5, 6-D2 uridine nucleoside/tide derivatives

Patent metadata

Field	Value
Publication number	US-10034893-B2
Application number	US-201414169387-A
Country	US
Kind code	B2
Filing date	Jan 31, 2014
Priority date	Feb 1, 2013
Publication date	Jul 31, 2018
Grant date	Jul 31, 2018

Abstract

In one aspect, the invention provides compounds represented by Formula I,

and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, and combinations thereof, pharmaceutical compositions comprising these compounds and the use of these compounds for treating a viral infection in a subject.

First claim

What is claimed is:

1. A compound represented by Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, or combination thereof:

wherein:
each D represents a position which is at least 80% deuterated;
R 3 is hydrogen, a hydroxy protecting group, —C(O)R 7 , —C(O)OR 7 , or —C(O)NR 8a R 8b ;
R 1 is selected from the group consisting of:
1) —C(O)R 7 , —C(O)OR 7 , and —C(O)NR 8a R 8b ;
2) —P(O)(OR 7a )(OR 7b ); wherein R 7a and R 7b are each independently selected from the group consisting of a) hydrogen; b) unsubstituted or substituted —C 1 -C 8 alkyl;
3) —P(O)(OR 7a )—O—P(O)(OR 7b )(OR 7c ); wherein R 7a and R 7b are previously defined; R 7c is selected from the group consisting of a) hydrogen; b) unsubstituted or substituted —C 1 -C 8 alkyl;
4) —P(O)(OR 7a )—O—P(O)(OR 7b )—O—P(O)(OR 7c )(OR 7d ); wherein R 7a , R 7b and R 7c are previously defined; R 7d is selected from the group consisting of a) hydrogen; b) unsubstituted or substituted —C 1 -C 8 alkyl;
5)

 where X is O or S; R 9 is R 7 ; R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen; and unsubstituted or substituted —C 1 -C 8 alkyl; or R 11 is hydrogen, and R 12 and R 10 are taken together with the atoms to which they are attached to form a heterocyclic ring; or R 10 is hydrogen or unsubstituted or substituted —C 1 -C 8 alkyl and R 11 and R 12 are taken together with the carbon atom to which they are attached to form a ring; and R 13 is hydrogen or R 7 and
6)

 where X is O or S; n is 1-4; R 14 is hydrogen or —(CO)—R 7 ;
Or, R1 and R 3 are taken together to form

 where X is O or S; and R 15 is selected from the group consisting of a) hydrogen; b) unsubstituted or substituted —C 1 -C 8 alkyl; c) substituted or unsubstituted —C 2 -C 8 alkenyl; d) substituted or unsubstituted —C 2 -C 8 alkynyl; e) substituted or unsubstituted aryl; and f) substituted or unsubstituted heteroaryl;

R 2 a at each occurrence is selected from the group consisting of:
1) hydrogen;
2) halogen;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl; and
5) Substituted or unsubstituted —C 2 -C 8 alkynyl;

R 2b and R 4 are independently selected from the group consisting of:
1) hydrogen;
2) halogen;
3) —CN;
4) —N 3 ; and
5) OR 9 ;

R 7 at each occurrence is independently selected from the group consisting of: substituted or unsubstituted —C 1 -C 8 alkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, substituted or unsubstituted —C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic;
R 8a and R 8b at each occurrence are independently selected from the group consisting of:
hydrogen and R 7 ; or alternatively R 8a and R 8b taken together with the nitrogen atom to which they are attached form a heterocyclic ring;
R 9 at each occurrence is selected from the group consisting of: hydrogen, hydroxy protecting group, R 10a , —C(O)R 10a , —C(O)OR 10a , and —C(O)NR 11a R 11b ; wherein R 10a at each occurrence is independently selected from the group consisting of: substituted or unsubstituted —C 1 -C 8 alkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, substituted or unsubstituted —C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic; R 11a and R 11b at each occurrence are each independently selected from the group consisting of: hydrogen and R 10a ; or alternatively R 11a and R 11b taken together with the nitrogen atom to which they are attached form a heterocyclic ring;
R 5a and R 5b are independently selected from the group consisting of:
1) hydrogen;
2) substituted or unsubstituted —C 1 -C 8 alkyl;
3) substituted or unsubstituted —C 2 -C 8 alkenyl; and
4) substituted or unsubstituted —C 2 -C 8 alkynyl;
or R 5 a and R 5 b are taken together with the carbon atom to which they are attached to form a group selected from —C 3 -C 8 cycloalkyl, —C 3 -C 8 cycloalkenyl, or —C 3 -C 8 cycloalkynyl.

2. A compound of claim 1 represented by Formula III or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, or combination thereof:

wherein R 2a , R 2b , R 4 , R 5a , R 5b , and R 7 are as previously defined.

3. A compound of claim 1 represented by Formula IV or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, or combination thereof:

wherein X, R 2a , R 2b , R 3 , R 4 , R 5a , R 5b , R 9 , R 10 , R 11 , R 12 , and R 13 are as previously defined.

4. A compound of claim 1 represented by Formula V or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, or combination thereof:

wherein n, X, R 2a , R 2b , R 3 , R 4 , R 5a , R 5b , R 8a , R 8b , and R 14 are as previously defined.

5. A compound of claim 1 represented by Formula VI or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, or combination thereof:

wherein X, R 2a , R 2b , R 5a , R 5b , and R 15 are as previously defined.

6. A compound selected from
(a) compounds represented by Formula VII wherein, R 2a , R 2b , R 9 , R 11 , R 12 , and R 13 are delineated for each compound in Table 1:

TABLE 1

Example
R 2a
R 2b
R 9
R 11
R 12
R 13

 1
Me
OH
Ph
Me
H
iPr

 2
Me
OH
Ph
Me
H
Me

 3
Me
OH
Ph
Me
H
Et

 4
Me
OH
Ph
Me
H
Bn

 5
Me
OH
Ph
Me

Assignees

• Enanta Pharm Inc

Inventors

• Luly Jay R
• Ma Jun
• Wang Guoqiang
• Or Yat Sun

Classifications

• C07H19/06

  Pyrimidine radicals · CPC title

• C07H19/10

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• A61K38/21

  Interferons {[IFN]} · CPC title

• A61K31/7056

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title