# US 10,501,444 B2 · Inhibitors of influenza virus replication, application methods and uses thereof

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- Number: US 10,501,444 B2
- Document ID: US10501444B2
- Status: Granted
- Kind: B2
- Application number: 16/326,189
- Filed: 2017-08-15
- Published: 2019-06-20
- Granted: 2019-12-10
- Earliest claimed: 2016-08-16
- Assignees: Sunshine Lake Pharma Co., Ltd.; North & South Brother Pharmacy Investment Company Limited
- Applicants: Sunshine Lake Pharma Co., Ltd.; North & South Brother Pharmacy Investment Company Limited
- Inventors: Qingyun Ren; Changhua Tang; Junjun Yin; Kai Yi; Yingjun Zhang
- Web page: https://patentgrep.com/patent/US10501444B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/52: Purines, e.g. adenine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/16: for influenza or rhinoviruses
- C07D 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 411/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 473/34: attached in position 6, e.g. adenine
- C07D 487/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

The invention provides a novel class of compounds as inhibitors of influenza virus replication, preparation methods thereof, pharmaceutical compositions containing these compounds, and uses of these compounds and pharmaceutical compositions thereof in the treatment of influenza.

## Claims

### Claim 1

A compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, or a pharmaceutically acceptable salt thereof,
wherein,
U is N or CR5;
each of R1, R2, R3, R4 and R5 is independently H, D, F, Cl, Br, CN, NO2, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, ORb, —NRcRd, RbO—C1-4 alkylene, RdRcN—C1-4 alkylene, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, and wherein each of the C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, ORb, —NRcRd, C1-6 alkyl, C1-6 haloalkyl, RbO—C1-4 alkylene or RdRcN—C1-4 alkylene;
R6 is ORb, C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, C3-12 carbocyclyl-C1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 16-membered heteroaryl or (5- to 16-membered heteroaryl)-C1-4 alkylene, and wherein each of the C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, C3-12 carbocyclyl-C1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 16-membered heteroaryl and (5- to 16-membered heteroaryl)-C1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′;
R7 is H, D, F, Cl, Br, CN, NO2, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, ORb, —NRcRd, RbO—C1-4 alkylene, RdRcN—C1-4 alkylene, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C3-12 cycloalkyl-C1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C1-4 alkylene, and wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C3-12 cycloalkyl-C1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 10-membered heteroaryl and (5- to 10-membered heteroaryl)-C1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′;
or, R6 and R7, together with the carbon atoms to which they are attached, form a C3-12 carbocyclic ring, 3- to 12-membered heterocyclic ring, C6-10 aromatic ring or 5- to 10-membered heteroaromatic ring, and wherein each of the C3-12 carbocyclic ring, 3- to 12-membered heterocyclic ring, C6-10 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, NO2, ORb, —NRcRd, RbO—C1-4 alkylene, RdRcN—C1-4 alkylene, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-12 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkylene, 3- to 8-membered heterocyclyl, (3- to 8-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 8-membered heteroaryl or (5- to 8-membered heteroaryl)-C1-4 alkylene, and wherein each of the C1-12 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkylene, 3- to 8-membered heterocyclyl, (3- to 8-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 8-membered heteroaryl and (5- to 8-membered heteroaryl)-C1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, NO2, ORb, —NRcRd, C1-6 alkyl, C1-6 haloalkyl, RbO—C1-4 alkylene or RdRcN—C1-4 alkylene;
R8 is H, D or C1-6 alkyl, and wherein C1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, NO2 or ORb;
W is one of the following sub-formulae:
wherein n is 0, 1, 2, 3, or 4;
each Rw is independently D, F, Cl, Br, CN, NO2, oxo (═O), —C(═O)Ra, —C(═O)ORb, —NReC(═O)Ra, —NReC(═O)NRcRd, —S(═O)2Rf, —S(═O)2NReC(═O)Ra, —S(═O)2NRcRd, (RbO)2P(═O)—C0-2 alkylene, ORb, RbO—C1-2 alkylene, C1-6 alkyl or 5- to 6-membered heteroaryl, and wherein each of the C1-6 alkyl 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, N3, oxo (═O), NO2, ORb, C1-6 alkyl or C1-6 haloalkyl;
each Ra, Rb, Rc, Rd, Re and Rf is independently H, D, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, C3-6 carbocyclyl-C1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)-C1-4 alkylene; or, Rc and Rd, 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 the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, C3-6 carbocyclyl-C1-4 alkylene, 3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)-C1-4 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, NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 alkylamino.

### Claim 2 (depends on 1)

The compound of claim 1 having Formula (II),

### Claim 3 (depends on 1)

The compound of claim 1 having Formula (III),
wherein, A is a C3-12 carbocyclic ring, 3- to 12-membered heterocyclic ring, C6-10 aromatic ring or 5- to 10-membered heteroaromatic ring; and
q is 0, 1, 2, 3, 4 or 5.

