MASP-2 inhibitors and methods of use
The present disclosure provides, inter alia, compounds with MASP-2 inhibitory activity, compositions of such compounds, and methods of making and using such compounds.
1. A compound having the following Structure (I):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 is a substituted aryl or a substituted or unsubstituted heteroaryl;
R 2 is methyl;
R 4 is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl;
R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, phosphonalkyl, (CH 2 ) m C(═O)OR 6 , C(═O)R 6 , C(═O)OR 6 , (CH 2 ) m NR 6 S(O) 2 R 7 , or C(═O)NR 6 R 7 ;
R 6 and R 7 are, at each occurrence, independently hydrogen, alkyl, haloalkyl, cycloalkyl, or arylalkyl;
L 1 is a direct bond, —CR 8a R 8b —, —S(O) t —, NR 8c , or —O—;
R 8a and R 8b are each independently hydrogen or alkyl, or R 8a and R 8b , together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl;
R 8c is hydrogen, alkyl, haloalkyl, (C═O)alkyl, (C═O)Oalkyl, (C═O)cycloalkyl, (C═O)Ocycloalkyl, (C═O)aryl, (C═O)Oaryl, (C═O)heteroaryl, (C═O)Oheteroaryl, (C═O)heterocyclyl, (C═O)O heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted cycloalkylalkyl, or a substituted or unsubstituted heterocyclylalkyl;
m is 1, 2, 3, 4, 5, or 6; and
t is 0, 1, or 2.
2. The compound of claim 1 , wherein R 1 is a substituted phenyl.
3. The compound of claim 1 , wherein R 1 has one of the following structures:
4. The compound of claim 1 , wherein R 1 is a substituted or unsubstituted heteroaryl.
5. The compound of claim 1 , wherein R 1 has one of the following structures:
6. The compound of claim 1 , wherein R 4 is a substituted or unsubstituted aryl.
7. The compound of claim 1 , wherein R 4 is a substituted or unsubstituted phenyl.
8. The compound of claim 1 , wherein R 4 has one of the following structures:
9. The compound of claim 1 , wherein R 4 is a substituted or unsubstituted heteroaryl.
10. The compound of claim 1 , wherein R 4 has one of the following structures:
11. The compound of claim 1 , wherein R 5 is hydrogen, alkyl, phosphonalkyl, (CH 2 ) m NR 6 S(O) 2 R 7 , or (CH 2 ) m C(═O)OR 6 .
12. The compound of claim 11 , wherein R 5 has one of the following structures:
13. The compound of claim 1 , wherein L 1 is a direct bond, —O—, or —CH 2 —.
14. The compound of claim 1 , wherein L 1 is —CR 8a R 8b — and R 8a and R 8b together with the carbon to which they are attached form an optionally substituted 3, 4, or 5 membered cycloalkyl.
15. A compound having one of the structures:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier or excipient.
17. A method for relieving the symptoms from a MASP-2-associated disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 .
18. The compound of claim 1 , wherein R 1 has one of the following structures: