US Pat. No. 9,492,452

METHODS AND COMPOSITIONS FOR INHIBITION OF POLYMERASE

BioCryst Pharmaceuticals,...

1. A method of treating a viral infection, comprising administering to a subject in need thereof a therapeutically effective
amount of a compound having the following structure:

or a pharmaceutically acceptable salt or hydrate thereof; wherein the virus is a member of a virus family selected from the
group consisting of orthomyxoviridae, paramyxoviridae, arenaviridae, bunyaviridae, flaviviridae, filoviridae, togaviridae,
picornaviridae, poxviridae, adenoviridae, and coronaviridae virus families.

US Pat. No. 9,770,427

ANTIVIRAL TREATMENTS

BioCryst Pharmaceuticals,...

1. A method for treating a viral infection in a human comprising administering in a single intravenous administration per
day over a course of treatment an effective anti-viral amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, to the human, wherein the viral infection is a type A, type B, H3N2, H1N1,
H5N1, avian, or seasonal influenza infection.

US Pat. No. 9,580,428

COMPOSITIONS AND METHODS FOR INHIBITING VIRAL POLYMERASE

BioCryst Pharmaceuticals,...

16. A pharmaceutical composition, comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

US Pat. No. 9,499,554

ANTI-INFLUENZA COMPOSITIONS AND METHODS

BioCryst Pharmaceuticals,...

9. A method for inhibiting, treating or suppressing a viral infection, comprising administering to a subject in need thereof
an effective amount of a compound of formula I:

wherein
R1 is selected from


R2 is a bond, O, or S;

R3 is a bond, C(?O), C(?S), C(?NR10), OC(?O), OC(?S), OC(?NR10), N(R11)C(?O), N(R11)C(?S), or N(R11)C(?NR10);

R4 is OH or N(R15)2;

R5 is H or N(R15)2;

R6 is R11, C(?O)—R11, or SO2—R11;

R7 is H or R12, wherein R12 is optionally substituted with one or more groups selected from lower alkyl, OR11, O—C(?O)—R11, O—C(?O)O—R11, O—C(?O)N(R11)2, O—C(?S)—R11, O—C(?S)O—R11, and O—C(?S)N(R11)2;

R8 is OR11, O—C(?O)—R11, O—C(?O)O—R11, O—C(?O)N(R11)2, O—C(?S)—R11, O—C(?S)O—R11, O—C(?S)N(R11)2, N(R11)2, N(R11)C(?O)—R11, N(R11)C(?O)O(R11)2, N(R11)C(?O)N(R11)2, N(R11)C(?S)—R11, N(R11)C(?S)O—R11, N(R11)C(?S)N(R11)2, or N(R11)C(?NR10)N(R11)2;

R9 is H, OH, O—C(?O)O—R11, O—C(?O)N(R11)2, O—C(?S)—R11, O—C(?S)O—R11, O—C(?S)N(R11)2;

B is a bond, R12, R12—R13, R12—R13—R14, R12—O—R13, R12—S—R13, R12—N(R11)2—R13, R12—C(?O)—R13, R12—C(?S)—R13, R12—C(?NR10)—R13, R12—OC(?O)—R13, R12—OC(?S)—R13, R12—OC(?NR10)—R13, R12—SC(?O)—R13, R12—SC(?S)—R13, R12—SC(?NR10)—R13, R12—N(R11)C(?O)—R13, R12—N(R11)C(?S)—R13, R12—N(R11)C(?NR10)—R13, R12—OC(?O)—OR13, R12—OC(?S)—OR13, R12—OC(?NR10)—OR13, R12—OC(?O)—N(R11)R13, R12—OC(?S)—N(R11)R13, R12—OC(?NR10)—N(R11)R13, R12—OC(?O)—SR13, R12—OC(?S)—SR13, R12—OC(?NR10)—SR13, R12—N(R11)C(?O)—OR13, R12—N(R11)C(?S)—OR13, R12—N(R11)C(?NR10)—OR13, R12—N(R11)C(?O)—N(R11)R13, R12—N(R11)C(?S)—N(R11)R13, R12—N(R11)C(?NR10)—N(R11)R13, R12—N(R11)C(?O)—SR13, R12—N(R11)C(?S)—SR13, R12—N(R11)C(?NR10)—SR13, R12—SC(?O)—OR13, R12—SC(?S)—OR13, R12—SC(?NR10)—OR13, R12—SC(?O)—SR13, R12—SC(?S)—SR13, R12—SC(?NR10)—SR13, R12—SC(?O)—N(R11)R13, R12—SC(?S)—N(R11)R13, or R12—SC(?NR10)—N(R11)R13; wherein each R12, R13, and R14 are optionally substituted with one or more R15;

R10 is independently H, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, heteroaryl, OR11, or N(R11)2;

R11 is independently H, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl;

R12 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl;

R13 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl;

R14 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl; and

R15 is independently halogen, R10, OC(?O)R11, OC(?S)R11, OC(?NR10)R11, OC(?O)OR11, OC(?S)OR11, OC(?NR10)OR11, OC(?O)N(R11)2, OC(?S)N(R11)2, OC(?NR10)N(R11)2, N(R11)C(?O)R11, N(R11)C(?S)R11, N(R11)C(?NR10)R11, N(R11)C(?O)OR11, N(R11)C(?S)OR11, N(R11)C(?NR10)OR11, N(R11)C(?O)N(R11)2, N(R11)C(?S)N(R11)2, or N(R11)C(?NR10)N(R11)2;

or a pharmaceutically acceptable salt thereof.

US Pat. No. 10,759,759

PRODRUGS OF KALLIKREIN INHIBITORS

BioCryst Pharmaceuticals,...

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:
wherein, independently for each occurrence:
Z represents OR1 or NH(OH);
R1 represents

 —C(Ra)(Rb)—O—C(O)-M-R3, or (C2-C6)alkyl optionally substituted by hydroxyl or heterocycloalkyl;
Ra represents H or (C1-C6)alkyl;
Rb represents H or (C1-C6)alkyl;
Rx represents H or (C1-C6)alkyl;
M is a bond or represents O, S, NH, or N(CH3);
R2 represents H, —OH, —C(O)OR4, —C(O)SR4, —C(O)O—[C(Rc)(Rd)]n—O—C(O)-L-R5, or

R6 represents H, OH, —C(O)OR4, —C(O)SR4, —C(O)O—[C(Rc)(Rd)]n O—C(O)-L-R5, or

or R2 and R6, taken together with the atoms to which they are attached, form an optionally substituted 1,2,4-oxadiazol-5-one group;
L, independently for each occurrence, is a bond or represents O, S, NH, or N(CH3);
Rc, Rd, Re, and Rf each independently for each occurrence represent H or (C1-C6)alkyl;
R3 represents (C1-C6)alkyl, aralkyl, or cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of amino, hydroxyl, optionally substituted heterocycloalkyl, —C(O)OH, and —C(O)O((C1-C6)alkyl);
R4, independently for each occurrence, represents (C1-C6)alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of —C(O)OH, —C(O)O((C1-C6)alkyl), (C1-C6)alkoxy, hydroxyl, oxo, heterocycloalkyl, amino, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, and silyl ether;
R5, independently for each occurrence, represents (C1-C6)alkyl, aryl, or heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of amino, heterocycloalkyl, (C1-C6)alkoxy optionally substituted by (C1-C6)alkoxy or a polyether chain; and
n represents 1 or 2;
provided that at least one of R2 and R6 is not H; and
provided that if Z is OR1 and R1 is ethyl or 2-(morpholino)ethyl, then R4 is not hexyl or butyl.

US Pat. No. 10,022,375

METHODS AND COMPOSITIONS FOR INHIBITION OF POLYMERASE

BioCryst Pharmaceuticals,...

1. A method for treating a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the following structure:or a pharmaceutically acceptable salt or hydrate thereof; wherein the virus is selected from the group consisting of viruses of the orthomyxoviridae, paramyxoviridae, arenaviridae, bunyaviridae, flaviviridae, filoviridae, togaviridae, picornaviridae, and coronaviridae families.

US Pat. No. 10,562,850

HUMAN PLASMA KALLIKREIN INHIBITORS

BioCryst Pharmaceuticals,...

