Arginase inhibitors and methods of use thereof
Disclosed are compounds of formula (Ia) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of formula (Ia) and methods of using the same for treating cancer or a respiratory inflammatory disease and inhibiting arginase: wherein R 1 is —NHR 1a ; R 1a is —H or —C(O)CH(R 1b )NHR 1c ; R 1b is selected from —H, —(C 1 -C 4 ) alkyl and CH 2 OR 1d ; R 1c is —H; or R 1b and R 1c , together with the atom to which they are attached, form a 5-membered heterocyclic ring; and R 1d is H or —CH 3 .
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein
R 1 is —NHR 1a ;
R 1a is —H or —C(O)CH(R 1b )NHR 1c ; and
R 1b is selected from —H, —(C 1 -C 4 ) alkyl and CH 2 OR 1d and R 1c is —H; or
R 1b and R 1c , together with the atom to which they are attached, form a 5-membered heterocyclic ring; and
R 1d is H or —CH 3 .
2. The compound of claim 1 represented by formula (II), or a pharmaceutically acceptable salt thereof:
wherein
R 2 is —NHR 2a ;
R 2a is —H or —C(O)CH(R 2b )NHR 2c ;
R 2b is selected from —H, —(C 1 -C 4 ) alkyl and CH 2 OR 2d and R 2c is —H; or
R 2b and R 2c , together with the atoms to which they are attached, form a 5-membered heterocyclic ring; and
R 2d is —H or —CH 3 .
3. The compound of claim 1 represented by formula (III), or a pharmaceutically acceptable salt thereof:
wherein
R 3 is selected from —H, —(C 1 -C 4 ) alkyl and —CH 2 OR 3a ; and
R 3a is —H or —CH 3 .
4. The compound of claim 1 represented by formula (IV), or a pharmaceutically acceptable salt thereof:
wherein R 4 is —NH 2 .
5. The compound of claim 1 represented by formula (V), or a pharmaceutically acceptable salt thereof:
6. A compound of formula (VI), or a pharmaceutically acceptable salt thereof:
wherein
R 6a is —H or —CH 3 ;
R 6b is —C(O)C(R 6c R 6d )NH 2 ; or —(C 1 -C 3 ) alkyl which is substituted with 0 or 1 amino or —OR 6e ; and
R 6c is —(C 1 -C 3 ) alkyl which is substituted with 0 or 1 amino or —OR 6f ;
R 6d is H or —CH 3 ; and
R 6e and R 6f are independently —H or —CH 3 .
7. The compound of claim 6 represented by formula (VI), or a pharmaceutically acceptable salt thereof, wherein
R 6a is —H or —CH 3 ; and R 6b is —(C 1 -C 3 ) alkyl which is substituted with 0 or 1 amino; or alternatively,
R 6a is —H or —CH 3 ; R 6b is —C(O)C(R 6c R 6d )NH 2 ; R 6c is —(C 1 -C 3 ) alkyl which is substituted with 0 or 1 amino or —OH; and R 6d is H or —CH 3 .
8. A compound of formula (Ib), or a pharmaceutically acceptable salt thereof:
wherein
R 1 is —NHR 1a ;
R 1a is —H or —C(O)CH(R 1b )NHR 1c ; and
R 1b is selected from —H, —(C 1 -C 4 ) alkyl and CH 2 OR 1d and R 1c is —H; or
R 1b and R 1c , together with the atom to which they are attached, form a 5-membered heterocyclic ring; and
R 1d is H or —CH 3 .
9. The compound of claim 8 represented by formula (IIb), or a pharmaceutically acceptable salt thereof:
wherein
R 2 is —NHR 2a ;
R 2a is —H or —C(O)CH(R 2b )NHR 2c ;
R 2b is selected from —H, —(C 1 -C 4 ) alkyl and CH 2 OR 2d and R 2c is —H; or
R 2b and R 2c , together with the atoms to which they are attached, form a 5-membered heterocyclic ring; and
R 2d is —H or —CH 3 .
10. The compound of claim 8 represented by formula (IIIb), or a pharmaceutically acceptable salt thereof:
wherein
R 3 is selected from —H, —(C 1 -C 4 ) alkyl and —CH 2 OR 3a ; and
R 3a is —H or —CH 3 .
11. The compound of claim 8 represented by formula (IVb), or a pharmaceutically acceptable salt thereof:
wherein R 4 is —NH 2 .
12. The compound of claim 8 represented by formula (Vb), or a pharmaceutically acceptable salt thereof:
13. A compound of formula (VIb), or a pharmaceutically acceptable salt thereof:
wherein
R 6a is —H or —CH 3 ;
R 6b is —C(O)C(R 6c R 6d )NH 2 ; or —(C 1 -C 3 ) alkyl which is substituted with 0 or 1 amino or —OR 6e ; and
R 6c is —(C 1 -C 3 ) alkyl which is substituted with 0 or 1 amino or —OR 6f ;
R 6d is H or —CH 3 ; and
R 6e and R 6f are independently —H or —CH 3 .
14. The compound of claim 13 represented by formula (VIb), or a pharmaceutically acceptable salt thereof; wherein
R 6a is —H or —CH 3 ; and R 6b is —(C 1 -C 3 ) alkyl which is substituted with 0 or 1 amino; or alternatively,
R 6a is —H or —CH 3 ; R 6b is —C(O)C(R 6c R 6d )NH 2 ; R 6c is —(C 1 -C 3 ) alkyl which is substituted with 0 or 1 amino or —OH; and R 6d is H or —CH 3 .
15. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising a compound of claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising a compound of claim 8 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising a compound of claim 13 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.