Compounds (cystein based lipopeptides) and compositions as TLR2 agonists used for treating infections, inflammations, respiratory diseases etc

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

wherein:

R 1 is H, —C(O)—C 7 -C 18 alkyl or —C(O)—C 1 -C 6 alkyl;

R 2 is C 7 -C 18 alkyl;

R 3 is C 7 -C 18 alkyl;

L 1 is —CH 2 O—, —CH 2 NR 7 C(O)— or —CH 2 OC(O)NR 7 —;

L 2 is —O—, —NR 7 C(O)— or —OC(O)NR 7 —;

R 4 is -L 3 R 5 or -L 4 R 5 ;

R 5 is —N(R 7 ) 2 , -OR 7 , —P(O)(OR 7 ) 2 , —C(O)OR 7 , —NR 7 C(O)L 3 R 8 , —NR 7 C(O)L 4 R 8 , —OL 3 R 6 , —C(O)NR 7 L 3 R 8 , —C(O)NR 7 L 4 R 8 , —S(O) 2 0R 7 , —OS(O) 2 OR 7 , C 1 -C 6 alkyl, a C 6 aryl, a C 10 aryl, a C 14 aryl, 5 to 14 ring membered heteroaryl containing 1 to 3 heteroatoms selected from O, S and N, C 3 -C 8 cycloalkyl or a 5 to 6 ring membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, S and N, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 5 are each unsubstituted or the aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 5 are each substituted with 1 to 3 substituents independently selected from —OR 9 , —OL 3 R 6 , —OL 4 R 6 , —OR 7 , and —C(O)OR 7 ;

L 3 is a C 1 -C 10 alkylene, substituted with 1 to 4 R 6 groups, or the C 1 -C 10 alkylene of L 3 is substituted with 2 C 1 -C 6 alkyl groups on the same carbon atom which together, along with the carbon atom they are attached to, form a C 3 -C 8 cycloakyl;

L 4 is —((CR 7 R 7 ) p O) q (CR 10 R 10 ) p — or —(CR 11 R 11 )((CR 7 R 7 ) p O) q ((CR 10 R 10 ) p —, wherein each R 11 is a C 1 -C 6 alkyl groups which together, along with the carbon atom they are attached to, form a C 3 -C 8 cycloakyl;

each R 6 is independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-2 hydroxyl groups, —OR 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —P(O)(OR 7 ) 2 , a C 6 aryl, a C 10 aryl and a C 14 aryl;

each R 7 is independently selected from H and C 1 -C 6 alkyl;

R 8 is selected from —SR 7 , —C(O)OH, —P(O)(OR 7 ) 2 , and a 5 to 6 ring membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O and N;

R 9 is phenyl;

each R 10 is independently selected from H and halo;

each p is independently selected from 1, 2, 3, 4, 5 and 6, and

q is 1, 2, 3 or 4.

2. The compound of claim 1 , wherein:

R 1 is H, —C(O)—C 10 -C 18 alkyl;

R 2 is C 10 -C 18 alkyl ;

R 3 is C 10 -C 18 alkyl;

L 1 is —CH 2 OC(O) NR 7 — ;

L 2 is —OC(O) NR 7 ;

R 4 is -L 3 R 5 or -L 4 R 5 ;

R 5 is —N(R 7 ) 2 , OR 7 , —P(O)(OR 7 ) 2 , —C(O)OR 7 , —NR 7 C(O)L 3 R 8 , —OL 3 R 6 , —C(O)NR 7 L 3 R 8 , C 1 -C 6 alkyl, a C 6 aryl, a C 10 aryl, a C 14 aryl, 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from O, S and N, C 3 -C 8 cycloalkyl or a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, S and N, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 5 are each optionally substituted with 1 to 3 substituents independently selected from —OR 9 , —OL 3 R 6 , —OL 4 R 6 , —OR 7 , and —C(O)OR 7 ;

