IP Library › Granted Patent US 9,567,333

Granted Patent B2

US 9,567,333 · App. 14/886,563 · Granted Feb 14, 2017

Triazolopyridyl compounds as aldosterone synthase inhibitors

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Quick Facts

Patent No.: US 9,567,333
App. No.: 14/886,563
Granted: Feb 14, 2017
Kind: B2

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Abstract

This invention relates to triazolopyridyl 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.

Claims (71)

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:

Ring B is a heteroaromatic ring;

D is C;

E is N;

R 1 is H or alkyl;

R 2 is 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 10 )—R 7 , —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;

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 ; —SO 2 N(R 10 )—R 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 , —SO 2 N(R 10 )—R 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 , —SO 2 N(R 10 )—R 7 , —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)OR 7 , —SO 2 N(R 10 )—R 7 , —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 10 )—R 7 , —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)OR 7 , —SO 2 N(R 10 )—R 7 , —N(R 10 )SO 2 —R 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 ; —SO 2 N(R 10 )—R 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 , —SO 2 N(R 10 )—R 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 , —SO 2 N(R 10 )—R 7 , —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)OR 7 , —SO 2 N(R 10 )—R 7 , —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 10 )—R 7 , —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)OR 7 , —SO 2 N(R 10 )—R 7 , —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;

or R 4 and R 5 are joined together to form a 5-7 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 ; —SO 2 N(R 10 )—R 7 ; —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)OR 7 , —SO 2 N(R 10 )—R 7 , —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 10 )—R 7 , —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 7 )(R 8 ), —C(O)OR 7 , —SO 2 N(R 10 )—R 7 , —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 10 )—R 7 , —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)OR 7 , —SO 2 N(R 10 )—R 7 , —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)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 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 10 or —S(O) m —R 10 ; 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 10 or —S(O) m —R 10 ; 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 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 acceptable salt thereof, which has the structural formula Formula II

wherein:

R 2 is phenyl optionally substituted by halogen;

R 4 is H, halogen, —CN, alkyl, haloalkyl or cycloalkyl;

R 5 is:

i.) H, halogen, —CN, alkyl, —OR 7 , haloalkyl or phenyl optionally substituted by halogen, haloalkyl, cycloalkyl or —OR 7 ; 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; —OC 1 —C 3 -alkyl; —N(H)S(O) 2 —C 1 -C 3 -alkyl; optionally substituted with 1 to 3 —F; or —N(H)C(O)C 1 -C 3 -alkyl, optionally substituted with 1 to 3 —F;

R 7 is independently H, alkyl, haloalkyl, or phenyl optionally substituted by halogen; and

a is 1 or 2.

3. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula

wherein:

R 2 is phenyl optionally substituted by halogen;

R 6 is alkyl or halo;

R 7 is H, alkyl, haloalkyl, cycloalkyl, or phenyl optionally substituted by halogen;

a is 1 or 2; and

b is 0, 1 or 2.

4. The compound as defined in claim 1 which is:

8-phenyl-2-(pyridine-3-yl-[1,2,4]triazolo[1,5-a]pyridine or a pharmaceutically acceptable salt thereof.

5. 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.

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, a therapeutically effective amount of at least one additional therapeutic agent and a pharmaceutically acceptable carrier.

7. A method for the treatment or amelioration of one or more conditions associated with inhibiting CYP11B2,wherein the conditions are hypertension, heart failure such as congestive heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, hypokalemia, renal failure, restenosis, syndrome X, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction, cardiovascular diseases, renal dysfunction, liver diseases, vascular diseases, cerebrovascular diseases, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, ischemia, myocardial and vascular fibrosis, myocardial necrotic lesions, vascular damage, myocardial necrotic lesions, myocardial infarction, left ventricular hypertrophy, cardiac lesions, vascular wall hypertrophy, endothelial thickening or fibrinoid necrosis of coronary arteries, 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.

8. A method for inhibiting CYP11B2 in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of the formula

or a pharmaceutically acceptable salt thereof

wherein:

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

Ring B is a heteroaromatic ring;

D is C;

E is N;

R 1 is H or alkyl;

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 ; —SO 2 N(R 10 )—R 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 , —SO 2 N(R 10 )—R 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 , —SO 2 N(R 10 )—R 7 , —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)OR 7 , —SO 2 N(R 10 )—R 7 , —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 10 )—R 7 , —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)OR 7 , —SO 2 N(R 10 )—R 7 , —N(R 10 )SO 2 —R 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 ; —SO 2 N(R)—R 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 , —SO 2 N(R 10 )—R 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 , —SO 2 N(R 10 )—R 7 , —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)OR 7 , —SO 2 N(R 10 )—R 7 , —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 10 )—R 7 , —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)OR 7 , —SO 2 N(R 10 )—R 7 , —N(R 10 )SO 2 —R 7 or —S(O) m —R 7 ;

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 or alkyl;

a is 1, 2, 3 or 4;

n is 1 or 2; and

m is 0, 1 or 2.

Assignments (1)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →