Pyrrolidine compounds
A compound of the following formula: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , X, Y, and Z are as defined herein. Also disclosed is a method for inhibiting actively of fibroblast activation protein or for treating cancer or inflammation conditions with such a compound.
1. A compound of the following formula:
wherein
each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , independently, is H, halo, alkyl, cyano, nitro, amino, boronic acid, boronic ester, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
T is C(R a R b ), NR c , O, or S; in which each of R a and R b , independently, is H, alkyl, halo, cyano, nitro, amino, alkoxy, hydroxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R c is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
X is C(R d R e ), NR f , O, or S; in which each of R d and R e , independently, is H, alkyl, halo, cyano, nitro, alkoxy, hydroxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R f is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and
R is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(O)OR g , or —C(O)NR h R i ; in which R g is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and each of R h and R i , independently, is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or hydroxy, or R h and R i together with the N atom to which they are attached form a 5 or 6 membered ring, optionally substituted with alkyl, aryl, halo, hydroxy, alkoxy, nitro, amino, alkoxycarbonyl, or carboxy; and optionally fused with a 3-8 membered aromatic or non-aromatic ring containing 0, 1, 2, or 3 heteroatoms.
2. The compound of claim 1 , wherein R is —C(O)NR h R i ; R h and R i together with the N atom to which they are attached form a 5 or 6 membered ring, optionally substituted with alkyl, aryl, halo, hydroxy, alkoxy, nitro, amino, alkoxycarbonyl, or carboxy; and optionally fused with a 3-8 membered aromatic or non-aromatic ring containing 0, 1, 2, or 3 heteroatoms.
3. The compound of claim 1 , wherein R is —C(O)NR h R i ; each of R h and R i , independently, is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or hydroxyl hydroxy.
4. The compound of claim 1 , wherein T is S.
5. The compound of claim 1 , wherein R 1 is CN.
6. The compound of claim 1 , wherein the compound is
7. The compound of claim 1 , wherein R is —C(O)OR g or —C(O)NR h R i ; in which R g is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and each of R h and independently, is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or hydroxy, or R h and R i together with the N atom to which they are attached form a 5 or 6 membered ring, optionally substituted with alkyl, aryl, halo, hydroxy, alkoxy, nitro, amino, alkoxycarbonyl, or carboxy; and optionally fused with a 3-8 membered aromatic or non-aromatic ring containing 0, 1, 2, or 3 heteroatoms.
8. The compound of claim 7 , wherein X is CH 2 .
9. The compound of claim 8 , wherein T is CH 2 .
10. The compound of claim 9 , wherein R is —C(O)NR h R i ; R h and R i together with the N atom to which they are attached form a 5 or 6 membered ring, optionally substituted with alkyl, aryl, halo, hydroxy, alkoxy, nitro, amino, alkoxycarbonyl, or carboxy; and optionally fused with a 3-8 membered aromatic or non-aromatic ring containing 0, 1, 2, or 3 heteroatoms.
11. The compound of claim 10 , wherein R 1 is CN.
12. The compound of claim 1 , wherein T is CH 2 .
13. The compound of claim 12 , wherein R 1 is CN.
14. The compound of claim 13 , wherein R is —C(O)NR h R i ; R h and R i together with the N atom to which they are attached form a 5 or 6 membered ring, optionally substituted with alkyl, aryl, halo, hydroxy, alkoxy, nitro, amino, alkoxycarbonyl, or carboxy; and optionally fused with a 3-8 membered aromatic or non-aromatic ring containing 0, 1, 2, or 3 heteroatoms.
15. The compound of claim 14 , wherein R 1 is CN.
16. The compound of claim 15 , wherein R is —C(O)NR h R i ; R h and R i together with the N atom to which they are attached form a 5 or 6 membered ring, optionally substituted with alkyl, aryl, halo, hydroxy, alkoxy, nitro, amino, alkoxycarbonyl, or carboxy; and optionally fused with a 3-8 membered aromatic or non-aromatic ring containing 0, 1, 2, or 3 heteroatoms.
17. The compound of claim 1 , wherein the compound is selected from a group consisting of
18. A method of inhibiting activity of dipeptidyl peptidase, comprising contacting the fibroblast activation protein with an effective amount of a compound of claim 1 .
19. The method of claim 18 , wherein the dipeptidyl peptidase is FAP or DPP-IV.