Inhibitors of influenza virus replication, application methods and uses thereof

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

wherein

A is

wherein U 1 is N or CR 1 ; U 2 is N or CR 2 ; U 3 is N or CR 3 ; U 4 is N or CR 4 ;

each of R 1 , R 2 , R 3 , R 4 and R 5 is independently H, D, F, Cl, Br, CN, NO 2 , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OR b , —NR c R d , R b O—C 1-4 alkylene, R d R c N—C 1-4 alkylene, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, and wherein each of C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, —OR b , —NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, R b O—C 1-4 alkylene or R d R c N—C 1-4 alkylene;

each of R 6 and R 8 is independently H, D, F, Cl, Br, CN, NO 2 , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OR b , —NR c R d , R b O—C 1-4 alkylene, R d R c N—C 1-4 alkylene, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C 1-4 alkylene, and wherein each of R b O—C 1-4 alkylene, R d R c N—C 1-4 alkylene, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 10-membered heteroaryl and (5- to 10-membered heteroaryl)-C 1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′;

R 7 is —OR g , methyl, C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, C 3-12 carbocyclyl-C 1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 16-membered heteroaryl or (5- to 16-membered heteroaryl)-C 1-4 alkylene, and wherein each of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, C 3-12 carbocyclyl-C 1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 16-membered heteroaryl and (5- to 16-membered heteroaryl)-C 1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′;

or, R 6 and R 7 , together with the carbon atoms to which they are attached, or R 7 and R 8 , together with the carbon atoms to which they are attached, form a C 3-12 carbocyclic ring, 3- to 12-membered heterocyclic ring, C 6-10 aromatic ring or 5- to 10-membered heteroaromatic ring, and wherein each of C 3-12 carbocyclic ring, 3- to 12-membered heterocyclic ring, C 6-10 aromatic ring and 5- to 10-membered heteroaromatic ring is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′;

each R′ is independently D, F, Cl, Br, CN, NO 2 , —OR b , —NR c R d , R b O—C 1-4 alkylene, R d R e N—C 1-4 alkylene, —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 3- to 8-membered heterocyclyl, (3- to 8-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 8-membered heteroaryl or (5- to 8-membered heteroaryl)-C 1-4 alkylene, and wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 3- to 8-membered heterocyclyl, (3- to 8-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 8-membered heteroaryl and (5- to 8-membered heteroaryl)-C 1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, NO 2 , —OR b , —NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, R b O—C 1-4 alkylene or R d R c N—C 1-4 alkylene;

R 9 is H, D or C 1-6 alkyl, and wherein C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, NO 2 or —OR b ;

W is C 1-8 alkyl, C 3-12 carbocyclyl or 3- to 12-membered heterocyclyl, and wherein each of C 1-8 alkyl, C 3-12 carbocyclyl and 3- to 12-membered heterocyclyl is independently unsubstituted or substituted with 1, 2, 3 or 4 R w ;

each R w is independently D, F, Cl, Br, CN, NO 2 , oxo (═O), —C(═O)R a , —C(═O)OR b , —C(═O)NR c R h , —NR e C(═O)R a , —NR e C(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 NR e C(═O)R a , —S(═O) 2 NR c R d , (R b O) 2 P(═O)—C 0-2 alkylene, —OR b , R b O—C 1 I 2 alkylene, C 1-6 alkyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl, and wherein each of C 1-6 alkyl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N 3 , oxo (═O), NO 2 , —OR b , C 1-6 alkyl or C 1-6 haloalkyl;

each R a , R b , R c , R d , R e and R f is independently H, D, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl-C 1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)-C 1-4 alkylene; or, R c and R d , together with the nitrogen atom to which they are attached, form 3- to 8-membered heterocyclyl or 5- to 8-membered heteroaryl, and wherein each of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl-C 1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)-C 1-4 alkylene, 3- to 8-membered heterocyclyl and 5- to 8-membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, OH, NH 2 , NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;

