# US 2019/0169221 A1 · Substituted nucleosides, nucleotides and analogs thereof

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- Number: US 2019/0169221 A1
- Document ID: US20190169221A1
- Status: Published application
- Kind: A1
- Application number: 16/324,862
- Filed: 2017-08-10
- Published: 2019-06-06
- Earliest claimed: 2016-08-12
- Assignees: Janssen BioPharma, Inc.
- Applicants: Janssen BioPharma, Inc.
- Inventors: Guangyi WANG; Leonid BEIGELMAN; Jerome DEVAL; Christian Andreas JEKLE
- Web page: https://patentgrep.com/patent/US20190169221A1

## CPC

- C07H 19/16: Purine radicals
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/16: for influenza or rhinoviruses
- C07H 19/052: Imidazole radicals
- C07H 19/12: Triazine radicals
- C07H 19/14: Pyrrolo-pyrimidine radicals
- C07H 19/167: with ribosyl as the saccharide radical
- C07H 19/20: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H 19/23: Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein are nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a Picornaviridae and/or Flaviviridae viral infections with one or more nucleotide analogs.

## Claims

### Claim 1

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
B1A is
X1 is N (nitrogen) or —CRB6;
X2 is N (nitrogen) or —CRB6a;
X3 is N (nitrogen) or —CRB6b;
X4 is N (nitrogen) or —CRB6c;
RB1, RB1a, RB1b and RB1c are independently hydrogen or deuterium;
RB2 is NRB4aRB4b;
RB2b is NRB4a1RB4b1;
RB2c is NRB4a2RB4b2;
RB2a is selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C3-6 cycloalkyl;
RB3 is hydrogen, deuterium, halogen or NRB5aRB5b;
RB3b is hydrogen, deuterium, halogen or NRB5a1RB5b1;
RB3c is hydrogen, deuterium, halogen or NRB5a2RB5b2;
RB4a, RB4a1 and RB4a2 are independently hydrogen or deuterium;
RB4b, RB4b1 and RB4b2 are independently selected from the group consisting of hydrogen, deuterium, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C3-6 cycloalkyl, —C(═O)RB7 and —C(═O)ORB8;
RB5a is hydrogen or deuterium;
RB5b is selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C3-6 cycloalkyl, —C(═O)RB9 and —C(═O)ORB10;
RB5a1 and RB5a2 are independently hydrogen or deuterium;
RB5b1 and RB5b2 are independently selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C3-6 cycloalkyl, —C(═O)RB9 and —C(═O)ORB10;
RB6a, RB6b and RB6c are independently selected from the group consisting of hydrogen, deuterium, halogen, —C≡N, —C(═O)NH2, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C2-6 alkynyl;
RB7, RB8, RB9 and RB10 are independently selected from the group consisting of an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C5-10 cycloalkenyl, an optionally substituted C6-10 aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl (C1-6 alkyl), an optionally substituted heteroaryl (C1-6 alkyl) and an optionally substituted heterocyclyl (C1-6 alkyl);
R1A is hydrogen, deuterium, an optionally substituted acyl, an optionally substituted O-linked amino acid or
R2A, R3A, R5A and RA are independently hydrogen or deuterium;
R4A is fluoro;
R6A is selected from the group consisting of —OH, —OC(═O)R″A and an optionally substituted O-linked amino acid;
R7A is —OH, —OC(═O)R″B, fluoro or chloro;
R8A is an optionally substituted C1-3 alkyl, an optionally substituted C3-6 allenyl or an optionally substituted C2-6 alkynyl;
R9A and R10A are independently selected from the group consisting of O−, —OH, an optionally substituted —O—C1-24 alkyl, an optionally substituted —O—C2-24 alkenyl, an optionally substituted —O—C2-24 alkynyl, an optionally substituted —O—C3-6 cycloalkyl, an optionally substituted —O—C5-10 cycloalkenyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl, an optionally substituted —O-aryl (C1-6 alkyl), an optionally substituted *—O—(CR11AR12A)p—O—C1-24 alkyl, an optionally substituted *—O—(CR13AR14A)q—O—C2-24 alkenyl,
an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; or
R9A is
and R10A is O− or OH; or
R9A and R10A are taken together to form a moiety selected from an optionally substituted
and an optionally substituted
wherein the phosphorus and the moiety form a six-membered to ten-membered ring system and wherein the asterisks indicate the points of attachment of the moieties;
each R11A, each R12A, each R13A and each R14A are independently hydrogen, deuterium, an optionally substituted C1-24 alkyl or alkoxy;
R15A, R16A, R18A and R19A are independently selected from the group consisting of hydrogen, deuterium, an optionally substituted C1-24 alkyl and an optionally substituted aryl;
R17A and R20A are independently selected from the group consisting of hydrogen, deuterium, an optionally substituted C1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl;
R21A is selected from the group consisting of hydrogen, deuterium, an optionally substituted C1-24 alkyl and an optionally substituted aryl;
R22A and R23A are independently selected from the group consisting of —C≡N, an optionally substituted C2-8 organylcarbonyl, an optionally substituted C2-8 alkoxycarbonyl and an optionally substituted C2-8 organylaminocarbonyl;
R24A is selected from the group consisting of hydrogen, deuterium, an optionally substituted C1-24-alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally substituted C5-10 cycloalkenyl;
R25A, R26A and R27A are independently absent, hydrogen or deuterium;
p and q are independently selected from 1, 2 and 3;
r is 1 or 2;
s is 0 or 1;
R″A and R″B are independently an optionally substituted C1-24 alkyl; and
Z1A and Z2A are independently oxygen (O) or sulfur (S); and
provided that when X1 is N or CH, B1A is
and R1A is hydrogen or triphosphate, then R8A is not methyl; and
provided that the compound of Formula (I) is not
or a pharmaceutically acceptable salt thereof.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1A is hydrogen or deuterium.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1A is an optionally substituted acyl.

