Granted Patent B2

US 11,744,831 · App. 17/362,103 · Granted Sep 5, 2023

Inventors: Christina Gavegnano (Decatur, GA); Raymond F Schinazi (Miami, FL)

Assignees: Emory University; The United States Government as Represented by the Department of Veterans Affairs

A61K31/519A61K31/4045A61K31/513A61K31/52A61K31/536A61K31/66A61K31/7072A61K45/06Y02A50/30

Abstract

Claims (67)

1. A method for treating a Hepacivirus, Pestivirus, Flavivirus or Alphavirus infection, comprising administering to a patient in need thereof an effective amount of a compound of Formula A:

wherein:

or the pharmaceutically acceptable salt thereof; wherein

R 1 is a group of the formula

wherein y is 0, 1 or 2;

R 4 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 4 )alkoxy, (C 1 -C 6 )acyloxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, nitro, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 1 -C 6 )acylamino; or

R 4 is (C 3 -C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, cyano(C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, nitro, nitro(C 1 -C 6 )alkyl or (C 1 -C 6 )acylamino;

R 5 is (C 2 -C 9 )heterocycloalkyl wherein the heterocycloalkyl groups must be substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, amino(C 1 -C 6 )acyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S(O) m , R 15 R 16 NS(O) m , R 15 R 16 NS(O) m (C 1 -C 6 )alkyl, R 15 S(O) m R 16 N, R 15 S(O) m R 16 (C 1 -C 6 )alkyl wherein m is 0, 1 or 2 and R 15 and R 16 are each independently selected from hydrogen or (C 1 -C 6 )alkyl; or a group of the formula

wherein a is 0, 1, 2, 3 or 4;

b, c, e, f and g are each independently 0 or 1;

d is 0, 1, 2, or 3;

X is S(O) n wherein n is 0, 1 or 2; oxygen, carbonyl or —C(═N-cyano)-;

Y is S(O) n wherein n is 0, 1 or 2; or carbonyl; and

Z is carbonyl, C(O)O—, C(O)NR— or S(O) n wherein n is 0, 1 or 2;

R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen or (C 1 -C 6 )alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, cyano(C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, nitro, nitro(C 1 -C 6 )alkyl or (C 1 -C 6 )acylamino;

R 12 is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH, (C 1 -C 6 )alkylamino-CO—, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 )alkylamino, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )acylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamino, amino(C 1 -C 6 )acyl, amino(C 1 -C 6 )acyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )acyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )acyl, R 15 R 16 N—CO—O—, R 15 R 16 N—CO—(C 1 -C 6 )alkyl, R 15 C(O)NH, R 15 OC(O)NH, R 15 NHC(O)NH, (C 1 -C 6 )alkyl-S(O) m , (C 1 -C 6 )alkyl-S(O) m —(C 1 -C 6 )alkyl, R 15 R 16 NS(O) m , R 15 R 16 NS(O) m (C 1 -C 6 )alkyl, R 15 S(O) m R 16 N, R 15 S(O) m R 16 N(C 1 -C 6 )alkyl wherein m is 0, 1 or 2 and R 15 and R 16 are each independently selected from hydrogen or (C 1 -C 6 )alkyl;

R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 10 )cycloalkyl wherein the alkyl, alkoxy or cycloalkyl groups are optionally substituted by one to three groups selected from halo, hydroxy, carboxy, amino (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 5 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl, (C 3 -C 9 )cycloalkyl or (C 6 -C 10 )aryl; or R 2 and R 3 are each independently (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkoxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 6 -C 10 )arylamino, (C 1 -C 6 )alkylthio, (C 6 -C 10 )arylthio, (C 1 -C 6 )alkylsulfinyl, (C 6 -C 10 )arylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 6 -C 10 )arylsulfonyl, (C 1 -C 6 )acyl, (C 1 -C 6 )alkoxy-CO—NH—, (C 1 -C 6 )alkylamino-CO—, (C 5 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or (C 6 -C 10 )aryl wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted by one to three halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-CO—NH—, (C 1 -C 6 )alkoxy-CO—NH—, (C 1 -C 6 )alkyl-CO—NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH—(C 1 -C 6 )alkoxy, carboxy, carboxy(C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkoxy, benzyloxycarbonyl(C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 6 -C 10 )aryl, amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonylamino, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxycarbonylamino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, carboxy, carboxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO—NH—, (C 1 -C 6 )alkyl-CO—NH—, cyano, (C 5 -C 9 )heterocycloalkyl, amino-CO—NH—, (C 1 -C 6 )alkylamino-CO—NH—, ((C 1 -C 6 )alkyl) 2 amino-CO—NH—, (C 6 -C 10 )arylamino-CO—NH—, (C 5 -C 9 )heteroarylamino-C—NH—, (C 1 -C 6 )alkylamino-CO—NH—(C 1 -C 6 ) alkyl, ((C 1 -C 6 )alkyl) 2 amino-CO—NH—(C 1 -C 6 )alkyl, (C 6 -C 10 )arylamino-CO—NH—(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroarylamino-CO—NH—((C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 6 -C 10 )arylsulfonyl, (C 6 -C 10 )arylsulfonylamino, (C 6 -C 10 )arylsulfonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonylamino(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl or (C 2 -C 9 )heterocycloalkyl;

or of Formula B:

including pharmaceutically acceptable salt forms or prodrugs thereof, wherein:

A 1 and A 2 are independently selected from C and N;

T, U, and V are independently selected from O, S, N, CR 5 , and NR 6 ;

wherein the 5-membered ring formed by A 1 , A 2 , U, T, and V is aromatic;

X is N or CR 4 ;

Y is C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, (CR 11 R 12 ) p —(C 3-10 cycloalkylene)-(CR 11 R 12 ) q , (CR 11 R 12 ) p -(arylene)-(CR 11 R 12 ) q , (CR 11 R 12 ) p —(C 1-10 heterocycloalkylene)-(CR 11 R 12 ) q , (CR 11 R 12 ) p -(heteroarylene)-(CR 11 R 12 ) q , (CR 11 R 12 ) p O(CR 11 R 12 ) q , (CR 11 R 12 ) p S(CR 11 R 12 ) q , (CR 11 R 12 ) p C(O)(CR 11 R 12 ) q , (CR 11 R 12 ) p C(O)NR c (CR 11 R 12 ) q , (CR 11 R 12 ) p C(O)O(CR 11 R 12 ) q , (CR 11 R 12 ) p OC(O)(CR 11 R 12 ) q , (CR 11 R 12 ) p OC(O)NR c (CR 11 R 12 ) q , (CR 11 R 12 ) p NR c (CR 11 R 12 ) q , (CR 11 R 12 ) p NR c C(O)NR d (CR 11 R 12 ) q , (CR 11 R 21 ) p S(O)(CR 11 R 12 ) q , (CR 11 R 12 ) p S(O)NR c (CR 11 R 12 ) q , (CR 11 R 12 ) p S(O) 2 (CR 11 R 12 ) q , or (CR 11 R 12 ) p S(O) 2 NR c (CR 11 R 12 ) q , wherein said C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D 1 -D 2 -D 3 -D 4 ;

Z is H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, halosulfanyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, ═C—R i , ═N—R i , Cy 1 , CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c (O)R d , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR i )NR c R d , NR c C(═NR i )NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , C(═NOH)R b , C(═NO(C 1-6 alkyl)R b , and S(O) 2 NR c R d , wherein said C 1-8 alkyl, C 2-8 alkenyl, or C 2-8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, halosulfanyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, Cy 1 , CN, N 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR i )NR c R d , NR c C(═NR i )NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , C(═NOH)R b , C(═NO(C 1-6 alkyl))R b , and S(O) 2 NR c R d ;

wherein when Z is H, n is 1;

or the —(Y) n —Z moiety is taken together with i) A 2 to which the moiety is attached, ii) R 5 or R 6 of either T or V, and iii) the C or N atom to which the R 5 or R 6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A 1 A 2 , U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from —(W) m -Q;

W is C 1-8 alkylenyl, C 2-8 alkenylenyl, C 2-8 alkynylenyl, O, S, C(O), C(O)NR c′ , C(O)O, OC(O), OC(O)NR c′ , NR c′ , NR c′ C(O)NR d′ , S(O), S(O)NR c′ , S(O) 2 , or S(O) 2 NR c′ ;

