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 method for inhibiting MASP-2 in a subject having a MASP-2-associated disease or disorder, the method comprising administering to the subject an effective amount of a compound of Structure (I):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 is
R 2a , R 2b , R 2c , and R 2d are each independently selected from the group consisting of hydrogen, C(═O)OR 5 , alkoxy, alkoxyalkyl, cyano, C(═O)NR 5 R 6 , N(R 5 )C(═O)R 6 , a five-membered heteroaryl, a five-membered heterocyclyl, a phenyl, and provided that at least one of R 2a , R 2b , R 2c , and R 2d is not hydrogen;
R 3 is NR 3a R 3b ;
R 3a and R 3b are each independently hydrogen or (CH 2 ) n C(═O)OR 6 ;
R 4 is
R 5 and R 6 are, at each occurrence, independently hydrogen or alkyl; and
n is an integer from 0-6,
wherein the MASP-2-associated disease or disorder is a thrombotic microangiopathy (TMA), a graft-versus-host disease (GVHD), diffuse alveolar hemorrhage (DAH), veno-occlusive disease (VOD), idiopathic pneumonia syndrome (IPS), capillary leak syndrome (CLS), engraftment syndrome (ES), fluid overload (FO), mesangioproliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), acute post infectious glomerulonephritis (poststreptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, pauci-immune necrotizing crescentic glomerulonephritis, Henoch-Schonlein purpura nephritis, renal fibrosis, Rheumatoid arthritis, inflammatory reaction resulting from tissue or solid organ transplantation, ischemia reperfusion injury (I/R), disseminated intravascular coagulation (DIC), acute radiation syndrome, Catastrophic Antiphospholipid Syndrome (CAPS), aHUS, HSCT-TMA, IgAN, or Lupus Nepthritis (LN).
2 . The method of claim 1 , wherein the compound has one of the following structures:
3 . The method of claim 1 , wherein at least one of R 2a , R 2b , R 2c , and R 2d has one of the following structures:
4 . The method of claim 1 , wherein R 3 is
5 . The method of claim 1 , wherein n is 0, 1, or 2.
6 . The method of claim 1 , wherein n is 2.
7 . The method of claim 1 , wherein the compound of Structure (I) has one of the structures:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
8 . The method of claim 1 , wherein the compound of Structure (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or excipient.
9 . The method of claim 1 , wherein the MASP-2-associated disease or disorder is a thrombotic microangiopathy (TMA), a graft-versus-host disease (GVHD), diffuse alveolar hemorrhage (DAH), veno-occlusive disease (VOD), mesangioproliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), acute post infectious glomerulonephritis (poststreptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, pauci-immune necrotizing crescentic glomerulonephritis, Henoch-Schonlein purpura nephritis, renal fibrosis, Rheumatoid arthritis, inflammatory reaction resulting from tissue or solid organ transplantation, ischemia reperfusion injury (I/R), disseminated intravascular coagulation (DIC), acute radiation syndrome, Catastrophic Antiphospholipid Syndrome (CAPS), aHUS, HSCT-TMA, IgAN, or Lupus Nepthritis (LN).
10 . A method for treating a MASP-2-associated disease or disorder in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of Structure (I-A):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 is
R 2a , R 2b , R 2c , and R 2d are each independently selected from the group consisting of hydrogen, C(═O)OR 5 , alkoxyalkyl, cyano,
and provided that at least one of R 2a , R 2b , R 2c , and R 2d is not hydrogen;
R 3 is NR 3a R 3b ;
R 3a and R 3b are each independently hydrogen or (CH 2 ) n C(═O)OR 6
R 4 is
R 5 and R 6 are hydrogen or alkyl; and
n is an integer from 0-6,
wherein the MASP-2-associated disease or disorder is a thrombotic microangiopathy (TMA), a graft-versus-host disease (GVHD), diffuse alveolar hemorrhage (DAH), veno-occlusive disease (VOD), idiopathic pneumonia syndrome (IPS), capillary leak syndrome (CLS), engraftment syndrome (ES), fluid overload (FO), mesangioproliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), acute post infectious glomerulonephritis (poststreptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, pauci-immune necrotizing crescentic glomerulonephritis, Henoch-Schonlein purpura nephritis, renal fibrosis, Rheumatoid arthritis, inflammatory reaction resulting from tissue or solid organ transplantation, ischemia reperfusion injury (J/R), disseminated intravascular coagulation (DIC), acute radiation syndrome, Catastrophic Antiphospholipid Syndrome (CAPS), aHUS, HSCT-TMA, IgAN, or Lupus Nepthritis (LN).
11 . The method of claim 10 , wherein the compound of Structure (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or excipient.
12 . The method of claim 10 , wherein at least one of R 2a , R 2b , R 2c , and R 2d has one of the following structures:
13 . The method of claim 10 , wherein the compound of Structure (I-A) has one of the structures:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.