U.S. patent application number 15/884052 was filed with the patent office on 2018-06-07 for substituted nucleosides, nucleotides and analogs thereof.
The applicant listed for this patent is Alios BioPharma, Inc.. Invention is credited to Leonid Beigelman, Christian Andreas Jekle, David Bernard Smith, Guangyi Wang.
Application Number | 20180155384 15/884052 |
Document ID | / |
Family ID | 56127561 |
Filed Date | 2018-06-07 |
United States Patent
Application |
20180155384 |
Kind Code |
A1 |
Wang; Guangyi ; et
al. |
June 7, 2018 |
SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
Abstract
Disclosed herein are nucleosides, nucleotides and nucleotide
analogs, methods of synthesizing the same and methods of treating
diseases and/or conditions such as a Picornavirus infection with
one or more nucleosides, nucleotides and nucleotide analogs.
Inventors: |
Wang; Guangyi; (Carlsbad,
CA) ; Smith; David Bernard; (San Mateo, CA) ;
Beigelman; Leonid; (San Mateo, CA) ; Jekle; Christian
Andreas; (San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alios BioPharma, Inc. |
South San Francisco |
CA |
US |
|
|
Family ID: |
56127561 |
Appl. No.: |
15/884052 |
Filed: |
January 30, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14971926 |
Dec 16, 2015 |
9890188 |
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15884052 |
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62094418 |
Dec 19, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07H 19/10 20130101;
A61P 31/14 20180101; C07H 19/06 20130101; A61P 31/16 20180101 |
International
Class: |
C07H 19/06 20060101
C07H019/06; C07H 19/10 20060101 C07H019/10 |
Claims
1. A compound of Formula (I), or a pharmaceutically acceptable salt
thereof, ##STR00140## wherein: B.sup.1A is an optionally
substituted heterocyclic base or an optionally substituted
heterocyclic base with a protected amino group; R.sup.A is hydrogen
or deuterium; R.sup.1A is selected from the group consisting of
hydrogen, an optionally substituted acyl, an optionally substituted
O-linked amino acid, ##STR00141## R.sup.a1 and R.sup.a2 are
independently hydrogen or deuterium; R.sup.2A is an unsubstituted
C.sub.1-4 alkyl, an unsubstituted C.sub.2-4 alkenyl, an
unsubstituted C.sub.2-4 alkynyl, a C.sub.1-6 haloalkyl, a C.sub.1-6
azidoalkyl or a C.sub.1-6 aminoalkyl; R.sup.3A is selected from the
group consisting of hydrogen, deuterium, halo, OH,
--OC(.dbd.O)R'.sup.A and an optionally substituted O-linked amino
acid; R.sup.4A is hydrogen or deuterium; R.sup.5A is hydrogen,
deuterium, halogen, N.sub.3, OH, an optionally substituted
C.sub.1-6 alkyl, an optionally substituted C.sub.2-6 alkenyl and an
optionally substituted C.sub.2-6 alkynyl; R.sup.6A, R.sup.7A and
R.sup.8A are independently selected from the group consisting of
absent, hydrogen, an optionally substituted C.sub.1-24 alkyl, an
optionally substituted C.sub.3-24 alkenyl, an optionally
substituted C.sub.3-24 alkynyl, an optionally substituted C.sub.3-6
cycloalkyl, an optionally substituted C.sub.3-6 cycloalkenyl, an
optionally substituted aryl, an optionally substituted heteroaryl,
an optionally substituted aryl(C.sub.1-6 alkyl), an optionally
substituted *--(CR.sup.15AR.sup.16A).sub.p--O--C.sub.1-24 alkyl, an
optionally substituted
*--(CR.sup.17AR.sup.18A).sub.q--O--C.sub.1-24 alkenyl, ##STR00142##
R.sup.6A is ##STR00143## and R.sup.7A is absent or hydrogen; or
R.sup.6A and R.sup.7A are taken together to form a moiety selected
from the group consisting of an optionally substituted ##STR00144##
and an optionally substituted ##STR00145## wherein the oxygens
connected to R.sup.6A and R.sup.7A, the phosphorus and the moiety
form a six-membered to ten-membered ring system; R.sup.9A is
independently selected from the group consisting of an optionally
substituted C.sub.1-24 alkyl, an optionally substituted C.sub.2-24
alkenyl, an optionally substituted C.sub.2-24 alkynyl, an
optionally substituted C.sub.3-6 cycloalkyl, an optionally
substituted C.sub.3-6 cycloalkenyl, NR.sup.31AR.sup.32A an
optionally substituted N-linked amino acid and an optionally
substituted N-linked amino acid ester derivative; R.sup.10A and
R.sup.11A are independently an optionally substituted N-linked
amino acid or an optionally substituted N-linked amino acid ester
derivative; R.sup.12A and R.sup.13A are independently absent or
hydrogen; R.sup.14A is O--, OH or methyl; each R.sup.15A, each
R.sup.16A, each R.sup.17A and each R.sup.18A are independently
hydrogen, an optionally substituted C.sub.1-24 alkyl or alkoxy;
R.sup.19A, R.sup.20A, R.sup.22A and R.sup.23A are independently
