Diacylglycerol acyltransferase 2 inhibitors

Patent metadata

Field	Value
Publication number	US-9296745-B2
Application number	US-201314384508-A
Country	US
Kind code	B2
Filing date	Mar 26, 2013
Priority date	Apr 6, 2012
Publication date	Mar 29, 2016
Grant date	Mar 29, 2016

Abstract

Derivatives of purine, 3H-imidazo[4,5-b]pyrimidine and 1H-imidazo[4,5-d]pyrazine 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.

First claim

What is claimed is:

1. A compound of Formula (I)

wherein:
A is CR 6 R 7 , O or S;
B is a bond, oxetanyl,

wherein m is 0, 1 or 2;
p is 1, 2, 3 or 4;
C and D are each individually selected from N, CH, CF and C(CH 3 ), wherein if C is N then D is CH, CF or C(CH 3 ) and if D is N then C is CH, CF or C(CH 3 );
R 1 is —C(O)-heterocyclyl, —C(O)—NR 4 R 5 , or a heteroaryl, wherein said heterocyclyl or heteroaryl is optionally substituted with 1 or 2 substituents selected independently from (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkoxy, (C 3 -C 6 )cycloalkoxy, halo, hydroxy(C 1 -C 4 )alkyl, mono-N- or di-N,N—(C 1 -C 4 )alkylamino, mono-N- or di-N,N—(C 3 -C 6 )cycloalkylamino, heterocyclyl, hydroxyl and cyano;
R 2 is (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, aryl, aryloxy, heteroaryloxy, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, —C(O)-heterocyclyl, —C(O)—NR 4 R 5 , or —NR 4 —C(O)—R 5 , wherein alkyl, alkoxy, cycloalkyl, cycloalkoxy, aralkyl, heteroaralkyl, aryl, aryloxy, heteroaryloxy, heteroaryl, heterocyclyl are each optionally substituted with one, two or three substituents selected independently from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, —C(O)—(C 1 -C 4 )alkyl, —C(O)—(C 3 -C 6 )cycloalkyl, halo, —C(O)—(C 1 -C 4 )alkoxy, —C(O)—(C 3 -C 6 )cycloalkoxy, mono-N- or di-N,N—(C 1 -C 4 )alkylamino, mono-N- or di-N,N—(C 3 -C 6 )cycloalkylamino, (C 1 -C 4 )alkylcarbonylamino, (C 3 -C 6 )cycloalkylcarbonylamino, (C 1 -C 4 )alkylcarbonyl-N—(C 1 -C 4 )alkylamino, (C 1 -C 4 )alkylcarbonyl-N—(C 3 -C 6 )cycloalkylamino, (C 3 -C 6 )cycloalkylcarbonyl-N—(C 1 -C 4 )alkylamino, (C 3 -C 6 )cycloalkylcarbonyl-N—(C 3 -C 6 )cycloalkylamino, aminocarbonyl, mono-N- or di-N,N—(C 1 -C 4 )alkylaminocarbonyl, mono-N- or di-N,N—(C 3 -C 6 )cycloaminocarbonyl, mono-N- or di-N,N—(C 1 -C 4 )alkylcarbonyl, mono-N- or di-N,N—(C 3 -C 6 )cycloalkylcarbonyl, mono-N- or di-N,N—(C 1 -C 4 )alkoxycarbonyl, mono-N- or di-N,N—(C 3 -C 6 )cycloalkoxycarbonyl, (C 1 -C 4 )alkylthio, (C 3 -C 6 )cycloalkylthio, aminosulfonyl, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 3 -C 6 )cycloalkylsulfinyl, (C 3 -C 6 )cycloalkylsulfonyl, mono-N- or di-N,N—(C 1 -C 4 )alkylaminosulfonyl, mono-N- or di-N,N—(C 3 -C 6 )cycloalkylaminosulfonyl, (C 1 -C 4 )alkylsulfonylamino, (C 3 -C 6 )cycloalkylsulfonylamino, (C 1 -C 4 )alkylsulfonyl-N—(C 1 -C 4 )alkylamino, (C 1 -C 4 )alkylsulfonyl-N—(C 3 -C 6 )cycloalkylamino, (C 3 -C 6 )cycloalkylsulfonyl-N—(C 1 -C 4 )alkylamino, (C 3 -C 6 )cycloalkylsulfonyl-N—(C 3 -C 6 )cycloalkylamino, aryl, heteroaryl, heterocyclyl, oxo, carboxyl, amino, hydroxyl and cyano, wherein said alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxy and cycloalkoxy are optionally substituted independently with one to nine fluoro, or 1, 2 or 3 substituents selected from halo, —C(O)—OH, —C(O)—(C 1 -C 4 )alkoxy, aminocarbonyl, mono-N- or di-N,N—(C 1 -C 4 )alkylcarbonyl, mono-N- or di-N,N—(C 3 -C 6 )cycloalkylcarbonyl, cyano, amino and hydroxyl;
R 3 is (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxyl or fluoro, wherein said alkyl is optionally substituted with one to nine fluoros and said (C 3 -C 6 )cycloalkyl is optionally substituted with one to six fluoros;
R 4 and R 5 are each independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyl, heteroaralkyl, heterocyclyl, (C 1 -C 4 )alkoxy, and (C 3 -C 6 )cycloalkoxy, wherein R 4 and R 5 are each optionally substituted with (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, halo or cyano, wherein each of said alkyl, cycloalkyl, alkoxy or cycloalkoxy is optionally substituted with one to nine fluoros;
R 6 and R 7 are each independently hydrogen, (C 1 -C 4 )alkyl, fluoro, (C 1 -C 4 )alkoxy, hydroxyl or cyano, wherein said alkyl is optionally substituted with one to nine fluoros;
R 8 is selected from fluoro, methyl or trifluoromethyl;
R 9 and R 10 are each independently selected from hydrogen, fluoro, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, aryl or heteroaryl, wherein said alkyl is optionally substituted with one to nine fluoros, and said cycloalkyl is optionally substituted with one to six fluoros, and said aryl and heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, methyl, ethyl, isopropyl, cyclopropyl, methylthio, methoxy, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, oxo and trifluoromethylthio; and
n is 0, 1 or 2;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

