropylcarbonyl)-2,3-dihydro-1H-indol-5-yl]isoquinoline; and

4-(1-acetyl-1H-indol-5-yl)isoquinoline.

6. 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.

7. 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.

8. A method for the treatment or amelioration of one or more conditions associated with inhibiting CYP11B2 comprising 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.

9. 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)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 ; 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(Ro)SO 2 —R 7 or —S(O) m —R; 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 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;

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;

is a single or double bond; and

m is 0, 1 or 2.

10. The method according to claim 8 wherein the condition of heart failure is congestive heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, and systolic dysfunction.

Assignments (1)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →

Continuity (3)

Continuation 14433441

Provisional Application 61710197 · Oct 5, 2012

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