selected from the group consisting of hydrogen, an optionally
substituted C.sub.1-24 alkyl and an optionally substituted aryl;
R.sup.21A and R.sup.24A are independently selected from the group
consisting of hydrogen, an optionally substituted C.sub.1-24 alkyl,
an optionally substituted aryl, an optionally substituted
--O--C.sub.1-24 alkyl, an optionally substituted --O-aryl an
optionally substituted --O-heteroaryl, an optionally substituted
--O-monocyclic heterocyclyl and ##STR00146## R.sup.25A, R.sup.26A
and R.sup.30A are independently selected from the group consisting
of hydrogen, an optionally substituted C.sub.1-24 alkyl and an
optionally substituted aryl; R.sup.27A and R.sup.28A are
independently --C.ident.N or an optionally substituted substituent
selected from the group consisting of C.sub.2-8 organylcarbonyl,
C.sub.2-8 alkoxycarbonyl and C.sub.2-8 organylaminocarbonyl;
R.sup.29A is selected from the group consisting of hydrogen, an
optionally substituted C.sub.1-24 alkyl, an optionally substituted
C.sub.2-24 alkenyl, an optionally substituted C.sub.2-24 alkynyl,
an optionally substituted C.sub.3-6 cycloalkyl and an optionally
substituted C.sub.3-6 cycloalkenyl; R.sup.31A and R.sup.32A are
independently selected from the group consisting of hydrogen, an
optionally substituted C.sub.1-24 alkyl, an optionally substituted
C.sub.2-24 alkenyl, an optionally substituted C.sub.2-24 alkynyl,
an optionally substituted C.sub.3-6 cycloalkyl, an optionally
substituted C.sub.3-6 cycloalkenyl and an optionally substituted
aryl(C.sub.1-4 alkyl); R''.sup.A is an optionally substituted
C.sub.1-24 alkyl; m and t are independently 0 or 1; p and q are
independently selected from the group consisting of 1, 2 and 3; s
is 0, 1, 2 or 3; r and u are independently 1 or 2; y is 3, 4 or 5;
and Z.sup.1A, Z.sup.2A, Z.sup.3A and Z.sup.4A are independently O
or S.
2. A method for ameliorating or treating a picornavirus viral
infection comprising administering to a subject identified as
suffering from the picornavirus viral infection an effective amount
of a compound of claim 1 or a pharmaceutically acceptable salt
thereof.
Description
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
[0001] Any and all applications for which a foreign or domestic
priority claim is identified, for example, in the Application Data
Sheet or Request as filed with the present application, are hereby
incorporated by reference under 37 CFR 1.57, and Rules 4.18 and
20.6.
BACKGROUND
Field
[0002] The present application relates to the fields of chemistry,
biochemistry and medicine. More particularly, disclosed herein are
nucleotide analogs, pharmaceutical compositions that include one or
more nucleosides and/or nucleotide analogs and methods of
synthesizing the same. Also disclosed herein are methods of
treating diseases and/or conditions with a nucleoside and/or a
nucleotide analog, alone or in combination therapy with one or more
other agents.
Description
[0003] Nucleoside analogs are a class of compounds that have been
shown to exert antiviral and anticancer activity both in vitro and
in vivo, and thus, have been the subject of widespread research for
the treatment of viral infections. Nucleoside analogs are usually
therapeutically inactive compounds that are converted by host or
viral enzymes to their respective active anti-metabolites, which,
in turn, may inhibit polymerases involved in viral or cell
proliferation. The activation occurs by a variety of mechanisms,
such as the addition of one or more phosphate groups and, or in
combination with, other metabolic processes.
SUMMARY
[0004] Some embodiments disclosed herein relate to a compound of
Formula (I), or a pharmaceutically acceptable salt thereof.
[0005] Some embodiments disclosed herein relate to a method of
ameliorating and/or treating a picornavirus infection that can
include administering to a subject identified as suffering from the
picornavirus infection an effective amount of one or more compounds
of Formula (I), or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes one or more compounds of
Formula (I), or a pharmaceutically acceptable salt thereof. Other
embodiments described herein relate to using one or more compounds
of Formula (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for ameliorating and/or treating a
picornavirus infection. Still other embodiments described herein
relate to one or more compounds of Formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more compounds of Formula (I), or
a pharmaceutically acceptable salt thereof, that can be used for
ameliorating and/or treating a picornavirus infection.
