Inhibitors of influenza virus replication, application methods and uses thereof

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

wherein A is a C 3-12 carbocyclic ring, 3- to 12-membered heterocyclic ring, C 6-10 aromatic ring or 5- to 10-membered heteroaromatic ring;

q is 0, 1, 2, 3, 4 or 5;

each R 1 and R 3 is independently H, 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 3-8 cycloalkyl, C 3-8 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 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 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 one, two, three or four substituents independently selected from 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;

n is 0, 1, 2 or 3;

each R′ is independently F, Cl, Br, CN, NO 2 , OR b , —NR c R d , R b O—C 1-4 alkylene, R d R c 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 6-membered heterocyclyl, (3- 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 the C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 3- to 6-membered heterocyclyl, (3- 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 one, two, three, or four substituents independently selected from 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;

X has one of the following sub-formulae:

wherein each R w is independently F, Cl, Br, CN, NO 2 , ═O, —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —S(═O) 2 R e , —S(═O) 2 NR c C(═O)R a , —S(═O) 2 NR c R d , (R b O) 2 P(═O)—C 0-2 alkylene, OR b , —NR c R d , R b O—C 1-2 alkylene, R d R c N—C 1-2 alkylene, C 1-6 alkyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl, and wherein each of the C 1-6 alkyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl is independently unsubstituted or substituted with one, two, three, or four U;

each U is independently F, Cl, Br, NO 2 , CN, ═O, N 3 , OR b , —NR c R d , C 1-6 alkyl or C 1-6 haloalkyl;

each s is independently 0, 1, 2 or 3; and

each R a , R b , R c , R d and R e is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 3- to 6-membered heterocyclyl, (3- to 6-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 a 3- to 6-membered heterocyclic ring, and wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 3- to 6-membered heterocyclyl, (3- to 6-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 and 3- to 6-membered heterocyclic ring is independently unsubstituted or substituted with one, two, three, or four substituents independently selected from F, Cl, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino.

2. The compound of claim 1 , wherein each R 1 and R 3 is independently H, F, Cl, —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 3-6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, and wherein each of the C 1-3 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl is independently unsubstituted or substituted with one, two, three or four substituents independently selected from F, Cl, OR b , —NR c R d , C 1-3 alkyl, C 1-3 haloalkyl or R b O—C 1-2 alkylene.

3. The compound of claim 1 , wherein each R′ is independently F, Cl, Br, CN, NO 2 , OR b , —NR c R d , —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 the C 1-4 alkyl, C 1-3 haloalkyl, 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 one, two, three, or four substituents independently selected from F, Cl, Br, CN, NO 2 , OR b , —NR c R d , methyl, ethyl, n-propyl or i-propyl.

4. The compound of claim 1 , wherein each R a , R b , R c , R d and R e is independently H, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, phenyl, phenyl-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 heterocyclic ring, and wherein each of methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, phenyl, phenyl-C 1-2 alkylene and 5- to 6-membered heterocyclic ring is independently unsubstituted or substituted with one, two, three, or four substituents independently selected from F, Cl, CN, OH, NH 2 , C 1-3 alkyl, C 1-3 haloalkyl or methoxy.

5. The compound of claim 1 , wherein each R w is independently F, Cl, Br, CN, NO 2 , ═O, —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —S(═O) 2 R e , —S(═O) 2 NR c C(═O)R a , —S(═O) 2 NR c R d , (R b O) 2 P(═O)—C 0-2 alkylene, OR b , —NR c R d , R b O—C 1-2 alkylene, R d R c N—C 1-2 alkylene, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or pyrazolyl, and wherein each of methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and pyrazolyl is independently unsubstituted or substituted with one, two, three, or four U; and

each U is independently F, Cl, Br, CF 3 , NO 2 , CN, ═O, N 3 , OR b , —NR c R d , methyl, ethyl, i-propyl, n-propyl, n-butyl or t-butyl.

6. The compound of claim 1 , wherein A is a C 5-6 carbocyclic ring, 5- to 6-membered heterocyclic ring, benzene ring, naphthalene ring or 5- to 6-membered heteroaromatic ring.

7. The compound of claim 1 , wherein A is a C 5-6 carbocyclic ring, 5- to 6-membered heterocyclic ring, benzene, naphthalene, furan, benzofuran, pyrrole, pyridine, pyrazole, imidazole, benzoimidazole, triazole, tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, thiophene, benzothiphene, pyrazine, pyridazine, pyrimidine, indole, purine, quinoline or isoquinoline.

