# US 10,370,401 B2 · Substituted nucleosides, nucleotides and analogs thereof

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- Number: US 10,370,401 B2
- Document ID: US10370401B2
- Status: Granted
- Kind: B2
- Application number: 15/790,764
- Filed: 2017-10-23
- Published: 2018-02-15
- Granted: 2019-08-06
- Earliest claimed: 2013-10-11
- Assignees: Janssen BioPharma, Inc.
- Applicants: Alios BioPharma, Inc.
- Inventors: Leonid Beigelman; Guangyi Wang; David Bernard Smith; Marija Prhavc; Christian Andreas Jekle; Jerome Deval
- Web page: https://patentgrep.com/patent/US10370401B2

## CPC

- C07H 19/20: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- A61K 31/7052: having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K 31/7064: containing condensed or non-condensed pyrimidines
- 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
- A61K 31/708: having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
- A61P 31/14: for RNA viruses
- A61P 31/16: for influenza or rhinoviruses
- C07H 19/06: Pyrimidine radicals
- C07H 19/10: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H 19/11: containing cyclic phosphate
- C07H 19/16: Purine radicals
- C07H 19/207: the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
- C07H 19/213: containing cyclic phosphate
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- 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
- 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 Picornavirus and/or Flaviviridae infection with one or more nucleosides, nucleotides and nucleotide analogs.

## Claims

### Claim 1

A method for ameliorating or treating a Picornaviridae viral infection comprising contacting a cell infected with the Picornaviridae 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 selected from the group consisting of OH, OC(═O)R″A and an unsubstituted O-linked α-amino acid;
R4A is selected from the group consisting of OH and 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;
R5A is selected from the group consisting of an unsubstituted C1-6 alkyl and an unsubstituted C2-6 alkenyl;
R6A and R7A are independently selected from the group consisting of absent, hydrogen and
or
R6A is
and R7A is absent or hydrogen; or
R8A is absent, hydrogen, an optionally substituted phenyl or an optionally substituted naphthyl;
R9A is an optionally substituted N-linked amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine, or an optionally substituted N-linked α-amino acid ester derivative, wherein the optionally substituted N-linked α-amino acid ester derivative is an unsubstituted C1-6 alkyl ester, an optionally substituted C3-6 cycloalkyl ester, an optionally substituted C6 aryl ester, an optionally substituted C10 aryl ester or an optionally substituted benzyl ester of an N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine;
R10A and R11A are independently an optionally substituted N-linked amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine, or an optionally substituted N-linked α-amino acid ester derivative, wherein the optionally substituted N-linked α-amino acid ester derivative is an unsubstituted C1-6 alkyl ester, an optionally substituted C3-6 cycloalkyl ester, an optionally substituted C6 aryl ester, an optionally substituted Cm aryl ester or an optionally substituted benzyl ester of an N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine;
R12A and R13A are independently absent or hydrogen;
R14A is O−, OH or methyl;
R22A and R23A are each hydrogen;
R24A is selected from the group consisting of hydrogen, an unsubstituted C1-24 alkyl, and an unsubstituted —O—C1-24 alkyl;
R″A is an unsubstituted C1-24 alkyl;
m is 0 or 1;
s is 0, 1, 2 or 3; and
Z1A, Z2A, Z3A and Z4A are each O.

### Claim 2 (depends on 1)

The method of claim 1, wherein the virus is an Enterovirus.

### Claim 3 (depends on 1)

The method of claim 1, wherein the virus is a Rhinovirus.

### Claim 4 (depends on 1)

The method of claim 1, wherein B1A is

### Claim 5 (depends on 1)

The method of claim 1, wherein B1A is
wherein RG2 is ethyl.

### Claim 6 (depends on 1)

The method of claim 1, wherein R2A is fluoro.

### Claim 7 (depends on 1)

The method of claim 1, wherein R3A is OH.

### Claim 8 (depends on 1)

The method of claim 1, wherein R3A is —OC(═O)R″A, wherein R″A is an unsubstituted C1-4 alkyl.

### Claim 9 (depends on 1)

The method of claim 1, wherein R4A is OH.

### Claim 10 (depends on 1)

The method of claim 1, wherein R4A is -halo.

### Claim 11 (depends on 10)

The method of claim 10, wherein R4A is fluoro.

### Claim 12 (depends on 1)

The method of claim 1, wherein R5A is an unsubstituted C1-6 alkyl.

### Claim 13 (depends on 12)

The method of claim 12, wherein R5A is methyl.

### Claim 14 (depends on 1)

The method of claim 1, wherein R1A is hydrogen.

### Claim 15 (depends on 1)

The method of claim 1, wherein R1A is

### Claim 16 (depends on 15)

The method of claim 15, wherein R6A is
R7A, R12A and R13A are independently absent or hydrogen; R14A is O− and OH; and m is 0 or 1.

### Claim 17 (depends on 16)

The method of claim 16, wherein m is 1.

### Claim 18 (depends on 1)

The method of claim 1, wherein Ra1 and Ra2 are each hydrogen.

### Claim 19 (depends on 1)

The method of claim 1, wherein RA is hydrogen.

### Claim 20 (depends on 15)

The method of claim 15, wherein R6A and R7A are independently absent or hydrogen.

### Claim 21 (depends on 15)

The method of claim 15, wherein R6A and R7A are each
wherein s is 0.

### Claim 22 (depends on 15)

The method of claim 15, wherein R6A and R7A are each isopropyloxycarbonyloxymethyl.

### 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.

### Claim 25 (depends on 24)

The method of claim 24, wherein R8A is an unsubstituted phenyl.

### Claim 26 (depends on 25)

The method of claim 25, 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 27 (depends on 25)

The method of claim 25, wherein R9A is selected from the group consisting of

### Claim 28 (depends on 1)

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

### Claim 29 (depends on 28)

The method of claim 28, wherein B1A is
wherein RG2 is —CH2CH3.

### Claim 30 (depends on 28)

The method of claim 28, wherein R1A is H.

### Claim 31 (depends on 28)

The method of claim 28, wherein R1A is
R6A is
R7A, R12A and R13A are independently absent or hydrogen; m is 1;
and R14A is O− or OH.

### Claim 32 (depends on 28)

The method of claim 28, wherein R1A is
R6A and R7A are each
s is 0; R22A and R23A are each hydrogen; and R24A is an unsubstituted tert-butyl.

### Claim 33 (depends on 28)

The method of claim 28, wherein R1A is
R6A and R7A are each
s is 0; R22A and R23A are each hydrogen; and R24A is an unsubstituted O-isopropyl.

### Claim 34 (depends on 28)

The method of claim 28, wherein R1A is
R8A is an unsubstituted phenyl; and R9A is

### Claim 35 (depends on 28)

The method of claim 28, wherein R1A is
R8A is an unsubstituted phenyl; and R9A is

### Claim 36 (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 37 (depends on 1)

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

### Claim 38 (depends on 1)

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

### Claim 39 (depends on 1)

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

### Claim 40 (depends on 1)

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

### Claim 41 (depends on 1)

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