Inhibitors of Flaviviridae viruses

A compound of Formula I:

• or a pharmaceutically acceptable salt or ester thereof, wherein:
• R1 is -(L1)m-(L2)n-X1;
• L1 is selected from the group consisting of alkynylene and optionally substituted arylene;
• m is 1;
• when L1 is substituted, L1 is substituted with one or more Q6;
• L2 is selected from the group consisting of —NHC(O)— and optionally substituted alkylene;
• n is 0 or 1;
• when L2 is substituted, L2 is substituted with one or more Q6;
• X1 is selected from the group consisting of
• a)—P(O)RxRy,
• b) —P(O)ORxRy,
• c)—OP(O)RxRy and
• d) optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• each of Rx and Ry independently is selected from the group consisting of H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• or Rx and Ry taken together with the atoms to which they are attached form a 3 to 10 membered heterocyclyl;
• when either Rx or Ry is substituted, Rx or Ry is substituted with one or more Q6;
• when X1 is selected from d) and is substituted, X1 is substituted with one or more Q1;
• each Q1 individually is selected from the group consisting of halogen, oxo, oxide, —NO2, —SR11, —S(O)R10, —S(O)2R10, —S(O)2NR12R11, —NR12C(O)R11, —NR12C(O)NR11R12, —NR11S(O)R10, —NR11S(O)2R10, —NR12S(O)2NR11R12, —CR12(═NNR11R12), —CR12(═NOR11), —ONR12R11, —ON(═CR12R11), —NR12OR11, —OH, —NR11R12, —C(O)OR12, —CN, —N3, —C(═NR13)NR11R12, —NR12C(═NR13)NR11R12, —NR12C(O)OR11, —OC(O)NR11R12, —OP(O)R11R12, —P(O)R11R12, —P(O)OR11R12, —C(O)NR11R12, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted C6-12 arylalkyl, optionally substituted C6-12 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted C1-6alkyloxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, optionally substituted C3-6 cycloalkyloxy, optionally substituted C6-12 aryloxy, optionally substituted 3-14 membered heteroaryloxy, optionally substituted 4-12 membered heterocyclyloxy, optionally substituted —C(O)C1-6 alkyl, optionally substituted —C(O)C2-6 alkenyl, optionally substituted —C(O)C2-6 alkynyl, optionally substituted —C(O)C3-6 cycloalkyl, optionally substituted —C(O)C6-12 aryl, optionally substituted —C(O)-3-14 membered heteroaryl, optionally substituted —C(O)C6-12 arylalkyl and optionally substituted-3-10 membered heterocyclyl;
• wherein each R10, independently, is selected from the group consisting of optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• wherein each R11 and R12, independently, is selected from the group consisting of H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• or R11 and R12 taken together with the atoms to which they are attached form a 4 to 10 membered heterocyclyl;
• or R10 and R11 taken together with the atoms to which they are attached form a 4 to 10 membered heterocyclyl;
• each R13 independently is selected from the group consisting of H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl, optionally substituted C6-18 arylalkyl, —CN, —C(O)R14, —CHO and —S(O)2R14;
• where each R14 individually is optionally substituted C1-12 alkyl;
• when Q1 is substituted, Q1 is substituted with one or more Q6;
• R2 is selected from the group consisting of optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• wherein, when R2 is substituted, R2 is substituted with one or more Q2;
• where each Q2 individually is selected from the group consisting of halogen, oxo, oxide, —NO2, —SR21, —S(O)R20, —S(O)2R20, —S(O)2NR22R21, —NR22C(O)R21, —NR22C(O)NR21R22, —NR21S(O)R20, —NR21S(O)2R20, —NR22S(O)2NR21R22, —CR22(═NNR21R22), —CR22(═NOR21), —ONR22R21, —ON(═CR22R21), —NR22OR21, —OH, —NR21R22, —C(O)OR22, —CN, —N3, —C(═NR23)NR21R22, —NR22C(═NR23)NR21R22, —NR22C(O)OR21, —OC(O)NR21R22, —OP(O)R21R22, —P(O)R21R22, P(O)OR21R22, —C(O)NR21R22, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted C6-12 arylalkyl, optionally substituted C6-12 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted C1-6 alkyloxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, optionally substituted C3-6 cycloalkyloxy, optionally substituted C6-12 aryloxy, optionally substituted 3-14 membered heteroaryloxy, optionally substituted 4-12 membered heterocyclyloxy, optionally substituted —C(O)C1-6 alkyl, optionally substituted —C(O)C2-6 alkenyl, optionally substituted —C(O)C2-6 alkynyl, optionally substituted —C(O)C3-6 cycloalkyl, optionally substituted —C(O)C6-12 aryl, optionally substituted —C(O)-3-14 membered heteroaryl, optionally substituted —C(O)C6-12 arylalkyl and optionally substituted 3-10 membered heterocyclyl;
