IP Library › Granted Patent US 9,440,949
Granted Patent B2
US 9,440,949 · App. 14/643,210 · Granted Sep 13, 2016

Diacylglycerol acyltransferase 2 inhibitors

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Quick Facts
Patent No.
US 9,440,949
App. No.
14/643,210
Granted
Sep 13, 2016
Kind
B2
Abstract

Compounds of Formula I that inhibit the activity of the diacylglycerol acyltransferase 2 (DGAT2) and their uses in the treatment of diseases linked thereto in animals are described herein.

Claims (57)

1. A compound of Formula (I)

wherein

D is N, CH, or CF;

R 1 is (C 1 -C 4 )alkyl optionally substituted with one, two or three substituents each independently selected from fluoro and (C 3 -C 6 )cycloalkyl;

R 2 is fluoro or (C 1 -C 4 )alkyl;

R 3 is H, (C 1 -C 4 )alkyl, or (C 3 -C 6 )cycloalkyl;

R 4 is H, —(C 1 -C 4 )alkyl, —((C 1 -C 4 )alkyl) p -(C 3 -C 6 )cycloalkyl, —((C 1 -C 4 )alkyl) p -(C 3 -C 6 )heterocyclyl, —((C 1 -C 4 )alkyl) p -aryl, or —((C 1 -C 4 )alkyl) p -heteroaryl wherein R 4 is optionally substituted with one, two, three, or four substituents selected from halo, cyano, oxo, aminyl, iminyl, —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )fluoroalkyl, —(C 1 -C 4 )alkoxy, —(C 3 -C 6 )cycloalkoxy, —(C 1 -C 4 )fluoroalkoxy, —((C 1 -C 4 )alkyl) q -COOH, —((C 1 -C 4 )alkyl) q -(C 3 -C 6 )cycloalkyl-COOH, —((C 1 -C 4 )alkyl) q -(C 3 -C 6 )heterocyclyl-COOH, —((C 1 -C 4 )alkyl) q -aryl-COOH, —((C 1 -C 4 )alkyl) q -heteroaryl-COOH, —O—((C 1 -C 4 )alkyl) q -COOH, —O—((C 1 -C 4 )alkyl) q -aryl-COOH, —O((C 1 -C 4 )alkyl) q -heteroaryl-COOH, —((C 1 -C 4 )alkyl) q -(C 3 -C 6 )cycloalkyl, —((C 1 -C 4 )alkyl) q -(C 3 -C 6 )heterocyclyl, —((C 1 -C 4 )alkyl) q -aryl, —((C 1 -C 4 )alkyl) q -heteroaryl, —C(O)—(C 1 -C 4 )alkyl, —C(O)—(C 1 -C 4 )alkoxy, —C(O)—(C 3 -C 6 )cycloalkyl, —C(O)—(C 3 -C 6 )heterocyclyl, —C(O)—NR 6 R 7 , —C(O)—((C 1 -C 4 )alkyl) q -aryl, —C(O)—((C 1 -C 4 )alkyl) q -heteroaryl, —NR 6 R 7 , —NR 6 —C(O)—R 7 , —((C 1 -C 4 )alkyl) q -O-aryl, —((C 1 -C 4 )alkyl) q -O-heteroaryl, —S(O) 2 —R 7 , and —S(O) 2 —NR 6 R 7 ;