1. A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof:
wherein, independently for each occurrence:
R1 represents —OH, —ORc, —NH2, —NHRc, —NRcRd, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, —C(O)Rc, —C(O)OH, —C(O)ORc, —OC(O)Rc, —C(O)NH2, —C(O)NHRc, —C(O)NRcRd, —NHC(O)Rc, or —NRcC(O)Rd; or two geminal occurrences of R1 taken together with the carbon to which they are attached represent —C(O)—; or two vicinal or geminal occurrences of R1 taken together form an optionally substituted fused or spirocyclic carbocyclic or heterocyclic ring;
W is —C(O)NH- or —C(O)N(Rc)—;
R2 represents optionally substituted aryl or heteroaryl;
Z is absent or represents one or more substituents independently selected from the group consisting of halo, haloalkyl, -NO2, —CN, —C(O)Rc, —C(O)OH, —C(O)ORc, —OC(O)Rc, —C(O)NH2, —C(O)NHRc, —C(O)NRcRd, —NHC(O)Rc, -N(Rc)C(O)Rd, -OS(O)p(Rc), —NHS(O)p(Rc), and —NRcS(O)p(Rc);
X represents —C(NH2)—, —C(NH(Rc))—, —C(NRcRd)—, —C(NHS(O)pRc)—, —C(NHC(O)Rc)—, —C(NHC(O)NH2)—, —C(NHC(O)NHRc)—, —C(NHC(O)NRcRd)—, —C(OH)—, —C(O(alkyl))-, —C(N3)—, —C(CN)—, —C(NO2)—, —C(S(O)nRa)—, —C[—C(?O)Rc]—, —C[—C(?O)NRcRd]-, —C[—C(?O)SRc]—, —C[—S(O)Rc]-, —C[—S(O)2Rc]—, —C[S(O)(ORc)]—, —C[—S(O)2(ORc)]—, —C[—SO2NRcRd]—, —C(halogen)-, —C(alkyl), —C((cycloalkyl)alkyl), —C(alkenyl)-, —C(alkynyl)-, or —C(aralkyl)-;
R3 represents optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
R3a is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, alkyl, —CF3, —OCF3, alkoxy, aryl, heteroaryl, aryloxy, amino, aminoalkyl, —C(O)NH2, cyano, —NHC(O)alkyl, —SO2alkyl, —SO2NH2, cycloalkyl, —(CH2)rORa, —NO2, —(CH2)rNRaRb, —(CH2)rC(O)Ra, —NRaC(O)Rb, —C(O)NRcRd, —NRaC(O)NRcRd, —C(?NRa)NRcRd, —NHC(?NRa)NRcRd, —NRaRb, —SO2NRcRd, —NRaSO2NRcRd, —NRaSO2alkyl, —NRaSO2Ra, —S(O)pRa, —(CF2)rCF3, —NHCH2Ra, —OCH2Ra, —SCH2Ra, —NH(CH2)2(CH2)rRa, —O(CH2)2(CH2)rRa, or —S(CH2)2(CH2)rRa;
Y represents a bond; or —Y—R4 represents optionally substituted -alkylene-R4, —CH2C(O)—R4, —CH2NH—R4, —CH2N(alkyl)-R4, —CRaRb—R4, —NH—R4, —NHCH2—R4, —NHC(O)—R4, —N(alkyl)-R4, —N(alkyl)CH2-R4, —N((CH2)2OH)—R4, —N((cycloalkyl)alkyl)R4, -heterocyclyl-R4, —OR4, —OCH2—R4, —OC(O)—R4, —OC(O)NRaRb, —SCH2R4, or —SR4;
R4 represents hydrogen, hydroxy, optionally substituted alkyl, cycloalkyl, (heterocycloalkyl)alkyl, (cycloalkyl)alkyl, —CH2OH, —CH(alkyl)OH, —CH(NH2)CH(alkyl)2, aryl, aralkyl, heteroaryl, heteroaralkyl, —CH2S(alkyl), amino, or cyano; or —(CRaRb)r(CRaRb)p— fused to the 4-position of the ring bearing Z to form a 5- to 7-membered heterocyclic ring with optional substituents; or,
when R3 is phenyl, R4 can represent —NRa— fused to the position ortho to X on that phenyl;
each Ra and Rb is independently H, alkyl, alkenyl, alkynyl, aralkyl, (cycloalkyl)alkyl, —C(?O)Rc, —C(?O)ORc, —C(?O)NRcRd, —C(?O)SRc, —S(O)Rc, —S(O)2Rc, —S(O)(ORc), or —SO2NRcRd;
Rc and Rd represent, independently for each occurrence, optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, —C(O)alkyl, or —S(O)p(alkyl); or Rc and Rd can be taken together to form an optionally substituted heterocyclic ring;
can represent
r is 0, 1, 2, or 3;
n is an integer from 0 to 6; and
p is 0, 1, or 2.

US Pat. No. 10,633,345

HUMAN PLASMA KALLIKREIN INHIBITORS

BioCryst Pharmaceuticals,...

