3,3′-disubstituted indolines as inhibitors of cholesterol ester transfer protein

Patent metadata

Field	Value
Publication number	US-9688630-B2
Application number	US-201415028306-A
Country	US
Kind code	B2
Filing date	Oct 6, 2014
Priority date	Oct 10, 2013
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

3,3′-Disubstituted indoline compounds, including pharmaceutically acceptable salts of the compounds, 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 1-2 carbon atoms in the phenyl ring of Formula I are optionally replaced with 1-2 heteroatoms selected from NH, S, and O to create a 5-6 membered heteroaromatic ring, wherein:
Each R 1 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 9 R 10 , —CO 2 R 8 , —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , HET(1), phenyl, 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 1-9 halogens, and wherein HET(1), phenyl, 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 2 , R 3 , R 4 , R 5 , R 6 , and R 7 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 9 R 10 , —CO 2 R 8 , —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , HET(1), phenyl, 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 1-9 halogens, and wherein HET(1), phenyl, 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 8 is H or —C 1-5 alkyl optionally substituted with 1-9 halogens;
R 9 and R 10 are each independently H, —C 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, phenyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein phenyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, and HET(1) 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;
HET(1) is a 3-7 membered heterocyclic or heteroaromatic ring having 1-4 heteroatoms or heteroatom groups which are each independently N, NH, O, S, S(O), or S(O) 2 and optionally having 1-3 double bonds;
Ar 1 and Ar 2 are each independently phenyl, naphthyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein Ar 1 and Ar 2 are each optionally substituted with 1-5 substituents which are 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 9 R 10 , —CO 2 R 8 , —SO 2 C 1 -C 5 alkyl, —C(O)C 1 -C 5 alkyl, —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , or —NR 9 C(O)NR 9 R 10 , and optionally 1-2 substituents which are phenyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, HET(1), or HET(2), 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, —OC 2 -C 5 alkynyl, —SO 2 C 1 -C 5 alkyl, and —C(O)C 1 -C 5 alkyl are optionally substituted with 1-9 halogens, and wherein when phenyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, HET(1), and HET(2) are substituents on Ar 1 and Ar 2 , then phenyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, HET(1), and HET(2) are optionally substituted with 1-3 substituent groups which are each independently halogen, —OH, —CN, —NR 9 R 10 , —CO 2 R 8 , —C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens and optionally with 1-2 groups which are —OH, halogen, —CN, —NR 9 R 10 , and —CO 2 R 8 ;
HET(2) is a bicyclic or spirocyclic heterocycle having two 3-6 membered heterocyclic rings which are fused or are connected through a single carbon atom to make a spirocyclic connection, wherein HET(2) has 2-4 heteroatoms or heteroatom groups which are O, S, S(O) 2 , N, or NH, and optionally comprises 1-2 double bonds; and
n is 0 or an integer from 1-4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
The phenyl ring in Formula I has no optional heteroatoms;
Each R 1 is independently —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —OH, halogen, —CN, —NR 9 R 10 , —CO 2 R 8 , —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , phenyl, or C 3-6 cycloalkyl, wherein —C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are each optionally substituted with 1-9 halogens, and wherein phenyl and C 3-6 cycloalkyl are each optionally substituted with 1-3 groups which are independently halogen, —C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 are each optionally substituted with 1-7 halogens;
R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently H, —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —OH, halogen, —CN, —NR 9 R 10 , —CO 2 R 8 , —C(O)NR 9 R 10 , or —SO 2 NR 9 R 10 , wherein —C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are each optionally substituted with 1-9 halogens;
R 8 is H or —C 1-5 alkyl optionally substituted with 1-9 halogens;
R 9 and R 10 are each independently H, —C 1 -C 5 alkyl, phenyl, C 3-6 cycloalkyl, or HET(1), wherein phenyl, C 3-6 cycloalkyl, and HET(1) are optionally substituted with 1-3 substituent groups 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;
HET(1) is a 3-7 membered heterocyclic or heteroaromatic ring having 1-4 heteroatoms or heteroatom groups which are each independently N, NH, O, S, S(O), or S(O) 2 and optionally having 1-3 double bonds;
Ar 1 and Ar 2 are each independently phenyl, C 3-6 cycloalkyl, or HET(1), wherein Ar 1 and Ar 2 are each optionally substituted with 1-5 substituents which are independently —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —OH, halogen, —CN, —NR 9 R 10 , —CO 2 R 8 , —SO 2 C 1 -C 5 alkyl, —C(O)C 1 -C 5 alkyl, —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , or —NR 9 C(O)NR 9 R 10 , and optionally one substituent which is phenyl, C 3-6 cycloalkyl, HET(1), or HET(2), wherein —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —SO 2 C 1 -C 5 alkyl, and —C(O)C 1 -C 5 alkyl are optionally substituted with 1-7 halogens, and wherein when phenyl, C 3-6 cycloalkyl, HET(1), and HET(2) are substituents on Ar 1 and Ar 2 , then phenyl, C 3-6 cycloalkyl, HET(1), and HET(2) are optionally substituted with 1-3 substituent groups which are each independently halogen, —OH, —CN, —NR 9 R 10 , —CO 2 R 8 , —C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens;
HET(2) is a bicyclic or spirocyclic heterocycle having two 3-6 membered heterocyclic rings which are fused or are connected through a single carbon atom to make a spirocyclic connection, wherein HET(2) has 2-4 heteroatoms or heteroatom groups whi

Assignees

• Merck Sharp & Dohme

Inventors

• Wilson Jonathan E
• Vachal Petr
• Kurukulasuriya Ravi

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C07D209/18

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D209/24

  with an alkyl or cycloalkyl radical attached to the ring nitrogen atom · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title