Benzodiazepine derivatives as RSV inhibitors

Patent metadata

Field	Value
Publication number	US-9957281-B2
Application number	US-201615216119-A
Country	US
Kind code	B2
Filing date	Jul 21, 2016
Priority date	Jul 22, 2015
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof:

which inhibit Respiratory Syncytial Virus (RSV). The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from RSV infection. The invention also relates to methods of treating an RSV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

First claim

What is claimed:

1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) CN;
4) Optionally substituted —C 1 -C 8 alkyl; and
5) Optionally substituted —C 1 -C 8 alkyl —O—R 11 ;

R 2 and R 5 are each independently selected from the group consisting of:
1) Hydrogen; and
2) Optionally substituted —C 1 -C 8 alkyl;

A is selected from the group consisting of:
1) Optionally substituted —C 3 -C 12 cycloalkyl;
2) Optionally substituted —C 3 -C 12 cycloalkenyl;
3) Optionally substituted aryl; and
4) Optionally substituted heteroaryl

R 3 is hydrogen or R 11 ;
R 4 is selected from the group consisting of:
1) Optionally substituted —C 3 -C 12 cycloalkyl;
2) Optionally substituted —C 3 -C 12 cycloalkenyl;
3) Optionally substituted 3- to 12-membered heterocyclic;
4) Optionally substituted aryl;
5) Optionally substituted heteroaryl;
6) Optionally substituted aryl-O—;
7) Optionally substituted heteroaryl-O;
8) Optionally substituted aryl-C 1 -C 4 -alkyl; and
9) Optionally substituted heteroaryl-C 1 -C 4 -alkyl;

wherein R 4 is optionally substituted with 1 to 3 substituents independently selected from halo, —CH 3 , —CF 3 , —OCF 3 , —CN, —NH 2 , —OH, —CH 2 N(CH 3 ) 2 , —C(O)CH 3 , —NH—(C 1 -C 6 )alkyl, —NH—(C 1 -C 6 )alkyl-(C 1 -C 6 )alkoxy, —SO 2 —(C 1 -C 6 )alkyl, —SO 2 —NH—(C 1 -C 6 )alkyl, —NH—SO 2 —(C 1 -C 6 )alkyl, 3- to 12-membered heterocyclic, aryl, heteroaryl, C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, C 1 -C 8 -alkoxy, CH 3 OCH 2 —, CH 3 OCH 2 CH 2 O—,

each R 6 is independently selected from hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, amino, protected amino, nitro, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy, optionally substituted —NHC 1 -C 8 alkyl, optionally substituted —S—(—C 1 -C 8 alkyl), optionally substituted —SO 2 —(—C 1 -C 8 alkyl), -optionally substituted —SO 2 —NH—(—C 1 -C 8 alkyl), optionally substituted —NH—SO 2 —(—C 1 -C 8 alkyl), —CO 2 R 12 , —NR 13 R 14 , and —CO—NR 13 R 14 ;
R 11 and R 12 are each independently selected from the group consisting of:
1) Optionally substituted —C 1 -C 8 alkyl;
2) Optionally substituted —C 2 -C 8 alkenyl;
3) Optionally substituted —C 2 -C 8 alkynyl;
4) Optionally substituted —C 3 -C 8 cycloalkyl;
5) Optionally substituted —C 3 -C 8 cycloalkenyl;
6) Optionally substituted 3- to 8-membered heterocyclic;
7) Optionally substituted aryl; and
8) Optionally substituted heteroaryl;

