Therapeutic thiazolidinone compounds

Patent metadata

Field	Value
Publication number	US-9376408-B2
Application number	US-201314653437-A
Country	US
Kind code	B2
Filing date	Dec 17, 2013
Priority date	Dec 20, 2012
Publication date	Jun 28, 2016
Grant date	Jun 28, 2016

Abstract

Thiazolidinone 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 having formula I, or a pharmaceutically acceptable salt thereof,

Wherein each R is independently H or —C 1 -C 3 alkyl;
R 1 is H or —C 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl is optionally substituted with 1-5 halogens;
A and B are each A 1 or A 2 , wherein one of A and B is A 1 and the other of A and B is A 2 ,
A 1 has the structure:

wherein D is selected from the group consisting of:
(a) phenyl, and
(b) HET(1);

wherein ring D comprises at least two carbon atoms that are bonded to each other, wherein one of the two carbon atoms that are bonded to each other in ring D is connected to the group A 3 and the other of the two carbon atoms that are bonded to each other in ring D is connected to the remainder of the structure of Formula I, so that A 3 and the remainder of the structure of formula I are ortho to each other on ring D;
wherein HET(1) is a monocyclic 5-8-membered heterocyclic or heteroaromatic ring having 1-4 heteroatom groups independently selected from N, NH, S, O, —S(O)—, —S(O) 2 —, —C(═O)—, and —N(O)—, wherein HET(1) optionally comprises 1-4 double bonds;
A 3 is
(a) phenyl, or
(b) HET(1), wherein

A 3 is optionally substituted with 1-5 substituent groups independently selected from R a and optionally one or two groups X;
provided that when B is A 1 ; and D and A 3 are both phenyl, then A 2 is HET(1), or A 3 is substituted with one group X, wherein X is phenyl or HET(1);
A 2 is
(a) phenyl,
(b) HET(1), or
(c) —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds;

wherein A 2 is optionally substituted with 1-5 substituent groups independently selected from R a ;
Each R a is independently selected from the group consisting of —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OC 1 -C 6 alkyl, —OC 2 -C 6 alkenyl, —OC 2 -C 6 alkynyl, —C(═O)C 1 -C 6 alkyl, —C(═O)H, —OH, —NR 6 R 7 , —C(═O)NR 6 R 7 , —NR 6 C(═O)OC 1 -C 6 alkyl, —NR 6 C(═O)NR 6 R 7 , —S(O) x C 1 -C 6 alkyl, —S(O) y NR 6 R 7 , —NR 6 S(O) y NR 6 R 7 , —NR 6 S(O) y C 1 -C 6 alkyl, halogen; —CN, —NO 2 , or a 3-7-membered heterocycle having heteroatoms which are independently N, S or O, and optionally one group —C(═O)—, wherein the heterocycle optionally has 1-3 double bonds and is optionally substituted with 1-3 substituent groups which are independently halogen, CH 3 , CF 3 , —OCH 3 , or —OCF 3 ;
wherein for compounds in which R a is selected from the group consisting of —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OC 1 -C 6 alkyl, —OC 2 -C 6 alkenyl, —OC 2 -C 6 alkynyl, —C(═O)C 1 -C 6 alkyl, —NR 6 C(═O)OC 1 -C 6 alkyl, —S(O) x C 1 -C 6 alkyl, and —NR 6 S(O) y C 1 -C 6 alkyl, R a is optionally substituted with 1-11 halogens;
X is (a) C 3 -C 8 cycloalkyl which optionally comprises 1-2 double bonds and which is optionally substituted with 1-2 groups D1 and optionally with 1-5 substituent groups which are independently halogen, C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —CN, or —OH, wherein C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are optionally substituted with 1-11 halogens and optionally 1-2 groups —OH; (b) C 1 -C 5 alkyl which is optionally substituted with 1-2 groups D1 and optionally with 1-2-OH and 1-11 halogens; (c) phenyl which is optionally substituted with 1-2 groups D1 and optionally with 1-5 substituent groups which are halogen, C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —CN, or —OH, wherein C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are optionally substituted with 1-11 halogens and optionally 1-2 groups —OH; (d) HET(1) which is optionally substituted with 1-2 groups D1 and optionally with 1-5 substituent groups which are halogen, C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —CN, or —OH, wherein C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are optionally substituted with 1-11 halogens and optionally with 1-2 groups —OH; or (e) D1;
D 1 is —CO 2 R 8 , —C(O)NR 6 R 7 , SO 2 NR 6 R 7 , or HET(1);
R 6 and R 7 are each independently H or —C 1-5 alkyl;
R 8 is H or —C 1-5 alkyl optionally substituted with 1-7 halogens;
p is an integer from 0-4;
x is 0, 1, or 2; and
y is 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is A 1 and A is A 2 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is A 2 and A is A 1 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Each R is H or CH 3 ; and
p is an integer from 0-2.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein
R is H.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
D and A 3 are each independently phenyl, pyridyl, isoxazolyl, thienyl, imidazolyl, furyl, pyrrolyl, pyrazolyl, N-oxido-pyridyl, 1,3-thiazolyl, 1,3-oxazolyl, 1,2,4-triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrahydropyranyl, or tetrahydrofuryl; and
A 2 is phenyl, thienyl, imidazolyl, furyl, 1,3-thiazolyl, 1,3-oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, tetrazolyl, pyridyl, N-oxido-pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydropyranyl, or tetrahydrofuryl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R is H;
R 1 is CH 3 ;
B is A 1 , wherein A 1 has the structure of formula II:

wherein Y 1 , Y 2 , and Y 3 are each N or —CH—, wherein —CH— is optionally substituted with R a2 in place of H;
R a1 is (a) a 3-7-membered heterocycle having 1-2 heteroatoms which are independently N, S or O, and optionally one group —C(═O)— wherein the heterocycle optionally has 1-3 double bonds and is optionally substituted with 1-3 substituent groups which are independently halogen, CH 3 , CF 3 , —OCH 3 , or —OCF 3 ; (b) —NR 6 R 7 ; (c) —N(C 1 -C 3 alkyl)(SO 2 C 1 -C 3 alkyl); (d) C 1 -C 3 alkyl optionally substituted with 1-7 halogens; (e) —OC 1 -C 3 alkyl optionally substituted with 1-7 halogens; and (f) —SC 1 -C 3 alkyl optionally substituted with 1-7 halogens;
Each R a2 is optionally halogen, CH 3 , CF 3 , —OCH 3 , or —OCF 3 ;
A is A 2 , wherein A 2 is phenyl or pyridyl optionally substituted with 1-3 groups which are independently halogen, CH 3 , CF 3 , —OCH 3 , —OCF 3 , or —CN;
A 3 is phenyl or pyridyl, which is optionally substituted with one group X and with 1-4 substituent groups which are independently halogen, C 1 -C 3 alkyl optionally substituted with 1-7 halogens, or —OC 1 -C 3 alkyl optionally substituted with 1-7 halogens;
X is (a) C 3 -C 7 cycloalkyl optionally substituted with one group D1, and cycloalkyl is optionally substituted with 1-3 substituent groups which are independently halogen, —OH, 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 1-5 halogens and optionally with 1-2 groups —OH; (b) C 1 -C 3 alkyl-D1 in which alkyl is optionally substituted with 1-7 halogens and optionally with 1-2-OH; (c) phenyl optionally substituted with one group D1, wherein phenyl is optionally substituted with 1-3 substituent groups which are halogen, —OH, C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl in which C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substitute

Assignees

• Merck Sharp & Dohme

Inventors

• Shao Pengcheng Patrick
• Katipally Revathi Reddy

Classifications

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• C07D277/14 Primary

  Oxygen atoms · CPC title

• A61K31/4439

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

• C07D417/06

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

• C07D417/10

  linked by a carbon chain containing aromatic rings · CPC title