Q is H, halo, CN, NO 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, halosulfanyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, Cy 2 , CN, NO 2 , OR a′ , SR a′ , C(O)R b′ , C(O)NR c′ R d′ , C(O)OR a′ , OC(O)R b′ , OC(O)NR c′ R d′ , NR c′ R d′ , NR c′ C(O)R b′ , NR c′ C(O)NR c′ R d′ , NR c′ , C(O)OR a′ —, S(O)R b′ , S(O)NR c′ R d′ , S(O) 2 R b′ , NR c′ S(O) 2 R b′ , and S(O) 2 NR c′ R d′ ;

Cy 1 and Cy 2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, halosulfanyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, CN, NO 2 , OR a″ , SR a″ , C(O)R b″ , C(O)NR c″ R d″ , C(O)OR a″ , OC(O)R b″ , OC(O)NR c″ R d″ , NR c″ R d″ , NR c″ C(O)R b″ , NR c″ C(O)OR a″ , NR c″ S(O)R b″ , NR c″ S(O) 2 R b″ , S(O)R b″ , S(O)NR c″ R d″ , S(O) 2 R b″ , and S(O) 2 NR c″ R d″ ;

R 1 , R 2 , R 3 , and R 4 are independently selected from H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR 7 , SR 7 , C(O)R 8 , C(O)NR 9 R 10 , C(O)OR 7 OC(O)R 8 , OC(O)NR 9 R 10 , NR 9 R 10 , NR 9 C(O)R 8 , NR c C(O)OR 7 , S(O)R 8 , S(O)NR 9 R 10 , S(O) 2 R 8 , NR 9 S(O) 2 R 8 , and S(O) 2 NR 9 R 10 ;

R 5 is H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, halosulfanyl, CN, NO 2 , OR 7 , SR 7 , C(O)R 8 , C(O)NR 9 R 10 , C(O)OR 7 , OC(O)R 8 , OC(O)NR 9 R 10 , NR 9 R 10 , NR 9 C(O)R 8 , NR 9 C(O)OR 7 , S(O)R 8 , S(O)NR 9 R 10 , S(O) 2 R 8 , NR 9 S(O) 2 R 8 , or S(O) 2 NR 9 R 10 ;

R 6 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, OR 7 , C(O)R 8 , C(O)NR 9 R 10 , C(O)OR 7 , S(O)R 8 , S(O)NR 9 R 10 , S(O) 2 R 8 , or S(O) 2 NR 9 R 10 ;

R 8 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;

R 8 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;

R 9 and R 10 are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylcarbonyl, arylcarbonyl, C 1-6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;

or R 9 and R 10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R 11 and R 12 are independently selected from H and -E 1 -E 2 -E 3 -E 4 ;

D 1 and E 1 are independently absent or independently selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and C 2-8 dialkylamino;

D 2 and E 2 are independently absent or independently selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, (C 1-6 alkylene) r -O—(C 1-6 alkylene) s , (C 1-6 alkylene) r -S—(C 1-6 alkylene) s , (C 1-6 alkylene) r -NR c —(C 1-6 alkylene), (C 1-6 alkylene) r -CO—(C 1-6 alkylene) s , (C 1-6 alkylene) r -COO—(C 1-6 alkylene) s , (C 1-6 alkylene) r -CONR c —(C 1-6 alkylene) s , (C 1-6 alkylene) r -SO—(C 1-6 alkylene) s , (C 1-6 alkylene) r -SO 2 —(C 1-6 alkylene) s , (C 1-6 alkylene) r -SONR c —(C 1-6 alkylene) s , and (C 1-6 alkylene) r -NR c CONR f —(C 1-6 alkylene) s , wherein each of the C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and C 2-8 dialkylamino;

D 3 and E 3 are independently absent or independently selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and C 2-8 dialkylamino;

E 3 and E 4 are independently selected from H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, halosulfanyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, Cy 1 , CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R a , C(O)OR a , OC(O)R b OC(O)NR c R d NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR i )NR c R d , NR c C(═NR i )NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , C(═NOH)R b , C(═NO(C 1-6 alkyl)R b , and S(O) 2 NR c R d , wherein said C 1-8 alkyl, C 2-8 alkenyl, or C 2-8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, halosulfanyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, Cy 1 , CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R a , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR i )NR c R d , NR c C(═NR i )NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , C(═NOH)R b , C(═NO(C 1-6 alkyl))R b , and S(O) 2 NR c R d ;