[0006] Some embodiments disclosed herein relate to a method of
ameliorating and/or treating a picornavirus infection that can
include contacting a cell infected with the picornavirus with an
effective amount of one or more compounds described herein (for
example, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof), or a pharmaceutical composition that
includes one or more compounds described herein, or a
pharmaceutically acceptable salt thereof. Other embodiments
described herein relate to using one or more compounds described
herein (for example, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof) in the manufacture of a
medicament for ameliorating and/or treating a picornavirus
infection that can include contacting a cell infected with the
picornavirus with an effective amount of said compound(s). Still
other embodiments described herein relate to one or more compounds
described herein (for example, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof), or a pharmaceutical
composition that includes one or more compounds described herein,
or a pharmaceutically acceptable salt thereof, that can be used for
ameliorating and/or treating a picornavirus infection by contacting
a cell infected with the picornavirus with an effective amount of
said compound(s).
[0007] Some embodiments disclosed herein relate to a method of
inhibiting replication of a picornavirus that can include
contacting a cell infected with the picornavirus with an effective
amount of one or more compounds described herein (for example, a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof), or a pharmaceutical composition that includes one or more
compounds described herein, or a pharmaceutically acceptable salt
thereof. Other embodiments described herein relate to using one or
more compounds described herein (for example, a compound of Formula
(I), or a pharmaceutically acceptable salt thereof) in the
manufacture of a medicament for inhibiting replication of a
picornavirus that can include contacting a cell infected with the
picornavirus with an effective amount of said compound(s). Still
other embodiments described herein relate to one or more compounds
described herein (for example, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof), or a pharmaceutical
composition that includes one or more compounds described herein,
or a pharmaceutically acceptable salt thereof, that can be used for
inhibiting replication of a picornavirus by contacting a cell
infected with the picornavirus with an effective amount of said
compound(s). In some embodiments, the picornavirus can be selected
from a rhinovirus, hepatitis A virus, a coxasackie virus and an
enterovirus.
DETAILED DESCRIPTION
[0008] The viruses within the Picornaviridae family are
non-enveloped, positive sense, single-stranded, spherical RNA
viruses with an icosahedral capsid. Picornavirus genomes are
approximately 7-8 kilobases long and have an IRES (Internal
Ribosomal Entry Site). These viruses are polyadenylated at the 3'
end, and has a VPg protein at the 5' end in place of a cap. Genera
within the Picornaviridae family include Aphthovirus, Aquamavirus,
Avihepatovirus, Cardiovirus, Cosavirus, Dicipivirus, Enterovirus,
Erbovirus, Hepatovirus, Kobuvirus, Megrivirus, Parechovirus,
Rhinovirus, Salivirus, Sapelovirus, Senecavirus, Teschovirus and
Tremovirus.
[0009] Enteroviruses are transmitted through the fecal-oral route
and/or via aerosols of respiratory droplets, and are highly
communicable. The genus of Enterovirus includes several species,
including: enterovirus A, enterovirus B, enterovirus C, enterovirus
D, enterovirus E, enterovirus F, enterovirus G, enterovirus
Henterovirus J, rhinovirus A, rhinovirus B and rhinovirus C. Within
a species of the aforementioned enteroviruses are the following
serotypes: polioviruses, rhinoviruses, coxsackieviruses,
echoviruses and enterovirus.
[0010] Rhinoviruses are the cause of the common cold. Rhinoviruses
are named because of their transmission through the respiratory
route and replication in the nose. A person can be infected with
numerous rhinoviruses over their lifetime because immunity develops
for each serotype. Thus, each serotype can cause a new
infection.
[0011] A hepatitis A infection is the result of an infection with a
Hepatitis A virus. Hepatovirus is transmitted through the
fecal-oral route. Transmission can occur via person-to-person by
ingestion of contaminated food or water, or through direct contact
with an infectious person.
[0012] Parechovirus include human parechovirus 1 (echovirus 22),
human parechovirus 2 (echovirus 23), human parechovirus 3, human
parechovirus 4, human parechovirus 5 and human parechovirus 6.
Definitions
[0013] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art. All patents, applications, published
applications and other publications referenced herein are
incorporated by reference in their entirety unless stated
otherwise. In the event that there are a plurality of definitions
for a term herein, those in this section prevail unless stated
otherwise.
[0014] As used herein, any "R" group(s) such as, without
limitation, R.sup.1A, R.sup.2A, R.sup.3A, R.sup.4A, R.sup.5A,
R.sup.6A, R.sup.7A, R.sup.8A, R.sup.9A, R.sup.10A, R.sup.11A,
R.sup.12A, R.sup.13A, R.sup.14A, R.sup.15A, R.sup.16A, R.sup.17A,
R.sup.18A, R.sup.19A, R.sup.20A, R.sup.21A, R.sup.22A, R.sup.23A,
R.sup.24A, R.sup.25A, R.sup.26A, R.sup.27A, R.sup.28A, R.sup.29A,
R.sup.30A, R.sup.31A, R.sup.32A, R.sup.33A, R.sup.34A, R.sup.35A,
R.sup.36A, R.sup.37A and R.sup.38A represent substituents that can
be attached to the indicated atom. An R group may be substituted or
unsubstituted. If two "R" groups are described as being "taken
together" the R groups and the atoms they are attached to can form
a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For
example, without limitation, if R.sup.a and R.sup.b of an
NR.sup.aR.sup.b group are indicated to be "taken together," it
means that they are covalently bonded to one another to form a
ring:
##STR00001##
In addition, if two "R" groups are described as being "taken
together" with the atom(s) to which they are attached to form a
ring as an alternative, the R groups are not limited to the
variables or substituents defined previously.
[0015] Whenever a group is described as being "optionally
substituted" that group may be unsubstituted or substituted with
one or more of the indicated substituents. Likewise, when a group
is described as being "unsubstituted or substituted" if
substituted, the substituent(s) may be selected from one or more of
the indicated substituents. If no substituents are indicated, it is
meant that the indicated "optionally substituted" or "substituted"
group may be substituted with one or more group(s) individually and
independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),
heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl,
cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,
N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,
isothiocyanato, azido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl,
haloalkyl, haloalkoxy, trihalomethanesulfonyl,
trihalomethanesulfonamido, an amino, a mono-substituted amino group
and a di-substituted amino group.
[0016] As used herein, "C.sub.a to C.sub.b" in which "a" and "b"
are integers refer to the number of carbon atoms in an alkyl,
alkenyl or alkynyl group, or the number of carbon atoms in the ring
of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heteroalicyclyl
group. That is, the alkyl, alkenyl, alkynyl, ring(s) of the
cycloalkyl, ring(s) of the cycloalkenyl, ring(s) of the aryl,
ring(s) of the heteroaryl or ring(s) of the heterocyclyl can
contain from "a" to "b", inclusive, carbon atoms. Thus, for
example, a "C.sub.1 to C.sub.4 alkyl" group refers to all alkyl
groups having from 1 to 4 carbons, that is, CH.sub.3--,
CH.sub.3CH.sub.2--, CH.sub.3CH.sub.2CH.sub.2--,
(CH.sub.3).sub.2CH--, CH.sub.3CH.sub.2CH.sub.2CH.sub.2--,
CH.sub.3CH.sub.2CH(CH.sub.3)-- and (CH.sub.3).sub.3C--. If no "a"
and "b" are designated with regard to an alkyl, alkenyl, alkynyl,
cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group,
the broadest range described in these definitions is to be
assumed.
[0017] As used herein, "alkyl" refers to a straight or branched
hydrocarbon chain that comprises a fully saturated (no double or
triple bonds) hydrocarbon group. The alkyl group may have 1 to 20
carbon atoms (whenever it appears herein, a numerical range such as
"1 to 20" refers to each integer in the given range; e.g., "1 to 20
carbon atoms" means that the alkyl group may consist of 1 carbon
atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20
carbon atoms, although the present definition also covers the
occurrence of the term "alkyl" where no numerical range is
designated). The alkyl group may also be a medium size alkyl having
1 to 10 carbon atoms. The alkyl group could also be a lower alkyl
having 1 to 6 carbon atoms. The alkyl group of the compounds may be
designated as "C.sub.1-C.sub.4 alkyl" or similar designations. By
way of example only, "C.sub.1-C.sub.4 alkyl" indicates that there
are one to four carbon atoms in the alkyl chain, i.e., the alkyl
chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include,
but are in no way limited to, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group
may be substituted or unsubstituted.
[0018] As used herein, "alkenyl" refers to an alkyl group that
contains in the straight or branched hydrocarbon chain one or more
double bonds. Examples of alkenyl groups include allenyl,
vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or
substituted.
[0019] As used herein, "alkynyl" refers to an alkyl group that
contains in the straight or branched hydrocarbon chain one or more
triple bonds. Examples of alkynyls include ethynyl and propynyl. An
alkynyl group may be unsubstituted or substituted.
[0020] As used herein, "cycloalkyl" refers to a completely
saturated (no double or triple bonds) mono- or multi-cyclic
hydrocarbon ring system. When composed of two or more rings, the
rings may be joined together in a fused fashion. Cycloalkyl groups
can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the
ring(s). A cycloalkyl group may be unsubstituted or substituted.
Typical cycloalkyl groups include, but are in no way limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl.
[0021] As used herein, "cycloalkenyl" refers to a mono- or
multi-cyclic hydrocarbon ring system that contains one or more
double bonds in at least one ring; although, if there is more than
one, the double bonds cannot form a fully delocalized pi-electron
system throughout all the rings (otherwise the group would be
"aryl," as defined herein). When composed of two or more rings, the
rings may be connected together in a fused fashion. A cycloalkenyl
can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the
ring(s). A cycloalkenyl group may be unsubstituted or
substituted.
