Compounds and compositions as toll-like receptor 7 agonists

Patent metadata

Field	Value
Publication number	US-9902730-B2
Application number	US-201515307525-A
Country	US
Kind code	B2
Filing date	Apr 29, 2015
Priority date	May 1, 2014
Publication date	Feb 27, 2018
Grant date	Feb 27, 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 having the structure of Formula (I), or a pharmaceutical salt thereof:

wherein:
R 1 is —NHR 6 or —NHCHR 6 R 9 ;
R 3 is H, -L 2 R 12 , —OL 2 R 12 , —C(CH 3 ) 2 R 12 , —P(═O)(OH) 2 , —P(═O)OH(OR 7 ), —CF 2 R 12 , —CF 2 C(═O)OH, —CH═CHC(═O)OH, —C(═O)OH, -L 2 C(═O)OH, -L 7 C(═O)OH, —OL 2 C(═O)OH or tetrazolyl;
R 4 is H, -L 2 R 12 , —OL 2 R 12 , —C(CH 3 ) 2 R 12 , —P(═O)(OH) 2 , —P(═O)OH(OR 7 ), —CF 2 R 12 , —CF 2 C(═O)OH, —CH═CHC(═O)OH, —C(═O)OH, -L 2 C(═O)OH, -L 7 C(═O)OH, —OL 2 C(═O)OH or tetrazolyl;
where, when R 3 is H, then R 4 is -L 2 R 12 , —OL 2 R 12 , —C(CH 3 ) 2 R 12 , —P(═O)(OH) 2 , —P(═O)OH(OR 7 ), —CF 2 R 12 , —CF 2 C(═O)OH, —CH═CHC(═O)OH, —C(═O)OH, -L 2 C(═O)OH, -L 7 C(═O)OH, —OL 2 C(═O)OH or tetrazolyl;
or when R 4 is H, then R 3 is -L 2 R 12 , —OL 2 R 12 , —C(CH 3 ) 2 R 12 , —P(═O)(OH) 2 , —P(═O)OH(OR 7 ), —CF 2 R 12 , —CF 2 C(═O)OH, —CH═CHC(═O)OH, —C(═O)OH, -L 2 C(═O)OH, -L 7 C(═O)OH, —OL 2 C(═O)OH or tetrazolyl;

L 1 is —(CH 2 ) m —;
L 2 is —(CH 2 ) m —;
L 7 =—(CH 2 ) m (CHR 11 CH 2 ) m (CH 2 ) n —;
R 6 is —C 3 -C 6 alkyl;
R 7 is —C 1 -C 3 alkyl;
R 9 is L 1 OH;
each R 11 is independently selected from —OH;
R 12 is
a) an unsubstituted tetrazolyl;
b) a tetrazolyl substituted with -L 1 C(═O)OH;
or
c) a 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N and O substituted with —C(═O)OH;

each m is independently selected from 1, 2, 3, and 4,
and
each n is independently selected from 0, 1, 2, 3, and 4.

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

3. The compound of claim 1 , wherein:
R 1 is —NHR 6 or —NHCHR 6 R 9 ;
R 3 is H, —OL 2 C(═O)OH or tetrazolyl;
R 4 is H, -L 2 R 12 , —OL 2 R 12 , —C(CH 3 ) 2 R 12 , —P(═O)(OH) 2 , —P(═O)OH(OR 7 ), —CF 2 R 12 , —CF 2 C(═O)OH, —CH═CHC(═O)OH, —C(═O)OH, -L 2 C(═O)OH, -L 7 C(═O)OH or tetrazolyl;
where, when R 3 is H, then R 4 is -L 2 R 12 , —OL 2 R 12 , —C(CH 3 ) 2 R 12 , —P(═O)(OH) 2 , —P(═O)OH(OR 7 ), —CF 2 R 12 , —CF 2 C(═O)OH, —CH═CHC(═O)OH, —C(═O)OH, -L 2 C(═O)OH, -L 7 C(═O)OH or tetrazolyl;
or when R 4 is H, then R 3 is —OL 2 C(═O)OH or tetrazolyl;

L 1 is —(CH 2 ) m —;
L 2 is —(CH 2 ) m —;
L 7 =—(CH 2 ) m (CHR 11 CH 2 ) m (CH 2 ) n —;
R 6 is —C 3 -C 6 alkyl;
R 7 is —C 1 -C 3 alkyl; methyl
R 9 is L 1 OH;
each R 11 is independently selected from —OH;
R 12 is
a) an unsubstituted tetrazolyl;
b) a tetrazolyl substituted with —L 1 C(═O)OH;
or
c) a 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N and O substituted with —C(═O)OH;

each m is independently selected from 1, 2, 3, and 4,
and
each n is independently selected from 0, 1, 2, 3, and 4.

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

R 4 is H, -L 2 R 12 , —OL 2 R 12 , —C(CH 3 ) 2 R 12 , —P(═O)(OH) 2 , —P(═O)OH(OR 7 ), —CF 2 R 12 , —CF 2 C(═O)OH, —CH═CHC(═O)OH, —C(═O)OH, -L 2 C(═O)OH, -L 7 C(═O)OH, —OL 2 C(═O)OH,

where, when R 3 is H, then R 4 is -L 2 R 12 , —OL 2 R 12 , —C(CH 3 ) 2 R 12 , —P(═O)(OH) 2 , —P(═O)OH(OR 7 ), —CF 2 R 12 , —CF 2 C(═O)OH, —CH═CHC(═O)OH, —C(═O)OH, -L 2 C(═O)OH, -L 7 C(═O)OH, —OL 2 C(═O)OH,

or when R 4 is H, then R 3 is -L 2 R 12 , —OL 2 R 12 , —C(CH 3 ) 2 R 12 , —P(═O)(OH) 2 , —P(═O)OH(OR 7 ), —CF 2 R 12 , —CF 2 C(═O)OH, —CH═CHC(═O)OH, —C(═O)OH, -L 2 C(═O)OH, -L 7 C(═O)OH, —OL 2 C(═O)OH,

L 1 is —(CH 2 ) m —;
L 2 is —(CH 2 ) m —;
L 7 =—(CH 2 ) m (CHR 11 CH 2 ) m (CH 2 ) n —;
R 6 is —C 3 -C 6 alkyl;
R 7 is —C 1 -C 3 alkyl;
R 9 is L 1 OH;
each R 11 is independently selected from —OH;
R 12 is

each m is independently selected from 1, 2, 3, and 4,
and
each n is independently selected from 0, 1, 2, 3, and 4.

5. The compound of claim 1 , wherein:
R 1 is —NHR 6 or —NHCHR 6 R 9 ;
R 3 is H, —OL 2 C(═O)OH,

R 4 is H, -L 2 R 12 , —OL 2 R 12 , —C(CH 3 ) 2 R 12 , —P(═O)(OH) 2 , —P(═O)OH(OR 7 ), —CF 2 R 12 , —CF 2 C(═O)OH, —CH═CHC(═O)OH, —C(═O)OH, -L 2 C(═O)OH, -L 7 C(═O)OH,

where, when R 3 is H, then R 4 is -L 2 R 12 , —OL 2 R 12 , —C(CH 3 ) 2 R 12 , —P(═O)(OH) 2 , —P(═O)OH(OR 7 ), —CF 2 R 12 , —CF 2 C(═O)OH, —CH═CHC(═O)OH, —C(═O)OH, -L 2 C(═O)OH, -L 7 C(═O)OH,

or when R 4 is H, then R 3 is —OL 2 C(═O)OH,

L 1 is —(CH 2 ) m —;
L 2 is —(CH 2 ) m —;
L 7 =—(CH 2 ) m (CHR 11 CH 2 ) m (CH 2 ) n —;
R 6 is —C 3 -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;
R 12 is

each m is independently selected from 1, 2, 3, and 4,
and
each n is independently selected from 0, 1, 2, 3, and 4.

6. The compound of claim 1 , wherein:
L 1 is —CH 2 —;
L 2 is —CH 2 — or —CH 2 CH 2 —;
L 7 =—(CH 2 ) 2 (CHR 11 CH 2 ) 2 —;
R 6 is —C 4 alkyl or —C 5 alkyl;
R 7 is methyl, ethyl or propyl, and
R 11 is OH.

7. The compound of claim 1 , wherein:
R 1 is —NHR 6 ;
R 3 is H;
R 4 is -L 2 R 12 ;
L 2 is —(CH 2 ) m —;
R 6 is —C 3 -C 6 alkyl;
R 12 is
a) an unsubstituted tetrazolyl;
b) a tetrazolyl substituted with -L 1 C(═O)OH;
or
c) a 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N and O substituted with —C(═O)OH, and each m is independently selected from 1, 2, 3, and 4.

8. The compound of claim 1 , wherein:
R 1 is —NHR 6 ;
R 3 is H;
R 4 is -L 2 R 12 ;
L 2 is —CH 2 — or —CH 2 CH 2 —;
R 6 is —C 5 alkyl;
and
R 12 is

9. The compound of claim 1 , wherein:
R 1 is —NHR 6 ;
R 3 is H;
R 4 is -L 2 R 12 ;
L 2 is —CH 2 — or —CH 2 CH 2 —;
R 6 is —C 5 alkyl;
and
R 12 is

10. The compound of claim 1 , wherein:
R 1 is —NHR 6 ;
R 3 is H;
R 4 is -L 2 C(═O)OH;
L 2 is —CH 2 — or —CH 2 CH 2 —;
and
R 6 is —C 5 alkyl.

11. The compound of claim 1 , wherein the compound is selected

Assignees

• Novartis Ag

Inventors

• Li Yongkai
• Mo Tingting
• Va Porino
• Wu Tom Yao Hsiang
• Zhang Xiaoyue

Classifications

• A61P37/06

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

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

• A61P37/04

  Immunostimulants · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title