1. A compound, or a pharmaceutically acceptable salt thereof, represented by formula XXVI:
wherein:
X represents CH, C(OH), —C(NH2), or —C(NRaRb);
provided that:
if X represents CH, then —Y—R4 represents —H or —OH, or both Y and R4 are present;
if X represents C(OH), —C(NH2), or —C(NRaRb), then —Y—R4 is present;
—Y—R4, when present, represents —((C1-C6)alkyl)-R4, —CH2C(O)—R4, —CH2NH—R4, —CH2N((C1-C6)alkyl)-R4, —CRaRb—R4, —NH—R4, —NHCH2—R4, —NHC(O)—R4, —N((C1-C6)alkyl)-R4, —N((C1-C6)alkyl)CH2—R4, —N((CH2)2OH)-R4, —N[(C3-C8)cycloalkyl(C1-C6)alkyl]R4, -heterocyclyl-R4, —OR4, —OCH2—R4, —OC(O)—R4, —OC(O)NRaRb, —SCH2R4, or —SR4, wherein the (C1-C6)alkyl moiety of —((C1-C6)alkyl)-R4 is optionally substituted;
Z is absent or represents halo, hydroxy, (C1-C6)alkyl, —CF3, —OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, —C(O)NH2, cyano, —NHC(O)(C1-C6)alkyl, —SO2(C1-C6)alkyl, —SO2NH2, or (C3-C8)cycloalkyl;
R1c represents halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, —SO2CH3, formyl, acyl, —NH2, or optionally substituted aryl;
R2 represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, —OCH3, —Si(CH3)3, —CONH2, —C(O)OH, cyano, or phenyl;
R3 represents —NH—, —O—, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;
R3a is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, —CF3, —OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, —C(O)NH2, cyano, —NHC(O)(C1-C6)alkyl, —SO2(C1-C6)alkyl, and —SO2NH2; and
R4 represents hydrogen, hydroxy, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, —CH2OH, —CH((C1-C6)alkyl)OH, —CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, —CH2S(C1-C6)alkyl, amino, or cyano; or —CH2— fused to the 4-position of the ring bearing Z to form a 5- to 7-membered heterocyclic ring with optional substituents; or, when R3 is phenyl, can represent —NH— fused to the position ortho to X on that phenyl;
each Ra and Rb is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, (C3-C8)carbocyclyl, —C(?O)Rc, —C(?O)ORc, —C(?O)NRcRd, —C(?O)SRc, —S(O)Rc, —S(O)2Rc, —S(O)(ORc), or —SO2NRcRd;
each Rc and Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8) carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(?O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl, or aryl(C1-C8)alkyl; or when Rc and Rd are bonded to a common nitrogen atom, then they may form a 3- to 7-membered heterocyclic ring wherein optionally a carbon atom of said heterocyclic ring may be replaced with —O—, —S— or —NRa—;

n is 2 or 3; and
the stereochemical configuration at any chiral center is R, S, or a mixture of R and S.

US Pat. No. 10,391,075

ANTIVIRAL TREATMENTS

BioCryst Pharmaceuticals,...

1. A method for treating an influenza viral infection in a human comprising administering in a single intravenous administration an effective anti-viral amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof, to the human, wherein the effective anti-viral amount is less than or equal to 600 mg and the influenza viral infection is a type A, type B, H3N2, H1N1, H5N1, avian, or seasonal influenza viral infection.

US Pat. No. 10,125,102

HUMAN PLASMA KALLIKREIN INHIBITORS

BioCryst Pharmaceuticals,...

