FAP inhibitors
View Patent ↗The present invention relates to novel inhibitors having high selectivity and specificity for FAP (fibroblast activation protein). Said inhibitors are useful as a human and/or veterinary medicine, in particular for the treatment and/or prevention of FAP-related disorders such as but not limited to proliferative disorders.
1. A compound of Formula X or a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof,
Wherein
R 1 and R 2 are each independently selected from the group consisting of —H, OH, -halo, C 1-6 alkyl, —O—C 1-6 alkyl, and S—C 1-6 alkyl;
R 3 is selected from the group consisting of —H, —CN, —B(OH) 2 , —C(O)alkyl, —C(O)aryl-, —C═C—C(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 4 is —H;
R 5 , R 6 and R 7 are each independently selected from the group consisting of —H, —OH, -oxo, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 8 R 9 , —OR 12 -Het 2 and —Ar 2 ; each of said C 1-6 alkyl being optionally substituted with from 1 to 3 substituents selected from —OH and -halo;
R 8 , R 9 and R 12 are each independently selected from the group consisting of —H, —OH, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —Ar 3 ;
R 10 , R 11 , R 13 and R 14 are each independently selected from the group consisting of —H, —OH, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
Ar 1 , 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 said Ar 1 , Ar 2 and Ar 3 being optionally and independently substituted with from 1 to 3 substituents selected from —NR 10 R 11 , —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; said Het 2 being optionally substituted with from 1 to 3 substituents selected from —NR 13 R 14 , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
n is 0, 1, 2, or 3; and
represents a 5 to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, said heterocycle optionally further comprising 1, 2 or 3 heteroatoms selected from O, N and S.
2. The compound according to claim 1 , and represented by Formula I or a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof,
Wherein
R 1 and R 2 are each independently selected from the group consisting of —H, OH, -halo, C 1-6 alkyl, —O—C 1-6 alkyl, and S—C 1-6 alkyl;
R 3 is selected from the group consisting of —H, —CN, —B(OH) 2 , —C(O)alkyl, —C(O)aryl-, —C═C—C(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 4 is —H;
R 5 , R 6 and R 7 are each independently selected from the group consisting of —H, —OH, -oxo, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 8 R 9 , —OR 12 -Het 2 and —Ar 2 ; each of said C 1-6 alkyl being optionally substituted with from 1 to 3 substituents selected from —OH and -halo;
R 8 , R 9 and R 12 are each independently selected from the group consisting of —H, —OH, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —Ar 3 ;
R 10 , R 11 , R 13 and R 14 are each independently selected from the group consisting of —H, —OH, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
Ar 1 , 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 said Ar 1 , Ar 2 and Ar 3 being optionally and independently substituted with from 1 to 3 substituents selected from —NR 10 R 11 , —C 1-6 alkyl, —O—C 1-6 alkyl, —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; said Het 2 being optionally substituted with from 1 to 3 substituents selected from —NR 13 R 14 , —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl;
n is 0, 1, 2, or 3; and
is selected from the group consisting of:
3. The compound according to claim 2 , wherein:
R 1 and R 2 are each independently selected from the group consisting of —H and -halo;
R 3 is —CN or —B(OH) 2
R 4 is —H;
R 5 , R 6 and R 7 are each independently selected from the group consisting of —H, —OH, -oxo, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, Ar 2 and —NR 8 R 9 ; each of said C 1-6 alkyl being optionally substituted with from 1 to 3 substituents selected from —OH, -halo;
R 8 and R 9 are each independently selected from the group consisting of —H and —Ar 3
Ar 2 and Ar 3 are each independently -phenyl optionally substituted with from 1 to 3 —O—C 1-6 alkyl;
n is 0 or 1; and
represents a 9 to 10-membered N-containing aromatic or non-aromatic bicyclic heterocycle selected from the group consisting of:
4. The compound according to claim 2 , wherein
R 1 and R 2 are each independently selected from the group consisting of —H and —F;
R 3 is —CN or —B(OH) 2 ;
R 4 is —H;
R 5 , R 6 and R 7 are each independently selected from the group consisting of —H, -oxo, -halo, —C 1-6 alkyl, and —O—CF 3 ;
n is 0; and
represents a 9 to 10-membered N-containing aromatic or non-aromatic bicyclic heterocycle selected from the group consisting of:
