Aldosterone synthase inhibitors

Patent metadata

Field	Value
Publication number	US-9382226-B2
Application number	US-201113811059-A
Country	US
Kind code	B2
Filing date	Jul 20, 2011
Priority date	Jul 21, 2010
Publication date	Jul 5, 2016
Grant date	Jul 5, 2016

Abstract

The invention involves compounds of structural Formula (I) and the pharmaceutically acceptable salts thereof. The compounds of the invention are effective at selectively inhibiting CYP11B2, and are therefore useful for the treatment or prophylaxis of disorders that are associated with elevated aldosterone levels, including, but not limited to, hypertension and heart failure.

First claim

What is claimed is:

1. A compound of the formula Formula I

or a pharmaceutically acceptable salt thereof wherein:
Het is a heteroaromatic ring of the formula:

R 1a , R 1b and R 1c are independently selected from the group consisting of:
H; halogen; —CN; —OR 5 ; —NR 8 R 9 ; —N(R 13 )C(O)R 10 ; —N(R 13 )SO 2 —R 10 ; —C(O)R 10 ; —C(O)N(R 6 )(R 7 ), —C(O)OR 10 ; —SO 2 N(R 6 )(R 7 ) or —S(O) m ,—R 10 ; alkyl optionally substituted one or more times by halogen; cycloalkyl optionally substituted one or more times by halogen, alkyl, or haloalkyl; aryl optionally substituted one or more times by halogen, —OR 5 , alkyl, or haloalkyl or heteroaryl optionally substituted one or more times by halogen, —OR 5 , alkyl or haloalkyl;

R 2 is selected from the group consisting of:
—OR 5 , alkyl; alkyl—R 11 ; cycloalkyl optionally substituted one or more times by alkyl and halogen; and —C 1 -C 2 alkyl-cycloalkyl wherein the cycloalkyl group is optionally substituted one or more times by alkyl and halogen;

R 3 is selected from the group consisting of:
H; halogen; —CN; —NO 2 ; —OR 5a ; —NR 8 R 9 ; —N(R 13 )C(O)R 10 ; —C(O)R 10 —
C(O)N(R 6 )(R 7 ), —C(O)OR 10 or —S(O) m —R 10 ; alkyl optionally substituted one or more times by halogen or —OR 5a ; cycloalkyl optionally substituted one or more times by halogen, —OR 5a , alkyl, or haloalkyl; aryl optionally substituted one or more times by halogen, —OR 5a , alkyl, or haloalkyl or heteroaryl optionally substituted one or more times by halogen, —OR 5a , alkyl or haloalkyl;

R 4 is selected from the group consisting of:
H; halogen; —CN; —NO 2 ; —OR 5b ; —NR 8 R 9 ; —N(R 13 )C(O)R 10 ; —C(O)R 10 —C(O)N(R 6 )(R 7 ), —C(O)OR 10 or —S(O) m —R 10 ; alkyl optionally substituted one or more times by halogen or OR 5b ; cycloalkyl optionally substituted one or more times by halogen, alkyl, or haloalkyl; aryl optionally substituted one or more times by halogen, —OR 5b , alkyl, or haloalkyl or heteroaryl optionally substituted one or more times by halogen, —ORb 5 , alkyl or haloalkyl;

or R 3 and R 4 are joined together to form a 5-7 membered carbocyclic or heterocyclic ring that is fused to the pyridyl ring to which R 3 and R 4 are attached, wherein the ring formed by R 3 and R 4 is optionally substituted with 1 to 3 of R 12 ;
R 5 , R 5a and R 5b are each independently selected from the group consisting of H; alkyl optionally substituted with halogen; or aralkyl wherein the aryl ring is optionally substituted one or more times by halogen, —OR 5c , alkyl or haloalkyl;
R 5c is H or alkyl optionally substituted with halogen;
R 6 and R 7 are each independently selected from the group consisting of:
H, alkyl optionally substituted with halogen; cycloalkyl optionally substituted with alkyl or halogen; aryl optionally substituted one or more times by halogen, —OR 5 , alkyl, or haloalkyl or heteroaryl optionally substituted one or more times by halogen, —OR 5 , alkyl or haloalkyl;

or R 6 and R 7 join together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocyclic ring;
R 8 and R 9 are each independently selected from the group consisting of
H, alkyl or aralkyl wherein the aryl ring is optionally substituted one or more times by halogen, —OR 5 , alkyl or haloalkyl;

R 10 is selected from the group consisting of alkyl optionally substituted one or more time with halogen; cycloalkyl optionally substituted one or more times by halogen, alkyl or haloalkyl; or aryl wherein the aryl ring is optionally substituted one or more times by halogen, —OR 5 , alkyl or haloalkyl
R 11 is selected from the group consisting of haloalkyl or —OR 5 ;
R 12 is independently selected at each occurrence from the group consisting of halogen or alkyl optionally substituted one or more time by halogen;
R 13 is H or alkyl; and
m is 0, 1 or 2.

2. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof wherein:
R 1a , R 1b or R 1c is selected from the group consisting of —H, —F, —Cl, —Br, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with —OH or halogen, —OC 1 - 6 alkyl, —N(R 13 )C(O)—C 1 -C 6 alkyl, —C(O)N(H)C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 - 6 alkyl)( C 1 -C 6 alkyl), —C(O)O—C 1 -C 6 alkyl, —S—C 1 -C 6 alkyl, —S(O)—C 1 -C 6 alkyl, —S(O) 2 —C 1 -C 6 alkyl, —N(R 13 )S(O) 2 —C 1 -C 6 alkyl, or optionally C 1 -C 6 alkyl substituted heteroaryl, wherein the heteroaryl is an isooxazolyl, pyrazolyl, oxazolyl, imidazolyl or pyridyl ring;
R 2 is OH, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with —OH or halogen, —O—C 1 -C 6 alkyl, cyclopropyl optionally substituted by halogen, —OH or —O—C 1 -C 6 alkyl or —OCH 2 -phenyl, wherein the phenyl ring is optionally substituted by halogen, —OH or —O—C 1 -C 6 alkyl; and
R 3 and R 4 are independently H, halogen —CN, —C 1 -C 6 alkyl substituted optionally substituted with —OH, —O—C 1 -C 6 alkyl, or halogen, —O—C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OH, —C(O)O—C 1 -C 6 alkyl, —S—C 1 -C 6 alkyl, —S(O) —C 1 -C 6 alkyl, —S(O) 2 —C 1 -C 6 alkyl,—NH 2 , —NH(C 1-C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), optionally halo substituted phenyl, or optionally C 1 -C 6 alkyl substituted heteroaryl, wherein the heteroaryl is an isooxazolyl, pyrazolyl, oxazolyl, imidazolyl or pyridyl ring or R 3 and R 4 together with the pyridyl ring form:

3. The compound as defined in claim 1 having the structural formula

or a pharmaceutically acceptable salt thereof

wherein:
R 1a , R 1b and R 1c are independently selected from the group consisting of:
—H, —F, —Cl, —Br, —CN, —OR 5 , —SO 2 NR 6 R 7 ,
—C 1 -C 6 alkyl optionally substituted with 1 to 3 of —F, or
—C 3 -C 7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —CH 3 or —F;

R 2 is selected from the group consisting of:
(a) —C 1 -C 5 alkyl-R 11 , (b) —C 1 -C 4 alkyl; (c) cyclopropyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CH 3 or —F or —C 1 -C 2 alkyl-cyclopropyl wherein cyclopropyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CH 3 or —F;
R 3 is selected from the group consisting of:
—H, —F, —Cl, —Br, —CN, —OR 5a , —C 1 -C 6 perfluoroalkyl, —C 1 -C 6 alkyl optionally substituted with 1 to 3 of F or optionally substituted with —OH, or —C 3 -C 7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of —CH 3 and —F;

R 4 is selected from the group consisting of:
(a) —H, —F, —Cl, —Br, —CN, —OR 5 b, —NR 8 R 9 ,—CO 2 R 10 or—COR 10 ,
(b) —C 1 -C 6 perfluoroalkyl,
(c) —C 1 -C 7 alkyl optionally substituted with 1 to 6 of —F and optionally substituted with 1 or 2 substituents independently selected from the group consisting of (i) —OR 5 b or (ii) aryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, —Cl or —C 1 -C 3 alkyl optionally substituted with 1 to 3 of —F,
(d) —C 3 -C 7 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —C 1 -C6 alkyl, —CF 3 or F,
(e) aryl optionally substituted with 1 to 3 substituents i

Assignees

• Hoyt Scott B
• Park Min K
• London Clare
• Xiong Yusheng
• Bennett D Jonathan
• Cai Jiaqiang
• Ratcliffe Paul
• Cooke Andrew
• Carswell Emma
• Maclean John
• Saxena Rohit
• Kulkarni Bheemashankar A
• Gupta Archana
• Merck Sharp & Dohme

Inventors

• Hoyt Scott B
• Park Min K
• London Clare
• Xiong Yusheng
• Bennett D Jonathan
• Cai Jiaqiang
• Ratcliffe Paul
• Cooke Andrew
• Carswell Emma
• Maclean John
• Saxena Rohit
• Kulkarni Bheemashankar A
• Gupta Archana

Classifications

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title