# US 8,541,434 B2 · Ethynyl-substituted pyridine and pyrimidine derivatives and their use in treating viral infections

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- Number: US 8,541,434 B2
- Document ID: US8541434B2
- Status: Granted
- Kind: B2
- Application number: 13/059,195
- Filed: 2009-08-19
- Published: 2012-05-03
- Granted: 2013-09-24
- Earliest claimed: 2008-08-20
- Assignees: Merck Sharp & Dohme Corp.; Southern Research Institute
- Applicants: Cecil D. Kwong; F. George Njoroge; Subramaniam Ananthan; Ashok Arasappan; Frank Bennett; Jeremy Clark; Anita T. Fowler; Feng Geng; Hollis S. Kezar, III; Joseph A. Maddry; John J. Piwinski; Robert C. Reynolds; Abhijit Roychowdhury; John A. Secrist, III; Neng-Yang Shih
- Inventors: Cecil D. Kwong; F. George Njoroge; Subramaniam Ananthan; Ashok Arasappan; Frank Bennett; Jeremy Clark; Anita T. Fowler; Feng Geng; Hollis S. Kezar, III; Joseph A. Maddry; John J. Piwinski; Robert C. Reynolds; Abhijit Roychowdhury; John A. Secrist, III; Neng-Yang Shih
- Web page: https://patentgrep.com/patent/US8541434B2

## CPC

- C07D 239/46: Two or more oxygen, sulphur or nitrogen atoms
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 37/04: Immunostimulants
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/14: containing three or more hetero rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides compounds of Formula (I): and tautomers, isomers, and esters of said compounds, and pharmaceutically acceptable salts, solvates, and pro-drugs of said compounds, wherein each of R, R1, X, Y, Z, R2, R3, R4, R5, R6, R7, R8, R9, R18, R19 and n is selected independently and as defined herein. Compositions comprising such compounds are also provided. The compounds of the invention are effective as inhibitors of HCV, and are useful, alone and together with other therapeutic agents, in treating or preventing diseases or disorders such as viral infections and virus-related disorders.

## Claims

### Claim 1

A compound having the general structure shown in Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein each of R, R1, X, Y, Z, R2, R3, R4, R5, R6, R7, R8, R9, R18, R19 and n are selected independently and wherein:
R is heteroaryl,
wherein said heteroaryl is unsubstituted or optionally independently substituted with from one to five substituents, which are the same or different, each substituent being independently selected from halo, —OH, —CN, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heterohaloalkyl, -alkyl-OH, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, heteroarylalkyl-, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, heterocycloalkylalkyl-, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)-cycloalkyl, —C(O)-heterocycloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —C(O)O-haloalkyl, —C(O)O-cycloalkyl, —C(O)O-heterocycloalkyl, —OC(O)-alkyl, —OC(O)-haloalkyl, —OC(O)-cycloalkyl, —OC(O)-heterocycloalkyl, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —OC(O)NH2, —CO(O)NHR10, —CO(O)NR10R11, —NH2, —NHR10, —NR10R11, —NO2, —S(O)NHR10, —S(O)NR10R11, —S(O)R10, —S(O)2NH2, —NHR10, —NR10R11, —NO2, —S(O)2NHR10, —S(O)2NR10R11, —S(O)2R10, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to five substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl;
X and Y are each independently selected from N and CH, with the proviso that at least one of X or Y is N;
Z═H, halo, —OH, —SH, —CN, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterohaloalkyl, —S-alkyl, —O-alkyl, —O-aryl, —O-heteroaryl, cycloalkyl, aryl, heteroaryl, —NH2, —NHR12, and —NR12R13;
R1 is selected from H, halo, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, heteroaryl, —OH, —O-alkyl, —O-aryl, —O-heteroalkyl, —O-heteroaryl, —SH, —S-alkyl, —S-aryl, —S-heteroalkyl, —S-heteroaryl, —NH2, —NHR14, —NR14R15, —NO2, —S(O)NHR10, —S(O)NR10R11, —S(O)R10, —S(O)2NHR10, —S(O)2NR10R11, and —S(O)2R10;
R2 (when R2 is not joined with R9) is selected from H and alkyl;
n=0, 1, or 2;
R3 is selected from H, -alkyl, -alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl,
wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, and said cycloalkyl, is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
R4 is selected from —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH2, —NO2, —NHR10, —NR10R11, —C(O)OH, —C(O)OR10, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —S(O)NHR10, —S(O)NR10R11, —S(O)R10, —S(O)2NHR10, —S(O)2NR10R11, and —S(O)2R10,
wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
R5 is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH2, —NO2, —NHR10, —NR10R11, —C(O)OH, —C(O)OR10, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —S(O)NHR10, —S(O)NR10R11, —S(O)R10, —S(O)2NHR10, —S(O)2NR10R11, and —S(O)2R10,
wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
or, alternatively, R4 and R5 are taken together with the carbon atom to which they are shown attached to form a 3- to 7-membered, saturated or partially unsaturated, spirocycloalkyl ring containing from 0 to 3 spiro ring heteroatoms selected from O, N, and S;
R6 is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH2, —NO2, —NHR10, —NR10R11, —C(O)OH, —C(O)OR10, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —S(O)NHR10, —S(O)NR10R11, —S(O)R10, —S(O)2NHR10, —S(O)2NR10R11, and —S(O)2R10,
wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
or, alternatively, R5 and R6 are taken together to form a double bond;
R7 is selected from —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH2, —NO2, —NHR10, —NR10R11, —C(O)OH, —C(O)OR10, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —S(O)NHR10, —S(O)NR10R11, —S(O)R10, —S(O)2NHR10, —S(O)2NR10R11, and —S(O)2R10,
wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
or, alternatively, R6 and R7 are taken together with the carbon atom to which they are shown attached to form a 3- to 7-membered, saturated or partially unsaturated, spirocycloalkyl ring containing from 0 to 3 spiro ring heteroatoms selected from O, N, and S;
R8 is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH2, —NO2, —NHR10, —NR10R11, —C(O)OH, —C(O)OR10, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —S(O)NHR10, —S(O)NR10R11, —S(O)R10, —S(O)2NHR10, —S(O)2NR10R11, and —S(O)2R10,
wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to five substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —O(C)O—N(R10)R11, —O(C)O—NHR11, —O(C)O—NH2, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)2R10, —Se, —S(O)2NHR10, —S(O)2NR10R11, —CN, —NH2, —NHR16, and —NR16R17, —N(R10)S(O)2R10, —NHS(O)2R10, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
R9 is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH2, —NO2, —NHR10, —NR10R11, —C(O)OH, —C(O)OR10, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —S(O)NHR10, —S(O)NR10R11, —S(O)R10, —S(O)2NHR10, —S(O)2NR10R11, and —S(O)2R10,
wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to five substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —O(C)O—N(R10)R11, —O(C)O—NHR11, —O(C)O—NH2, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)2R10, —Se, —S(O)2NHR10, —S(O)2NR10R11, —CN, —NH2, —NHR16, and —NR16R17,)—N(R10)S(O)2R10, —NHS(O)2R10, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
or, alternatively, R8 and R9 are taken together with the carbon atom to which they are shown attached to form a 3- to 7-membered, saturated or partially unsaturated, spirocycloalkyl ring containing from 0 to 3 spiro ring heteroatoms selected from O, N, and S;
each R18 (when present) is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH2, —NO2, —NHR10, —NR10R11, —C(O)OH, —C(O)OR10, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —S(O)NHR10, —S(O)NR10R11, —S(O)R10, —S(O)2NHR10, —S(O)2NR10R11, and —S(O)2R10,
wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
each R19 (when present) is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH2, —NO2, —NHR10, —NR10R11, —C(O)OH, —C(O)OR10, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —S(O)NHR10, —S(O)NR10R11, —S(O)R10, —S(O)2NHR10, —S(O)2NR10R11, and —S(O)2R10,
wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
or, alternatively, n is 1 and R18 and R19 are taken together with the carbon atom to which they are attached to form a 3- to 7-membered, saturated or partially unsaturated, spirocycloalkyl ring containing from 0 to 3 spiro ring heteroatoms selected from O, N, and S;
or, alternatively, R4 and R7, together with the carbon atoms to which they are shown attached, form a moiety (1C):
wherein R20 and R21 are each independently selected from H, alkyl, and heteroalkyl and wherein R5 and R6 are defined above, with the proviso that when R4 and R7 form a moiety (1C), then R5 and R6 are not taken together to form a double bond;
or, alternatively, R4 and R7, together with the carbon atoms to which they are shown attached, form a moiety (1D):
wherein R5 and R6 are as defined above;
or, alternatively, R4 and R7, together with the carbon atoms to which they are shown attached, form a moiety (1E):
wherein R5 and R6 are as defined above;
each R10 is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)2-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)2, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl;
each R11 is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)2-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)2, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl;
or, alternatively, R10 and R11 are linked together with the nitrogen to which they are attached to form an unsubstituted or substituted 4- or 6-membered heterocycloalkyl;
each R12 is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)2-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)2, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl;
each R13 is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)2-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)2, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl;
or, alternatively, R12 and R13 are linked together with the nitrogen to which they are attached to form an unsubstituted or substituted 4- to 6-membered heterocycloalkyl;
each R14 is independently selected from alkyl, alkoxy, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, alkylamino, alkylthio, heteroalkenyl, haloalkenyl, —S(O)2-alkyl, -alkyl-OH, -alkyl-O-Acyl, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl, cycloalkyl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, heterocycloalkenyl, heterocycloalkenyl-alkyl-, aryl, aryl-alkyl-, heteroaryl, and heteroaryl-alkyl-,
wherein each said alkyl, each said alkoxy, each said alkenyl, each said haloalkyl, each said heteroalkyl, each said heterohaloalkyl, each said alkylamino, each said alkylthio, each said heteroalkenyl, each said haloalkenyl, each said —S(O)2-alkyl, each said -alkyl-OH, each said -alkyl-O-Acyl, each said —C(O)Oalkyl, each said —C(O)alkyl, each said cycloalkyl, each said cycloalkyl-alkyl-, each said heterocycloalkyl, each said heterocycloalkyl-alkyl-, each said heterocycloalkenyl, each said heterocycloalkenyl-alkyl-, each said aryl, each said aryl-alkyl-, each said heteroaryl, and each said heteroaryl-alkyl-, is unsubstituted or optionally independently substituted with from one to five substituent, which can be the same or different, each substitutent being independently selected from —OH, halo, —NH2, —NHR10, —NR10R11, —C(O)OH, —C(O)OR10, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —S(O)2alkyl, —S(O)2aryl, alkyl, alkoxy, haloalkyl, haloalkoxy, heteroaryl, heteroalkyl, heterohaloalkyl, aryl, cycloalkyl, and heterocycloalkyl;
each R15 is independently selected from alkyl, alkoxy, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, alkylamino, alkylthio, heteroalkenyl, haloalkenyl, —S(O)2-alkyl, -alkyl-OH, -alkyl-O-Acyl, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl, cycloalkyl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, heterocycloalkenyl, heterocycloalkenyl-alkyl-, aryl, aryl-alkyl-, heteroaryl, and heteroaryl-alkyl-,
wherein each said alkyl, each said alkoxy, each said alkenyl, each said haloalkyl, each said heteroalkyl, each said heterohaloalkyl, each said alkylamino, each said alkylthio, each said heteroalkenyl, each said haloalkenyl, each said —S(O)2-alkyl, each said -alkyl-OH, each said -alkyl-O-Acyl, each said —C(O)Oalkyl, each said —C(O)alkyl, each said cycloalkyl, each said cycloalkyl-alkyl-, each said heterocycloalkyl, each said heterocycloalkyl-alkyl-, each said heterocycloalkenyl, each said heterocycloalkenyl-alkyl-, each said aryl, each said aryl-alkyl-, each said heteroaryl, and each said heteroaryl-alkyl-, is unsubstituted or optionally independently substituted with from one to five substituent, which can be the same or different, each substitutent being independently selected from —OH, halo, —NH2, —NHR10, —NR10R11, —C(O)OH, —C(O)OR10, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —S(O)2alkyl, —S(O)2aryl, alkyl, alkoxy, haloalkyl, haloalkoxy, heteroaryl, heteroalkyl, heterohaloalkyl, aryl, cycloalkyl, and heterocycloalkyl;
or, alternatively, R14 and R15 are linked together with the nitrogen to which they are attached to form an unsubstituted or substituted 4- to 6-membered heterocycloalkyl;
each R16 is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)2-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)2, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; and
each R17 is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)2-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)2, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl;
or, alternatively, R16 and R17 are linked together with the nitrogen to which they are attached to form an unsubstituted or substituted 4- or 6-membered heterocycloalkyl.

### Claim 2 (depends on 1)

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R is selected from heteroaryl and benzo-fused heteroaryl,
wherein each of said heteroaryl and said benzo-fused heteroaryl is unsubstituted or optionally independently substituted with from one to three substituents, which are the same or different, each substituent being independently selected from halo, —OH, —CN, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heterohaloalkyl, -alkyl-OH, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —C(O)ONH2, —C(O)ONHR10, —C(O)ONR10R11, —NH2, —NHR10, —NR10R11, —NO2, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to three substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl;
X is N;
Y is N;
R2 is H;
R1 is selected from —NH2, —NHR14, and —NR14R15; and
Z is selected from H, halo, alkyl, —OH, haloalkyl, and cycloalkyl.

### Claim 3 (depends on 1)

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Y is N;
R is selected from the group consisting of:
(a) an unsubstituted or substituted heteroaryl moiety selected from the group consisting of:
wherein the wavy line represents the point of attachment of R to the rest of the molecule, and wherein each of Ra, Rb, Rc, Rd, and Re, is independently selected from H, halo, —OH, —CN, alkyl, haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —C(O)ONH2, —C(O)ONHR10, —C(O)ONR10R11, —NH2, —NHR10, —NR10R11, —NO2, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to three substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl, and
(b) an unsubstituted or an substituted bicyclic heteroaryl moiety selected from the group consisting of:
wherein the wavy line represents the point of attachment of R to the rest of the molecule, and wherein each of Ra, Rb, Rc, Rd, and Re, is independently selected from H, halo, —OH, —CN, alkyl, haloalkyl, cycloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —C(O)ONH2, —C(O)ONHR10, —C(O)ONR10R11, —NH2, —NHR10, —NR10R11, —NO2, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to three substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl;
R1 is selected from the group consisting of:
wherein the wavy line represents the point of attachment of R1 to the rest of the molecule, and wherein each Raa is independently selected from haloalkyl, Rab is selected from OH, OAc, and —O-alkyl, —O-haloalkyl, —NH2, —NHalkyl, and —N(alkyl)2,
wherein the wavy line represents the point of attachment of R1 to the rest of the molecule, and wherein Raf is selected from H and acetyl,
wherein the wavy line represents the point of attachment of R1 to the rest of the molecule, and wherein each of Ra, Rb, Rc, Rd, and Re, is independently selected from H, halo, —OH, —CN, alkyl, haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —C(O)ONH2, —C(O)ONHR10, —C(O)ONR10R11, —NH2, —NHR10, —NR10R11, —NO2, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to three substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl, and wherein each Rad and each Rae is independently selected from alkyl and haloalkyl,
wherein the wavy line represents the point of attachment of R1 to the rest of the molecule, and wherein each Raa is independently selected from haloalkyl, Rab is selected from OH, OAc, and —O-alkyl, —O-haloalkyl, —NH2, —NHalkyl, and —N(alkyl)2,
wherein the wavy line represents the point of attachment of R1 to the rest of the molecule, and wherein Raf is selected from H and acetyl,
wherein the wavy line represents the point of attachment of R1 to the rest of the molecule, and wherein each of Ra, Rb, Rc, Rd, and Re, is independently selected from H, halo, —OH, —CN, alkyl, haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH2, —C(O)NHR10, —C(O)NR10R11, —C(O)ONH2, —C(O)ONHR10, —C(O)ONR10R11, —NH2, —NHR10R11, —NO2, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to three substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl, and wherein each Rad and each Rae is independently selected from alkyl and haloalkyl, and
wherein X is selected from O, NH, and NMe; and
Z is selected from the group consisting of H, halo, —OH, —SH, —CN, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterohaloalkyl, —S-alkyl, —O-alkyl, —O-aryl, —O-heteroaryl, cycloalkyl, aryl, heteroaryl, —NH2, —NHR12, and —NR12R13.