R a is H, Cy 1 , —(C 1-6 alkyl)-Cy 1 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R b is H, Cy 1 , —(C 1-6 alkyl)-Cy 1 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R a′ and R a″ are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R b′ and R b″ are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R c and R d are independently selected from H, Cy 1 , —(C 1-6 alkyl)-Cy 1 , C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 1-6 alkynyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , —(C 1-6 alkyl)-Cy 1 , OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, and halosulfanyl;

or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , —(C 1-6 alkyl)-Cy 1 , OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, and halosulfanyl;

R c′ and R d′ are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

or R c′ and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R c″ and R d″ are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, halosulfanyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

or R c″ and R d″ , together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R i is H, CN, NO 2 , or C 1-6 alkyl;

R e and R f are independently selected from H and C 1-6 alkyl;

R i is H, CN, or NO 2 ;

m is 0 or 1;

n is 0 or 1;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 0, 1, 2, 3, 4, 5 or 6;

r is 0 or 1; and

s is 0 or 1.

2. A method for treating a Hepacivirus, Pestivirus, Flavivirus or Alphavirus infection, comprising administering to a patient in need thereof an effective antiviral amount of a JAK inhibitors selected from the group consisting of CEP-701 (Lestaurtinib), AZD1480, LY3009104/INCB28050 Pacritinib/SB1518, VX-509, GLPG0634, INC424, R-348, CYT387, TG 10138, AEG 3482, 7-iodo-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(4-aminophenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, N-(4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acryl amide, 7-(3-aminophenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2amine, N-(3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phen-yl)acrylamide, N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, methyl 2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidine-7-carboxylate, N-(4-morpholinophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine, 7-(4-amino-3-methoxyphenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N,Ndimethyl-3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, 1-ethyl-3-(2-methoxy-4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)urea, N-(4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)metha-nesulfonamide, 2-methoxy-4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)pheno-1, 2-cyano-N-(3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl-)phenyl)acetamide, N-(cyanomethyl)-2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidine-7-carboxamide, N-(3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, 1-ethyl-3-(4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)-2-(-trifluoromethoxy)phenyl)urea N-(3-nitrophenyl)-7-phenylthieno[3,2-d]pyrimidin2-amine, 7-iodo-N-(3-nitrophenyl)thieno[3,2-d]pyrimidin-2-amine, N1-(7-(2-ethylphenyl)thieno[3,2-d]pyrimidin-2-yl)benzene-1,3-diamine, N-tert-butyl-3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)be-nzenesulfonamide, N1-(7-iodothieno[3,2-d]pyrimidin-2-yl)benzene-1,3-diamine, 7-(4-amino-3-(trifluoromethoxy)phenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(2-ethylphenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl-)acetamide, N-(cyanomethyl)-N-(3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, N-(cyanomethyl)-N-(4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, N-(3-(5-methyl-2-(4-morpholinophenylamino)-5H-pyrrolo[3,2-5 d]pyrimidin-7-yl)phenyl)methanesulfonamide, 4-(5-methyl-2-(4-morpholinophenylamino)-5Hpyrrolo[3,2-d]pyrimidin-7-yl)b-enzenesulfonamide, N-(4-(5-methyl-2-(4-morpholinophenylamino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, 7-iodo-N-(4-morpholinophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine, 7-(2-isopropylphenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-bromo-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine N7-(2-isopropylphenyl)-N2-(4-morpholinophenyl)thieno[3,2-d]pyrimidine-2,7-diamine, N7-(4-isopropylphenyl)-N2-(4-morpholinophenyl)thieno[3,2-d]pyrimidine-2,7-diamine, 7-(5-amino-2-methylphenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzamide, 7-iodo-N-(3-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(4-amino-3-nitrophenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(2-methoxypyridin-3-yl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, (3-(7-iodothieno[3,2-d]pyrimidin-2-ylamino)phenyl)methanol, N-tert-butyl-3-(2-(3-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)be-nzenesulfonamide, N-tertbutyl-3-(2-(3-(hydroxymethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N-(4-morpholinophenyl)-7-(4-nitrophenylthio)-5Hpyrrolo[3,2-d]pyrimidin-2-amine, N-tert-butyl-3-(2-(3,4,5-trimethoxyphenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, 7-(4-amino-3-nitrophenyl)-N-(3,4-dimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine N-(3,4-dimethoxyphenyl)-7-(2-methoxypyridin-3-yl)thieno[3,2-d]pyrimidin-2-amine, N-tert-butyl-3-(2-(3,4-dimethoxyphenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, 7-(2-aminopyrimidin-5-yl)-N-(3,4-dimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3,4-dimethoxyphenyl)-7-(2,6-dimethoxypyridin-3-yl)thieno[3,2-d]pyrimidin-2-amine, N-(3,4-dimethoxyphenyl)-7-(2,4-dimethoxypyrimidin-5-yl)thieno[3,2-d]pyrimidin-2-amine, 7-iodo-N-(4-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-2-amine, N-tert-butyl-3-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)2-cyano-N-(4-methyl-3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, ethyl 3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzoate, 7-bromo-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3-(2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, N-(cyanomethyl)-5 3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl-)benzamide, N-tert-butyl-3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzamide, N-tert-butyl-3-(2-(4-(1-ethylpiperidin-4-yloxy)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, tert-butyl-4-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazole-1-carboxylate, 7-bromo-N-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidin-2-amine, N-tert-butyl-3-(2-(4-((4-ethylpiperazin-1-yl)methyl)phenylamino)thieno[3,-2-d]pyrimidin-7-yl)benzenesulfonamide, N-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-7-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-2-amine, N-(cyanomethyl)-3-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzamide, N-tert-butyl-3-(2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)thieno[3,2-d]-pyrimidin-7-yl)benzenesulfonamide, tert-butylpyrrolidin-1-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzylcarbamate, 3-(2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, 7-(3-chloro-4-fluorophenyl)-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thieno-[3,2-d]pyrimidin-2-amine, tert-butyl 4-(2-(4-(1-ethylpiperidin-4-yloxy)phenylamino)thieno[3,2-d]pyrimidin-7-yl-)-1H-pyrazole-1-carboxylate, 7-(benzo[d][1,3]dioxol-5-yl)-N-(4-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-2-amine, tert-butyl 5-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)-1H-indole-1-carboxylate, 7-(2-aminopyrimidin-5-yl)-N-(4-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-2-amine, tert-butyl 4-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)-5,6-di-hydropyridine-1(2H)-carboxylate, tert-butylmorpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzylcarbamate, N-(3-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)-phenyl)acetamide, N-(4-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, N-(3-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, 7-(4-(4-methylpiperazin-1-yl)phenyl)-N-(4-(morpholinomethyl)phenyl)thieno-[3,2-d]pyrimidin-2-amine, N-(2-methoxy-4-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, 7-bromo-N-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, (3-(2-(3,4,5-trimethoxyphenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanol, (4-(2-(3,4,5-trimethoxyphenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)5 methanol, (3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanol, (4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanol, N-(pyrrolidin-1-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzyl)methanesulfonamide, tert-butylmorpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzylcarbamate, N-(4-(morpholinomethyl)phenyl)-7-(3-(piperazin-1-yl)phenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(6-(2-morpholinoethylamino)pyridin-3-yl)-N-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(2-ethylphenyl)-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(4-(aminomethyl)phenyl)-N-(4-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-2-amine, N-(4-(1-ethylpiperidin-4-yloxy)phenyl)-7-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-2-amine, N-(2,4-dimethoxyphenyl)-7-phenylthieno[3,2-d]pyrimidin-2-amine, 7-bromo-N-(3,4-dimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3,4-dimethoxyphenyl)-7-phenylthieno[3,2-d]pyrimidin-2-amine, and pharmaceutically acceptable salts and prodrugs thereof.

3. The method of claim 1 , further comprising the co-administration of at least one additional antiviral agent selected from the group consisting of non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors.

4. The method of claim 1 , wherein the compound of Formula A is

or a pharmaceutically acceptable salt or prodrug thereof.

5. The method of claim 1 , wherein the compound of Formula B is

or a pharmaceutically acceptable salt or prodrug thereof.

Continuity (8)