### Claim 4 (depends on 1)

The compound of claim 1, wherein each of R1, R2, R3, R4 and R5 is independently H, D, F, Cl, Br, CN, NO2, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, ORb, —NRcRd, 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, ORb, —NRcRd or C1-3 haloalkyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R6 is ORb, C2-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 carbocyclyl, C3-6 carbocyclyl-C1-4 alkylene, 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 14-membered heteroaryl or (5- to 14-membered heteroaryl)-C1-4 alkylene, and wherein each of the C2-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 carbocyclyl, C3-6 carbocyclyl-C1-4 alkylene, 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 14-membered heteroaryl and (5- to 14-membered heteroaryl)-C1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′;
R7 is H, D, F, Cl, Br, CN, NO2, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, ORb, —NRcRd, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkylene, 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 6-membered heteroaryl or (5- to 6-membered heteroaryl)-C1-4 alkylene, and wherein each of the C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkylene, 5- to 6-membered heterocyclyl, (5- to 6-membered heterocyclyl)-C1-4 alkylene, C6-10 aryl, C6-10 aryl-C1-4 alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-C1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′;
or, R6 and R7, together with the carbon atoms to which they are attached, form a C3-6 carbocyclic ring, 3- to 6-membered heterocyclic ring, C6-10 aromatic ring or 5- to 10-membered heteroaromatic ring, and wherein each of the C3-6 carbocyclic ring, 3- to 6-membered heterocyclic ring, C6-10 aromatic ring and 5- to 10-membered heteroaromatic ring is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′.

### Claim 6 (depends on 1)

The compound of claim 1, wherein each R′ is independently D, F, Cl, Br, CN, NO2, ORb, —NRcRd, —C(═O)Ra, —C(═O)NRcRd, C1-9 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, phenyl-C1-2 alkylene or 5- to 6-membered heteroaryl, and wherein each of the C1-9 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, phenyl-C1-2 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, NO2, ORb, —NRcRd, methyl, ethyl, n-propyl or i-propyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R8 is H, D, CF3, methyl, ethyl, n-propyl or i-propyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein each Rw is independently D, F, Cl, Br, CN, NO2, oxo (═O), —C(═O)OCH3, —C(═O)OCH2CH3, —C(═O)OH, —NHC(═O)Ra, —NHC(═O)NRcRd, —S(═O)2Rf, —S(═O)2NHC(═O)Ra, —S(═O)2NReRd, (RbO)2P(═O)—C0-2 alkylene, ORb, methyl, ethyl, n-propyl, i-propyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imdazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or primidinyl, 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 and primidinyl independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, oxo (═O), NO2, —OCH3, C1-3 alkyl or C1-3 haloalkyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein each Ra, Rb, Rc, Rd, Re and Rf is independently H, D, trifluoromethyl, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C3-6 carbocyclyl, 5- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl)-C1-4 alkylene; or, Rc and Rd, 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, C3-6 carbocyclyl, 5- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-C1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, OH, NH2, C1-3 alkyl, C1-3 haloalkyl or methoxy.

### Claim 10 (depends on 3)

The compound of claim 3, wherein, A is a C3-6 carbocyclic ring, 3- to 6-membered heterocyclic ring, C6-10 aromatic ring or 5- to 10-membered heteroaryl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R6 is ORb, C2-4 alkynyl, C3-6 carbocyclyl, 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 C2-4 alkynyl, C3-6 carbocyclyl, 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′.

### Claim 12 (depends on 3)

The compound of claim 3, wherein A is a C3-6 carbocyclic ring, 3- 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.

### Claim 13 (depends on 1)

The compound of claim 1 having Formula (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) or (XV),
wherein, A is a C3-12 carbocyclic ring, 3- to 12-membered heterocyclic ring, C6-10 aromatic ring or 5- to 10-membered heteroaromatic ring; and
q is 0, 1,2,3, 4 or 5.

### Claim 14

A compound having one of the following structures,
or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 15)

The pharmaceutical composition of claim 15 further comprising one or more other therapeutic agents, and wherein the other therapeutic agent is an anti-influenza virus agent or anti-influenza virus vaccine.

### Claim 17 (depends on 16)

The pharmaceutical composition of claim 16, wherein the other therapeutic agent is amantadine, rimantadine, oseltamivir, zanamivir, peramivir, laninamivir, laninamivir octanoate hydrate, favipiravir, arbidol, ribavirin, stachyflin, ingavirin, fludase, CAS no. 1422050-75-6, JNJ-872, an influenza vaccine or a combination thereof.

### Claim 18 (depends on 1)

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

### Claim 19 (depends on 1)

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

### Claim 20 (depends on 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 in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 15, wherein the virus infection is an influenza virus infection.

### Claim 21 (depends on 15)

A method of inhibiting an influenza virus RNA polymerase in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 15.