5. The compound according to claim 1 and represented by Formula II or a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof,
wherein
R 1 and R 2 are each independently selected from the group consisting of —H, OH, -halo, C 1-6 alkyl, —O—C 1-6 alkyl, and S—C 1-6 alkyl;
R 3 is selected from the group consisting of —H, —CN, and —B(OH) 2 ;
R 4 is —H;
R 5 , R 6 and R 7 are each independently selected from the group consisting of —H, —OH, -oxo, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 8 R 9 , and —Ar 2 ; each of said C 1-6 alkyl being optionally substituted with from 1 to 3 substituents selected from —OH and -halo;
R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of —H, —OH, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
Ar 2 is a 5- or 6-membered aromatic monocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; Ar 2 being optionally and independently substituted with from 1 to 3 substituents selected from —NR 10 R 11 , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
n is 0, 1, 2, or 3;
m is 1 or 2; and
is selected from the group consisting of:
6. The compound according to claim 5 , wherein:
R 5 and R 6 are each —H;
R 7 is selected from the group consisting of —H, —OH, -oxo, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 8 R 9 , and —Ar 2 ; each of said C 1-6 alkyl being optionally substituted with from 1 to 3 substituents selected from —OH, -halo; and
R 7 is attached to position 2 or 3 as represented in
7. The compound according to claim 1 and represented by Formula IIIa, or a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof,
wherein
R 1 and R 2 are each independently selected from the group consisting of —H, OH, -halo, C 1-6 alkyl, —O—C 1-6 alkyl, and S—C 1-6 alkyl;
R 3 is selected from the group consisting of —H, —CN, —B(OH) 2 , —C(O)alkyl, —C(O)aryl-, —C═C—C(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 4 is —H;
R 5 , R 6 and R 7 are each independently selected from the group consisting of —H, —OH, -oxo, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 8 R 9 , and —Ar 2 ; each of said C 1-6 alkyl being optionally substituted with from 1 to 3 substituents selected from —OH and -halo;
R 8 and R 9 , are each independently selected from the group consisting of —H, —OH, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —Ar 3 ;
R 10 and R 11 are each independently selected from the group consisting of —H, —OH, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
Ar 1 , 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 said Ar 1 , and Ar 2 being optionally and independently substituted with from 1 to 3 substituents selected from —NR 10 R 11 , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
n is 0, 1, 2, or 3;
m is 1 or 2; and
represents a 9 to 10-membered N-containing aromatic or non-aromatic bicyclic heterocycle optionally further comprising 1 or 2 heteroatoms selected from O, N and S.
8. The compound according to claim 7 , wherein:
R 1 and R 2 are each independently selected from the group consisting of —H, OH, -halo, C 1-6 alkyl, —O—C 1-6 alkyl, and S—C 1-6 alkyl;
R 3 is selected from the group consisting of —H, —CN, and —B(OH) 2 ;
R 4 is —H;
R 5 , R 6 and R 7 are each independently selected from the group consisting of —H, —OH, -oxo, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 8 R 9 , and —Ar 2 ; each of said C 1-6 alkyl being optionally substituted with from 1 to 3 substituents selected from —OH, -halo;
R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of —H, —OH, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
Ar 2 is a 5- or 6-membered aromatic monocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; Ar 2 being optionally and independently substituted with from 1 to 3 substituents selected from —NR 10 R 11 , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
n is 0, 1, 2, or 3;
m is 1 or 2; and
is selected from the group consisting of:
9. The compound according to claim 7 , wherein R 5 is attached to position 2 or 3 as represented in
10. A composition comprising the compound according to claim 1 , for use as a human or veterinary medicine.
11. A pharmaceutical composition comprising the compound according to claim 1 , for use as a human or veterinary medicine.
12. A method for inhibiting the activity of fibroblast activation protein (FAP), the method comprising administering to a subject in need thereof an effective amount of the compound according to claim 1 .
13. The pharmaceutical composition according to claim 11 , further comprising one or more pharmaceutically acceptable carriers, diluents, excipients, or adjuvants.