R 13 and R 14 are each independently selected from hydrogen, optionally substituted —C 1 -C 8 -alkyl, optionally substituted —C 2 -C 8 -alkenyl, optionally substituted —C 2 -C 8 -alkynyl; optionally substituted —C 3 -C 8 -cycloalkyl, —C(O)R 12 , —S(O) 2 R 12 , and —S(O) 2 NHR 12 , and optionally substituted —C 1 -C 8 -alkoxy; alternatively, R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; and n is 0, 1, 2, 3 or 4; and
wherein each substituted R 1 , R 2 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 and A is substituted by one or more substituents selected from deuterium, tritium, —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO 2 , —CN, —NH 2 , —N 3 , protected amino, alkoxy, thioalkoxy, oxo, thioxo, —C 1 -C 12 -alkyl, —C 2 -C 12 -alkenyl, —C 2 -C 12 -alkynyl, —C 3 -C 12 -cycloalkyl-halo-C 1 -C 12 -alkyl, -halo-C 2 -C 12 -alkenyl, -halo-C 2 -C 12 -alkynyl, -halo-C 3 -C 12 -cycloalkyl, —NH—C 1 -C 12 -alkyl, —NH—C 2 -C 12 -alkenyl, —NH—C 2 -C 12 -alkynyl, —NH—C 3 -C 12 -cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocyclic, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C 1 -C 12 -alkyl, —O—C 2 -C 12 -alkenyl, —O—C 2 -C 12 -alkynyl, —O—C 3 -C 12 -cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocyclic, —C(O)—C 1 -C 12 -alkyl, —C(O)—C 2 -C 12 -alkenyl, —C(O)—C 2 -C 12 -alkynyl, —C(O)—C 3 -C 12 -cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocyclic, —CONH 2 , —CONH—C 1 -C 12 -alkyl, —CONH—C 2 -C 12 -alkenyl, —CONH—C 2 -C 12 -alkynyl, —CONH—C 3 -C 12 -cycloalkyl, —CONH-aryl, —CONH-heteroaryl, —CONH-heterocyclic, —OCO 2 —C 1 -C 12 -alkyl, —OCO 2 —C 2 -C 12 -alkenyl, —OCO 2 —C 2 -C 12 -alkynyl, —OCO 2 —C 3 -C 12 -cycloalkyl, —OCO 2 -aryl, —OCO 2 -heteroaryl, —OCO 2 -heterocyclic, —OCONH 2 , —OCONH—C 1 -C 12 -alkyl, —OCONH—C 2 -C 12 -alkenyl, —OCONH—C 2 -C 12 -alkynyl, —OCONH—C 3 -C 12 -cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocyclic, —NHC(O)—C 1 -C 12 -alkyl, —NHC(O)—C 2 -C 12 -alkenyl, —NHC(O)—C 2 -C 12 -alkynyl, —NHC(O)—C 3 -C 12 -cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclic, —NHCO 2 —C 1 -C 12 -alkyl, —NHCO 2 —C 2 -C 12 -alkenyl, —NHCO 2 —C 2 -C 12 -alkynyl, —NHCO 2 —C 3 -C 12 -cycloalkyl, —NHCO 2 -aryl, —NHCO 2 -heteroaryl, —NHCO 2 -heterocyclic, —NHC(O)NH 2 , —NHC(O)NH—C 1 -C 12 -alkyl, —NHC(O)NH—C 2 -C 12 -alkenyl, —NHC(O)NH—C 2 -C 12 -alkynyl, —NHC(O)NH—C 3 -C 12 -cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH-heterocyclic, NHC(S)NH 2 , —NHC(S)NH—C 1 -C 12 -alkyl, —NHC(S)NH—C 2 -C 12 -alkenyl, —NHC(S)NH—C 2 -C 12 -alkynyl, —NHC(S)NH—C 3 -C 12 -cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocyclic, —NHC(NH)NH 2 , —NHC(NH)NH—C 1 -C 12 -alkyl, —NHC(NH)NH—C 2 -C 12 -alkenyl, —NHC(NH)NH—C 2 -C 12 -alkynyl, —NHC(NH)NH—C 3 -C 12 -cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocyclic, —NHC(NH)—C 1 -C 12 -alkyl, —NHC(NH)—C 2 -C 12 -alkenyl, —NHC(NH)—C 2 -C 12 -alkynyl, —NHC(NH)—C 3 -C 12 -cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)-heterocyclic, —C(NH)NH—C 1 -C 12 -alkyl, —C(NH)NH—C 2 -C 12 -alkenyl, —C(NH)NH—C 2 -C 12 -alkynyl, —C(NH)NH—C 3 -C 12 -cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocyclic, —S(O)—C 1 -C 12 -alkyl, —S(O)—C 2 -C 12 -alkenyl, —S(O)—C 2 -C 12 -alkynyl, —S(O)—C 3 -C 12 -cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocyclic —SO 2 NH 2 , —SO 2 NH—C 1 -C 12 -alkyl, —SO 2 NH—C 2 -C 12 -alkenyl, —SO 2 NH—C 2 -C 12 -alkynyl, —SO 2 NH—C 3 -C 12 -cycloalkyl, —SO 2 NH-aryl, —SO 2 NH-heteroaryl, —SO 2 NH-heterocyclic, —NHSO 2 —C 1 -C 12 -alkyl, —NHSO 2 —C 2 -C 12 -alkenyl, —NHSO 2 —C 2 -C 12 -alkynyl, —NHSO 2 —C 3 -C 12 -cycloalkyl, —NHSO 2 -aryl, —NHSO 2 -heteroaryl, —NHSO 2 -heterocyclic, —CH 2 NH 2 , —CH 2 SO 2 CH 3 , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocyclic, —C 3 -C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—C 1 -C 12 -alkyl, —S—C 2 -C 12 -alkenyl, —S—C 2 -C 12 -alkynyl, —S—C 3 -C 12 -cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocyclic, methylthiomethyl, or -L′-R′, wherein L′ is C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene, and R′ is aryl, heteroaryl, heterocyclic, C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl.

2. The compound of claim 1 , wherein the compound is represented by Formula (Ia) or Formula (Ib):

3. The compound of claim 1 , wherein A is selected from one of the following by removal of two hydrogen atoms:

wherein each of the above shown is optionally substituted when possible.

4. The compound of claim 1 , wherein R 4 is selected from one of the following by removal of one hydrogen atom:

wherein each of the above shown is

Assignees

• Enanta Pharm Inc

Inventors

• Shook Brian C
• Kim In Jong
• Blaisdell Thomas P
• Yu Jianming
• Panarese Joseph
• Or Yat Sun

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title