• wherein each R20, independently, is selected from the group consisting of optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• wherein each R21 and R22, independently, is selected from the group consisting of H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• or R21 and R22 taken together with the atoms to which they are attached form a 4 to 10 membered heterocyclyl;
• or R20 and R21 taken together with the atoms to which they are attached form a 4 to 10 membered heterocyclyl;
• each R23 independently is selected from the group consisting of H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl, optionally substituted C6-18 arylalkyl, —CN, —C(O)R24, CHO and —S(O)2R24;
• where each R24 individually is optionally substituted C1-12 alkyl;
• when Q2 is substituted, Q2 is substituted with one or more Q6;
• R3 is -(L3)p-(L4)q-(X3);
• L3 is selected from the group consisting of optionally substituted C1-12 alkylene, optionally substituted C2-12 alkenylene, optionally substituted C2-12 alkynylene, optionally substituted C3-12 cycloalkylene, optionally substituted C1-12 haloalkylene, optionally substituted C6-14 arylene, optionally substituted 3-12 membered heterocyclylene, optionally substituted 3-18 membered heteroarylalkylene and optionally substituted C6-18 arylalkylene;
• p is 0 or 1;
• when L3 is substituted, L3 is substituted with one or more Q3;
• each Q3 individually is selected from the group consisting of halogen, oxo, oxide, —NO2, —SR31, —S(O)R30, —S(O)2R30, —S(O)2NR32R31, —NR32C(O)R31, —NR32C(O)NR31R32, —NR31S(O)R30, —NR31S(O)2R30, —NR32S(O)2NR31R32, —CR32(═NNR31R32), —CR32(═NOR31), —ONR32R31, —ON(═CR32R31), —NR32OR31, —OH, —NR31R32, —C(O)OR32, —CN, —N3, —C(═NR33)NR31R32, —NR30C(═NR33)N R31R32, —NR30C(O)OR31, —OC(O)NR31R32, —OP(O)R31R32, —P(O)R31R32, —P(O)OR31R32—C(O)NR31R32, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted C6-12 arylalkyl, optionally substituted C6-12 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted C1-6 alkyloxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, optionally substituted C3-6 cycloalkyloxy, optionally substituted C6-12 aryloxy, optionally substituted 3-14 membered heteroaryloxy, optionally substituted 4-12 membered heterocyclyloxy, optionally substituted —C(O)C1-6 alkyl, optionally substituted —C(O)C2-6 alkenyl, optionally substituted —C(O)C2-6 alkynyl, optionally substituted —C(O)C3-6 cycloalkyl, optionally substituted —C(O)C6-12 aryl, optionally substituted —C(O)-3-14 membered heteroaryl, optionally substituted —C(O)C6-12 arylalkyl and optionally substituted 3-10 membered heterocyclyl;
• wherein each R30, independently, is selected from the group consisting of optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• wherein each R31 and R32, independently, is selected from the group consisting of H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• or R31 and R32 taken together with the atoms to which they are attached form a 4 to 10 membered heterocyclyl;
• or R30 and R31 taken together with the atoms to which they are attached form a 4 to 10 membered heterocyclyl;
• each R33 independently is selected from the group consisting of H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl, optionally substituted C6-18 arylalkyl, —CN, —C(O)R34, CHO and —S(O)2R34;
• where each R34 individually is optionally substituted C1-12 alkyl;
• when Q3 is substituted, Q3 is substituted with one or more Q6;
• L4 is selected from the group consisting of —NH—, and optionally substituted C1-12 alkylene;
• q is 0, 1 or 2;
• when L4 is substituted, L4 is substituted with one or more Q6;
• X3 is selected from the group consisting of:
• e) —P(O)RxRy,
• f) —P(O)ORxRy,
• g)—OP(O)RxRy,
• h) —P(O)(ORx)(ORy),
• i)
• wherein each A is a 4 to 6 membered ring, including the depicted P atom,
• j)
• and
• k) optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• each of Rx and Ry individually is as defined above;
• when X3 is selected from k) and is substituted, X3 is substituted with one or more Q4;
• each Q4 individually is selected from the group consisting of halogen, oxo, oxide, —NO2, —SR41, —S(O)R40, —S(O)2R40, —S(O)2NR42R41, —NR42C(O)R41, —NR42C(O)NR41R42, —NR41S(O)R40, —NR41S(O)2R40, —NR42S(O)2NR41R42, —CR42(═NNR41R42), —CR42(═NOR41), —ONR42R41, —ON(═CR42R41), —NR42OR41, —OH, —NR41R42, —C(O)OR42, —CN, —N3, —C(═NR43)NR41R42, —NR42C(═NR43)NR41R42, —NR42C(O)OR41, and —OC(O)NR41R42, —OP(O)R41R42, —P(O)R41R42, —P(O)OR41R42, —C(O)NR41R42, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted C6-12 arylalkyl, optionally substituted C6-12 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted C1-6 alkyloxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, optionally substituted C3-6 cycloalkyloxy, optionally substituted C6-12 aryloxy, optionally substituted 3-14 membered heteroaryloxy, optionally substituted 4-12 membered heterocyclyloxy, optionally substituted —C(O)C1-6 alkyl, optionally substituted —C(O)C2-6 alkenyl, optionally substituted —C(O)C2-6 alkynyl, optionally substituted —C(O)C3-6 cycloalkyl, optionally substituted —C(O)C6-12 aryl, optionally substituted —C(O)-3-14 membered heteroaryl, optionally substituted —C(O)C6-12 arylalkyl and optionally substituted-3-10 membered heterocyclyl;
• wherein each R40, independently, is selected from the group consisting of optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• wherein each R41 and R42, independently, is selected from the group consisting of H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl and optionally substituted C6-18 arylalkyl;
• or R41 and R42 taken together with the atoms to which they are attached form a 4 to 10 membered heterocyclyl;
• or R40 and R41 taken together with the atoms to which they are attached form a 4 to 10 membered heterocyclyl;
• each R43 independently is selected from the group consisting of H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted 3-14 membered heteroaryl, optionally substituted 3-12 membered heterocyclyl, optionally substituted 3-18 membered heteroarylalkyl, optionally substituted C6-18 arylalkyl, —CN, —C(O)R44, CHO and —S(O)2R44;
• where each R44 individually is optionally substituted C1-12 alkyl;
• when Q4 is substituted, Q4 is substituted with one or more Q6;
• and
• each Q6 individually is selected from the group consisting of halogen, oxo, oxide, —NO2, —N(═O), —SR61, —S(O)R60, —S(O)2R60, —S(O)2NR62R61, —NR62C(O)R61, —NR62C(O)NR61R62, —NR61S(O)R60, —NR61S(O)2R60, —NR62S(O)2NR61R62, —CR62(═NNR61R62), —CR62(═NOR61), —ONR62R61, —ON(═CR62R61), —NR62OR61, —OH, —NR61R62, —C(O)OR62, —CN, —N3, —C(═NR63)NR61R62, —NR62C(═NR63)NR61R62, —NR62C(O)OR61, —OC(O)NR61R62, —OP(O)R61R62, —P(O)R61R62, —P(O)OR61R62, —P(O)(OR61)OR62, —C(O)NR61R62, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-12 arylalkyl, C6-12 aryl, 3-14 membered heteroaryl, C1-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-6 cycloalkyloxy, C6-12 aryloxy, 3-14 membered heteroaryloxy, 4-12 membered heterocyclyloxy, —C(O)C1-6 alkyl, —C(O)C2-6 alkenyl, —C(O)C2-6 alkynyl, —C(O)C3-6 cycloalkyl, —C(O)C1-6 haloalkyl, —C(O)C6-12 aryl, —C(O)-3-14 membered heteroaryl, —C(O)C6-12 arylalkyl and 3-10 membered heterocyclyl;
• wherein each R60, independently, is selected from the group consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C1-12 haloalkyl, C6-14 aryl, 3-14 membered heteroaryl, 3-12 membered heterocyclyl, 3-18 membered heteroarylalkyl and C6-18 arylalkyl;
• wherein each R61 and R62, independently, is selected from the group consisting of H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C1-12 haloalkyl, C6-14 aryl, 3-14 membered heteroaryl, 3-12 membered heterocyclyl, 3-18 membered heteroarylalkyl and C6-18 arylalkyl;
• or R61 and R62 taken together with the atoms to which they are attached form a 4 to 10 membered heterocyclyl;
• or R60 and R61 taken together with the atoms to which they are attached form a 4 to 10 membered heterocyclyl;
• each R63 independently is selected from the group consisting of H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-14 aryl, 3-14 membered heteroaryl, 3-12 membered heterocyclyl, 3-18 membered heteroarylalkyl, C6-18 arylalkyl, —CN, —C(O)R64, —CHO and —S(O)2R64;
• where each R64 individually is C1-12 alkyl;
• provided, however, that when X1 is selected from d), then X3 is selected from the group consisting of e), f), g), h), i) and j).