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 or unsubstituted aryl, substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted heteroaryl, wherein the heteroaryl is selected from the group consisting of
R 2 is hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, or cycloalkyl;
R 3 is hydrogen, alkyl, haloalkyl, or cycloalkyl;
or R 2 and R 3 , together with the carbon and nitrogen to which they are attached, respectively, form an optionally substituted 4-7 membered heterocyclyl;
R 4 is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclyl;
R 5a is hydrogen, alkyl, haloalkyl, cycloalkyl, phosphonalkyl, (CH 2 ) n C(═O)OR 6 , C(═O)R 6 , C(═O)OR 6 , or C(═O)NR 6 R 7 ;
R 5b is an electron pair or alkyl;
R 6 and R 7 are, at each occurrence, independently hydrogen, alkyl, haloalkyl, cycloalkyl, or arylalkyl;
R 8 is alkyl, haloalkyl, aminylalkyl, substituted or unsubstituted arylalkyl; and
n is 1, 2, 3, 4, 5, 6, 7, or 8, provided that
A) R 5a is alkyl, haloalkyl, cycloalkyl, phosphonalkyl, (CH 2 ) n C(═O)OR 6 , C(═O)R 6 , C(═O)OR 6 , or C(═O)NR 6 R 7 or R 1 is substituted with one or more substituents selected from the group consisting of a substituted heteroaryl, C(═NH)NHC(═O)OR 8 , C(═NOC(═O)R 8 )NH 2 , C(═NOC(═O)OR 8 )NH 2 , and C(═NOH)NH 2 ; and
B) when R 5a is alkyl or (CH 2 ) n C(═O)OR 6 , R 1 does not have the following structure:
unless R 2 and R 3 , together with the carbon and nitrogen to which they are attached, respectively,
form an optionally substituted 4-7 membered heterocyclyl.
2. The compound of claim 1 , wherein R′ is a substituted or unsubstituted 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 is substituted with one or more substituents selected from the group consisting of a substituted heteroaryl, C(═NH)NHC(═O)OR 8 , C(═NOC(═O)R 8 )NH 2 , C(═NOC(═O)OR 8 )NH 2 , and C(═NOH)NH 2 .
6. The compound of claim 5 , wherein R 1 is substituted with C(═NH)NHC(═O)OR 8 and R 8 is a substituted or unsubstituted arylalkyl.
7. The compound of claim 5 , wherein R 1 is substituted with C(═NOC(═O)R 8 )NH 2 and R 8 is an aminylalkyl.
8. The compound of claim 5 , wherein R 1 is substituted with C(═NOC(═O)OR 8 )NH 2 and R 8 is an alkyl, a haloalkyl, or a substituted or unsubstituted arylalkyl.
9. The compound of claim 5 , wherein R 1 has one of the following structures:
10. The compound of claim 1 , wherein R 2 is hydrogen or C 1 -C 6 alkyl.
11. The compound of claim 1 , wherein R 2 is —CH 3 .
12. The compound of claim 1 , wherein R 2 and R 3 , together with the carbon and nitrogen to which they are attached, respectively, form an optionally substituted 4, 5, or 6 membered heterocyclyl.
13. The compound of claim 1 , wherein R 4 is a substituted or unsubstituted aryl.
14. The compound of claim 1 , wherein R 4 has one of the following structures:
15. The compound of claim 1 , wherein R 5a is alkyl, C(═O)OR 6 , phosphonalkyl, or (CH 2 ) n C(═O)OR 6 .
16. The compound of claim 15 , wherein R 5a has one of the following structures:
17. The compound of claim 1 , wherein R 5b is an electron pair.
18. The compound of claim 1 , wherein R 5b is alkyl.
19. A compound having one of the structures:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier or excipient.
21. A method for treating 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 .