1. A compound, or a pharmaceutically acceptable salt thereof, represented by formula II:wherein:X represents CH, C(OH), C(O(C1-C6)alkyl), —C(NH2), —C(NRaRb), —C(N3), —C(CN), —C(NO2), —C(S(O)nRa), —C[—C(?O)Rc], —C[—C(?O)Rc], —C[—C(?O)NRcRd], —C[—C(?O)SRc], —C[—S(O)Rc], —C[—S(O)2Rc], —C[S(O)(ORc)], —C[—S(O)2(ORc)], —C[—SO2NRcRd], —C(halogen), —C[(C1-C5)alkyl], —C[(C4-C8)carbocyclyl], —C[(C1-C8)substituted alkyl], —C[(C2-C8)alkenyl], —C[(C2-C8)substituted alkenyl], —C[(C2-C8)alkynyl], —C[(C2-C8)substituted alkynyl], —C[aryl(C1-C8)alkyl], C(O)N, CH2N, N, C(O), P(O), —O—, S(O)N, or S(O)2N;
provided that:
if X represents CH, then —Y—R4 represents —H or —OH, or both Y and R4 are present;
if X represents C(OH), C(O(C1-C6)alkyl), —C(NH2), —C(NRaRb), —C(N3), —C(CN), —C(NO2), —C(S(O)nRa), —C[—C(?O)Rc], —C[—C(?O)Rc], —C[—C(?O)NRcRd], —C[—C(?O)SRc], —C[—S(O)Rc], —C[—S(O)2Rc], —C[S(O)(ORc)], —C[—S(O)2(ORc)], —C[—SO2NRcRd], —C(halogen), —C[(C1-C8)alkyl], —C[(C4-C8)carbocyclyl], —C[(C1-C8)substituted alkyl], —C[(C2-C8)alkenyl], —C[(C2-C8)substituted alkenyl], —C[(C2-C8)alkynyl], —C[(C2-C8)substituted alkynyl], or —C[aryl(C1-C8)alkyl], then —Y—R4 is present;
if X represents C(O)N, then —Y—R4 represents H; or —Y—R4 represents H, and —R3-R3a represents H;
if X represents CH2N, then —Y—R4 represents (C1-C6)alkyl;
if X represents N, then —Y—R4 represents H, or both Y and R4 are present; and
if X represents C(O) or —O—, then —Y—R4 is absent;
Y—R4, when present, represents —((C1-C6)alkyl)-R4, —CH2C(O)—R4, —CH2NH—R4, —CH2N((C1-C6)alkyl)-R4, —CRaRb—R4, —NH—R4, —NHCH2-R4, —NHC(O)—R4, —N((C1-C6)alkyl)-R4, —N((C1-C6)alkyl)CH2-R4, —N((CH2)2OH)—R4, —N[(C3-C8)cycloalkyl(C1-C6)alkyl]R4, -heterocyclyl-R4, —OR4, —OCH2-R4, —OC(O)—R4, —OC(O)NRaRb, —SCH2R4, or —SR4, wherein the (C1-C6)alkyl moiety of —((C1-C6)alkyl)-R4 is optionally substituted;
Z is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, —CF3, —OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, —C(O)NH2, cyano, —NHC(O)(C1-C6)alkyl, —SO2(C1-C6)alkyl, —SO2NH2, (C3-C8)cycloalkyl, (CH2)rORa, NO2, (CH2)r NRaRb, (CH2)rC(O)Ra, NRaC(O)Rb, C(O)NRcRd, NRaC(O)NRcRd, —C(?NRa)NRcRd, NHC(?NRa)NRcRd, NRaRb, SO2NRcRd, NRaSO2NRcRd, NRaSO2—(C1-C6)alkyl, NRaSO2Ra, S(O)pRa, (CF2)rCF3, NHCH2Ra, OCH2Ra, SCH2Ra, NH(CH2)2(CH2)rRa, O(CH2)2(CH2)rRa, and S(CH2)2(CH2)rRa; or alternatively Z is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
R1c represents halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, —C(?NH)NH2, —CONRaRb, —(C1-C6)alkylCONRaRb, —SO2CH3, formyl, acyl, —NH2, —C(?NH)NH(OH), —C(?NH)NH(C(O)O—(C1-C6)alkyl), —C(?NH)NH(C(O)O—(C1-C6)haloalkyl), —C(?NH)NH(C(O)S—(C1-C6)alkyl), —C(?NH)NH(C(O)(OCH(C1-C6)alkyl)OC(O)(C1-C6)alkyl), optionally substituted aryl, or optionally substituted heteroaryl;
R2 represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, —OCH3, —Si(CH3)3, —CONH2, —C(O)OH, cyano, or phenyl;
R3, when present, represents —NH—, —O—, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;
R3a is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, —CF3, —OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, —C(O)NH2, cyano, —NHC(O)(C1-C6)alkyl, —SO2(C1-C6)alkyl, —SO2NH2, (C3-C8)cycloalkyl, (CH2)rORa, NO2, (CH2)r NRaRb, (CH2)rC(O)Ra, NRaC(O)Rb, C(O)NRcRd, NRaC(O)NRcRd, —C(?NRa)NRcRd, NHC(?NRa)NRcRd, NRaRb, SO2NRcRd, NRaSO2NRcRd, NRaSO2—(C1-C6)alkyl, NRaSO2Ra, S(O)pRa, (CF2)rCF3, NHCH2Ra, OCH2Ra, SCH2Ra, NH(CH2)2(CH2)rRa, O(CH2)2(CH2)rRa, or S(CH2)2(CH2)rRa; or alternatively R3a is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
R4 represents hydrogen, hydroxy, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, —CH2OH, —CH((C1-C6)alkyl)OH, —CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, —CH2S(C1-C6)alkyl, amino, or cyano; or —(CRaRb)r(CRaRb)p— fused to the 4-position of the ring bearing Z to form a 5- to 7-membered heterocyclic ring with optional substituents; or, when R3 is phenyl, can represent —NRa— fused to the position ortho to X on that phenyl;
each Ra and Rb is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, (C3-C8)carbocyclyl, —C(?O)Rc, —C(?O)ORc, —C(?O)NRcRd, —C(?O)SRc, —S(O)Rc, —S(O)2Rc, —S(O)(ORc), or —SO2NRcRd;
each Rc and Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8) carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(?O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl, or aryl(C1-C8)alkyl; or when Rc and Rd are bonded to a common nitrogen atom, then they may form a 3- to 7-membered heterocyclic ring wherein optionally a carbon atom of said heterocyclic ring may be replaced with —O—, —S— or —NRa—;
can represent
n is 2 or 3;
r is independently for each occurrence 0, 1, 2, or 3;
p is independently for each occurrence 0, 1, or 2; and
the stereochemical configuration at any chiral center is R, S, or a mixture of R and S.