or R 3 and R 4 may be joined together to form a 4- to 10-member fully saturated, or partially saturated ring system optionally substituted with one, two, three, or four substituents selected from halo, cyano, —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )fluoroalkyl, —(C 1 -C 4 )alkoxy, —(C 3 -C 6 )cycloalkoxy, —(C 1 -C 4 )fluoroalkoxy, —((C 1 -C 4 )alkyl) q -COOH, —((C 1 -C 4 )alkyl) q -(C 3 -C 6 )cycloalkyl-COOH, —((C 1 -C 4 )alkyl) q -(C 3 -C 6 )heterocyclyl-COOH, C 4 )alkyl) q -aryl-COOH, —((C 1 -C 4 )alkyl) q -heteroaryl-COOH, —O—((C 1 -C 4 )alkyl) q -COOH, —O—((C 1 -C 4 )alkyl) q -aryl-COOH, —O((C 1 -C 4 )alkyl) q -heteroaryl-COOH, —((C 1 -C 4 )alkyl) q -(C 3 -C 6 )cycloalkyl, —((C 1 -C 4 )alkyl) q -(C 3 -C 6 )heterocyclyl, —((C 1 -C 4 )alkyl) q -aryl, —((C 1 -C 4 )alkyl) q -heteroaryl, —C(O)—(C 1 -C 4 )alkyl, —C(O)—(C 3 -C 6 )cycloalkyl, —C(O)—(C 3 -C 6 )heterocyclyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)—NR 6 R 7 , —C(O)—(C 1 -C 4 )alkyl-aryl, —C(O)—(C 1 -C 4 )alkyl-heteroaryl, —NR 6 R 7 , —NR 6 —C(O)—R 7 , —O-aryl, —O-heteroaryl, —(C 1 -C 4 )alkyl-O-aryl, —(C 1 -C 4 )alkyl-O-heteroaryl, —O—(C 1 -C 4 )alkyl-aryl, and —O—(C 1 -C 4 )alkyl-heteroaryl;

R 5 is H, F, or cyano;

R 6 is H, (C 1 -C 4 )alkyl, or —S(O) 2 —R 7 ;

R 7 is H, (C 1 -C 4 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 3 -C 6 )heterocyclyl, aryl, or heteroaryl;

n is 0, 1, 2 or 3;

p is 0 or 1; and

q is 0 or 1;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 having the Formula (Ia)

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein D is N or C—F; and n is 0.

4. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is ethyl and R 2 is fluoro.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 5 is H; R 3 is H; and R 4 is (C 1 -C 2 )alkyl-aryl, (C 1 -C 2 )alkyl-heteroaryl, or (C 5 -C 6 )cycloalkyl, wherein R 4 is optionally substituted with one, two, three, or four substituents selected from fluoro, chloro, cyano, —((C 1 -C 2 )alkyl) q -COOH, —(C 1 -C 3 )alkyl, —(C 3 -C 6 )cycloalkyl, trifluoromethyl, difluoromethyl, —(C 1 -C 3 )alkoxy, trifluoromethoxy, and difluoromethoxy.

6. The compound

2-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinamido)cyclopentane-1-carboxylic acid;

(1R,2S)-2-(6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinamido)cyclopentane-1-carboxylic acid;

4-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-3-methylbenzoic acid;

(R)-4-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-3-methylbenzoic acid;

2-(2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)cyclopentane-1-carboxylic acid;

(1R,2S)-2-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)cyclopentane-1-carboxylic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4-methylbenzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4-methylbenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methylbenzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methylbenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-2-methoxybenzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-2-methoxybenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4-methoxybenzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4-methoxybenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4-fluorobenzoic acid;

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4-fluorobenzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methoxybenzoic acid; or

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methoxybenzoic acid;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein D is N or CH and R 4 is

wherein R 4 is optionally substituted with one, two, or three substituents selected from fluoro, chloro, methyl, cyano, cyclopropyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, and difluoromethoxy.

8. The compound:

3-(1-(2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)ethyl)benzoic acid;

3-((R)-1-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)ethyl)benzoic acid;

3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinamido)methyl)benzoic acid;

(R)-3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinamido)methyl)benzoic acid;

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid; or

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid;

or a pharmaceutically acceptable salt thereof.

9. The compound:

3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid; or

(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid;

or a pharmaceutically acceptable salt thereof.

10. The compound having the structure:

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound according to any of claims 8 - 10 or a pharmaceutically acceptable salt of said compound, present in a therapeutically effective amount, in admixture with at least one pharmaceutically acceptable excipient.

Assignments (1)
ASSIGNEE ADDRESS CORRECTION Recorded Mar 20, 2023
From: PFIZER INC.
To: PFIZER INC.
Reel/Frame 063119/0087 →