Therapeutic methods

A composition comprising a compound of Formula (IIB):

• wherein:
• R is F or Cl;
• R1 is —C(O)NHR5;
• R2 is C3-6cycloalkyl;
• R3 is —S(O)2R7;
• R4 is
• (a) heteroaryl substituted with B(R8)(R9) or X B(R8)(R9), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10, C3-6cycloalkyl, and heterocyclyl;
• (b) C6-10aryl substituted with B(R8)(R9), or XB(R8)(R9), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10, C3-6cycloalkyl, and heterocyclyl;
• or
• (c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10, C3-6cycloalkyl, and heterocyclyl;
• Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 11-membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms;
• one boron atom, one oxygen atom, and one nitrogen atom;
• or one boron atom and one or more nitrogen atoms;
• R5 is C1-6alkyl;
• R6 is C1-6alkyl or C3-6cycloalkyl;
• R7 is C1-6alkyl, hydroxyalkyl, or aminoalkyl;
• R8 and R9 are each independently hydroxy, alkoxy, or aminoalkyl;
• or R8 and R9 together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O;
• said ring may be optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH, C(O)OXOR13, C(O)N(R10)(R11), N(R10)(R11), and C3-6cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, C(O)OH, C(O)N(R10)(R11), and N(R10)(R11);
• R10 and R11 are each independently hydrogen or C1-6alkyl;
• R13 is alkoxy;
• X is alkylene or —O-alkylene, wherein alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10 and C3-6cycloalkyl;
• or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from the group consisting of an HCV NS2 protease inhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicase inhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5A replication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCV entry inhibitor, an HCV internal ribosome entry site inhibitor, a microsomal triglyceride transfer protein inhibitor, an α-glucosidase inhibitor, a caspase inhibitor, a cyclophilin inhibitor, an immunomodulator, a metabolic pathway inhibitor, an interferon, and a nucleoside analogue.

A pharmaceutical composition comprising a compound of Formula (II):

• wherein:
• R is independently selected from the group consisting of halogen, C1-6alkyl, alkoxy, —CN, —CF3, —O— C6-10aryl optionally substituted by halogen, and —O-heteroaryl optionally substituted by halogen;
• R1 is —C(O)OH, —C(O)NHR5 or heterocyclyl;
• R2 is C1-6alkyl, C3-6cycloalkyl, —C(H)F2, —CF3, or —OR6;
• R3 is —S(O)2R7 or —C(O)R7;
• R4 is
• (a) heteroaryl substituted with B(R8)(R9), X B(R8)(R9), OXB(R8(R9), B− (R8)(R9)(R12), XB(R8)R9)(R12), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10, C3-6cycloalkyl, and heterocyclyl;
• (b) C6-10aryl substituted with B(R8)(R9), X B(R8)(R9), OXB(R8(R9), B− (R8)(R9)(R12), XB(R8)R9)(R12), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10, C3-6cycloalkyl, and heterocyclyl;
• or
• (c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10, C3-6cycloalkyl, and heterocyclyl;
• Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 11-membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms;
• or one boron atom and one or more nitrogen atoms;
• R5 is hydrogen, C1-6alkyl, hydroxy, or —OR6;
• R6 is C1-6alkyl or C3-6cycloalkyl;
• R7 is C1-6alkyl, hydroxyalkyl, or aminoalkyl;
• R8, R9, and R12 are each independently hydroxy, alkoxy, or aminoalkyl;
• or R8 and R9 or R8, R9, and R12 together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O;
• said ring may be optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH, C(O)OXOR13, C(O)N(R10)(R11), N(R10)(R11), and C3-6cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, C(O)OH, C(O)N(R10)(R1l), and N(R10)(R11);
• R10 and R11 are each independently hydrogen or C1-6alkyl;
• R13 is alkoxy;
• X is alkylene or —O-alkylene, wherein alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10 and C3-6cycloalkyl;
• m is 1,2, or 3;
• or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from the group consisting of an HCV NS2 protease inhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicase inhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5A replication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCV entry inhibitor, an HCV internal ribosome entry site inhibitor, a microsomal triglyceride transfer protein inhibitor, an α-glucosidase inhibitor, a caspase inhibitor, a cyclophilin inhibitor, an immunomodulator, a metabolic pathway inhibitor, an interferon, and a nucleoside analogue, or a pharmaceutically acceptable salt thereof;
• and a pharmaceutically acceptable carrier.

A pharmaceutical composition comprising a compound of Formula (IIB):

• wherein:
• R is F or Cl;
• R1 is —C(O)NHR5;
• R2 is C3-6cycloalkyl;
• R3 is —S(O)2R7;
• R4 is
• (a) heteroaryl substituted with B(R8)(R9) or X B(R8)(R9), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10, C3-6cycloalkyl, and heterocyclyl;
• (b) C6-10aryl substituted with B(R8)(R9), or XB(R8)(R9), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10, C3-6cycloalkyl, and heterocyclyl;
• or
• (c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10, C3-6cycloalkyl, and heterocyclyl;
• Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 11-membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms;
• one boron atom, one oxygen atom, and one nitrogen atom;
• or one boron atom and one or more nitrogen atoms;
• R5 is C1-6alkyl;
• R6 is C1-6alkyl or C3-6cycloalkyl;
• R7 is C1-6alkyl, hydroxyalkyl, or aminoalkyl;
• R8 and R9 are each independently hydroxy, alkoxy, or aminoalkyl;
• or R8 and R9 together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O;
• said ring may be optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(O)OH, C(O)OXOR13, C(O)N(R10)(R11), N(R10)(R1), and C3-6cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, C(O)OH, C(O)N(R10)(R11), and N(R10)(R11);
• R10 and R11 are each independently hydrogen or C1-6alkyl;
• R13 is alkoxy;
• X is alkylene or —O-alkylene, wherein alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6alkoxy, —C(H)F2, —CF3, C1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —C(O)NH2, —C(O)OH, —C(O)NHR5, —S(O)2 R6, —S(O)2NH2, —CN, —OCF3, —OR6, —NR10R11, —NHC(O)R10 and C3-6cycloalkyl;
• or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from the group consisting of an HCV NS2 protease inhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicase inhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5A replication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCV entry inhibitor, an HCV internal ribosome entry site inhibitor, a microsomal triglyceride transfer protein inhibitor, an α-glucosidase inhibitor, a caspase inhibitor, a cyclophilin inhibitor, an immunomodulator, a metabolic pathway inhibitor, an interferon, and a nucleoside analogue, or a pharmaceutically acceptable salt thereof;
• and a pharmaceutically acceptable carrier.