### Claim 4 (depends on 1)

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, said compound having the general structure shown in Formula (I.a):
wherein each of R, R1, X, Y, Z, R2, R4, R5, R7, and R9 is selected independently and defined in claim 1.

### Claim 5 (depends on 4)

A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein:
n is 1;
R2 is H;
R4 is OH;
R7 is OH;
R5 is selected from H, halo, and alkyl; and
R9 is alkyl, wherein said alkyl is unsubstituted or substituted with from one to five substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —O(C)O—NHR10, —O(C)O—N(R10)R11, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)2R10, —Se, —S(O)2NHR10, —S(O)2NR10R11, —CN, —NH2, —NHR16, and —NR16R17, —NHS(O)2R10) —N(R10)S(O)2R10, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl.

### Claim 6 (depends on 4)

A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein:
n is 1;
R2 is H;
R4 is OH;
R7 is OH;
R5 is H; and
R9 is alkyl, wherein said alkyl is unsubstituted or substituted with from one to five groups independently selected from —OH, halo, —CN, —NH2, —NHR16, —NR16R17, —NHS(O)2R10,) —N(R10)S(O)2R10, —Oalkyl, —Ocycloalkyl, —O-alkyl-cycloalkyl, —OC(O)-alkyl, —O(C)O—NHR10, —O(C)O—N(R10)R11, —C(O)O-alkyl, —S(O)2R10, —Se, —S(O)2NHR10, and —S(O)2NR10R11.

### Claim 7 (depends on 4)

A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein:
n is 1,
R2 is H,
R4 is OH;
R7 is OH;
R5 is —CH3, and
R9 is methyl, wherein said methyl is unsubstituted or substituted with from one to three groups independently selected from —OH, halo, alkyl, —CN, —NH2, —NHR16, —NR16R17, —NHS(O)2R10,)—N(R10)S(O)2R10, -Oalkyl, -Ocycloalkyl, —O-alkyl-cycloalkyl, —OC(O)-alkyl, —O(C)O—NHR10, —O(C)O—N(R10)R11, —C(O)O-alkyl, —S(O)2R10, —SR10, —S(O)2NHR10, and —S(O)2NR10R11.

### Claim 8 (depends on 4)

A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein:
X and Y are each N;
R is selected from the group consisting of substituted or unsubstituted heteroaryl and substituted or unsubstituted benzo-fused heteroaryl, each of said substituents being independently selected from the group consisting of alkyl, —O-alkyl, and cycloalkyl;
Z is selected from H, halo, alkyl, fluoroalkyl, cyclopropyl, and —NH2;
R1 is selected from —NH2, —NHR14, and —NR14R15; and
R2 is selected from H.

### Claim 9 (depends on 4)

A compound according to claim 4, or a pharmaceutically acceptable salt thereof, said compound having the general structure shown in Formula (I.a.10.j):
wherein CB is a moiety selected from the group consisting of:
wherein each R10 is independently selected from the group consisting of methyl, ethyl, and cyclopropyl.

### Claim 10 (depends on 4)

A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein:
X is N; Y is N; R2 is H; and Z is selected from the group consisting of H, methyl, and chloro.

### Claim 11 (depends on 1)

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, said compound having the general structure shown in Formula (I.C):
wherein each of R, R1, X, Y, Z, R2, R3, R4, R5, R6, R7, R8, R9, R18, R19, R20, R21, and n is selected independently and defined in claim 1, with the proviso that R5 and R6 are not taken together to form a double bond.

### Claim 12 (depends on 1)

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, said compound having the general structure shown in Formula (I.D):
wherein each of R, R1, X, Y, Z, R2, R3, R4, R5, R6, R7, R8, R9, R18, R19 and n is selected independently and defined in claim 1.

### Claim 13 (depends on 1)

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, said compound having the general structure shown in Formula (I.E):
wherein each of R, R1, X, Y, Z, R2, R3, R4, R5, R6, R7, R8, R9, R18, R19 and n is selected independently and defined in Formula (I).

### Claim 14

A compound selected from the group consisting of:
Compd
#
Structure
1
2
3
4
5
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising at least one compound according claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 1)

A method of treating a viral infection or a virus-related disorder comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

A method according to claim 16, wherein said viral infection or virus-related disorder is an HCV infection.