IP Library › Granted Patent US 9,902,730

Granted Patent B2

US 9,902,730 · App. 15/307,525 · Granted Feb 27, 2018

Compounds and compositions as toll-like receptor 7 agonists

Inventors: Yongkai Li (Del Mar, CA); Tingting Mo (Saratoga, CA); Porino Va (San Diego, CA); Tom Yao-Hsiang Wu (San Diego, CA); Xiaoyue Zhang (San Diego, CA)

Assignee: Novartis AG

C07D487/04

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,902,730
App. No.: 15/307,525
Granted: Feb 27, 2018
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

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.

Claims (185)

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;

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;

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,

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;

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 from:

5-(5-((1H-tetrazol-5-yl)methoxy)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine;

5-(5-((1H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine;

(S)-2-((5-(5-((1H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol;

(S)-2-((5-(5-((1H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-2-amino-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol;

5-(5-(2-(1H-tetrazol-5-yl)ethyl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine;

N4-hexyl-5-(2-methoxy-5-(1H-tetrazol-5-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine;

(S)-2-((2-amino-5-(2-methoxy-5-(1H-tetrazol-5-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol;

2-(5-(3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxybenzyl)-2H-tetrazol-2-yl)acetic acid;

5-(2-methoxy-4-(1H-tetrazol-5-yl)benzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine;

5-(2-methoxy-5-(1H-tetrazol-5-yl)benzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine;

5-(5-(2-(1H-tetrazol-5-yl)propan-2-yl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine;

(S)-2-((5-(5-(2-(1H-tetrazol-5-yl)propan-2-yl)-2-methoxybenzyl)-2-amino-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol;

5-(5-(difluoro(1H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine;

2-(3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxyphenyl)-2,2-difluoroacetic acid;

(3R,5R)-7-(3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yemethyl)-4-methoxyphenyl)-3,5-dihydroxyheptanoic acid;

2-(3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxyphenyl)acetic acid;

(S)-2-(3-((2-amino-4-((1-hydroxyhexan-2-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxyphenyl)acetic acid;

3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxybenzoic acid;

(3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxyphenyl)phosphonic acid;

methyl hydrogen (3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxyphenyl)phosphonate;

(E)-3-(3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxyphenyl)acrylic acid;

3-(3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxyphenyl)propanoic acid;

(S)-3-(3-((2-amino-4-((1-hydroxyhexan-2-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxyphenyl)propanoic acid;

(S)-1-(4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)pyrrolidine-2-carboxylic acid;

(R)-1-(3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxybenzyl)pyrrolidine-2-carboxylic acid, and

2-(4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxyphenoxy)acetic acid.

12. The compound of claim 1 , wherein the compound is selected from:

2-(3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxyphenyl)acetic acid;

3-(2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxybenzoic acid;

5-(5-((1H-tetrazol-5-yl)methyl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine;

5-(5-(2-(1H-tetrazol-5-yl)ethyl)-2-methoxybenzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine;

(S)-1-(4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)pyrrolidine-2-carboxylic acid, and

(R)-1-(3-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-4-methoxybenzyl)pyrrolidine-2-carboxylic acid.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

14. A method for treating a disease or disorder associated with TLR7 activity, wherein the method comprises administering to a system or subject in need of such treatment an effective amount of a compound of claim 1 .

15. The method of claim 14 , wherein the disease is an infectious disease, a viral infectious disease, an inflammatory disease, a respiratory disease, a dermatological disease, an autoimmune disease, a cell-proliferative disease or cancer.

16. The method of claim 14 , wherein the disease or condition is asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis, dermatitis, actinic keratosis, basal cell carcinoma, bladder cancer, allergic rhinitis, psoriasis, scleroderma, urticaria, rheumatoid arthritis, multiple sclerosis, cancer, breast cancer, HIV, hepatitis, hepatitis C or lupus.

17. The method of claim 14 , wherein the disease or condition is hepatitis B, hepatitis C, colorectal cancer or hepatocellular carcinoma.

18. The pharmaceutical composition of claim 13 , wherein the compound is selected from: