# US 10,307,439 B2 · Substituted nucleosides, nucleotides and analogs thereof

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- Number: US 10,307,439 B2
- Document ID: US10307439B2
- Status: Granted
- Kind: B2
- Application number: 15/423,270
- Filed: 2017-02-02
- Published: 2017-05-25
- Granted: 2019-06-04
- Earliest claimed: 2014-06-24
- Assignees: Alios BioPharma, Inc.
- Applicants: Alios Biopharma, Inc.
- Inventors: Lawrence M. Blatt; Leonid Beigelman; Julian Alexander Symons; David Bernard Smith
- Web page: https://patentgrep.com/patent/US10307439B2

## CPC

- A61K 31/708: having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07F 9/65586: {at least one of the hetero rings does not contain nitrogen as ring hetero atom}
- C07F 9/65742: {non-condensed with carbocyclic rings or heterocyclic rings or ring systems}
- 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
- 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
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Coronaviridae virus, a Togaviridae virus, a Hepeviridae virus and/or a Bunyaviridae virus infection with one or more nucleosides, nucleotides and nucleotide analogs.

## Claims

### Claim 1

A method for ameliorating or treating a betacoronavirus infection comprising contacting a cell infected with the betacoronavirus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure:
wherein:
B1A is
wherein RG2 is an unsubstituted C1-6 alkyl;
R3A is halo, OH, —OC(═O)R″A or an unsubstituted O-linked α-amino acid;
R4A is OH or halo;
Ra1 and Ra2 are independently hydrogen or deuterium;
RA is hydrogen or deuterium;
R1A is selected from the group consisting of hydrogen,
R2A is halo or —(CH2)1-6halogen;
R5A is selected from the group consisting of an unsubstituted C1-6 alkyl, an unsubstituted C2-6 alkenyl and an unsubstituted C2-6 alkynyl;
R6A and R7A are independently selected from the group consisting of absent, hydrogen and
or
R6A is
and R7A is absent or hydrogen;
R8A is an absent, hydrogen, an optionally substituted phenyl or an optionally substituted naphthyl;
R9A is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative, wherein the main-chain carboxylic acid group has been converted to an ester group;
R10A and R11A are independently an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative, wherein the main-chain carboxylic acid group has been converted to an ester group;
R12A and R13A are independently absent or hydrogen;
R14A is O− or OH;
R22A and R23A are each hydrogen;
R24A is selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted —O—C1-24 alkyl;
m is 0 or 1;
s is 0, 1, 2 or 3; and
Z1A, Z2A, Z3A and Z4A are each O; and
wherein when a group is substituted, the group is substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, -thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.

### Claim 2 (depends on 1)

The method of claim 1, wherein the cell is in a human subject.

### Claim 3 (depends on 1)

The method of claim 1, wherein the betacoronavirus is MERS-CoV.

### Claim 4 (depends on 1)

The method of claim 1, wherein the betacoronavirus is SARS-CoV.

### Claim 5 (depends on 1)

The method of claim 1, wherein R2A is F.

### Claim 6 (depends on 1)

The method of claim 1, wherein R2A is —(CH2)1-6F.

### Claim 7 (depends on 6)

The method of claim 6, wherein R2A is —CH2) F.

### Claim 8 (depends on 1)

The method of claim 1, wherein R3A is OH.

### Claim 9 (depends on 1)

The method of claim 1, wherein R3A is F.

### Claim 10 (depends on 1)

The method of claim 1, wherein R4A is OH.

### Claim 11 (depends on 1)

The method of claim 1, wherein R4A is F.

### Claim 12 (depends on 1)

The method of claim 1, wherein R5A is methyl.

### Claim 13 (depends on 1)

The method of claim 1, wherein R5A is ethynyl.

### Claim 14 (depends on 1)

The method of claim 1, wherein B1A is
wherein RG2 is CH2CH3; Ra1 and Ra2 are each hydrogen; RA is hydrogen; R2A is F or CH2F; R3A is OH or F; R4A is OH or F; and R5A is methyl or ethynyl.

### Claim 15 (depends on 1)

The method of claim 1, wherein B1A is
wherein RG2 is CH2CH3; Ra1 and Ra2 are each hydrogen; RA is hydrogen; R2A is F; R3A is OH; R4A is F; and R5A is methyl.

### Claim 16 (depends on 1)

The method of claim 1, wherein B1A is
wherein RG2 is CH2CH3; Ra1 and Ra2 are each hydrogen; RA is hydrogen; R2A is F; R3A is F; R4A is OH; and R5A is methyl.

### Claim 17 (depends on 1)

The method of claim 1, wherein R1A is hydrogen.

### Claim 18 (depends on 1)

The method of claim 1, wherein R1A is

### Claim 19 (depends on 18)

The method of claim 18, wherein R6A is absent or hydrogen; and R7A is absent or hydrogen.

### Claim 20 (depends on 18)

The method of claim 18, wherein R6A and R7A are independently
s is 0; and R24A is an unsubstituted C1-4 alkyl or an unsubstituted —O—C1-4 alkyl.

### Claim 21 (depends on 18)

The method of claim 18, wherein R6A is
m is 0, and R7A, R12A and R13A are independently absent or hydrogen.

### Claim 22 (depends on 18)

The method of claim 18, wherein R6A is
m is 1,R7A, R12A and R13A are independently absent or hydrogen; and R14A is O− or OH.

### Claim 23 (depends on 1)

The method of claim 1, wherein R1A is

### Claim 24 (depends on 23)

The method of claim 23, wherein R8A is an optionally substituted phenyl or an optionally substituted naphthyl; and R9A is an optionally substituted N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked glycine, N-linked valine and N-linked leucine, or an optionally substituted N-linked α-amino acid ester derivative, wherein the N-linked α-amino acid is selected from the group consisting of N-linked alanine, N-linked glycine, N-linked valine and N-linked leucine, and the ester is selected from the group consisting of alkyl ester, cycloalkyl ester, an optionally substituted phenyl ester and an optionally substituted benzyl ester.

### Claim 25 (depends on 24)

The method of claim 24, wherein R8A is an optionally substituted phenyl or an optionally substituted naphthyl; and R9A is selected from the group consisting of N-linked alanine, N-linked alanine isopropyl ester, N-linked alanine cyclohexyl ester and N-linked alanine neopentyl ester.

### Claim 26 (depends on 1)

The method of claim 1, wherein B1A is

### Claim 27 (depends on 1)

The method of claim 1, wherein B1A is
wherein RG2 is —CH2CH3.

### Claim 28 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 29 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 30 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 31 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 32

A method for ameliorating or treating a MERS viral infection comprising contacting a cell infected with the MERS virus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure:
wherein:
B1A is
wherein RG2 is an unsubstituted C1-6 alkyl;
R3A is halo, OH, —OC(═O)R″A or an unsubstituted O-linked α-amino acid;
R4A is OH or halo;
Ra1 and Ra2 are independently hydrogen or deuterium;
RA is hydrogen or deuterium;
R1A is selected from the group consisting of hydrogen,
R2A is halo or —(CH2)1-6halogen;
R5A is selected from the group consisting of an unsubstituted C1-6 alkyl, an unsubstituted C2-6 alkenyl and an unsubstituted C2-6 alkynyl;
R6A and R7A are independently selected from the group consisting of absent, hydrogen and
or
R6A is
and R7A is absent or hydrogen;
R8A is an optionally substituted phenyl or an optionally substituted naphthyl;
R9A is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative, wherein the main-chain carboxylic acid group has been converted to an ester group;
R10A and R11A are independently an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative;
R12A and R13A are independently absent or hydrogen;
R14A is O− or OH;
R22A and R23A are each hydrogen;
R24A is selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted —O—C1-24 alkyl;
m is 0 or 1;
s is 0, 1, 2 or 3; and
Z1A, Z2A, Z3A and Z4A are O; and
wherein when a group is substituted, the group is substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.

### Claim 33 (depends on 32)

The method of claim 32, wherein the cell is in a human subject.

### Claim 34 (depends on 32)

The method of claim 32, wherein B1A is

### Claim 35 (depends on 32)

The method of claim 32, wherein B1A is
wherein RG2 is —CH2CH3.

### Claim 36 (depends on 32)

The method of claim 32, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the forgoing.

### Claim 37 (depends on 18)

The method of claim 18, wherein R6A and R7A are each isopropyloxycarbonyloxymethyl.

### Claim 38 (depends on 23)

The method of claim 23, wherein R8A is an unsubstituted phenyl.

### Claim 39 (depends on 38)

The method of claim 38, wherein R9A is an unsubstituted C1-6 alkyl ester or an unsubstituted C3-6 cycloalkyl ester of an N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked isoleucine, N-linked leucine and N-linked valine.

### Claim 40 (depends on 38)

The method of claim 38, wherein R9A is selected from the group consisting of

### Claim 41 (depends on 1)

The method of claim 1, wherein:
R2A is F;
R3A is OH or F;
R4A is OH or F; and
R5A is methyl or ethynyl.

### Claim 42 (depends on 32)

The method of claim 32, wherein:
R2A is F;
R3A is OH or F;
R4A is OH or F; and
R5A is methyl or ethynyl.

### Claim 43 (depends on 32)

The method of claim 32, wherein B1A is
or
wherein RG2 is CH2CH3; Ra1 and Ra2 are each hydrogen; RA is hydrogen; R2A is F or CH2F; R3A is OH or F; R4A is OH or F; and R5A is methyl or ethynyl.

### Claim 44 (depends on 39)

The method of claim 39, wherein B1A is
or
wherein RG2 is CH2CH3; Ra1 and Ra2 are each hydrogen; RA is hydrogen; R2A is F; R3A is OH; R4A is F; and R5A is methyl.

### Claim 45 (depends on 39)

The method of claim 39, wherein B1A is
or
wherein RG2 is CH2CH3; Ra1 and Ra2 are each hydrogen; RA is hydrogen; R2A is F; R3A is F; R4A is OH; and R5A is methyl.

### Claim 46 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof, wherein B1A is
RG2 is —CH2CH3; and R1A is hydrogen.

### Claim 47 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof, wherein B1A is
RG2 is —CH2CH3; and R1A is hydrogen.

### Claim 48 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof, wherein B1A is
RG2 is —CH2CH3; and R1A is hydrogen.

### Claim 49 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof, wherein B1A is
RG2 is —CH2CH3; and R1A is hydrogen.

### Claim 50 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 51 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 52 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 53 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 54 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 55 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 56 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 57 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 58 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 59 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 60 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 61 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 62 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 63 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.