# US 10,246,486 B2 · Macrocyclic inhibitors of flaviviridae viruses

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- Number: US 10,246,486 B2
- Document ID: US10246486B2
- Status: Granted
- Kind: B2
- Application number: 15/465,492
- Filed: 2017-03-21
- Published: 2017-07-06
- Granted: 2019-04-02
- Earliest claimed: 2012-06-08
- Assignees: Gilead Sciences, Inc.; Cypralis Limited
- Applicants: Gilead Sciences, Inc.; Cypralis Limited
- Inventors: Caroline Aciro; David Kenneth Dean; Neil Andrew Dunbar; Adrian John Highton; Petr Jansa; Kapil Kumar Karki; Andrew John Keats; Linos Lazarides; Richard Mackman; Simon Neil Pettit; Karine G. Poullennec; Adam James Schrier; Dustin Scott Siegel; Victoria Alexandra Steadman
- Web page: https://patentgrep.com/patent/US10246486B2

## CPC

- C07K 5/06034: {the side chain containing 2 to 4 carbon atoms}
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 31/497: containing further heterocyclic rings
- A61K 31/504: forming part of bridged ring systems
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61K 38/05: Dipeptides
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 38/21: Interferons {[IFN]}
- A61K 38/55: Protease inhibitors
- A61K 39/29: Hepatitis virus
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/18: Bridged systems
- C07D 487/08: Bridged systems
- C07D 498/08: Bridged systems
- C07D 498/18: Bridged systems
- C07D 498/22: in which the condensed system contains four or more hetero rings
- C07K 5/02: containing at least one abnormal peptide link
- C07K 5/06052: {Val-amino acid}
- C07K 5/0606: {the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr}
- C07K 5/06078: {and aromatic or cycloaliphatic}
- C07K 5/06086: {with the first amino acid being basic}
- C07K 5/06139: {with the first amino acid being heterocyclic}
- C07K 5/06191: {containing heteroatoms different from O, S, or N}
- C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 38/15: Depsipeptides; Derivatives thereof
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Provided are compounds of Formula I: and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.

## Claims

### Claim 1

A compound of Formula I:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein:
A1 is (C2-C5)alkylene, (C2-C5)alkenylene, (C2-C5)alkynylene, —O—(C2-C4)alkylene, —O—(C2-C4)alkenylene, arylene, aryl(C1-C2)alkylene, heterocycloalkylene, pyrazolylene, pyridylene, pyrimidinylene or heterocycloalkyl(C1-C2)alkylene, wherein a sp3 carbon atom of A1 is optionally substituted with one or more (C1-C4)alkyl;
A2 is arylene or heteroarylene, wherein A2 is optionally substituted with halo;
X1 is —O—, —NH— or —N((C1-C4)alkyl)-;
R1a and R1b are independently H, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl;
R2 is H, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl;
R3a and R3b are independently H or (C1-C8)alkyl;
R4a and R4b are independently H, —OH, (C1-C4)alkoxy, halo(C1-C4)alkoxy or (C1-C8)alkyl;
R5 is H, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl, or
R5 forms a cyclic moiety along with —N((C1-C4)alkyl)- of X1 or arylene of A2; and
R6 is H or (C1-C4)alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein A1 is ethenylene, propenylene, butenylene, ethylene, propylene, butylene, oxypropylene, oxypropenylene, pyrazolylene, phenylene, pyridylene or pyrimidinylene.

### Claim 3 (depends on 1)

The compound of claim 1, wherein A2 is isoquinolinylene, phenylene or halophenylene.

### Claim 4 (depends on 1)

The compound of claim 1, wherein X1 is —O— or —NH—; one of R1a and R1b is H and the other is methyl; R2 is iso-propyl; R5 is methyl and R6 is H or methyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R3a is H or methyl; R3b is H; R4a is H, —OH, methoxy, trifluoroethoxy; and R4b is H.

### Claim 6 (depends on 1)

The compound of claim 1, which is a compound of Formula II:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein:
A1 is ethenylene,
A2 is
X1 is —O— or —NH—;
R3a is H or methyl;
R4a is H, —OH, (C1-C4)alkoxy, halo(C1-C4)alkoxy or (C1-C8)alkyl; and
R5 is H or (C1-C4)alkyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein A2 is heteroarylene; A1 is (C2-C5)alkylene, (C2-C5)alkenylene, (C2-C5)alkynylene, wherein A1 is optionally substituted with one or more (C1-C4)alkyl; R3a is H or methyl; and R4a is H, —OH or (C1-C4)alkoxy.

### Claim 8 (depends on 1)

The compound of claim 1, wherein A2 is arylene; and A1 is (C2-C5)alkylene, (C2-C5)alkenylene, (C2-C5)alkynylene, O—(C2-C4)alkylene, —O—(C2-C4)alkenylene, wherein A1 is optionally substituted with one or more (C1-C4)alkyl; R3a is H or methyl; and R4a is H, —OH, (C1-C4)alkoxy or halo(C1-C4)alkoxy.

### Claim 9

A compound selected from:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.

### Claim 10 (depends on 1)

The compound of claim 1, wherein A2 is arylene; and A1 is pyrazolylene, phenylene or pyridylene.

### Claim 11 (depends on 1)

The compound of claim 1, wherein A2 is halophenylene; and A1 is —O—(C2-C4)alkylene or —O—(C2-C4)alkenylene.

### Claim 12 (depends on 1)

The compound of claim 1, wherein A1 is (C2-C5)alkylene or (C2-C4)alkenylene; R5 is methyl, or R5 form
along with arylene of A2, or R5 form
along with —N((C1-C4)alkyl)- of X1; and R6 is H or methyl.

### Claim 13

A compound selected from:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof and a pharmaceutically acceptable excipient.

### Claim 15 (depends on 14)

The pharmaceutical composition of claim 14, further comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin, HCV NS3 protease inhibitors, HCV NS5a inhibitors, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, and TLR-7 agonists; or a mixture thereof.

### Claim 16 (depends on 15)

The pharmaceutical composition of claim 15, wherein the at least one additional therapeutic agent is ribavirin, telaprevir, boceprevir or sofosbuvir.