[0022] As used herein, "aryl" refers to a carbocyclic (all carbon)
monocyclic or multicyclic aromatic ring system (including fused
ring systems where two carbocyclic rings share a chemical bond)
that has a fully delocalized pi-electron system throughout all the
rings. The number of carbon atoms in an aryl group can vary. For
example, the aryl group can be a C.sub.6-C.sub.14 aryl group, a
C.sub.6-C.sub.10 aryl group, or a C.sub.6 aryl group. Examples of
aryl groups include, but are not limited to, benzene, naphthalene
and azulene. An aryl group may be substituted or unsubstituted.
[0023] As used herein, "heteroaryl" refers to a monocyclic or
multicyclic aromatic ring system (a ring system with fully
delocalized pi-electron system) that contain(s) one or more
heteroatoms (for example, 1 to 5 heteroatoms), that is, an element
other than carbon, including but not limited to, nitrogen, oxygen
and sulfur. The number of atoms in the ring(s) of a heteroaryl
group can vary. For example, the heteroaryl group can contain 4 to
14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6
atoms in the ring(s). Furthermore, the term "heteroaryl" includes
fused ring systems where two rings, such as at least one aryl ring
and at least one heteroaryl ring, or at least two heteroaryl rings,
share at least one chemical bond. Examples of heteroaryl rings
include, but are not limited to, furan, furazan, thiophene,
benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole,
1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole,
1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole,
indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,
isothiazole, triazole, benzotriazole, thiadiazole, tetrazole,
pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine,
quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and
triazine. A heteroaryl group may be substituted or
unsubstituted.
[0024] As used herein, "heterocyclyl" or "heteroalicyclyl" refers
to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to
18-membered monocyclic, bicyclic, and tricyclic ring system wherein
carbon atoms together with from 1 to 5 heteroatoms constitute said
ring system. A heterocycle may optionally contain one or more
unsaturated bonds situated in such a way, however, that a fully
delocalized pi-electron system does not occur throughout all the
rings. The heteroatom(s) is an element other than carbon including,
but not limited to, oxygen, sulfur, and nitrogen. A heterocycle may
further contain one or more carbonyl or thiocarbonyl
functionalities, so as to make the definition include oxo-systems
and thio-systems such as lactams, lactones, cyclic imides, cyclic
thioimides and cyclic carbamates. When composed of two or more
rings, the rings may be joined together in a fused fashion.
Additionally, any nitrogens in a heterocyclyl or a heteroalicyclyl
may be quaternized. Heterocyclyl or heteroalicyclic groups may be
unsubstituted or substituted. Examples of such "heterocyclyl" or
"heteroalicyclyl" groups include but are not limited to,
1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane,
1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane,
1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane,
tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,
barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,
dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline,
imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine,
oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane,
piperidine N-Oxide, piperidine, piperazine, pyrrolidine,
pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine,
2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran,
thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone
and their benzo-fused analogs (e.g., benzimidazolidinone,
tetrahydroquinoline and 3,4-methylenedioxyphenyl).
[0025] As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl
group connected, as a substituent, via a lower alkylene group. The
lower alkylene and aryl group of an aralkyl may be substituted or
unsubstituted. Examples include but are not limited to benzyl,
2-phenyl(alkyl), 3-phenyl(alkyl) and naphthyl(alkyl).
[0026] As used herein, "heteroaralkyl" and "heteroaryl(alkyl)"
refer to a heteroaryl group connected, as a substituent, via a
lower alkylene group. The lower alkylene and heteroaryl group of
heteroaralkyl may be substituted or unsubstituted. Examples include
but are not limited to 2-thienyl(alkyl), 3-thienyl(alkyl),
furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl),
isoxazolyl(alkyl), imidazolyl(alkyl) and their benzo-fused
analogs.
[0027] A "heteroalicyclyl(alkyl)" and "heterocyclyl(alkyl)" refer
to a heterocyclic or a heteroalicyclylic group connected, as a
substituent, via a lower alkylene group. The lower alkylene and
heterocyclyl of a heteroalicyclyl(alkyl) may be substituted or
unsubstituted. Examples include but are not limited
tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl),
piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and
1,3-thiazinan-4-yl(methyl).
[0028] "Lower alkylene groups" are straight-chained --CH.sub.2--
tethering groups, forming bonds to connect molecular fragments via
their terminal carbon atoms. Examples include but are not limited
to methylene (--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--),
propylene (--CH.sub.2CH.sub.2CH.sub.2--), and butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--). A lower alkylene group can
be substituted by replacing one or more hydrogen of the lower
alkylene group with a substituent(s) listed under the definition of
"substituted."