### Claim 5 (depends on 4)

The compound of claim 4, wherein the optionally substituted acyl is —C(═O)R″A1, wherein R″A1 is an unsubstituted C1-12-alkyl.

### Claim 6

(canceled)

### Claim 7

(canceled)

### Claim 8

(canceled)

### Claim 9

(canceled)

### Claim 10 (depends on 1)

The compound of claim 1, wherein R1A is

### Claim 11

(canceled)

### Claim 12

(canceled)

### Claim 13

(canceled)

### Claim 14

(canceled)

### Claim 15

(canceled)

### Claim 16

(canceled)

### Claim 17

(canceled)

### Claim 18

(canceled)

### Claim 19

(canceled)

### Claim 20

(canceled)

### Claim 21

(canceled)

### Claim 22

(canceled)

### Claim 23

(canceled)

### Claim 24

(canceled)

### Claim 25

(canceled)

### Claim 26

(canceled)

### Claim 27

(canceled)

### Claim 28

(canceled)

### Claim 29

(canceled)

### Claim 30

(canceled)

### Claim 31 (depends on 10)

The compound of claim 10, wherein R9A and R10A are independently O− or —OH.

### Claim 32

(canceled)

### Claim 33 (depends on 10)

The compound of claim 10, wherein R9A is
s is 0 or 1; R25A, R26A and R27A are independently absent, hydrogen or deuterium; and R10A is O− or —OH.

### Claim 34 (depends on 1)

The compound of claim 1, wherein R6A is —OH.

### Claim 35 (depends on 1)

The compound of claim 1, wherein R6A is —OC(═O)R″A.

### Claim 36 (depends on 35)

The compound of claim 35, wherein R″A is an unsubstituted C1-12 alkyl.

### Claim 37

(canceled)

### Claim 38

(canceled)

### Claim 39

(canceled)

### Claim 40 (depends on 1)

The compound of claim 1, wherein R7A is —OH.

### Claim 41

(canceled)

### Claim 42

(canceled)

### Claim 43 (depends on 1)

The compound of claim 1, wherein R7A is —OC(═O)R″B, wherein R″B is an unsubstituted C1-12 alkyl.

### Claim 44

(canceled)

### Claim 45

(canceled)

### Claim 46

(canceled)

### Claim 47 (depends on 1)

The compound of claim 1, wherein R8A is an optionally substituted C2-6 alkynyl.

### Claim 48

(canceled)

### Claim 49 (depends on 47)

The compound of claim 47, wherein R8A is an unsubstituted ethynyl.

### Claim 50

(canceled)

### Claim 51 (depends on 1)

The compound of claim 1, wherein B1A is an optionally substituted

### Claim 52

(canceled)

### Claim 53

(canceled)

### Claim 54

(canceled)

### Claim 55

(canceled)

### Claim 56

(canceled)

### Claim 57

(canceled)

### Claim 58 (depends on 51)

The compound of claim 51, wherein B1A is an unsubstituted

### Claim 59

(canceled)

### Claim 60

(canceled)

### Claim 61

(canceled)

### Claim 62

(canceled)

### Claim 63

(canceled)

### Claim 64

(canceled)

### Claim 65

(canceled)

### Claim 66

(canceled)

### Claim 67

(canceled)

### Claim 68

(canceled)

### Claim 69

(canceled)

### Claim 70

(canceled)

### Claim 71

(canceled)

### Claim 72

(canceled)

### Claim 73

(canceled)

### Claim 74

(canceled)

### Claim 75

(canceled)

### Claim 76

(canceled)

### Claim 77

(canceled)

### Claim 78

(canceled)

### Claim 79

(canceled)

### Claim 80

(canceled)

### Claim 81 (depends on 1)

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

### Claim 82 (depends on 1)

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

### Claim 83

(canceled)

### Claim 84

(canceled)

### Claim 85

(canceled)

### Claim 86

(canceled)

### Claim 87

(canceled)

### Claim 88

(canceled)

### Claim 89

(canceled)

### Claim 90

(canceled)

### Claim 91

(canceled)

### Claim 92

(canceled)

### Claim 93

(canceled)

### Claim 94

(canceled)

### Claim 95

(canceled)

### Claim 96

(canceled)

### Claim 97

(canceled)

### Claim 98

(canceled)

### Claim 99 (depends on 1)

A method of ameliorating and/or treating a Picornaviridae viral infection, comprising administering to a subject identified as suffering from the Picornaviridae viral infection an effective amount of one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 100 (depends on 1)

A method of ameliorating and/or treating a Flaviviridae viral infection, comprising administering to a subject identified as suffering from the Flaviviridae viral infection an effective amount of one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof.