Compounds and compositions as toll-like receptor 7 agonists

Patent metadata

Field	Value
Publication number	US-9944649-B2
Application number	US-201515307510-A
Country	US
Kind code	B2
Filing date	Apr 29, 2015
Priority date	May 1, 2014
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

The invention provides a compounds, immunogenic compositions and pharmaceutical compositions comprising such compounds and methods of using such compounds to treat diseases or disorders associated with Toll-Like Receptor 7 activity.

First claim

We claim:

1. A compound of Formula (I), or pharmaceutically acceptable salt thereof:

wherein:
R 1 is —NHR 6 or —NHCHR 6 R 9 ;
R 3 is -L 2 C(═O)OR 7 , —C(═O)OL 6 R 12 , —C(═O)OL 2 R 12 , -L 2 C(═O)OL 2 R 12 , -L 4 C(═O)OL 5 OH, -L 4 R 12 , -L 2 C(═O)OL 4 C(═O)L 2 R 12 , -L 2 C(═O)OL 6 R 12 , -L 2 C(═O)OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OL 4 C(═O)R 12 , -L 4 C(═O)OL 2 C(═O)R 12 , —CF 2 C(═O)R 7 , —CH═CHC(═O)OL 4 C(═O)R 12 , —OL 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 R 12 , —OL 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
R 4 is -L 2 C(═O)OR 7 , —C(═O)OL 6 R 12 , —C(═O)OL 2 R 12 , -L 2 C(═O)OL 2 R 12 , -L 4 C(═O)OL 5 OH, -L 4 R 12 , -L 2 C(═O)OL 4 C(═O)L 2 R 12 , -L 2 C(═O)OL 6 R 12 , -L 2 C(═O)OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OL 4 C(═O)R 12 , -L 4 C(═O)OL 2 C(═O)R 12 , —CF 2 C(═O)R 7 , —CH═CHC(═O)OL 4 C(═O)R 12 , —OL 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 R 12 , —OL 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
or R 4 is H, and R 3 is -L 2 C(═O)OR 7 , —C(═O)OL 6 R 12 , —C(═O)OL 2 R 12 , -L 2 C(═O)OL 2 R 12 , -L 4 C(═O)OL 5 OH, -L 4 R 12 , -L 2 C(═O)OL 4 C(═O)L 2 R 12 , -L 2 C(═O)OL 6 R 12 , -L 2 C(═O)OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OL 4 C(═O)R 12 , -L 4 C(═O)OL 2 C(═O)R 12 , —CF 2 C(═O)R 7 , —CF 2 C(═O)OR 7 , —N(R 11 ) 2 , —CH═CHC(═O)OL 4 C(═O)R 12 , —OL 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 R 12 , —OL 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
or R 3 is H, and R 4 is -L 2 C(═O)OR 7 , —C(═O)OL 6 R 12 , —C(═O)OL 2 R 12 , -L 2 C(═O)OL 2 R 12 , -L 4 C(═O)OL 5 OH, -L 4 R 12 , -L 2 C(═O)OL 4 C(═O)L 2 R 12 , -L 2 C(═O)OL 6 R 12 , -L 2 C(═O)OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OL 4 C(═O)R 12 , -L 4 C(═O)OL 2 C(═O)R 12 , —CF 2 C(═O)R 7 , —CF 2 C(═O)OR 7 , —N(R 11 ) 2 , —CH═CHC(═O)OL 4 C(═O)R 12 , —OL 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 R 12 , —OL 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
L 1 is —(CH 2 ) m —;
L 2 is —(CH 2 ) m —;
L 3 is —(CH 2 ) m —;
L 4 is —(CH 2 ) m —;
L 5 is —(CH 2 ) m —;
L 6 is —(CH 2 ) m O(CH 2 ) m —;
R 6 is —C 4 -C 6 alkyl;
R 7 is —C 1 -C 3 alkyl;
R 9 is L 1 OH;
each R 11 is independently selected from H or —C 1 -C 3 alkyl;
R 12 is
a) —N(R 11 ) 2 ;
b) an unsubstituted 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N and O;
c) a 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N and O substituted with ═O;
d) a 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N and O substituted with C 1 -C 3 alkyl or —C(═O)OR 7 ;
or
e) an unsubstituted phenyl;

and
each m is independently selected from 1, 2, 3, and 4.

2. The compound of Formula (I) of claim 1 , or pharmaceutically acceptable salt thereof:
wherein:
R 1 is —NHR 6 or —NHCHR 6 R 9 ;
R 3 is -L 2 C(═O)OR 7 , —C(═O)OL 6 R 12 , —C(═O)OL 2 R 12 , -L 2 C(═O)OL 2 R 12 , -L 4 C(═O)OL 5 OH, -L 4 R 12 , -L 2 C(═O)OL 4 C(═O)L 2 R 12 , -L 2 C(═O)OL 6 R 12 , -L 2 C(═O)OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OL 4 C(═O)R 12 , -L 4 C(═O)OL 2 C(═O)R 12 , —CF 2 C(═O)R 7 , —CH═CHC(═O)OL 4 C(═O)R 12 , —OL 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 R 12 , —OL 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
R 4 is -L 2 C(═O)OR 7 , —C(═O)OL 6 R 12 , —C(═O)OL 2 R 12 , -L 2 C(═O)OL 2 R 12 , -L 4 C(═O)OL 5 OH, -L 4 R 12 , -L 2 C(═O)OL 4 C(═O)L 2 R 12 , -L 2 C(═O)OL 6 R 12 , -L 2 C(═O)OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OL 4 C(═O)R 12 , -L 4 C(═O)OL 2 C(═O)R 12 , —CF 2 C(═O)R 7 , —CH═CHC(═O)OL 4 C(═O)R 12 , —OL 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 R 12 , —OL 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
or R 4 is H, and R 3 is -L 2 C(═O)OR 7 , —C(═O)OL 6 R 12 , —C(═O)OL 2 R 12 , -L 2 C(═O)OL 2 R 12 , -L 4 C(═O)OL 5 OH, -L 4 R 12 , -L 2 C(═O)OL 4 C(═O)L 2 R 12 , -L 2 C(═O)OL 6 R 12 , -L 2 C(═O)OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OL 4 C(═O)R 12 , -L 4 C(═O)OL 2 C(═O)R 12 , —CF 2 C(═O)R 7 , —CH═CHC(═O)OL 4 C(═O)R 12 , —OL 2 C(═O)OL 5 C(═O)R 12 , —OL 4 C(═O)OL 2 R 12 , —OL 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
or R 3 is H, and R 4 is -L 2 C(═O)OR 7 , —C(═O)OL 6 R 12 , —C(═O)OL 2 R 12 , -L 2 C(═O)OL 2 R 12 , -L 4 C(═O)OL 5 OH, -L 4 R 12 , -L 2 C(═O)OL 4 C(═O)L 2 R 12 , -L 2 C(═O)OL 6 R 12 , -L 2 C(═O)OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OL 4 C(═O)R 12 , -L 4 C(═O)OL 2 C(═O)R 12 , —CF 2 C(═O)R 7 , —CH═CHC(═O)OL 4 C(═O)R 12 , —OL 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 R 12 , —OL 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
L 1 is —(CH 2 ) m —;
L 2 is —(CH 2 ) m —;
L 3 is —(CH 2 ) m —;
L 4 is —(CH 2 ) m —;
L 5 is —(CH 2 ) m —;
L 6 is —(CH 2 ) m O(CH 2 ) m —;
R 6 is —C 4 -C 6 alkyl;
R 7 is —C 1 -C 3 alkyl;
R 9 is L 1 OH;
each R 11 is independently selected from H or —C 1 -C 3 alkyl;
R 12 is
a) —N(R 11 ) 2 ;
b) an unsubstituted 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N and O;
c) a 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N and O substituted with ═O;
d) a 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N and O substituted with C 1 -C 3 alkyl or —C(═O)OR 7 ;
or
e) an unsubstituted phenyl;

and
each m is independently selected from 1, 2, 3, and 4.

3. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ia) or Formula (Ib):

4. The compound of claim 1 , wherein,
R 1 is —NHR 6 or —NHCHR 6 R 9 ;
R 3 is -L 2 C(═O)OR 7 , —C(═O)OL 6 R 12 , —C(═O)OL 2 R 12 , -L 2 C(═O)OL 2 R 12 , -L 4 C(═O)OL 5 OH, -L 4 R 12 , -L 2 C(═O)OL 4 C(═O)L 2 R 12 , -L 2 C(═O)OL 6 R 12 , -L 2 C(═O)OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OL 4 C(═O)R 12 , -L 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
R 4 is —CF 2 C(═O)R 7 , -L 4 R 12 , —CH═CHC(═O)OL 4 C(═O)R 12 , —OL 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OR 7 , -L 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
or R 4 is H, and R 3 is -L 2 C(═O)OR 7 , —C(═O)OL 6 R 12 , —C(═O)OL 2 R 12 , -L 2 C(═O)OL 2 R 12 , -L 4 C(═O)OL 5 OH, -L 4 R 12 , -L 2 C(═O)OL 4 C(═O)L 2 R 12 , -L 2 C(═O)OL 6 R 12 , -L 2 C(═O)OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OL 4 C(═O)R 12 , -L 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
or R 3 is H, and R 4 is —CF 2 C(═O)R 7 , -L 4 R 12 , —CH═CHC(═O)OL 4 C(═O)R 12 , —OL 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OR 7 , -L 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 C(═O)R 12 or -L 2 C(═O)OL 3 R 12 ;
L 1 is —CH 2 —;
L 2 is —CH 2 — or —CH 2 CH 2 —;
L 3 is —CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
L 4 is —CH 2 —,
L 5 is —CH 2 CH 2 —,
L 6 is —(CH 2 ) 2 O(CH 2 ) 2 —;
R 6 is —C 4 alkyl or —C 5 alkyl;
R 7 is methyl, ethyl or propyl;
R 9 is LiOH;
each R 11 is independently selected from —C 1 -C 3 alkyl;
and
R 12 is
a) —N(R 11 ) 2 ;
b) an unsubstituted piperazinyl or an unsubstituted morpholinyl;
c) a 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N and O substituted with ═O;
d) a piperazinyl substituted with C 1 -C 3 alkyl or —C(═O)OR 7 ;
or
an unsubstituted phenyl.

5. The compound of claim 1 , wherein,
R 1 is —NHR 6 or —NHCHR 6 R 9 ;
R 4 is H, and R 3 is -L 2 C(═O)OR 7 , —C(═O)OL 6 R 12 , —C(═O)OL 2 R 12 , -L 2 C(═O)OL 2 R 12 , -L 4 C(═O)OL 5 OH, -L 4 R 12 , -L 2 C(═O)OL 4 C(═O)L 2 R 12 , -L 2 C(═O)OL 6 R 12 , -L 2 C(═O)OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OL 4 C(═O)R 12 , -L 4 C(═O)OL 2 C(═O)R 12 , —CF 2 C(═O)OR 7 , —N(R 11 ) 2 or -L 2 C(═O)OL 3 R 12 ;
or R 3 is H, and R 4 is —CF 2 C(═O)R 7 , -L 4 R 12 , —CH═CHC(═O)OL 4 C(═O)R 12 , —OL 2 C(═O)OL 4 C(═O)R 12 , —OL 4 C(═O)OL 2 R 12 , -L 2 C(═O)OR 7 , -L 2 C(═O)OL 4 C(═O)R 12 , —OL

Assignees

• Cortez Alex
• Hoffman Timothy
• Li Yongkai
• Wu Tom Yao Hsiang
• Zhang Xiaoyue
• Novartis Ag

Inventors

• Cortez Alex
• Hoffman Timothy
• Li Yongkai
• Wu Tom Yao-Hsiang
• Zhang Xiaoyue

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/20

  for DNA viruses · CPC title