[0029] As used herein, "alkoxy" refers to the formula --OR wherein
R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a
cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),
heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A
non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy,
1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy,
tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or
unsubstituted.
[0030] As used herein, "acyl" refers to a hydrogen, an alkyl, an
alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,
heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or
heterocyclyl(alkyl) connected, as substituents, via a carbonyl
group. Examples include formyl, acetyl, propanoyl, benzoyl and
acryl. An acyl may be substituted or unsubstituted.
[0031] As used herein, "hydroxyalkyl" refers to an alkyl group in
which one or more of the hydrogen atoms are replaced by a hydroxy
group. Exemplary hydroxyalkyl groups include but are not limited
to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and
2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or
unsubstituted.
[0032] As used herein, "haloalkyl" refers to an alkyl group in
which one or more of the hydrogen atoms are replaced by a halogen
(e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups
include but are not limited to, chloromethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and
2-fluoroisobutyl. A haloalkyl may be substituted or
unsubstituted.
[0033] As used herein, "haloalkoxy" refers to an alkoxy group in
which one or more of the hydrogen atoms are replaced by a halogen
(e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such
groups include but are not limited to, chloromethoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy,
1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be
substituted or unsubstituted.
[0034] A "sulfenyl" group refers to an "--SR" group in which R can
be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or
heterocyclyl(alkyl). A sulfenyl may be substituted or
unsubstituted.
[0035] A "sulfinyl" group refers to an "--S(.dbd.O)--R" group in
which R can be the same as defined with respect to sulfenyl. A
sulfinyl may be substituted or unsubstituted.
[0036] A "sulfonyl" group refers to an "SO.sub.2R" group in which R
can be the same as defined with respect to sulfenyl. A sulfonyl may
be substituted or unsubstituted.
[0037] An "O-carboxy" group refers to a "RC(.dbd.O)O--" group in
which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),
heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An
O-carboxy may be substituted or unsubstituted.
[0038] The terms "ester" and "C-carboxy" refer to a "--C(.dbd.O)OR"
group in which R can be the same as defined with respect to
O-carboxy. An ester and C-carboxy may be substituted or
unsubstituted.
[0039] A "thiocarbonyl" group refers to a "--C(.dbd.S)R" group in
which R can be the same as defined with respect to O-carboxy. A
thiocarbonyl may be substituted or unsubstituted.
[0040] A "trihalomethanesulfonyl" group refers to an
"X.sub.3CSO.sub.2--" group wherein each X is a halogen.
[0041] A "trihalomethanesulfonamido" group refers to an
"X.sub.3CS(O).sub.2N(R.sub.A)--" group wherein each X is a halogen,
and R.sub.A hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),
heteroaryl(alkyl) or heterocyclyl(alkyl).
[0042] The term "amino" as used herein refers to a --NH.sub.2
group.
[0043] As used herein, the term "hydroxy" refers to a --OH
group.
[0044] A "cyano" group refers to a "--CN" group.
[0045] The term "azido" as used herein refers to a --N.sub.3
group.
[0046] An "isocyanato" group refers to a "--NCO" group.
[0047] A "thiocyanato" group refers to a "--CNS" group.
[0048] An "isothiocyanato" group refers to an "--NCS" group.
[0049] A "carbonyl" group refers to a C.dbd.O group.
[0050] An "S-sulfonamido" group refers to a
"--SO.sub.2N(R.sub.AR.sub.B)" group in which R.sub.A and R.sub.B
can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),
heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be
substituted or unsubstituted.
[0051] An "N-sulfonamido" group refers to a "RSO.sub.2N(R.sub.A)--"
group in which R and R.sub.A can be independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,
heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or
heterocyclyl(alkyl). An N-sulfonamido may be substituted or
unsubstituted.
[0052] An "O-carbamyl" group refers to a
"--OC(.dbd.O)N(R.sub.AR.sub.B)" group in which R.sub.A and R.sub.B
can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),
heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be
substituted or unsubstituted.
[0053] An "N-carbamyl" group refers to an "ROC(.dbd.O)N(R.sub.A)--"
group in which R and R.sub.A can be independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,
heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or
heterocyclyl(alkyl). An N-carbamyl may be substituted or
unsubstituted.
[0054] An "O-thiocarbamyl" group refers to a
"--OC(.dbd.S)--N(R.sub.AR.sub.B)" group in which R.sub.A and
R.sub.B can be independently hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl,
aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An
O-thiocarbamyl may be substituted or unsubstituted.
[0055] An "N-thiocarbamyl" group refers to an
"ROC(.dbd.S)N(R.sub.A)--" group in which R and R.sub.A can be
independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),
heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be
substituted or unsubstituted.
