Alkynyl nucleoside analogs as inhibitors of human rhinovirus

Patent metadata

Field	Value
Publication number	US-9988416-B2
Application number	US-201715465485-A
Country	US
Kind code	B2
Filing date	Mar 21, 2017
Priority date	Mar 24, 2016
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

The present invention provides a compound of Formula (I) or a salt thereof;

and therapeutic uses of these compounds. The invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds with a therapeutic co-agent, and methods of using the compounds and compositions for treatment of viral infections, especially HRV.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
R 1 is Me, Et, iPr, or cyclopropyl;
R 2 is H, phosphate, diphosphate, triphosphate, —P(═X)(OR 4 ) 2 , —P(═X)(OR 4 )(NR 5 R 6 ), or —P(═X)(NR 5 R 6 ) 2 , and R 3 is H or —C(O)R;
or R 3 and R 2 taken together form —P(═X)(OR 4 )— or —P(═X)(NR 5 R 6 )—;
X at each occurrence is independently O or S;
R 4 is selected from H, phenyl optionally substituted with one or two groups selected from List A, and C 1 -C 4 alkyl optionally substituted with one or two groups selected from halo, —OR, —OC(O)R, —OC(O)—OR, —NR 2 , —C(O)R, COOR and —C(O)NR 2 ;
each R 5 is independently H, C(O)R, COOR, or C 1 -C 4 alkyl optionally substituted with OH, amino, or COOR;
each R 6 is independently selected from H, phenyl optionally substituted with one or two groups selected from List A, and C 1 -C 4 alkyl optionally substituted with one or two groups selected from List B;
each R is independently H or a C 1 -C 4 alkyl group optionally substituted with one to three groups selected from halo, hydroxy, CN, amino, C 1 -C 3 alkoxy, —C(O)R 7 , —OC(O)R 7 , —C(O)—OR 7 , and —OC(O)—OR 7 ;
R 7 is selected from H, C 1 -C 4 alkyl optionally substituted with one to three groups selected from halo, hydroxy, CN, amino, and C 1 -C 3 alkoxy, and phenyl optionally substituted with one or two groups selected from List A;
List A is selected from halo, hydroxy, —NO 2 , CN, —OR 8 , —OC(O)R 8 , —OC(O)—OR 8 , —N(R 8 ) 2 , —C(O)R 8 , COOR 8 , —C(O)N(R 8 ) 2 , and C 1 -C 3 alkyl optionally substituted with one to three groups selected from halo, hydroxy, CN, amino, and C 1 -C 3 alkoxy;
List B is selected from halo, hydroxy, oxo, CN, —OR 8 , —OC(O)R 8 , —OC(O)-OR 8 , —N(R 8 ) 2 , —C(O)R 8 , COOR 8 and —C(O)N(R 8 ) 2 ; and
R 8 is independently at each occurrence selected from H and C 1 -C 4 alkyl optionally substituted with one to three groups selected from halo, hydroxy, CN, amino, and C 1 -C 3 alkoxy,
and two R 8 attached to the same nitrogen atom can optionally cyclize to form a 3-7 membered heterocycle, which optionally contains an additional N, O or S as a ring member, and can be substituted by one or two groups selected from oxo, halo, OH, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 is methyl, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein R 2 is H or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , wherein R 2 is phosphate, diphosphate or triphosphate, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 , wherein R 2 is —P(═X)(OR 4 ) 2 ,
or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , wherein each R 4 is selected from —CH 2 —O—C(O)—R and —CH 2 —O—C(O)—OR, wherein each R is independently C 1 -C 4 alkyl,
or a pharmaceutically acceptable salt thereof.

7. The compound of claim 2 , wherein R 3 and R 2 taken together form —P(═O)(OR 4 )— or —P(═O)—(NR 5 R 6 )—, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2 , wherein R 3 is H.

9. The compound of claim 1 , which is:

wherein R 2 is H, phosphate, diphosphate, or triphosphate;
or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , which is of the formula:

or a pharmaceutically acceptable salt thereof.

11. A compound of claim 1 , which is of the formula:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , which is selected from:

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of any of the preceding claims or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

14. A combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents.

15. A method of treating an human rhinovirus infection (HRV) infection or a chikungunya infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of claims 1 - 12 or a pharmaceutically acceptable salt thereof.

Assignees

• Novartis Ag

Inventors

• Fenaux Martijn
• Saunders Oliver
• Yokokawa Fumiaki
• Zhong Weidong

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P31/14

  for RNA viruses · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/7064

  containing condensed or non-condensed pyrimidines · CPC title

• C07H19/04

  Heterocyclic radicals containing only nitrogen atoms as ring hetero atom · CPC title