US Pat. No. 10,329,260

HUMAN PLASMA KALLIKREIN INHIBITORS

BioCryst Pharmaceuticals,...

1. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

US Pat. No. 10,420,769

METHODS AND COMPOSITIONS FOR INHIBITION OF POLYMERASE

BioCryst Pharmaceuticals,...

1. A method for treating a viral infection, comprising administering to a human subject in need thereof a therapeutically effective amount of a compound having the following structure:
or a pharmaceutically acceptable salt or hydrate thereof; wherein the virus is selected from the group consisting of viruses of the orthomyxoviridae, bunyaviridae, flaviviridae, and filoviridae families.

US Pat. No. 10,689,346

HUMAN PLASMA KALLIKREIN INHIBITORS

BioCryst Pharmaceuticals,...

1. A method of treating a disease or condition characterized by unwanted plasma kallikrein activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof:
wherein:
X represents CH, C(OH), C(O(C1-C6)alkyl), —C(NH2), —C(NRaRb), —C(N3), —C(CN), —C(NO2), —C(S(O)nRa), —C[—C(?O)Rc], —C[—C(?O)NRcRd], —C[—C(?O)SRc], —C[—S(O)Rc], —C[—S(O)2Rc], —C[S(O)(ORc)], —C[—S(O)2(ORc)], —C[—SO2NRcRd], —C(halogen), —C[(C1-C5)alkyl], —C[(C4-C5)carbocyclyl], —C[(C1-C8)substituted alkyl], —C[(C2-C8)alkenyl], —C[(C2-C8)substituted alkenyl], —C[(C2-C8)alkynyl], —C[(C2-C8)substituted alkynyl], —C[aryl(C1-C5)alkyl] or N;
—Y—R4 represents —((C1-C6)alkyl)-R4, —CH2C(O)—R4, —CH2NH-R4, —CH2N((C1-C6)alkyl)-R4, —CRaRb—R4, —NH—R4, —NHCH2—R4, —NHC(O)—R4, —N((C1-C6)alkyl)-R4, —N((C1-C6)alkyl)CH2—R4, —N((CH2)2OH)—R4, —N[(C3-C8)cycloalkyl(C1-C6)alkyl]R4, -heterocyclyl-R4, —OR4, —OCH2—R4, —OC(O)—R4, —SCH2R4, or —SR4, wherein the (C1-C6)alkyl moiety of —((C1-C6)alkyl)-R4 is optionally substituted;
Z is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, —CF3, —OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, —C(O)NH2, cyano, —NHC(O)(C1-C6)alkyl, —SO2(C1-C6)alkyl, —SO2NH2, (C3-C5)cycloalkyl, (CH2)rORa, N02, (CH2)rNRaRb, (CH2)rC(O)Ra, NRaC(O)Rb, C(O)NRcRd, NRaC(O)NRcRd, —C(?NRa)NRcRd, NHC(?NRa)NRcRd, NRaRb, SO2NRcRd, NRaSO2NRcRd, NRaSO2-(C1-C6)alkyl, NRaSO2Ra, S(O)pRa, (CF2)rCF3, NHCH2Ra, OCH2Ra, SCH2Ra, NH(CH2)2(CH2)rRa, O(CH2)2(CH2)rRa, and S(CH2)2(CH2)rRa; or alternatively Z is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
R1c represents halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, —C(?NH)NH2, —CONRaRb, —(C1-C6)alkylCONRaRb, —SO2CH3, formyl, acyl, —NH2, —C(?NH)NH(OH), —C(?NH)NH(C(O)O—(C1-C6)alkyl), —C(?NH)NH(C(O)O—(C1-C6)haloalkyl), —C(?NH)NH(C(O)S—(C1-C6)alkyl), —C(?NH)NH(C(O)(OCH(C1-C6)alkyl)OC(O)(C1-C6)alkyl), optionally substituted aryl, or optionally substituted heteroaryl;
R2 represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, —OCH3, —Si(CH3)3, —CONH2, —C(O)OH, cyano, or phenyl;
R3 represents —NH—, —O—, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;
R3a is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, —CF3, —OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, —C(O)NH2, cyano, —NHC(O)(C1-C6)alkyl, —SO2(C1-C6)alkyl, —SO2NH2, (C3-C8)cycloalkyl, (CH2)rORa, NO2, (CH2)rNRaRb, (CH2)rC(O)Ra, NRaC(O)Rb, C(O)NRcRd, NRaC(O)NRcRd, —C(?NRa)NRcRd, NHC(?NRa)NRcRd, NRaRb, SO2NRcRd, NRaSO2NRcRd, NRaSO2-(C1-C6)alkyl, NRaSO2Ra, S(O)pRa, (CF2)rCF3, NHCH2Ra, OCH2Ra, SCH2Ra, NH(CH2)2(CH2)rRa, O(CH2)2(CH2)rRa, or S(CH2)2(CH2)rRa; or alternatively R3a is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
R4 represents hydrogen, hydroxy, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, —CH2OH, —CH((C1-C6)alkyl)OH, —CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, —CH2S(C1-C6)alkyl, amino, or cyano;
each Ra and Rb is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, (C3-C8)carbocyclyl, —C(?O)Rc, —C(?O)ORc, —C(?O)NRcRd, —C(?O)SRc, —S(O)Rc, —S(O)2Rc, —S(O)(ORc), or —SO2NRcRd;
each Rc and Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8) carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(?O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl, or aryl(C1-C8)alkyl; or when R and Rd are bonded to a common nitrogen atom, then they may form a 3- to 7-membered heterocyclic ring wherein optionally a carbon atom of said heterocyclic ring may be replaced with —O—, —S— or —NRa—;
n is 2 or 3;
r is independently for each occurrence 0, 1, 2, or 3;
p is independently for each occurrence 0, 1, or 2; and
the stereochemical configuration at any chiral center is R, S, or a mixture of R and S.

