Bicyclic ureas and thiadiazolidine-1, 1-dioxides as CETP inhibitors

Patent metadata

Field	Value
Publication number	US-9981970-B2
Application number	US-201414908180-A
Country	US
Kind code	B2
Filing date	Jul 28, 2014
Priority date	Jul 30, 2013
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

Compounds having the structure of Formula I, including pharmaceutically acceptable salts of the compounds, wherein X is —C(═O) or —S(O) 2 —, are CETP inhibitors and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis.

First claim

What is claimed is:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein X is —C(═O),
R 1 is H, —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, —OC 2 -C 5 alkynyl, —OH, halogen, —CN, —NR 6 R 7 , —CO 2 R 8 , —C(O)NR 6 R 7 , —SO 2 NR 6 R 7 , HET(3), or C 3-6 cycloalkyl optionally having 1-2 double bonds, wherein —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, and —OC 2 -C 5 alkynyl are each optionally substituted with 1-7 halogens, and wherein HET(3) and C 3-6 cycloalkyl optionally having 1-2 double bonds are optionally substituted with 1-3 substituent groups which are each independently halogen, —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —OC 2 -C 3 alkenyl, —C 2 -C 3 alkynyl, or —OC 2 -C 3 alkynyl, wherein —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —OC 2 -C 3 alkenyl, —C 2 -C 3 alkynyl, and —OC 2 -C 3 alkynyl are each optionally substituted with 1-7 halogens;
R 6 and R 7 are each independently H, —C 1 -C 5 alkyl, phenyl, naphthyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, or HET(3), wherein phenyl, naphthyl, C 3-6 cycloalkyl, and HET(3) are optionally substituted with 1-3 substituent groups which are each independently halogen, —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —OC 2 -C 3 alkenyl, —C 2 -C 3 alkynyl, or —OC 2 -C 3 alkynyl, wherein —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —OC 2 -C 3 alkenyl, —C 2 -C 3 alkynyl, and —OC 2 -C 3 alkynyl are each optionally substituted with 1-7 halogens;
R 8 is H or —C 1-5 alkyl optionally substituted with 1-7 halogens;
R 9 is H or —C 1-5 alkyl optionally substituted with 1-7 halogens;
HET(3) is a 3-6 membered heterocyclic ring having 1-3 heteroatom groups which are each independently N, NH, O, S, S(O), or S(O) 2 and optionally having 1-3 double bonds;
The dashed line in Formula I represents an optional double bond;
D 1 is CR 2 ;
D 2 is CR 3 ;
D 3 is CR 4 ;
R 2 , R 3 , and R 4 are each independently H, —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, —OC 2 -C 5 alkynyl, —OH, halogen, —CN, —NR 6 R 7 , —CO 2 R 8 , —C(O)NR 6 R 7 , or —SO 2 NR 6 R 7 , wherein —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, and —OC 2 -C 5 alkynyl are optionally substituted with 1-7 halogens;
Each R 5 is independently —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, —OC 2 -C 5 alkynyl, —OH, halogen, —CN, —NR 6 R 7 , —CO 2 R 8 , —C(O)NR 6 R 7 , or —SO 2 NR 6 R 7 , wherein —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, and —OC 2 -C 5 alkynyl are optionally substituted with 1-7 halogens;
A 1 is phenyl, HET(1), or C 3 -C 8 cycloalkyl optionally having 1-2 double bonds, wherein A 1 is optionally substituted with one substituent group Z and is optionally substituted with 1-3 groups which are each independently —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, —OC 2 -C 5 alkynyl, halogen, —OH, or —CN, wherein —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, and —OC 2 -C 5 alkynyl are optionally substituted with 1-7 halogens;
HET(1) is a 5- or 6-membered heterocyclic ring having 1-4 heteroatom groups which are each independently —N—, —NH—, —S—, —O—, —S(O)—, or —S(O) 2 —, optionally having one group —C(═O)—, and optionally having 1-3 double bonds;
Z is A 3 , —C 1 -C 3 alkylene-CO 2 R 8 , —C 1 -C 3 alkylene-C(O)NR 6 R 7 , —C 1 -C 3 alkylene-SO 2 NR 6 R 7 , —CO 2 R 8 , —C(O)NR 6 R 7 , —SO 2 NR 6 R 7 , or —C 1 -C 3 alkylene-HET(2), wherein —C 1 -C 3 alkylene in all uses is optionally substituted with 1-7 halogens, and HET(2) is optionally substituted with 1-3 substituents which are independently —C 1-3 alkyl optionally substituted with 1-5 halogens, —OC 1-3 alkyl optionally substituted with 1-5 halogens, halogen or NR 6 R 7 ;
