| 主权项 |
1. A combination comprising an NS5A-targeting compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein
L is absent or selected from C2alkyl, C2alkenyl, C2alkynyl, C4alkynyl, and C3cycloalkyl A is absent or selected from isoquinolinyl, naphthyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, and quinolinyl; B is selected from anthracenyl, benzofuranyl, bicycloalkyl, indanyl, indolyl, naphthyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, tetrahydronaphthyl, thienyl, and each X is independently selected from O and NRq′, wherein Rq′ is selected from hydrogen, alkyl, hydroxy, and —NH2; each R1 is independently selected from alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heterocyclyl, and hydroxyalkyl; each R1a is independently selected from hydrogen and alkyl; or R1 and R1a, together with the carbon atom to which they are attached, form a saturated or unsaturated 3- to 6-membered spirocyclic ring, wherein the spirocyclic ring, when between 4- and 6-members, can be optionally fused to a phenyl ring, and wherein each ring system is optionally substituted with one or two groups independently selected from alkyl and halo; each Rf is independently selected from hydrogen, methyl, hydroxy, and —NH2(Rz), wherein Rz is alkyl; each Rp is independently selected from hydrogen, alkyl, cyano, halo, haloalkoxy, and haloalkyl; each Rq is independently selected from hydrogen, alkyl, halo, and —P(O)—(OR)2, wherein each R is the same or a different alkyl group; and each R2 is independently selected from hydrogen, alkenylcarbonyl, alkoxyalkylcarbonyl, alkoxyalkylcarbonylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, alkyl, alkylcarbonyl, alkylcarbonylalkylcarbonyl, alkylcarbonylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, alkynyloxycarbonyl, alkynylcarbonyl, arylcarbonyl, arylcarbonylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, arylsulfanylalkylcarbonyl, arylsulfinyl, arylsulfonyl, bicycloalkylcarbonyl, carboxyalkylcarbonyl, carboxycarbonyl, cyanoalkylcarbonyl, (cycloalkenyl)alkylcarbonyl, (cycloalkyl)alkyl, (cycloalkyl)alkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonylcarbonyl, cycloalkyloxycarbonyl, haloalkenylcarbonyl, haloalkoxyalkylcarbonyl, haloalkylcarbonyl, haloalkylcarbonylcarbonyl, heterocyclyl, (heterocyclyl)alkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkylcarbonyl, heterocyclylcarbonylcarbonyl, hydroxyalkenylcarbonyl, hydroxyalkylcarbonyl, (NRcRd)alkylcarbonyl, (NRcRd)carbonyl, (NRcRd)carbonylalkylcarbonyl, (NRcRd)carbonylcarbonyl, andwherein R and R′ are each alkyl, or, together with the carbon atom to which they are attached, form a five- or six-membered ring optionally containing one oxygen or nitrogen atom; or
R2 and Rf, together with the nitrogen atom to which they are attached, forms a five- or six-membered ring optionally substituted with one or two groups independently selected from alkoxycarbonylamino and oxo; or R2 and Rf, together with the nitrogen atom to which they are attached, formand an NS5A synergist of formula (VII):or a pharmaceutically acceptable salt thereof, wherein:
L is absent or selected from —O—, —CH2—O—CH2—, —OCH2—, C2alkyl, C2alkynyl, cyclopropyl, ethynylbenzyl, phenyl, pyrazinyl, and pyridinyl; A is selected from aryl, cycloalkenyl, and heteroaryl; B is selected from aryl, bicycloalkyl, cycloalkenyl, and heteroaryl; each R1 is independently selected fromeach m is independently 0, 1, or 2;
each X is independently selected from CH2, NH, and NRa; wherein Ra is alkyl; each R2 is independently selected from alkyl, halo, and hydroxy; wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon, a bridged four- or five-membered ring with another carbon atom on the ring, or a spirocyclic three- to six-membered ring with the carbon atom to which it is attached; wherein each ring is optionally substituted with one or two groups independently selected from alkyl, halo, and haloalkyl; or R2, together with the carbon atom to which it is attached, forms a C2 olefin; each R3 is independently selected from alkoxy, alkyl, arylalkoxy, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, (NRcRd)alkenyl, and (NRcRd)alkyl; each R4 is independently selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; each R5 is independently selected from hydrogen and alkyl; each Rp is independently selected from hydrogen, alkyl, cyano, halo, haloalkoxy, and haloalkyl; and each Rq is independently selected from hydrogen, alkyl, halo, and —P(O)—(OR)2, wherein each R is the same or a different alkyl group;which, when administered, provides synergistic anti-HCV activity against variants that contain mutation(s) conferring resistance to the NS5A-targeting compound alone. |
