Preparation and use of bicyclic himbacine derivatives as PAR-1 receptor antagonists

Patent metadata

Field	Value
Publication number	US-9340530-B2
Application number	US-201314383176-A
Country	US
Kind code	B2
Filing date	Feb 27, 2013
Priority date	Mar 6, 2012
Publication date	May 17, 2016
Grant date	May 17, 2016

Abstract

The present invention relates to bicyclic himbacine derivatives of the formula or a pharmaceutically acceptable salt thereof, wherein: X is —O—, —N(R), —C(R 8 )(R 9 ) or —C(O)—; and Y is —O—, —N(R), —C(R 8 )(R 9 ) or —C(O)— and the remaining variables are described herein. The compounds of the invention are effective inhibitors of the PAR-1 receptor. The inventive compounds may be used for the treatment or prophylaxis of disease states such as ACS, secondary prevention of myocardial infarction or stroke, or PAD.

First claim

We claim:

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:
X is —O—, —N(R), —C(R 8 )(R 9 ) or —C(O)—;
Y is —O—, —N(R), —C(R 8 )(R 9 ) or —C(O)—;
R is H, alkyl or —S(O) 2 —R 9
R 1 is H, alkyl or haloalkyl;
R 2 is H, alkyl or haloalkyl;
R 3 is —N 3 , —CN; halogen, —OR 12 , —N(R 25 )(R 26 ), —C(O)OR 12 , —C(O)N(R 25 )(R 26 ), —SO 2 (R 12 ), R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl or R 17 -heteroaryl;
R 4 is H, alkyl or haloalkyl;
R 5 is H, alkyl or haloalkyl;
R 6 is H or alkyl;
R 7 is H or alkyl;
R 8 independently is H or alkyl;
R 9 independently is H or alkyl;
R 10 is fluoro;
R 11 is fluoro;
R 12 independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;
R 13 is independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;
R 14 is independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, —C(O)R 12 , —S(O) 2 —R 12 , R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;
or R 13 and R 14 taken together with the nitrogen atom to which they are attached are —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 —N(R 8 )—(CH 2 ) 2 —;

Het is a 5- or 6-membered heterocycloalkyl, heterocyclenyl or a heteroaryl ring containing 3 to 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of N, O or S, with the proviso that there are no adjacent oxygen or sulfur atoms present in said groups, and when Het is a N-containing heteraromatic group with one heteroatom present, then the ring nitrogen can form an N-oxide or a quaternary group with an alkyl group; wherein: 1) Het is attached to the double bond by a carbon atom ring member of Het; and 2) Het is substituted by 1 to 4 moieties, W,
where each W is independently hydrogen, alkyl, haloalkyl, R 17 -cycloalkyl, R 17 -heterocycloalkyl, R 16 -alkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -heteroarylalkyl, R 17 -heteroarylalkenyl, hydroxyalkyl, dihydroxyalkyl, aminoalkyl, alkylaminoalkyl, di-(alkyl)-aminoalkyl, alkoxy, -alkyl-SH, —S-alkyl, alkenyloxy, halogen, —NR 13 R 14 , —CN, —OH, —C(O)OR 12 , —COR 12 , —OS(O 2 )CF 3 , —CH 2 OCH 2 CF 3 , —C(O)NR 13 NR 14 , —OCHR 15 -phenyl, phenoxyalkyl, —NR 8 COR 12 , —NR 8 SO 2 R 12 , —C(O)NR 13 R 14 , —OC(R 15 ) 2 COOR 12 , —OC(R 15 ) 2 C(O)NR 13 R 14 , alkoxy optionally substituted by alkyl, amino or —NR 8 C(O)OR 12 , or alkyl optionally substituted with —NR 13 R 14 , —NR 13 COR 12 , —NR 8 CONR 13 R 14 , —NR 8 C(O)OR 12 , —NR 8 S(O) 2 NR 13 R 14 , —C(O)OR 12 , —CONR 13 R 14 or —OH;

