Biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds as CETP inhibitors

Patent metadata

Field	Value
Publication number	US-9493430-B2
Application number	US-201414651211-A
Country	US
Kind code	B2
Filing date	Jan 29, 2014
Priority date	Jan 31, 2013
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

The present invention provides biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds, isomers thereof, or pharmaceutically acceptable salts. The compounds of the invention show a CETP inhibitory effect that increases HDL-cholesterol levels and reduces LDL-cholesterol levels. Pharmaceutical compositions comprising the compounds are useful for the prevention or treatment of dyslipidemia or dyslipidemia-related diseases.

First claim

The invention claimed is:

1. A compound of Formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
R 1 is —H or —C 1 -C 3 alkyl;
R 2 is —H, halogen or —C 1 -C 3 alkyl;
R 3 , R 4 , R 5 and R 6 are each independently —H, halogen, —NO 2 , —C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl;
R 7 is —H, —(C═O)OR 8 , or

R 8 is —H or —C 1 -C 3 alkyl;
R 11 and R 12 are each independently —H or —C 1 -C 3 alkyl or may form a 4- to 6-membered non-aromatic ring, wherein the non-aromatic ring may contain 0 to 2 N or O heteroatoms, and one or more H in the non-aromatic ring may substituted with halogen or —OH;
A 1 , A 2 and A 3 are each independently N or CR 9 , wherein if A 2 or A 3 is N, A 1 is CR 9 ;
R 9 is —H, halogen, —C 1 -C 3 alkyl or —OC 1 -C 3 alkyl;
B is N or CR 10 ;
R 10 is H, halogen, —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —(C═O)OR 8 , or

provided that one or more —H atoms in the —C 1 -C 3 alkyl or the —OC 1 -C 3 alkyl may be substituted with —F or —CH 3 , and if R 7 is —H, B is CR 10 , and R 10 is —(C═O)OR 8 or

and if R 7 is not —H, R 10 cannot be —(C═O)OR 8 or

2. The compound of claim 1 , wherein:
R 1 is —H or —CH 3 ;
R 2 is —F or —CF 3 ;
R 3 , R 4 , R 5 and R 6 are each independently —H, —F, —NO 2 , —CH 3 , —CH(CH 3 ) 2 , —CF 3 or —OCH 3 ;
R 7 is —H, —(C═O)OR 8 , or

R 8 is —H, —CH 3 or —CH 2 CH 3 ;
R 11 and R 12 are each independently —H, —CH 3 or —CH 2 CH 3 or may form 4- to 6-membered non-aromatic ring, wherein the non-aromatic ring may contain 0 to 2 N or O heteroatoms, and one or more —H atoms in the non-aromatic ring may be substituted with —F or —OH;
A 1 , A 2 and A 3 are each independently N or CR 9 , wherein if A 2 or A 3 is N, A 1 is CR 9 ;
R 9 is —H, —F, —CH 3 , —CF 3 or —OCH 3 ;
B is N or CR 10 ;
R 10 is —H, —F, —CH 3 , —OCH 3 , —CO 2 H, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , or

provided that if R 7 is —H, B is CR 10 , and R 10 is —CO 2 H, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , or

and if R 7 is not —H, R 10 is not —CO 2 H, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , or

3. The compound of claim 2 , wherein:
R 1 is —CH 3 ;
R 2 is —CF 3 ;
R 3 is —H, —F, —Cl or —OCH 3 ;
R 4 is —H, —F, —Cl, —CH 3 , —CH(CH 3 ) 2 , —CF 3 or —OCH 3 ;
R 5 is —H, —F or —Cl;
R 6 is —H;
R 7 is —H, —(C═O)OH,

A 1 , A 2 and A 3 are each independently N or CR 9 , wherein if A 2 or A 3 is N, A 1 is CR 9 ;
R 9 is —H, —F, —CH 3 , —CF 3 or —OCH 3 ;
B is CR 10 ;
R 10 is —H, —F or —CO 2 CH 3 ;

provided that if R 7 is —H, B is CR 10 , and R 10 is —CO 2 CH 3 , and if R 7 is not —H, R 10 is not —CO 2 CH 3 .

4. The compound of claim 3 , wherein:
R 3 is —H, —F or —OCH 3 ;
R 4 is —H, —F, —Cl, —CH 3 or —CF 3 ;
R 5 is —H or —F;
R 7 is —(C═O)OH;
A 1 is N or CR 9 ;
A 2 and A 3 are each independently CR 9 ;
R 9 is —H or —F; and
B is CH.

5. The compound of claim 1 , wherein the compound is selected from among the following compounds:
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyephenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2-methyl-biphenyl-4-carboxylate;
3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2-methyl-biphenyl-4-carboxylic acid;
methyl 4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-methylbenzoate;
methyl 4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-benzoate;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-methyl-benzoic acid;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)benzoic acid;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxybiphenyl-4-carboxylate;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4′-methoxybiphenyl-4-carboxylate;
3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4′-methoxybiphenyl-4-carboxylic acid;
methyl 5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-picolinate;
3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxybiphenyl-4-carboxylic acid;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxybiphenyl-3-carboxylate;
3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxybiphenyl-3-carboxylic acid;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2-nitrobiphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluoro-4′-methoxy-2-methylbiphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluoro-4′-methoxy-biphenyl-4-carboxylate;
5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluoro-4′-methoxy-2-methylbiphenyl-4-carboxylic acid;
5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluoro-4′-methoxybiphenyl-4-carboxylic acid;
methyl 4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-isopropylbenzoate;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-isopropyl-benzoic acid;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)cyclohex-1-enyl)-4′-methoxy-2-methylbiphenyl-4-carboxylate;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)cyclohex-1-enyl)-2-fluoro-4′-methoxybiphenyl-4-carboxylate;
3′-(2-(((4S,

Assignees

• Chong Kun Dang Pharmaceutical Corp

Inventors

• Lee Jae Kwang
• Oh Jung Taek
• Lee Jae Won
• Lee Seo Hee
• Kim Il-Hyang
• Lee Jae Young
• Bae Su Yeal
• Lee Se Ra
• Kim Yun Tae

Classifications

• C07D413/08

  linked by a carbon chain containing alicyclic rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61K31/443

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title

• C07D263/24

  with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms · CPC title