Heterocyclic aspartyl protease inhibitors

Patent metadata

Field	Value
Publication number	US-9416108-B2
Application number	US-201414575418-A
Country	US
Kind code	B2
Filing date	Dec 18, 2014
Priority date	Dec 15, 2003
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

Abstract

Disclosed are compounds of the formula I

or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein
W is a bond, —C(═S)—, —S(O)—, —S(O) 2 —, —C(═O)—, —O—, —C(R 6 )(R 7 )—, —N(R 5 )— or —C(═N(R 5 ))—; X is —O—, —N(R 5 )— or —C(R 6 )(R 7 )—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O) 2 —, —C(═O)— or —C(═NR 5 )—; U is a bond, —S(O)—, —S(O) 2 —, —C(O)—, —O—, —P(O)(OR 15 )—, —C(═NR 5 )—, —(C(R 6 )(R 7 )) b — or —N(R 5 )—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, U is not —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—; provided that when X is —N(R 5 )— and W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, then U is not a bond; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined in the specification;

and pharmaceutical compositions comprising the compounds of formula I.

Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes.
Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic antagonist.

First claim

We claim:

1. A compound having the structural formula

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
W is —O—;
X is —O—, —N(R 5 )— or —C(R 6 )(R 7 )—; provided that when X is —O—, U is not —C(═O)— or —C(═NR 5 )—;
U is —C(O)—, —P(O)(OR 15 )—, —C(═NR 5 )—, or —(C(R 6 )(R 7 )) b —; wherein b is 1 or 2;
R 1 and R 5 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, —OR 15 —, —CN, —C(O)R 8 , —C(O)OR 9 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)N(R 11 )(R 12 ), —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —NO 2 , —N═C(R 8 ) 2 and —N(R 8 ) 2 , provided that R 1 and R 5 are not both selected from —NO 2 , —N═C(R 8 ) 2 and —N(R 8 ) 2 ;
R 2 is H;
R 3 , R 4 , R 6 and R 7 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CH 2 —O—Si(R 9 )(R 10 )(R 19 ), —SH, —CN, —OR 9 , —C(O)R 8 , —C(O)OR 9 , —C(O)N(R 11 )(R 12 ), —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), —N(R 11 )C(O)OR 9 and —C(═NOH)R 8 ; provided that when U is —O— or —N(R 5 )—, then R 3 , R 4 , R 6 and R 7 are not halo, —SH, —OR 9 , —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), or —N(R 11 )C(O)OR 9 ; provided that R 3 and R 4 are not halo, —SH, —OR 9 , —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), or —N(R 11 )C(O)OR 9 ;

or R 3 , R 4 , R 6 and R 7 , together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group optionally substituted by R 14 or a 3-7 membered cycloalkylether optionally substituted by R 14
or R 3 and R 4 or R 6 and R 7 together with the carbon to which they are attached, are combined to form multicyclic groups such as

wherein M is —CH 2 —, S, —N(R 19 )— or O, A and B are independently aryl or heteroaryl and q is 0, 1 or 2 provided that when q is 2, one M must be a carbon atom and when q is 2, M is optionally a double bond; and with the proviso that when R 3 , R 4 , R 6 and R 7 form said multicyclic groups

then adjacent R 3 and R 4 or R 6 and R 7 groups cannot be combined to form said multicyclic groups;
R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR 15 , —N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) and —N(R 15 )C(O)OR 16 ;
R 9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
R 10 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —N(R 15 )(R 16 );
R 11 , R 12 and R 13 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —C(O)R 8 , —C(O)OR 9 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)N(R 15 )(R 16 ), —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ) and —CN;
R 14 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) and —N(R 15 )C(O)OR 16 ;
R 15 , R 16 and R 17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R 18 -alkyl, R 18 -cycloalkyl, R 18 -cycloalkylalkyl, R 18 -heterocycloalkyl, R 18 -heterocycloalkylalkyl, R 18 -aryl, R 18 -arylalkyl, R 18 -heteroaryl and R 18 -heteroarylalkyl; or
R 15 , R 16 and R 17 are

wherein R 23 numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5;
R 18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO 2 , halo, heteroaryl, HO-alkyoxyalkyl, —CF 3 , —CN, alkyl-CN, —C(O)R 19 , —C(O)OH, —C(O)OR 19 , —C(O)NHR 20 , —C(O)NH 2 , —C(O)NH 2 —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 19 , —S(O) 2 R 20 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 19 , —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OCF 3 , —OH, —OR 20 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 20 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R 20 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 20 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);
or two R 18 moieties on adjacent carbons can be linked together to form

R 19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;
R 20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;
and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently unsubstituted or substituted by 1 to 5 R 21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —CH(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —R 15 ; —CH 2 N(R 15 )(R 16 ), —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —S(O)R 15 , ═NOR 15 , —N 3 , —NO 2 and —S(O) 2 R 15 ; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heter

Assignees

• Merck Sharp & Dohme

Inventors

• Zhu Zhaoning
• Stamford Andrew W

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P31/18

  for HIV · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P33/06

  Antimalarials · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title