2',2'-dihalo nucleoside analogs for treatment of the flaviviridae family of viruses and cancer

Patent metadata

Field	Value
Publication number	US-2017334941-A1
Application number	US-201515522056-A
Country	US
Kind code	A1
Filing date	Oct 30, 2015
Priority date	Oct 31, 2014
Publication date	Nov 23, 2017
Grant date	—

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 Ebola and West Nile virus), RSV, HEV, and influenza infection and cancer in human subjects or other animal hosts.

First claim

1 . A compound of Formula (A)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
X 3 and X 4 are independently selected from the group consisting of Cl, Br, and I,
R 1 is independently H or Me, wherein, when one R 1 is Me, the carbon atom to which it is attached 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 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,
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, S, 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)—C 6-10 -aryl, C(O)NH—C 6-10 -aryl or OR 8 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-O—C 1-20 alkyl, aryl, and heteroaryl, wherein aryl and heteroaryl 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 an 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;

SC is optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, hydroxyalkyl, hydroxybranchedalkyl, amino, heterocyclyl or heteroaryl,
Base is selected from the group consisting of:

X 1 is CH, CF, CCN, C(C 2 )alkynyl or N,
R 9 is OH, NH 2 , O(C 1-10 )alkyl, NH(C 1-10 )alkyl, N((C 1-10 )alkyl) 2 , NH(C 3-6 )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, O—C 1-3 alkyl, N 3 , NH(CO)—C 1-20 alkyl, NH(CO)O—C 1-20 alkyl or NH 2 ,
with the proviso that R 3 is not CN when R 4 is H, the base is

R 9 is NH 2 , X 1 is CH, and X 2 is H,
and pharmaceutically-acceptable salts or prodrugs thereof, wherein the compounds can optionally include a radiolabel at any position.

2 . The compounds of claim 1 , wherein the compounds are in the □-D or □-L configuration.

3 . A compound of claim 1 , wherein the compound is of Formula (A) or Formula (B)

where 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, and
Base is selected from the group consisting of

and pharmaceutically-acceptable salts or prodrugs thereof.

4 . The compounds of claim 3 , wherein the compounds are in the □-D or □-L configuration.

5 . A compound of claim 1 selected from the group consisting of:

Assignees

• Cocrystal Pharma Inc
• Univ Emory

Inventors

• Coats Steven J
• Amblard Franck
• Garnier-Amblard Ethel
• Schinazi Raymond F

Classifications

• A61K38/21

  Interferons {[IFN]} · CPC title

• A61K31/7072

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

• C07H19/20

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

• C07H19/06

  Pyrimidine radicals · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title