# US 8,569,302 B2 · Inhibitors of flaviviridae viruses

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- Number: US 8,569,302 B2
- Document ID: US8569302B2
- Status: Granted
- Kind: B2
- Application number: 12/838,684
- Filed: 2010-07-19
- Published: 2011-01-27
- Granted: 2013-10-29
- Earliest claimed: 2009-07-21
- Assignees: Gilead Sciences, Inc.
- Applicants: Eda Canales; Lee S. Chong; Michael O'Neil Hanrahan Clarke; Edward Doerffler; Scott E. Lazerwith; Willard Lew; Qi Liu; Michael Mertzman; Philip A. Morganelli; William J. Watkins; Hong Ye
- Inventors: Eda Canales; Lee S. Chong; Michael O'Neil Hanrahan Clarke; Edward Doerffler; Scott E. Lazerwith; Willard Lew; Qi Liu; Michael Mertzman; Philip A. Morganelli; William J. Watkins; Hong Ye
- Web page: https://patentgrep.com/patent/US8569302B2

## CPC

- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4436: containing a heterocyclic ring having sulfur as a ring hetero atom
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/497: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 333/68: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 487/04: Ortho-condensed systems
- C07D 493/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided are compounds of Formula I: and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections.

## Claims

### Claim 1

A compound of Formula I:
or a pharmaceutically acceptable salt or ester thereof, wherein:
R1 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, optionally substituted 3-18 membered heterocyclylalkyl and optionally substituted C6-18 arylalkyl, wherein, each substituted R1 is substituted with one or more Q1;
each Q1 is independently selected from the group consisting of halogen, oxo, oxide, —NO2, —N(═O), —SR10, —S(O)R10, —S(O)2R10, —S(O)2NR10R11, —NR10C(O)R11, —NR10C(O)NR11R12, —NR10S(O)R11, —NR10S(O)2R11, —OP(O)R11R12, —P(O)R11R12, —P(O)OR11R12, —P(O)(OR11)OR12, —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 C1-6 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, optionally substituted -3-10 membered heterocyclyl, —OH, —NR11R12, —C(O)OR10, —CN, —N3, —C(═NR13)NR11R12, —C(═NR13)OR10, —NR10C(═NR13)NR11R12, —NR11C(O)OR10, and —OC(O)NR11R12;
each R10, 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 3 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;
each R14, independently, is optionally substituted C1-12 alkyl;
wherein, each substituted Q1, substituted R10, substituted R11, substituted R12, substituted R13, or substituted R14 is independently 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, each substituted R2 is substituted with one or more Q2;
each Q2, independently, is selected from the group consisting of halogen, oxo, oxide, —NO2, —N(═O), —SR20, —S(O)R20, —S(O)2R20, —S(O)2NR20R21, —NR20C(O)R21, —NR20C(O)NR21R22, —NR20S(O)R21, —NR20S(O)2R21, —OP(O)R21R22, —P(O)R21R22, —P(O)OR21R22, —P(O)(OR21)OR22, —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, optionally substituted 3-10 membered
heterocyclyl, —OH, —NR21R22, —C(O)OR20, —CN, —N3, —C(═NR23)NR21R22, —C(═NR23)OR20, —NR20C(═NR23)NR21R22, —NR21C(O)OR20, and —OC(O)NR21R22;
each R20, 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 3 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;
each R24 individually is optionally substituted C1-12 alkyl;
wherein, each substituted Q2, substituted R20, substituted R21, substituted R22, substituted R23, or substituted R24 is independently substituted with one or more Q6;
R3 is selected from the group consisting of optionally substituted C1-12 alkylene, C2-12 alkenylene, substituted C2-12 alkenylene, C2-12 alkynylene, substituted C2-12 alkynylene, C3-12 cycloalkylene, substituted C3-12 cycloalkylene, optionally substituted C6-14 arylene, optionally substituted 3-14 membered heteroarylene, optionally substituted 3-12 membered heterocyclylene, optionally substituted 3-18 membered heteroarylalkylene, and optionally substituted C6-18 arylalkylene;
wherein each substituted R3 is substituted with one or more Q3;