R 15 independently is H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl or phenyl;
R 16 is 1 to 3 moieties and each R 16 is independently hydrogen, halogen, —OH, alkoxy, -alkyl-SH, —S-alkyl, R 24 -aryl, R 24 -heteroaryl, R 24 -heterocycloalkyl, R 24 -cycloalkyl, R 24 -cycloalkenyl, R 24 -heterocyclenyl, —OC(O)R 20 , —C(O)OR 20 , —C(O)R 20 , —C(O)NR 21 R 22 , —NR 21 R 22 , —NR 8 C(O)R 20 , —NR 8 C(O)NR 21 R 22 , —NR 8 SO 2 R 20 , —OC(O)NR 21 R 22 , R 23 -alkenyloxy, R 23 -alkynyloxy, R 23 -heterocycloalkyloxy, R 24 -cycloalkyloxy, R 24 -cycloalkenyloxy, R 24 -aryloxy, R 24 -heteroaryloxy, R 24 -cycloalkyl-NH—, —NR 8 SO 2 NHR 21 or —C(═NOR 18 )R 19 ;
R 17 is 1 to 3 moieties and each R 17 independently hydrogen, R 23 -alkyl, halogen, —CN, —NO 2 , —OH, R 23 -alkoxy, —OC(O)R 20 , —C(O)OR 20 , —C(O)R 20 , —C(O)NR 21 R 22 , —NR 21 R 22 , —NR 8 C(O)R 20 , —NR 8 C(O)NR 21 R 22 , —NR 8 SO 2 R 20 , —OC(O)NR 21 R 22 , —S(O)R 20 , —S(O) 2 R 20 , —SR 20 , —SO 2 NR 21 R 22 , —NHCOR 20 , —C(NH)—NH 2 , —C(O)NR 21 R 22 , R 23 -alkenyloxy, R 23 -alkynyloxy, R 24 -cycloalkyl, R 24 -cycloalkenyl, R 24 -heterocycloalkyl, R 24 -aryl, R 24 -heteroaryl, R 24 -heterocycloalkyloxy, R 24 -cycloalkyloxy, R 24 -cycloalkenyloxy, R 24 -aryloxy, R 24 -heteroaryloxy, R 24 -cycloalkyl-NH—, —NR 8 SO 2 NHR 21 or —C(═NOR 18 )R 19 ;
R 18 is H, alkyl, phenyl or benzyl;
R 19 is H, alkyl, phenyl or benzyl;
R 20 , R 21 and R 22 are independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halocycloalkyl or alkoxyalkyl;
R 23 is 1 to 3 moieties and each R 23 is independently hydrogen, halogen, —OH, alkyl, haloalkyl, alkoxy, —CN, amino, alkylamino, dialkylamino, di(alkyl)amino, haloalkoxy, hydroxyalkyl, —CHO, —C(O)alkylamino, —C(O)alkylamino, —NHC(O)alkyl or —N(alkyl)C(O)alkyl;
R 24 is 1 to 3 moieties and each R 24 is independently hydrogen, halogen, —OH, alkyl, haloalkyl, alkoxy, —CN, amino, alkylamino, dialkylamino, di(alkyl)amino, haloalkoxy, hydroxyalkyl, —CHO, —C(O)alkylamino, C(O)alkylamino, NHC(O)alkyl or —N(alkyl)C(O)alkyl;
R 25 is H, R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl, R 17 -aryl or R 17 -heteroaryl; and
R 26 is H, OH, —C(O)N(R 21 )(R 22 ), —C(S)N(R 21 )(R 22 ), —C(O)R 12 , —S(O) 2 R 12 ; R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl, or R 17 -heteroaryl.

2. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula

wherein:
R 1 is H, alkyl or haloalkyl;
R 2 is H, alkyl or haloalkyl;
R 3 is —N 3 , —CN; halogen, —OR 12 , —N(R 25 )(R 26 ), —C(O)OR 12 , —C(O)N(R 25 )(R 26 ), —SO 2 (R 12 ), R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl or R 17 -heteroaryl;
R 4 is H, alkyl or haloalkyl;
R 5 is H, alkyl or haloalkyl;
R 6 is H or alkyl;
R 7 is H or alkyl;
R 8 independently is H or alkyl;
R 10 is fluoro;
R 11 is fluoro;
R 12 independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;
R 13 is independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;
R 14 is independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, —C(O)R 12 , —S(O) 2 —R 12 , R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;
or R 13 and R 14 taken together with the nitrogen atom to which they are attached are —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 —N(R 8 )—(CH 2 ) 2 —;

W is independently hydrogen, alkyl, haloalkyl, R 17 -cycloalkyl, R 17 -heterocycloalkyl, R 16 -alkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -heteroarylalkyl, R 17 -heteroarylalkenyl, hydroxyalkyl, dihydroxyalkyl, aminoalkyl, alkylaminoalkyl, di-(alkyl)-aminoalkyl, alkoxy, -alkyl-SH, —S-alkyl, alkenyloxy, halogen, —NR 13 R 14 , —CN, —OH, —C(O)OR 12 , —COR 12 , —OS(O 2 )CF 3 , —CH 2 OCH 2 CF 3 , —C(O)NR 13 NR 14 , —OCHR 15 -phenyl, phenoxyalkyl, —NR 8 COR 12 , —NR 8 SO 2 R 12 , —C(O)NR 13 R 14 , —OC(R 15 ) 2 COOR 12 , —OC(R 15 ) 2 C(O)NR 13 R 14 , alkoxy optionally substituted by alkyl, amino or —NR 8 C(O)OR 12 , or alkyl optionally substituted with —NR 13 R 14 , —NR 13 COR 12 , —NR 8 CONR 13 R 14 , —NR 8 C(O)OR 12 , —NR 8 S(O) 2 NR 13 R 14 , —C(O)OR 12 , —CONR 13 R 14 or —OH;
R 15 independently is H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl or phenyl;
R 16 is 1 to 3 moieties and each R 16 is independently hydrogen, halogen, —OH, alkoxy, -alkyl-SH,

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

• Mandal Mihir
• Blizzard Timothy A
• Chen Helen
• Chobanian Harry
• Guo Yan
• Pio Barbara
• Wu Zhicai
• Biftu Tesfaye
• Greenlee William J
• Zhu Johnny Zhaoning

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title