L 3 is a C 1 -C 10 alkylene, substituted with 1 to 4 R 6 groups, or the C 1 -C 6 alkylene of L 3 is substituted with 2 C 1 -C 6 alkyl groups on the same carbon atom which together, along with the carbon atom they are attached to, form a C 3 -C 8 cycloakyl;

L 4 is —((CR 7 R 7 ) p O) q (CR 10 R 10 ) p — or —(CR 11 R 11 )((CR 7 R 7 ) p O) q (CR 10 R 10 ) p —, wherein each R 11 is a C 1 -C 6 alkyl groups which together, along with the carbon atom they are attached to, form a C 3 -C 8 cycloakyl;

each R 6 is independently selected from halo, C 1 -C 6 alkyl, —OR 7 , N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —P(O)(OR 7 ) 2 , a C 6 aryl, a C 10 aryl and a C 14 aryl;

each R 7 is independently selected from H and C 1 -C 6 alkyl;

R 8 is selected from —SR 7 , —C(O)OH and a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O and N;

R 9 is phenyl;

each R 10 is independently selected from H and halo;

each p is independently selected from 1, 2, 3, 4, 5 and 6, and

q is 1, 2, 3 or 4.

3. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1 is H.

4. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1 is —C(O)—C 15 alkyl.

5. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein:

L 1 is —CH 2 O— and L 2 is —O—, —NR 7 C(O)— or —OC(O)NR 7 —;

or L 1 is —CH 2 NR 7 C(O)— and L 2 is —O—, —NR 7 C(O)— or —OC(O)NR 7 —;

or L 1 is —CH 2 OC(O)NR 7 — and L 2 is —O—, NR 7 C(O)— or —OC(O)NR 7 —.

6. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein:

L 1 is —CH 2 O— and L 2 is —O—;

or L 1 is —CH 2 O— and L 2 is —NHC(O)—;

or L 1 is —CH 2 OC(O)NH— and L 2 is —OC(O)NH—.

7. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein:

R 2 is —C 11 alkyl and R 3 is —C 11 alkyl;

or R 2 is —C 16 alkyl and R 3 is —C 16 alkyl;

or R 2 is —C 16 alkyl and R 3 is —C 11 alkyl;

or R 2 is —C 12 alkyl and R 3 is —C 12 alkyl;

or R 2 is —C 7 alkyl and R 3 is —C 7 alkyl;

or R 2 is —C 9 alkyl and R 3 is —C 9 alkyl;

or R 2 is —C 8 alkyl and R 3 is —C 8 alkyl;

or R 2 is —C 13 alkyl and R 3 is —C 13 alkyl;

or R 2 is —C 12 alkyl and R 3 is —C 11 alkyl;

or R 2 is —C 10 alkyl and R 3 is —C 10 alkyl;

or R 2 is —C 15 alkyl and R 3 is —C 15 alkyl.

8. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2 is —C 11 alkyl and R 3 is —C 11 alkyl.

9. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 5 is —NH 2 , —N(CH 2 CH 3 ) 2 , —OH, —OCH 3 , —P(O)(OH) 2 , —C(O)OH, —S(O) 2 OH, —OS(O) 2 OH, —NHC(O)L 3 R 8 , —OL 3 R 6 , —C(O)NHL 4 R 8 or —C(O)NHL 3 R 8 .

10. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 5 is —NH 2 , —N(CH 2 CH 3 ) 2 , —OH, —OCH 3 , —P(O)(OH) 2 , —C(O)OH, —NHC(O)L 3 R 8 , —S(O) 2 OH, —OS(O) 2 OH and —OL 3 R 6 .

11. The compound of claim 1 , wherein R 5 is C 1 -C 6 alkyl, phenyl, pyridinyl, imidazolyl or morpholinyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from —OR 9 , —OL 3 R 6 , —OL 4 R 6 and —OH.

12. The compound of claim 1 , wherein R 8 is selected from —SH, —C(O)OH, —P(O)(OH) 2 , and a 5-6 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from O.

