Fibroblast activation protein (FAP)—targeted antifibrotic therapy
A compound of formula F a -L-I a (A) or F a -I a (B), wherein F a is a fibroblast activation protein alpha (FAPα) targeting moiety, L is a linker, and I a is an inhibitor of a signaling pathway necessary for fibrosis in cancer-associated fibroblasts (CAFs); a pharmaceutical composition comprising same; and methods for treating a tumor, a cancer or a fibrotic disease in a subject.
1 . A compound of formula (A) or (B):
or a pharmaceutically acceptable salt thereof, wherein:
I a is
wherein X is:
wherein * denotes the point of attachment of X to I a or L or F a ; and ** denotes the point of attachment of X to:
L is
x is an integer from 0 to 10; and
y is an integer from 3 to 100; or
L is:
wherein:
R 18a , R 18b , R 19a , and R 19b are independently H or C 1-6 alkyl; and
R 31 is H or C 1-6 alkyl;
F a is a fibroblast activation protein alpha (FAPα) targeting moiety having a structure represented by the following formula (X):
wherein:
wherein *** denotes the point of attachment to J;
R 1 is selected from the group consisting of —H, —CN, —B(OH) 2 , —C(O)alkyl, —C(O)aryl, —C═CC(O)aryl, —C═C—S(O) 2 aryl, —CO 2 H, —SO 3 H, —SO 2 NH 2 , —PO 3 H 2 , and 5-tetrazolyl,
R 2 , R 3a , R 3b and R 4 are each independently selected from the group consisting of —H, —OH, halogen, —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl,
R 5 is —CH 3 ,
R 6 , R 7 , and R 8 are each independently selected from the group consisting of —H, —OH, oxo, halogen, CF 3 , —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 9 R 10 , —OR 11 , —Het 2 , and —Ar 2 ;
each of —C 1-6 alkyl being optionally substituted with from 1 to 3 substituents selected from —OH and halogen;
R 9 , R 10 , and R 11 are each independently selected from the group consisting of —H, —OH, oxo, halogen, CF 3 , —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —Ar 3 ,
Ar 2 and Ar 3 are each independently a 5- or 6-membered aromatic monocycle optionally comprising 1 or 2 heteroatoms selected from O, N, and S; each of Ar 2 and Ar 3 being optionally and independently substituted with from 1 to 3 substituents selected from —NR 12 R 13 , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl,
R 12 and R 13 are each independently selected from the group consisting of —H, —OH, CF 3 , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl,
Het 2 is a 5- or 6-membered non-aromatic monocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S;
Het 2 being optionally substituted with from 1 to 3 substituents selected from —NR 14 R 15 , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl,
R 14 and R 15 are each independently selected from the group consisting of —H, —OH, halogen, CF 3 , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
J is selected from the group consisting of a bond, —C 1-3 alkyl, —C 1-3 alkyl-NH—, C═O, and —O;
and the compound is not
2 . The compound of claim 1 , wherein R 1 is —CN, —CH 2 CN or —B(OH) 2 .
3 . The compound of claim 1 , wherein R 3a and R 3b are halogen or hydrogen.
4 . The compound of claim 1 , wherein R 6 , R 7 , and R 8 are hydrogen.
5 . The compound of claim 1 , wherein R 6 and R 7 are hydrogen.
6 . The compound of claim 1 , wherein R 8 is hydrogen or chloro.
7 . A compound of formula (A) or (B):
F a -L-I a (A)
F a -I a (B)
or a pharmaceutically acceptable salt thereof, wherein:
I a is
wherein X is:
wherein * denotes the point of attachment of X to I a or L or F a ; and ** denotes the point of attachment of X to:
L is
x is an integer from 0 to 10; and
y is an integer from 3 to 100; or
L is:
wherein:
R 18a , R 18b , R 19a , and R 19b are independently H or C 1-6 alkyl; and
R 31 is H or C 1-6 alkyl;
Fa is formula (Y)
wherein
Z is selected from the group consisting of:
wherein * indicates an attachment point to a carbonyl as shown in formula (Y);
indicates an attachment point to L in formula (A) and I a in formula (B);
R 20a and R 20b are the same or different and are each independently selected from the group consisting of hydrogen, halogen, and C 1-4 alkyl;
R 21 is selected from the group consisting of C 1-4 alkyl, nitrile, isonitrile, and boronic acid;
R 22 is —CH 3 ;
R 23 and R 24 are the same or different, and are each independently selected from the group consisting of hydrogen, halogen, and C 1-4 alkyl;
R 25 is selected from the group consisting of hydrogen, methoxy, halogen, CF 3 , and C 1-4 alkyl;
R 26 and R 27 are the same or different, and are each independently selected from the group consisting of hydrogen, halogen, and C 1-4 alkyl;
R 28 , R 29 , and R 30 are the same or different, and are each independently selected from the group consisting of hydrogen, methoxy, halogen, CF 3 , and C 1-4 alkyl;
and the compound is not
8 . The compound of claim 7 , wherein R 20a and R 20b are halogen or hydrogen.
9 . The compound of claim 7 , wherein R 21 is —CH 2 CN or boronic acid.
10 . The compound of claim 7 , wherein R 23 and R 25 are hydrogen.
11 . The compound of claim 7 , wherein R 24 is hydrogen or chloro.
12 . The compound of claim 7 , wherein R 26 , R 27 , R 28 , R 29 , and R 30 are hydrogen.
13 . The compound of claim 7 , wherein F a is selected from the group consisting of:
14 . The compound of claim 1 , wherein I a is:
15 . A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable excipients.