Bridged ring compounds as Hepatitis C virus inhibitors, pharmaceutical compositions and uses thereof

1. A compound having Formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof:

wherein X 3 is (CR 7 R 7a ) e ;

each R 7 and R 7a is independently H or C 1-3 alkyl;

e is 1 or 2;

each of A and A′ is independently

R 1 is C 1-4 alkyl, C 1-4 heteroalkyl or C 6-10 aryl;

R 2 is H, deuterium, C 1-4 alkyl, C 1-4 heteroalkyl or C 6-10 aryl;

R 3 and R 4 , together with N—CH to which they are attached, form one of the following groups:

wherein each R 15 is independently H, deuterium, F, Cl, Br, I, cyano, hydroxy, oxo(═O), phenyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 -alkyl, C 1-4 alkylamino, C 6-10 arylamino, C 6-10 aryloxy, C 1-9 heteroaryl, C 1-9 heteroaryloxy, C 2-6 alkenyl or C 2-10 heterocyclyl;

each R 6 is independently H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 amnioalkyl, C 1-6 alkoxy-C 1-4 -alkyl, C 1-6 alkylamino-C 1-4 -alkyl, C 6-10 aryl-C 1-4 -alkyl, C 6-10 aryl, C 2-10 heterocyclyl or C 3-8 cycloalkyl;

each n 1 and n 2 is independently 1, 2, 3 or 4;

each R 5a and R 6a is independently H, deuterium, oxo (═O), hydroxy, amino, F, Cl, Br, I, cyano, mercapto, nitro, C 1-6 alkoxy, C 1-6 alkyl, C 6-10 aryl, —CF 3 , C 1-6 alkylamino, C 3-10 cycloalkyl or C 6-10 aryloxy;

each R 9 and R 9a is independently H, deuterium, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 1-6 alkylamino-C 1-6 -alkyl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl-C C 2-10 heterocyclyl-C 1-6 -alkyl, C 3-8 cycloalkyl-C 1-6 -alkyl, C 6-10 aryl, C 1-9 heteroaryl, C 2-10 heterocyclyl or C 3-8 carbocyclyl;

each of R 8 and R 8a is independently H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 6-10 aryl, C 2-10 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl-C 1-6 -alkyl, C 2-10 heterocyclyl-C 1-6 -alkyl or C 3-8 cycloalkyl-C 1-6 -alkyl; and

f is 0, 1, 2, 3 or 4.

2. The compound according to claim 1 , wherein

X 3 is (CR 7 R 7a ) e ;

e is 1 or 2; and

each R 7 and R 7a is independently H.

3. The compound according to claim 1 , wherein R 3 and R 4 , together with N—CH to which they are attached, form one of the following groups:

wherein each R 15 is independently H, F, Cl, Br, I, cyano, hydroxy, phenyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 -alkyl, or C 2-10 heterocyclyl;

and

each n 1 and n 2 is independently 1, 2, 3 or 4.

4. The compound according to claim 1 having formula (II):

wherein each of A and A′ is independently

R 1 is methyl, ethyl, i-propyl, or phenyl;

R 2 is H, deuterium, methyl, ethyl, i-propyl, or phenyl;

each R 5a is independently H, deuterium, oxo (═O), —CF 3 , methyl, ethyl, phenyl, benzyl, F, Cl, Br or I;

each R 6a is independently H, deuterium, oxo (═O), hydroxy, amino, F, Cl, Br, I, cyano, methyl, ethyl, i-propyl, cyclohexyl, phenyl, benzyl, —CF 3 , —OCF 3 , mercapto, nitro, C 1-3 alkylamino or C 3-8 cycloalkyl;

each of R 8 and R 8a is independently H, deuterium, methyl, ethyl, phenyl, cyclohexyl, 1-methylpropyl, i-propyl or t-butyl;

each of R 9 and R 9a is independently H, deuterium, methyl, ethyl, 1-methylpropyl, phenyl, i-propyl, tetrahydropyranyl, or t-butyl;

each R 15 is independently H, deuterium, F, Cl, Br, I, cyano, hydroxy, methyl, ethyl, methoxylmethyl, i-propyl, i-butyl or phenyl;

n 1 is 1, 2, 3 or 4; and

f is 0, 1, 2, 3 or 4.

5. The compound according to claim 1 having one of the following formulae:

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising the compound according to claim 1 ; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

7. The pharmaceutical composition according to claim 6 further comprising an anti-HCV agent; wherein the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine5′-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, a HCV neutralizing polyclonal antibody (CIVACIR®), boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir, danoprevir, sovaprevir, grazoprevir, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA-975, ombitasvir, EDP-239, PPI-668, velpatasvir, samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, BI-2013335, ciluprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, sofosbuvir, INX-189, IDX-184, IDX102, R-1479, UNX-08189, PSI-6130, PSI-938, PSI-879, nesbuvir, HCV-371, VCH-916, lomibuvir, MK-3281, dasabuvir, ABT-072, filibuvir, deleobuvir, tegobuvir, A-837093, JKT-109, G1-59728, GL-60667, AZD-2795, TMC647055, MK-3682, GS-9669, odalasvir, furaprevir, setrobuvir, alisporivir, BIT-225, AV-4025, ACH-3422, MK-2748, MK-8325, JNJ-47910382, ABP-560, TD-6450, TVB-2640, ID-12, PPI-383, A-848837, RG-7795, BC-2125 or a combination thereof; and wherein the interferon is interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, consensus interferon-α, interferon γ or a combination thereof.

8. A method of inhibiting hepatitis C virus (HCV) replication comprising administering the compound according to claim 1 .

9. A method of treating hepatitis C virus (HCV) infection or disorder in a patient in need of a treatment for HCV infection or disorder, wherein the method comprises administering a therapeutically effective amount of the compound according to claim 1 to the patient.

10. A method of inhibiting hepatitis C virus (HCV) replication comprising administering the pharmaceutical composition according claim 6 .

11. A method of treating hepatitis C virus (HCV) infection or disorder in a patient in need of a treatment for HCV infection or disorder, wherein the method comprises administering a therapeutically effective amount of the pharmaceutical composition according claim 6 to the patient.