each Q3, independently, is selected from the group consisting of halogen, oxo, oxide, —NO2, —N(═O), —SR30, —S(O)R30, —S(O)2R30, —S(O)2NR30R31, —NR30C(O)R31, —NR30C(O)NR31R32, —NR30S(O)R31, —NR30S(O)2R31, —OP(O)R31R32, —P(O)R31R32, —P(O)OR31R32, —P(O)(OR31)OR32, —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 C1-6alkyloxy, 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, optionally substituted 3-10 membered heterocyclyl, —OH, —NR31R32, —C(O)OR30, —CN, —N3, —C(═NR33)NR31R32, —C(═NR33)OR30, —NR30C(═NR33)NR31R32, —NR31C(O)OR30, and —OC(O)NR31R32;
each R30, 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 3 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;
each R34 individually is optionally substituted C1-12 alkyl;
wherein, each substituted Q3, substituted R30, substituted R31, substituted R32, substituted R33, or substituted R34 is independently substituted with one or more Q6;
L is selected from the group consisting of —O—, —S—, —S(O)—, and —S(O)2—;
Het is an optionally substituted 3-12 membered heterocyclyl or optionally substituted 3-14 membered heteroaryl;
wherein, each substituted Het is substituted with one or more Q4;
each Q4, independently, is selected from the group consisting of
halogen, oxo, oxide, —NO2, —SR40, —S(O)R40, —S(O)2R40, —S(O)2NR40R41, —NR40C(O)R41, —NR40C(O)NR41R42, —NR40S(O)R41, —NR40S(O)2R41, —OP(O)R41R42, —P(O)OR41R42, —P(O)(OR41)OR42, —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, optionally substituted 3-10 membered heterocyclyl, —OH, —NR41R42, —C(O)OR40, —CN, —N3, —C(═NR43)NR41R42, —C(═NR43)OR40, —NR40C(═NR43)NR41R42, —NR41C(O)OR40, and —OC(O)NR41R42;
each R40, 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 3 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;
each R44 individually is optionally substituted C1-12 alkyl;
wherein, each substituted Q4, substituted R40, substituted R41, substituted R42, substituted R43, or substituted R44 is independently substituted with one or more Q5;
each Q5, individually, is selected from the group consisting of
halogen, oxo, oxide, —NO2, —N(═O), —SR50, —S(O)R50, —S(O)2R50, —S(O)2NR50R51, —NR50C(O)R51, —NR50C(O)NR51R52, —NR50S(O)R51, —NR50S(O)2R51, —OP(O)R51R52, —P(O)R51R52, —P(O)OR51R52, —P(O)(OR51)OR52, —C(O)NR51R52, 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, optionally substituted 3-10 membered heterocyclyl, —OH, —NR51R52, —C(O)OR50, —CN, —N3, —C(═NR53)NR51R52, —C(═NR53)OR50, —NR50C(═NR53)NR51R52, —NR51C(O)OR50, and —OC(O)NR51R52;
each R50, R51, and R52, 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 R51 and R52 taken together with the atoms to which they are attached form a 3 to 10 membered heterocyclyl;
each R53, 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)R54, —CHO and —S(O)2R54;
each R54, independently, is optionally substituted C1-12 alkyl;
wherein, each substituted Q5, substituted R50, substituted R51, substituted R52, substituted R53, or substituted R54 is independently substituted with one or more Q6;
each Q6, independently, is selected from the group consisting of halogen, oxo,
oxide, —NO2, —N(═O), —SR60, —S(O)R60, —S(O)2R60, —S(O)2NR60R61, —NR60C(O)R61, —NR60C(O)NR61R62, —NR60S(O)R61, —NR60S(O)2R61, —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, 3-10 membered heterocyclyl, —OH, —NR61R62, —C(O)OR60, —CN, —N3, —C(═NR63)NR61R62, —C(═NR63)OR60, —NR60C(═NR63)NR61R62, —NR61C(O)OR60, and —OC(O)NR61R62;
each R60, 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 3 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; and
each R64 individually is C1-12 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is optionally substituted C1-12 alkyl or optionally substituted C3-12 cycloalkyl.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R1 is optionally substituted C3-C7 secondary or tertiary alkyl or optionally substituted C3-C5 cycloalkyl.

### Claim 4 (depends on 2)

The compound of claim 2, wherein R2 is optionally substituted methylcyclohexyl or optionally substituted methylcyclohexenyl.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R2 is

### Claim 6 (depends on 4)

The compound of claim 4, wherein R2 is

### Claim 7 (depends on 2)

The compound of claim 2, wherein R3 is optionally substituted C1-12 alkylene, C3-12 cycloalkylene, substituted C3-12 cycloalkylene, optionally substituted C6-14 arylene or optionally substituted 3-12 membered heterocyclylene.