US Pat. No. 11,066,360

HUMAN PLASMA KALLIKREIN INHIBITORS

BioCryst Pharmaceuticals,...


1. A method of treating a disease or condition characterized by unwanted plasma kallikrein activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:




wherein, independently for each occurrence:R1 represents —OH, —ORc, —NH2, —NHRc, —NRcRd, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, —C(O)Rc, —C(O)OH, —C(O)ORc, —OC(O)Rc, —C(O)NH2, —C(O)NHRc, —C(O)NRcRd, —NHC(O)Rc, or —NRcC(O)Rd; or two geminal occurrences of R1 taken together with the carbon to which they are attached represent —C(O)—; or two vicinal or geminal occurrences of R1 taken together form an optionally substituted fused or spirocyclic carbocyclic or heterocyclic ring;
W is —C(O)NH— or —C(O)N(Rc)—;
R2 represents optionally substituted aryl or heteroaryl;
V represents optionally substituted aryl or heteroaryl;
Z is absent or represents one or more substituents independently selected from the group consisting of halo, haloalkyl, —NO2, —CN, —C(O)Rc, —C(O)OH, —C(O)ORc, —OC(O)Rc, —C(O)NH2, —C(O)NHRc, —C(O)NRcRd, —NHC(O)Rc, —N(Rc)C(O)Rd, —OS(O)p(Rc), —NHS(O)p(Rc), and —NRcS(O)p(Rc);
X represents —C(NH2)—, —C(NH(Rc))—, —C(NRcRd)—, —C(NHS(O)pRc)—, —C(NHC(O)Rc)—, —C(NHC(O)NH2)—, —C(NHC(O)NHRc)—, —C(NHC(O)NRcRd)—, —C(OH)—, —C(O(alkyl))-, —C(N3)—, —C(CN)—, —C(NO2)—, —C(S(O)nRa)—, —C[—C(?O)Rc]—, —C[—C(?O)NRcRd]—, —C[—C(?O)SRc]—, —C[—S(O)Rc]—, —C[—S(O)2Rc]—, —C[S(O)(ORc)]—, —C[—S(O)2(ORc)]—, —C[—SO2NRcRd]—, —C(halogen)-, —C(alkyl), —C((cycloalkyl)alkyl), —C(alkenyl)-, —C(alkynyl)-, or —C(aralkyl)-;
R3 represents optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
R3a is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, alkyl, —CF3, —OCF3, alkoxy, aryl, heteroaryl, aryloxy, amino, aminoalkyl, —C(O)NH2, cyano, —NHC(O)alkyl, —SO2alkyl, —SO2NH2, cycloalkyl, —(CH2)rORa, —NO2, —(CH2)rNRaRb, —(CH2)rC(O)Ra, —NRaC(O)Rb, —C(O)NRcRd, —NRaC(O)NRcRd, —C(?NRa)NRcRd, —NHC(?NRa)NRcRd, —NRaRb, —SO2NRcRd, —NRaSO2NRcRd, —NRaSO2alkyl, —NRaSO2Ra, —S(O)pRa, —(CF2)rCF3, —NHCH2Ra, —OCH2Ra, —SCH2Ra, —NH(CH2)2(CH2)rRa, —O(CH2)2(CH2)rRa, or —S(CH2)2(CH2)rRa;
Y represents a bond; or —Y—R4 represents optionally substituted -alkylene-R4, —CH2C(O)—R4, —CH2NH—R4, —CH2N(alkyl)-R4, —CRaRb—R4, —NH—R4, —NHCH2—R4, —NHC(O)—R4, —N(alkyl)-R4, —N(alkyl)CH2—R4, —N((CH2)2OH)—R4, —N((cycloalkyl)alkyl)R4, -heterocyclyl-R4, —OR4, —OCH2—R4, —OC(O)—R4, —OC(O)NRaRb, —SCH2R4, or —SR4;
R4 represents hydrogen, hydroxy, optionally substituted alkyl, cycloalkyl, (heterocycloalkyl)alkyl, (cycloalkyl)alkyl, —CH2OH, —CH(alkyl)OH, —CH(NH2)CH(alkyl)2, aryl, aralkyl, heteroaryl, heteroaralkyl, —CH2S(alkyl), amino, or cyano; or —(CRaRb)r(CRaRb)p— fused to the 4-position of the ring bearing Z to form a 5- to 7-membered heterocyclic ring with optional substituents; or,
when R3 is phenyl, R4 can represent —NRa— fused to the position ortho to X on that phenyl;
each Ra and Rb is independently H, alkyl, alkenyl, alkynyl, aralkyl, (cycloalkyl)alkyl, —C(?O)Rc, —C(?O)ORc, —C(?O)NRcRd, —C(?O)SRc, —S(O)Rc, —S(O)2Rc, —S(O)(ORc), or —SO2NRcRd;
Rc and Rd represent, independently for each occurrence, optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, —C(O)alkyl, or —S(O)p(alkyl); or Rc and Rd can be taken together to form an optionally substituted heterocyclic ring;





