Compounds and methods for antiviral treatment

Patent metadata

Field	Value
Publication number	US-9504689-B2
Application number	US-201514635830-A
Country	US
Kind code	B2
Filing date	Mar 2, 2015
Priority date	Apr 17, 2012
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

Compounds and pharmaceutically acceptable salts and esters and compositions thereof, for treating viral infections are provided. The compounds and compositions are useful for treating Pneumovirinae virus infections. The compounds, compositions, and methods provided are particularly useful for the treatment of Human respiratory syncytial virus infections.

First claim

What is claimed is:

1. A method of treating a Pneumovirinae virus infection in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of formula Im:

wherein:
Ar is a C 2 -C 20 heterocyclyl group or a C 6 -C 20 aryl group, wherein the C 2 -C 20 heterocyclyl group or the C 6 -C 20 aryl group is optionally substituted with 1 to 5 R 6 ;
X is —C(R 13 )(R 14 )—, —N(CH 2 R 14 )— or —NH—, or X is absent;
R 1 is H, —OR 11 , —NR 11 R 12 , —NR 11 C(O)R 11 , —NR 11 C(O)OR 11 , —NR 11 C(O)NR 11 R 12 , N 3 , CN, —NO 2 , —SR 11 , —S(O) p R a , NR 11 S(O) p R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O) p (OR 11 ), —SO 2 NR 11 R 12 , —NR 11 S(O) p (OR 11 ), —NR 11 SO p NR 11 R 12 , —NR 11 C(═NR 11 )NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, C 2 -C 20 heterocyclyl(C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 8 )alkyl;
R 2 is H, CN, NO 2 , halogen or (C 1 -C 8 )alkyl;
R 7 is H, OR 11 , —NR 11 R 12 , —NR 11 C(O)R 11 , —NR 11 C(O)OR 11 , —NR 11 C(O)NR 11 R 12 , N 3 , CN, NO 2 , —SR 11 , —S(O) p R a , —NR 11 S(O) p R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O) p (OR 11 ), —SO 2 NR 11 R 12 , —NR 11 S(O) p (OR 11 ), —NR 11 SO p NR 11 R 12 , —NR 11 C(═NR 11 )NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, C 2 -C 20 heterocyclyl(C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 8 )alkyl;
R 8 is H, —OR 11 , —NR 11 R 12 , NR 11 C(O)R 11 , —NR 11 C(O)OR 11 , —NR 11 C(O)NR 11 R 12 , N 3 , CN, NO 2 , —SR 11 , —S(O) p R a , —NR 11 S(O) p R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)(OR 11 ), —SO 2 NR 11 R 12 , —NR 11 S(O) p (OR 11 ), —NR 11 SO p NR 11 R 12 , NR 11 C(═NR 11 )NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, C 2 -C 20 heterocyclyl(C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 8 )alkyl;
each R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 8 )alkyl, —C(═O)R a or —S(O) p R a ; or when R 11 and R 12 are attached to a nitrogen they may optionally be taken together with the nitrogen to which they are both attached to form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S—, —S(O) p —, —NH—, —NR a — or —C(O)—;
R 13 is H or (C 1 -C 8 )alkyl;
R 14 is H, (C 1 -C 8 )alkyl, NR 11 R 12 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 12 , NR 11 S(O) p R a , —NR 11 S(O) p (OR 11 ) or NR 11 SO p NR 11 R 12 ; and
wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, C 2 -C 20 heterocyclyl(C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 8 )alkyl of each R 1 , R 2 , R 7 , R 8 , R 8′ , R 11 or R 12 is independently, optionally substituted with one or more oxo, halogen, hydroxy, —NH 2 , CN, N 3 , —N(R a ) 2 , —NHR a , —SH, —SR a , —S(O) p R a , —OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , —NHS(O) p R a , —NR a S(O) p R a , —NHC(O)R a , —NR a C(O)R a , —NHC(O)OR a , —NR a C(O)OR a , —NR a C(O)NHR a , —NR a C(O)N(R a ) 2 , —NR a C(O)NH 2 , —NHC(O)NHR a , —NHC(O)N(R a ) 2 , —NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , —NR a S(O) p NHR a , —NR a S(O) p N(R a ) 2 , —NR a S(O) p NH 2 , —NHS(O) p NHR a , —NHS(O) p N(R a ) 2 , —NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 or R a ;
each R a is independently (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, C 2 -C 20 heterocyclyl(C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 8 )alkyl wherein any (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl or (C 2 -C 8 )alkynyl of R a is optionally substituted with one or more OH, NH 2 , CO 2 H, C 2 -C 20 heterocyclyl, and wherein any aryl(C 1 -C 8 )alkyl, C 6 -C 20 aryl, C 2 -C 20 heterocyclyl, (C 3 -C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 8 )alkyl of R a is optionally substituted with one or more —OH, —NH 2 , CO 2 H, C 2 -C 20 heterocyclyl or (C 1 -C 8 )alkyl; and
p is 1 or 2;
or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein R 2 is H.