2. The compound of claim 1 wherein R 1 is —C(O)-heterocyclyl, —C(O)—NR 4 R 5 , pyridyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 6,7-dihydro-5H-pyrrolo[1,2-c]imidazolyl, wherein R 1 is optionally substituted with 1 or 2 substituents independently selected from fluoro, methyl, hydroxyl or —CH 2 OH;
D is CH, N, or CF;
B is a bond, oxetanyl or

wherein p is 1 or 2;
R 3 is fluoro or methyl;
R 6 and R 7 are each independently hydrogen, fluoro or methyl;
R 8 is selected from fluoro or methyl; and
R 9 and R 10 are each individually selected from hydrogen, fluoro, or methyl;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

3. The compound of claim 2 wherein R 1 is —C(O)-heterocyclyl or —C(O)—NR 4 R 5 wherein said heterocyclyl is optionally substituted with 1 or 2 substituents independently selected from fluoro and methyl;
B is a bond,

wherein p is 1 or 2;
R 2 is selected from phenyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-onyl, pyridazin-2(1H)-onyl, pyrimidin-2(1H)-onyl, pyrazin-2(1H)-onyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 2H-benzo[b][1,4]oxazin-3(4H)-onyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, phenyloxy, pyridinyloxy, benzyl, pyridinyl-(CH 2 )—, pyrazolyl-(CH 2 )—, cyclopropyl, and cyclobutyl; wherein said R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 3 -C 6 )cycloalkoxy, cyclopropyl, halo, hydroxyl, amino, dimethylamino, methylamino, cyclopropylamino, aminocarbonyl, methylaminocarbonyl, (C 1 -C 4 )alkylthio, (C 3 -C 6 )cycloalkylthio, aminosulfonyl, methylaminosulfonyl, phenyl, and heteroaryl wherein heteroaryl is selected from furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-onyl, pyridazin-2(1H)-onyl, pyrim

Assignees

• Pfizer

Inventors

• Ahn Kay
• Boehm Markus
• Cabral Shawn
• Carpino Philip A
• Futatsugi Kentaro
• Hepworth David
• Kung Daniel W
• Orr Suvi
• Wang Jian

Classifications

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/02

  Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives · CPC title

• 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