13. The compound of claim 1 , wherein L 3 is a C 1 -C 10 alkylene, substituted with 1 to 4 R 6 groups.

14. The compound of claim 1 , wherein:

L 1 is —((CR 7 R 7 ) p O) q (CR 10 R 10 ) p —,

each R 10 is independently selected from H and F;

each p is independently selected from 2, 3, and 4, and

q is 1, 2, 3 or 4.

15. The compound of claim 1 , wherein each R 6 is independently selected from methyl, ethyl, i-propyl, i-butyl,-CH 2 OH, —OH, —F, —NH 2 , —C(O)NH 2 , —P(O)(OH) 2 and phenyl.

16. The compound of claim 1 , wherein each R 7 is independently selected from H, methyl and ethyl.

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

(4R,7S,10R,14R)-10-amino-4-carbamoyl-7-ethyl-14-(hexadecyloxy)-6,9-dioxo-16-oxa-12-thia-5,8-diazadotriacontan-1-oic acid;

N-((R)-1-(((R)-2-amino-3-((1-(hydroxymethyl)cyclopropyl)amino)-3-oxopropyl)thio)-3-(hexadecyloxy)propan-2-yl)dodecanamide;

N,N′-((R)-3-(((R)-2-amino-3-((1-(hydroxymethyl)cyclopropyl)amino)-3-oxopropyl)thio)propane-1,2-diyl)didodecanamide;

((14R,18R)-14-amino-18-(dodecyloxy)-13-oxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontyl) phosphonic acid;

((12R,16R)-12-amino-16-(dodecyloxy)-1,1-difluoro-11-oxo-4,7,18-trioxa-14-thia-10-azatriacontyl) phosphonic acid;

((14R,18R)-14-amino-18-dodecanamido-13-oxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontyl) phosphonic acid;

((11S,14R,18R)-14-amino-18-dodecanamido-11-methyl-13-oxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontyl)phosphonic acid;

((11S,14R,18R)-14-amino-18-(dodecyloxy)-11-methyl-13-oxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontyl)phosphonic acid;

((11S,14R,18R)-14-amino-18-(dodecyloxy)-11-methyl-10,13-dioxo-3,6,20-trioxa-16-thia-9,12-diazadotriacontyl)phosphonic acid;

((11S,14R,18R)-14-amino-18-dodecanamido-11-methyl-10,13-dioxo-3,6,20-trioxa-16-thia-9,12-diazadotriacontyl)phosphonic acid;

(15R,19R)-15-amino-19-(dodecyloxy)-14-oxo-4,7,10,21-tetraoxa-17-thia-13-azatritriacontan-1-oic acid;

(15R,19R)-15-amino-19-dodecanamido-14-oxo-4,7,10,21-tetraoxa-17-thia-13-azatritriacontan-1-oic acid;

((12R,16R)-12-amino-16-dodecanamido-1,1-difluoro-11-oxo-4,7,18-trioxa-14-thia-10-azatriacontyl) phosphonic acid;

((14R,18R)-14-amino-18-((decylcarbamoyl)oxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontyl) phosphonic acid;

(15R,19R)-15-amino-19-((decylcarbamoyl)oxy)-14,22-dioxo-4,7,10,21-tetraoxa-17-thia-13,23-diazatritriacontan-1-oic acid;

((14R,18R)-14-amino-18-((octylcarbamoyl)oxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazatriacontyl) phosphonic acid;

((14R,18R)-18-((decylcarbamoyl)oxy)-13,21-dioxo-14-palmitamido-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontyl)phosphonic acid;

((14R,18R)-14-acetamido-18-((decylcarbamoyl)oxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontyl)phosphonic acid;

((14R,18R)-18-((decylcarbamoyl)oxy)-14-heptanamido-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontyl)phosphonic acid; 16-diazahexatriacontan-1-oic acid;

((14R,18R)-14-amino-18-((dodecyloxy)methyl)-13,20-dioxo-3,6,9,19-tetraoxa-16-thia-12,21-diazahentriacontyl)phosphonic acid; and

((14R,18R)-18-((decylcarbamoyl)oxy)-14-hexanamido-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontyl)phosphonic acid.

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