3. The method of claim 1 wherein X is —C(R 13 )(R 14 )— or X is absent.

4. The method of claim 3 wherein R 13 is H and R 14 is —NHS(O) 2 (C 1 -C 3 )alkyl.

5. The method of claim 1 wherein X is absent.

6. The method of claim 1 wherein R 7 is H or (C 1 -C 8 )alkyl, wherein (C 1 -C 8 )alkyl is optionally substituted with one or more substituents selected from the group of oxo, halogen, hydroxy, —NH 2 , CN, N 3 , —N(R a ) 2 , —NHR a , —SH, —SR a , —S(O) p R a , —OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , —NHS(O) p R a , —NR a S(O) p R a , —NHC(O)R a , —NR a C(O)R a , —NHC(O)OR a , —NR a C(O)OR a , —NR a C(O)NHR a , —NR a C(O)N(R a ) 2 , —NR a C(O)NH 2 , —NHC(O)NHR a , —NHC(O)N(R a ) 2 , —NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , —NR a S(O) p NHR a , —NR a S(O) p N(R a ) 2 , —NR a S(O) p NH 2 , —NHS(O) p NHR a , —NHS(O) p N(R a ) 2 , —NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 and R a .

7. The method of claim 1 wherein R 7 is H or methyl.

8. The method of claim 1 wherein R 1 is H, —NR 11 R 12 , (C 1 -C 8 )alkyl or C 2 -C 20 heterocyclyl wherein (C 1 -C 8 )alkyl or C 2 -C 20 heterocyclyl is optionally substituted with one or more substituents selected from the group of oxo, halogen, hydroxy, —NH 2 , CN, N 3 , —N(R a ) 2 , —NHR a , —SH, —SR a , —S(O) p R a , —OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , —NHS(O) p R a , —NR a S(O) p R a , —NHC(O)R a , —NR a C(O)R a , —NHC(O)OR a , —NR a C(O)OR a , —NR a C(O)NHR a , —NR a C(O)N(R a ) 2 , —NR a C(O)NH 2 , —NHC(O)NHR a , —NHC(O)N(R a ) 2 , —NHC(O)NH 2 , ═NH, ═NOH, ═NOR a , —NR a S(O) p NHR a , —NR a S(O) p N(R a ) 2 , —NR a S(O) p NH 2 , —NHS(O) p NHR a , —NHS(O) p N(R a ) 2 , —NHS(O) p NH 2 , —OC(═O)R a , —OP(O)(OH) 2 and R a .

9. The method of claim 1 wherein R 1 is H, (C 1 -C 3 )alkyl or —NR 11 R 12 , wherein each R 11 or R 12 is independently H or (C 1 -C 3 )alkyl; or R 11 and R 12 together with the nitrogen to which they are both attached to form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S—, —S(O) p —, —NH—, —NR a — or —C(O)—.

10. The method of claim 1 wherein R 1 is H, methyl or azetidinyl.

11. The method of claim 1 wherein R 8 is —NR 11 R 12 , (C 1 -C 8 )alkyl or C 2 -C 20 heterocyclyl wherein (C 1 -C 8 )alkyl or C 2 -C 20 heterocyclyl is optionally substituted with one or more substituents selected from the group of oxo, halogen, hydroxy, —NH 2 , CN, N 3 , —N(R a ) 2 , —NHR a , —SH, —SR a , —S(O) p R a , —OR a , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —C(O)R a , —C(O)H, —C(═O)OR a , —C(═O)OH, —C(═O)N(R a ) 2 , —C(═O)NHR a , —C(═O)NH 2 , —NHS(O) p R a , —NR a S(O) p R a , —NHC(O)R a , —NR a C(O)R

Assignees

• Gilead Sciences Inc

Inventors

• Siegel Dustin
• Sperandio David
• Yang Hai
• Sangi Michael
• Parrish Jay P
• Hui Hon Chung

Classifications

• A61P43/00

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

• A61P31/14

  for RNA viruses · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title