8. The compound of claim 5 having Formula (IV) or (VI),

9. A compound having one of the following structures:

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

10. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , optionally, further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

11. The pharmaceutical composition of claim 10 further comprising one or more therapeutic agents, and wherein the therapeutic agent is an anti-influenza virus agent or anti-influenza virus vaccine.

12. The pharmaceutical composition of claim 11 , wherein the therapeutic agent is amantadine, rimantadine, oseltamivir, zanamivir, peramivir, laninamivir, laninamivir octanoate hydrate, favipiravir, umifenovir, ribavirin, stachyflin, 5-[2-(1H-imidazol-5-yl)ethylamino]-5-oxopentanoic acid, (R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-4-yl)amino)-4,4-dimethyl pentanoic acid, pimodivir, an influenza vaccine or a combination thereof.

13. A method of 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 influenza virus infection.

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

15. A method of 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 10 , wherein the virus infection is influenza virus infection.

16. A method of inhibiting RNA polymerase of influenza virus in a patient, comprising administering to the patient a therapeutically effective amount of the compound of the pharmaceutical composition of claim 10 .

17. The compound of claim 5 , wherein X is

s is 1; R w is —C(═O)OR b ; R b is H; n is 1; R 1 is F; R 3 is H; m is 2; and two adjacent R 2 , together with the atoms to which they are attached, form a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring is pyrrolyl substituted with one R′; R′ is C 1-6 alkyl; and the C 1-6 alkyl is isopropyl;

or wherein X is

s is 1; R w is —C(═O)OR b ; R b is H; n is 1; R 1 is F; R 3 is H; m is 2; and two adjacent R 2 , together with the atoms to which they are attached, form a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring is pyrrolyl substituted with one R′; R′ is C 6-10 aryl; and the C 6-10 aryl is phenyl;

or wherein X is

s is 1; R w is —C(═O)OR b ; R b is H; n is 1; R 1 is F; R 3 is H; m is 2; and two adjacent R 2 , together with the atoms to which they are attached, form a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring is pyrrolyl substituted with one R′; R′ is C 3-6 cycloalkyl; and the C 3-6 cycloalkyl is cyclopropyl;

or wherein X is

s is 1; R w is —C(═O)OR b ; R b is H; n is 1; R 1 is F; R 3 is H; m is 2; and two adjacent R 2 , together with the atoms to which they are attached, form a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring is pyrrolyl;

or wherein X is

s is 1; R w is —C(═O)OR b ; R b is H; n is 1; R 1 is F; R 3 is H; m is 2; and two adjacent R 2 , together with the atoms to which they are attached, form a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring is pyrazole substituted with one R′; R′ is C 1-6 alkyl; and the C 1-6 alkyl is methyl;

or wherein X is

s is 1; R w is —C(═O)OR b ; R b is H; n is 1; R 1 is F; R 3 is H; m is 2; and two adjacent R 2 , together with the atoms to which they are attached, form a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring is pyrrolyl substituted with one R′; R′ is C 6-10 aryl-C 1-4 alkylene; and the C 6-10 aryl-C 1-4 alkylene is phenyl-methylene;

or wherein X is

s is 1; R w is —C(═O)OR b , R b is H; n is 1; R 1 is F; R 3 is H; m is 2; and two adjacent R 2 , together with the atoms to which they are attached, form a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring is pyrrolyl substituted with one R′; R′ is C 1-6 alkyl substituted with one OR b ; the C 1-6 alkyl is ethyl; and R b is H;

or wherein X is

s is 1; R w is —C(═O)OR b ; R b is H; n is 1; R 1 is F; R 3 is H; m is 2; and two adjacent R 2 , together with the atoms to which they are attached, form a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring is pyrrolyl substituted with one R′; R′ is C 1-6 alkyl; and the C 1-6 alkyl is methyl;

or wherein X is

R w is —C(═O)OR b ; R b is H; n is 1; R 1 is F; R 3 is H; m is 2; and two adjacent R 2 , together with the atoms to which they are attached, form a 5-membered heteroaromatic ring, wherein the 5-membered heteroaromatic ring is pyrrolyl substituted with one R′; R′ is C 1-6 alkyl; and the C 1-6 alkyl is isopropyl.