R g is C 1-6 haloalkyl, C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl-C 1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C 1-4 alkylene, and wherein each of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl-C 1-4 alkylene, 3- to 12-membered hereocyclyl, (3- to 12-membered hereocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 10-membered heteroaryl and (5- to 10-membered heteroaryl)-C 1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, OH, NH 2 , NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;

R h is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl-C 1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)-C 1-4 alkylene; or R c and R h , together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocyclyl or 5- to 8-membered heteroaryl, and wherein each of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl-C 1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)-C 1-4 alkylene, 3- to 8-membered heterocyclyl and 5- to 8-membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, Cl, CN, OH, NH 2 , NO 2 , C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino.

2. The compound of claim 1 , wherein A is one of the following sub-formulae:

3. The compound of claim 1 , wherein A is one of the following sub-formulae:

4. The compound of claim 1 , wherein each of R 1 , R 2 , R 3 , R 4 and R 5 is independently H, D, F, Cl, Br, CN, NO 2 , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OR b , —NR c R d , methyl, ethyl, n-propyl or i-propyl, and wherein each of methyl, ethyl, n-propyl and i-propyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, —OR b , —NR c R d and C 1-3 haloalkyl.

5. The compound of claim 1 , wherein each of R 6 and R 8 is independently H, D, F, Cl, Br, CN, NO 2 , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OR b , —NR c R d , C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 6-membered heteroaryl or (5- to 6-membered heteroaryl)-C 1-4 alkylene, and wherein each of C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-C 1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′;

R 7 is —OR g , methyl, C 2-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl-C 1-4 alkylene, 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 14-membered heteroaryl or (5- to 14-membered heteroaryl)-C 1-4 alkylene, and wherein each of C 2-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl-C 1-4 alkylene, 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5- to 14-membered heteroaryl and (5- to 14-membered heteroaryl)-C 1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′;

or, R 6 and R 7 , together with the carbon atoms to which they are attached, or R 7 and R 8 , together with the carbon atoms to which they are attached, form a C 3-6 carbocyclic ring, 3- to 6-membered heterocyclic ring, C 6-10 aromatic ring or 5- to 6-membered heteroaromatic ring, and wherein each of C 3-6 carbocyclic ring, 3- to 6-membered heterocyclic ring, C 6-10 aromatic ring and 5- to 6-membered heteroaromatic ring is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′;

each R′ is independently D, F, Cl, Br, CN, NO 2 , —OR b , —NR c R d , —C(═O)R a , —C(═O)NR c R d , C 1-4 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, phenyl-C 1-2 alkylene or 5- to 6-membered heteroaryl, and wherein each of C 1-4 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, phenyl-C 1-2 alkylene and 5- to 6-membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, NO 2 , —OR b , —NR c R d , methyl, ethyl, n-propyl or i-propyl.

6. The compound of claim 1 , wherein R 7 is —OR g , methyl, ethyl, n-propyl, i-propyl, C 2-4 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, 5- to 6-membered heterocyclyl, phenyl, naphthyl, furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imdazolyl, benzimdazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiinyl,

and wherein each of ethyl, n-propyl, i-propyl, C 2-4 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, 5- to 6-membered heterocyclyl, phenyl, naphthyl, furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imdazolyl, benzimdazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiinyl,

is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′;

or, R 6 and R 7 , together with the carbon atoms to which they are attached, or R 7 and R 8 , together with the carbon atoms to which they are attached, form a C 3-6 carbocyclic ring, 3- to 6-membered heterocyclic ring, phenyl, naphthyl, furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imdazolyl, benzimdazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl or isoquinolyl, and wherein each of the C 3-6 carbocyclic ring, 3- to 6-membered heterocyclic ring, phenyl, naphthyl, furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imdazolyl, benzimdazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl and isoquinolyl is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′.