A 3 is phenyl, C 3 -C 6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein A 3 is optionally substituted with 1-3 groups which are each independently —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, —OC 2 -C 5 alkynyl, halogen, —OH, or —CN, wherein —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, and —OC 2 -C 5 alkynyl are optionally substituted with 1-7 halogens; and A 3 is optionally substituted with one group which is HET(2), —C 1-4 alkylene-CO 2 R 8 , —C 1-4 alkylene-C(O)NR 6 R 7 , —C 1 -C 4 alkylene-SO 2 NR 6 R 7 , —CO 2 R 8 , —C(O)NR 6 R 7 , —SO 2 NR 6 R 7 , or —C(O)NR 6 C 3-6 cycloalkyl in which C 3-6 cycloalkyl is optionally substituted with 1-3 substituents which are independently selected from halogen, C 1-2 alkyl, and —CN, wherein —C 1 -C 4 alkylene in all uses is optionally substituted with 1-7 halogens; and wherein HET(2) is optionally substituted with 1-3 groups which are each independently halogen, —C 1-5 alkyl optionally substituted with 1-7 halogens, —OC 1-5 alkyl optionally substituted with 1-7 halogens, or NR 6 R 7 ;
HET(2) is a 5-6 membered heterocyclic ring having 1-3 heteroatom groups which are each independently N, NH, O, or S, optionally having one group —C(═O)—, and optionally having 1-3 double bonds;
A 2 is phenyl or HET(1), wherein A 2 is optionally substituted with 1-3 substituent groups which are each independently —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, —OC 2 -C 5 alkynyl, halogen, —CN, —OH, or C 3-6 cycloalkyl, wherein —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, and —OC 2 -C 5 alkynyl are optionally substituted with 1-7 halogens, and C 3-6 cycloalkyl is optionally substituted with 1-3 substituents which are each independently halogen, —C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are each optionally substituted with 1-7 halogens; and
a is 0 or an integer from 1-3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof:
wherein R 1 is —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, halogen, —NR 6 R 7 , HET(3), or C 3-6 cycloalkyl optionally having 1-2 double bonds, wherein —C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are optionally substituted with 1-7 halogens, and wherein HET(3) and C 3-6 cycloalkyl optionally having 1-2 double bonds are optionally substituted with 1-3 substituent groups which are each independently halogen, CH 3 , CF 3 , OCH 3 , or OCF 3 ;
R 2 , R 3 , and R 4 are each independently H, —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, or halogen, wherein —C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are optionally substituted with 1-7 halogens;
Each R 5 is independently —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, or halogen, wherein —C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are optionally substituted with 1-7 halogens;
A 1 is phenyl, HET(1), or C 3 -C 6 cycloalkyl optionally having 1-2 double bonds, wherein A 1 is optionally substituted with one substituent group Z and is optionally substituted with 1-3 groups which are each independently halogen, —OH, —CN, —C 1-5 alkyl optionally substituted with 1-7 halogens, or —OC 1-5 alkyl optionally substituted with 1-7 halogens;
A 3 is phenyl, C 3 -C 6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein A 3 is optionally substituted with 1-3 groups which are each independently —C 1 -C 5 alkyl optionally substituted w

Assignees

• Liu Jian
• Shao Pengcheng Patrick
• Krikorian Arto K
• Vachal Petr
• Merck Sharp & Dohme

Inventors

• Liu Jian
• Shao Pengcheng Patrick
• Krikorian Arto K
• Vachal Petr

Classifications

• C07D513/04

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/714

  Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12 · CPC title

• A61K31/4188

  condensed with other heterocyclic ring systems, e.g. biotin, sorbinil · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title