Nucleoside analogs for treatment of the flaviviridae family of viruses and cancer

Patent metadata

Field	Value
Publication number	US-10011629-B2
Application number	US-201615139924-A
Country	US
Kind code	B2
Filing date	Apr 27, 2016
Priority date	May 1, 2015
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

The present invention is directed to compounds, compositions and methods for treating or preventing Flaviviridae family of viruses (including HCV, Yellow fever, Dengue, Chikungunya and West Nile virus), RSV, HEV, and influenza infection and cancer in human subjects or other animal hosts.

First claim

We claim:

1. A compound of Formula (A) or (B):

or a pharmaceutically acceptable salt, wherein:
R 1 is H or Me, wherein, when R 1 is Me it may be wholly or partially R or S or any mixture thereof;
R 2 is H, N 3 , F, (C 1-8 )alkyl, (C 2-8 )alkenyl or (C 2-8 )alkynyl;
R 4 is H or P(O)R 6 R 7 , wherein, when chirality exists at the phosphorous center of R 4 , it may be wholly or partially R p or S p or any mixture thereof,
R 5 is O, CH 2 , S, Se, CHF, CF 2 , or C═CH 2 ,
R 3 is H or CN when R 5 is O, and
R 3 is selected from the group consisting of H, CN, (C 1-8 )alkyl, (C 2-8 )alkenyl, (C 2-8 )alkynyl and O—(C 1-8 ) alkyl when R 5 is CH 2 , CHF, CF 2 , or C═CH 2 ,
R 8 is selected from the group consisting of H, C(O)(C 1-8 )alkyl, C(O)(C 1-8 )branched alkyl, C(O)NH(C 1-8 )alkyl, C(O)NH(C 1-8 )branched alkyl, C(O)aryl C(O)(C 1-8 )alkyl-aryl, C(O)NH(C 1-8 )alkyl-aryl C(O)O(C 1-8 )alkyl, C(O)O(C 1-8 )branched alkyl, C(O)O(C 1-8 )alkyl-aryl or OR 8 as it appears in Formulas A or B is an ester derived from an alpha amino acid,
R 6 and R 7 are independently selected from the group consisting of:
(a) OR 15 where R 15 selected from the group consisting of H,

 Li, Na, K, C 1-20 alkyl, C 3-6 cycloalkyl, C 1-4 (alkyl)aryl, benzyl, C 1-6 haloalkyl, C 2-3 (alkyl)OC 1-20 alkyl,

 aryl, and heteroaryl, wherein phenyl and pyridinyl are optionally substituted with zero to three substituents independently selected from the group consisting of (CH 2 ) 0-6 CO 2 R 16 and (CH 2 ) 0-6 CON(R 16 ) 2 ;
R 16 is independently H, C 1-20 alkyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-5 alkyl, or C 1-5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl;

(c) the ester of a D- or L-amino acid

 where R 17 is restricted to those occurring in natural L-amino acids, and R 18 is H, C 1-20 alkyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-5 alkyl, or C 1-5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl;
(d) R 6 and R 7 can come together to form a ring

 where R 19 is H, C 1-20 alkyl, C 1-20 alkenyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-5 alkyl, or C 1-5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl;
(e) R 6 and R 7 can come together to form a ring selected from the group consisting of

where
R 20 is O or NH, and
R 21 is selected from the group consisting of H, C 1-20 alkyl, C 1-20 alkenyl, the carbon chain derived from a fatty acid, and C 1-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-5 alkyl, or C 1-5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl,
Base is selected from the group consisting of:

X 1 is CH, C—(C 1-6 )alkyl, C—(C 2-6 )alkenyl, C—(C 2-6 )alkynyl, C—(C 3-7 )cycloalkyl, C—(C 1-6 ) haloalkyl, C—(C 1-6 )hydroxyalkyl, C—OR 22 , C—N(R 22 ) 2 C-halo, C—CN or N,
R 22 is independently H, (C 1-10 )alkyl, (C 1-10 )haloalkyl or (C 3-7 )cycloalkyl,
R 9 is OH, NH 2 , O(C 1-10 )alkyl, O(C 3-7 )cycloalkyl, NH(C 1-10 )alkyl, N((C 1-10 )alkyl) 2 , NH(C 3-7 )cycloalkyl, NH(CO)(C 1-20 )alkyl, NH(CO)O(C 1-20 )alkyl, NHOH, NHO(CO)(C 1-20 )alkyl, NHO(CO)NH(C 1-20 )alkyl,
R 10 is H, F or CH 3 and
X 2 is H, F, Cl (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, C—(C 3-7 )cycloalkyl, C—(C 1-6 ) haloalkyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, (C 1-6 )hydroxyalkyl, OR 22 , SR 22 , N(R 22 ) 2 , NHC(O)OR 22 , NHC(O)N(R 22 ) 2 , NHC(O)R 22 , CN or NH 2 .

2. The compounds of claim 1 , wherein the compounds can be present in the β-D or β-L configuration.

3. The compounds of claim 1 , having one of the following formulas:

where R 4 and Base are as defined above in claim 1 .

4. A compound of claim 1 , having one of the following formulas:

or pharmaceutical

Assignees

• Cocrystal Pharma Inc
• Univ Emory

Inventors

• Coats Steven J
• Amblard Franck
• Mengshetti Seema
• Li Hao
• Schinazi Raymond F

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07H19/16

  Purine radicals · CPC title

• C07H19/14

  Pyrrolo-pyrimidine radicals · CPC title

• A61K31/7072

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title