7. The compound of claim 1 , wherein R g is C 1-3 haloalkyl, ethyl, n-propyl, i-propyl, C 5-6 carbocyclyl, C 5-6 carbocyclyl-C 1-2 alkylene, 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-C 1-2 alkylene, phenyl, naphthyl, phenyl-C 1-2 alkylene, naphthyl-C 1-2 alkylene, 5- to 6-membered heteroaryl or (5- to 6-membered heteroaryl)-C 1-2 alkylene, and wherein each of ethyl, n-propyl, i-propyl, C 5-6 carbocyclyl, C 5-6 carbocyclyl-C 1-2 alkylene, 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-C 1-2 alkylene, phenyl, naphthyl, phenyl-C 1-2 alkylene, naphthyl-C 1-2 alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-C 1-2 alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, OH, NH 2 , —CH 3 , —CH 2 CH 3 , —CF 3 , —OCH 3 , —OCH 2 CH 3 or C 1-3 alkylamino.

8. The compound of claim 1 , wherein R 9 is H, D, CF 3 , methyl, ethyl, n-propyl or i-propyl.

9. The compound of claim 1 , wherein W is C 1-6 alkyl, C 5-8 carbocyclyl or 5- to 8-membered heterocyclyl, and wherein each of C 1-6 alkyl, C 5-8 carbocyclyl and 5- to 8-membered heterocyclyl is independently unsubstituted or substituted with 1, 2, 3 or 4 R w ;

each R w is independently D, F, Cl, Br, CN, NO 2 , oxo (═O), —C(═O)OCH 3 , —C(═O)OCH 2 CH 3 , —C(═O)OH, —C(═O)NR c R h , —NHC(═O)R a , —NHC(═O)NR c R d , —S(═O) 2 R f , —S(═O) 2 NHC(═O)R a , —S(═O) 2 NR c R d , (R b O) 2 P(═O)—C 0-2 alkylene, —OR b , methyl, ethyl, n-propyl, i-propyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imdazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidyl or 5- to 6-membered heterocyclyl, and wherein each of methyl, ethyl, n-propyl, i-propyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imdazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidyl and 5- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N 3 , oxo (═O), NO 2 , —OCH 3 , C 1-3 alkyl or C 1-3 haloalkyl.

10. The compound of claim 1 , wherein W is one of the following sub-formulae:

wherein n is 0, 1, 2, 3 or 4.

11. The compound of claim 1 , wherein each R a , R b , R c , R d , R e and R f is independently H, D, trifluoromethyl, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C 3-6 carbocyclyl, 5- to 6-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C 1-2 alkylene; or, R c and R d , together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, and wherein each of methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C 3-6 carbocyclyl, 5- to 6-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl and (5- to 10-membered heteroaryl)-C 1-2 alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, OH, NH 2 , C 1-3 alkyl, C 1-3 haloalkyl or methoxy.

12. A compound having one of the following structures:

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

13. A pharmaceutical composition comprising the compound of claim 1 , and at least one of pharmaceutically acceptable carriers, adjuvants, vehicles or a combination thereof.

14. The pharmaceutical composition of claim 13 further comprising one or more therapeutic agents, and wherein the therapeutic agent is an anti-influenza virus agent or anti-influenza virus vaccine.

15. The pharmaceutical composition of claim 14 , wherein the anti-influenza virus agent is amantadine, rimantadine, oseltamivir, zanamivir, peramivir, laninamivir, laninamivir octanoate hydrate, favipiravir, arbidol, ribavirin, stachyflin, ingavirin, fludase, CAS no. 1422050-75-6, JNJ-872 or a combination thereof.

16. A method of preventing, managing, treating or lessening a disorder or disease caused by a virus infection in a patient, comprising administering to the patient a therapeutically effective amount of the compound of claim 1 , wherein the virus infection is an influenza virus infection.

17. A method of inhibiting an influenza virus RNA polymerase in a patient, comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .

18. A method of preventing, managing, treating or lessening a disorder or disease caused by a virus infection in a patient, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 13 , wherein the virus infection is an influenza virus infection.

19. A method of inhibiting an influenza virus RNA polymerase in a patient, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 13 .