### Claim 8 (depends on 2)

The compound of claim 2, wherein Het is an optionally substituted 3-12 membered heterocyclyl or optionally substituted 3-14 membered heteroaryl wherein said optionally substituted 3-12 membered heterocyclyl or optionally substituted 3-14 membered heteroaryl comprises one to four heteroatoms selected from O, S, or N.

### Claim 9 (depends on 8)

The compound of claim 8, wherein Het is optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted tetrahydro-2H-pyranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrothiophenyl, optionally substituted pyrazinyl, optionally substituted 1H-tetrazolyl, optionally substituted azetidinyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydro-2H-furo[2,3-b]furanyl, optionally substituted thiazoyl, optionally substituted 1H-imidazolyl, optionally substituted 4H-1,2,4-triazolyl, optionally substituted 1H-pyrazolyl, optionally substituted 1,3,4-thiadiazolyl, optionally substituted quinolinyl, optionally substituted [1,2,4]triazolo[4,3-a]pyridinyl, optionally substituted thiophenyl, optionally substituted 1,2,4-thiadiazolyl, optionally substituted pyrimidinyl, optionally substituted 1H-1,2,3-triazolyl, optionally substituted 1,3,4-oxadiazolyl or optionally substituted imidazo[1,2-b]pyridazinyl.

### Claim 10 (depends on 3)

The compound of claim 3 represented by Formula II:
or a pharmaceutically acceptable salt or ester thereof, wherein:
R2 is optionally substituted 4-methylcyclohexyl or optionally substituted methylcyclohexenyl.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R2 is

### Claim 12 (depends on 10)

The compound of claim 10, wherein R2 is

### Claim 13 (depends on 10)

The compound of claim 10, wherein R3 is optionally substituted C1-12 alkylene, C3-12 cycloalkylene, substituted C3-12 cycloalkylene, optionally substituted C6-14 arylene or optionally substituted 3-12 membered heterocyclylene.

### Claim 14 (depends on 13)

The compound of claim 13, wherein R3 is optionally substituted cyclohexylene.

### Claim 15 (depends on 10)

The compound of claim 10, wherein Het is an optionally substituted 3-12 membered heterocyclyl or optionally substituted 3-14 membered heteroaryl wherein said optionally substituted 3-12 membered heterocyclyl or optionally substituted 3-14 membered heteroaryl comprises one to four heteroatoms selected from O, S, or N.

### Claim 16 (depends on 10)

The compound of claim 10, wherein Het is optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted tetrahydro-2H-pyranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrothiophenyl, optionally substituted pyrazinyl, optionally substituted 1H-tetrazolyl, optionally substituted azetidinyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydro-2H-furo[2,3-b]furanyl, optionally substituted thiazoyl, optionally substituted 1H-imidazolyl, optionally substituted 4H-1,2,4-triazolyl, optionally substituted 1H-pyrazolyl, optionally substituted 1,3,4-thiadiazolyl, optionally substituted quinolinyl, optionally substituted [1,2,4]triazolo[4,3-a]pyridinyl, optionally substituted thiophenyl, optionally substituted 1,2,4-thiadiazolyl, optionally substituted pyrimidinyl, optionally substituted 1H-1,2,3-triazolyl, optionally substituted 1,3,4-oxadiazolyl or optionally substituted imidazo[1,2-b]pyridazinyl.

### Claim 17 (depends on 15)

The compound of claim 15, wherein Het is optionally substituted tetrahydrofuran-3-yl or optionally substituted pyridin-2-yl.

### Claim 18 (depends on 1)

The compound of claim 1 that is
or a pharmaceutically acceptable salt or ester thereof.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

### Claim 20 (depends on 19)

The pharmaceutical composition of claim 19 further comprising at least one therapeutic agent selected from the group consisting of an interferon, ribavirin or an analog thereof, an HCV NS3 protease inhibitor, an NS5a inhibitor, an alpha-glucosidase 1 inhibitor, a hepatoprotectant, a mevalonate decarboxylase antagonist, an antagonist of the renin-angiotensin system, an endothelin antagonist, other anti-fibrotic agents, a nucleoside or nucleotide inhibitor of HCV NS5B polymerase, a non-nucleoside inhibitor of HCV NS5B polymerase, an HCV NS5A inhibitor, a TLR-7 agonist, a cyclophillin inhibitor, an HCV IRES inhibitor, a pharmacokinetic enhancer and other drugs for treating HCV; or a mixture thereof.