can represent



r is 0, 1, 2, or 3;
n is an integer from 0 to 6;
p is 0, 1, or 2; and
the disease or condition characterized by unwanted plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post fibrinolytic treatment condition, angina, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, brain edema, increased albumin excretion, macroalbuminuria, and nephropathy.

US Pat. No. 10,662,160

CRYSTALLINE SALTS OF A PLASMA KALLIKREIN INHIBITOR

BioCryst Pharmaceuticals,...

1. A crystalline salt of Compound I,
wherein the salt is a bis(hydrochloride) salt.

US Pat. No. 11,021,458

SUBSTITUTED BENZOFURAN, BENZOPYRROLE, BENZOTHIOPHENE, AND STRUCTURALLY RELATED COMPLEMENT INHIBITORS

BioCryst Pharmaceuticals,...

1. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

US Pat. No. 10,905,683

COMPOSITIONS AND USES OF AMIDINE DERIVATIVES

BioCryst Pharmaceuticals,...

1. An oral unit dosage form composition for use in a method of treating a disease or condition treatable via a mechanism of plasma kallikrein inhibition in a human subject, the method comprising orally administering to the human subject a therapeutically effective amount of a compound of formula I:
wherein:
X is CH or N;
Y is CH or N;
A is C?O or CH2;
R1 is hydrogen or a C1-4 alkoxy group; and
R2 is a C1-4 alkyl group or a C3-6 cycloalkyl group, optionally substituted by 1 or 2 hydroxyl groups;
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof and wherein the compound of formula I is administered in an excipient mixture comprising 50% to 80% of a polyethylene glycol having a number average molecular weight of 200 to 1000, 0.1% to 1% of a vitamin E and 20% to 30% of a vitamin E poly(C2-3)alkylene glycol dicarboxylic ester, the percentages expressed by weight of the total weight of the excipients.

US Pat. No. 10,512,649

METHODS AND COMPOSITIONS FOR TREATMENT OF ZIKA VIRUS INFECTION

BioCryst Pharmaceuticals,...

1. A method of reducing the transmission of a Zika virus infection from a first subject to a second subject, the method comprising the step of administering to the first subject or the second subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof
wherein A is OH or NH2, and B is H or NH2.
US Pat. No. 11,110,092

METHODS OF TREATING HEMATOLOGIC CANCERS

BIOCRYST PHARMACEUTICALS,...


1. A method of treating a hematologic cancer in a subject comprising the steps of:a. administering to the subject an effective amount Forodesine; and
b. administering to the subject an effective amount of an alkylating agent, wherein the administration of Forodesine and the alkylating agent results in a synergistic effect, wherein the alkylating agent is Bendamustine and the hematologic cancer is resistant to Bendamustine and Fludarabine.

US Pat. No. 11,117,867

CRYSTALLINE SALTS OF A PLASMA KALLIKREIN INHIBITOR

BioCryst Pharmaceuticals,...


1. A pharmaceutical composition, comprising a crystalline salt of Compound I,




and a pharmaceutically acceptable carrier;wherein the pharmaceutical composition is an oral dosage form; and the oral dosage form contains about 75 mg to about 250 mg of the crystalline salt of Compound I.