[0056] A "C-amido" group refers to a "--C(.dbd.O)N(R.sub.AR.sub.B)"
group in which R.sub.A and R.sub.B can be independently hydrogen,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or
heterocyclyl(alkyl). A C-amido may be substituted or
unsubstituted.
[0057] An "N-amido" group refers to a "RC(.dbd.O)N(R.sub.A)--"
group in which R and R.sub.A can be independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,
heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or
heterocyclyl(alkyl). An N-amido may be substituted or
unsubstituted.
[0058] The term "halogen atom" or "halogen" as used herein, means
any one of the radio-stable atoms of column 7 of the Periodic Table
of the Elements, such as, fluorine, chlorine, bromine and
iodine.
[0059] Where the numbers of substituents is not specified (e.g.
haloalkyl), there may be one or more substituents present. For
example "haloalkyl" may include one or more of the same or
different halogens. As another example, "C.sub.1-C.sub.3
alkoxyphenyl" may include one or more of the same or different
alkoxy groups containing one, two or three atoms.
[0060] As used herein, the abbreviations for any protective groups,
amino acids and other compounds, are, unless indicated otherwise,
in accord with their common usage, recognized abbreviations, or the
IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem.
11:942-944 (1972)).
[0061] The term "nucleoside" is used herein in its ordinary sense
as understood by those skilled in the art, and refers to a compound
composed of an optionally substituted pentose moiety or modified
pentose moiety attached to a heterocyclic base or tautomer thereof
via a N-glycosidic bond, such as attached via the 9-position of a
purine-base or the 1-position of a pyrimidine-base. Examples
include, but are not limited to, a ribonucleoside comprising a
ribose moiety and a deoxyribonucleoside comprising a deoxyribose
moiety. A modified pentose moiety is a pentose moiety in which an
oxygen atom has been replaced with a carbon and/or a carbon has
been replaced with a sulfur or an oxygen atom. A "nucleoside" is a
monomer that can have a substituted base and/or sugar moiety.
Additionally, a nucleoside can be incorporated into larger DNA
and/or RNA polymers and oligomers. In some instances, the
nucleoside can be a nucleoside analog drug.
[0062] The term "nucleotide" is used herein in its ordinary sense
as understood by those skilled in the art, and refers to a
nucleoside having a phosphate ester bound to the pentose moiety,
for example, at the 5'-position.
[0063] As used herein, the term "heterocyclic base" refers to an
optionally substituted nitrogen-containing heterocyclyl that can be
attached to an optionally substituted pentose moiety or modified
pentose moiety. In some embodiments, the heterocyclic base can be
selected from an optionally substituted purine-base, an optionally
substituted pyrimidine-base and an optionally substituted
triazole-base (for example, a 1,2,4-triazole). The term
"purine-base" is used herein in its ordinary sense as understood by
those skilled in the art, and includes its tautomers. Similarly,
the term "pyrimidine-base" is used herein in its ordinary sense as
understood by those skilled in the art, and includes its tautomers.
A non-limiting list of optionally substituted purine-bases includes
purine, adenine, guanine, hypoxanthine, xanthine, alloxanthine,
7-alkylguanine (e.g. 7-methylguanine), theobromine, caffeine, uric
acid and isoguanine. Examples of pyrimidine-bases include, but are
not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil and
5-alkylcytosine (e.g., 5-methylcytosine). An example of an
optionally substituted triazole-base is
1,2,4-triazole-3-carboxamide. Other non-limiting examples of
heterocyclic bases include diaminopurine,
8-oxo-N.sup.6-alkyladenine (e.g., 8-oxo-N.sup.6-methyladenine),
7-deazaxanthine, 7-deazaguanine, 7-deazaadenine,
N.sup.4,N.sup.4-ethanocytosin,
N.sup.6,N.sup.6-ethano-2,6-diaminopurine, 5-halouracil (e.g.,
5-fluorouracil and 5-bromouracil), pseudoisocytosine, isocytosine,
isoguanine, and other heterocyclic bases described in U.S. Pat.
Nos. 5,432,272 and 7,125,855, which are incorporated herein by
reference for the limited purpose of disclosing additional
heterocyclic bases. In some embodiments, a heterocyclic base can be
optionally substituted with an amine or an enol protecting
group(s).
[0064] The term "--N-linked amino acid" refers to an amino acid
that is attached to the indicated moiety via a main-chain amino or
mono-substituted amino group. When the amino acid is attached in an
--N-linked amino acid, one of the hydrogens that is part of the
main-chain amino or mono-substituted amino group is not present and
the amino acid is attached via the nitrogen. N-linked amino acids
can be substituted or unsubstituted.
[0065] The term "--N-linked amino acid ester derivative" refers to
an amino acid in which a main-chain carboxylic acid group has been
converted to an ester group. In some embodiments, the ester group
has a formula selected from alkyl-O--C(.dbd.O)--,
cycloalkyl-O--C(.dbd.O)--, aryl-O--C(.dbd.O)-- and
aryl(alkyl)-O--C(.dbd.O)--. A non-limiting list of ester groups
include substituted and unsubstituted versions of the following:
methyl-O--C(.dbd.O)--, ethyl-O--C(.dbd.O)--,
n-propyl-O--C(.dbd.O)--, isopropyl-O--C(.dbd.O)--,
n-butyl-O--C(.dbd.O)--, isobutyl-O--C(.dbd.O)--,
tert-butyl-O--C(.dbd.O)--, neopentyl-O--C(.dbd.O)--,
cyclopropyl-O--C(.dbd.O)--, cyclobutyl-O--C(.dbd.O)--,
cyclopentyl-O--C(.dbd.O)--, cyclohexyl-O--C(.dbd.O)--,
phenyl-O--C(.dbd.O)--, benzyl-O--C(.dbd.O)--, and
naphthyl-O--C(.dbd.O)--. N-linked amino acid ester derivatives can
be substituted or unsubstituted.
[0066] The term "--O-linked amino acid" refers to an amino acid
that is attached to the indicated moiety via the hydroxy from its
main-chain carboxylic acid group. When the amino acid is attached
in an --O-linked amino acid, the hydrogen that is part of the
hydroxy from its main-chain carboxylic acid group is not present
and the amino acid is attached via the oxygen. O-linked amino acids
can be substituted or unsubstituted.
[0067] As used herein, the term "amino acid" refers to any amino
acid (both standard and non-standard amino acids), including, but
not limited to, .alpha.-amino acids, .beta.-amino acids,
.gamma.-amino acids and .delta.-amino acids. Examples of suitable
amino acids include, but are not limited to, alanine, asparagine,
aspartate, cysteine, glutamate, glutamine, glycine, proline,
serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, threonine, tryptophan and valine.
Additional examples of suitable amino acids include, but are not
limited to, ornithine, hypusine, 2-aminoisobutyric acid,
dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine,
alpha-ethyl-glycine, alpha-propyl-glycine and norleucine.
[0068] The term "interferon" is used herein as is commonly
understood by one of ordinary skill in the art. Several types of
interferons are known to those skilled in the art, such as Type I
interferons, Type 2 interferons and Type 3 interferons. A
non-limiting list of examples include: alpha-interferons,
beta-interferons, delta-interferons, gamma interferons, lambda
interferons, omega-interferons, tau-interferons, x-interferons,
consensus interferons and asialo-interferons. Interferons can be
pegylated. Examples of type 1 interferons include interferon alpha
1A, interferon alpha 1B, interferon alpha 2A, interferon alpha 2B,
pegylated-interferon alpha 2a (PEGASYS, Roche), recombinant
interferon alpha 2a (ROFERON, Roche), inhaled interferon alpha 2b
(AERX, Aradigm), pegylated-interferon alpha 2b (ALBUFERON, Human
Genome Sciences/Novartis, PEGINTRON, Schering), recombinant
interferon alpha 2b (INTRON A, Schering), pegylated interferon
alpha 2b (PEG-INTRON, Schering, VIRAFERONPEG, Schering), interferon
beta-1a (REBIF, Serono, Inc. and Pfizer), consensus interferon
alpha (INFERGEN, Valeant Pharmaceutical). Examples of type 2
interferons include interferon gamma 1, interferon gamma 2 and
pegylated interferon gamma; and examples of type 3 interferons
include interferon lambda 1, interferon lambda 2 and interferon
lambda 3.
[0069] The terms "phosphorothioate" and "phosphothioate" refer to a
compound of the general formula
##STR00002##
its protonated forms (for example,
##STR00003##
and its tautomers (such as
##STR00004##
[0070] As used herein, the term "phosphate" is used in its ordinary
sense as understood by those skilled in the art, and includes its
protonated forms (for example,
##STR00005##
As used herein, the terms "monophosphate," "diphosphate," and
"triphosphate" are used in their ordinary sense as understood by
those skilled in the art, and include protonated forms.
[0071] The terms "protecting group" and "protecting groups" as used
herein refer to any atom or group of atoms that is added to a
molecule in order to prevent existing groups in the molecule from
undergoing unwanted chemical reactions. Examples of protecting
group moieties are described in T. W. Greene and P. G. M. Wuts,
Protective Groups in Organic Synthesis, 3. Ed. John Wiley &
Sons, 1999, and in J. F. W. McOmie, Protective Groups in Organic
Chemistry Plenum Press, 1973, both of which are hereby incorporated
by reference for the limited purpose of disclosing suitable
protecting groups. The protecting group moiety may be chosen in
such a way, that they are stable to certain reaction conditions and
readily removed at a convenient stage using methodology known from
the art. A non-limiting list of protecting groups include benzyl;
substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g.,
t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls
and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted
methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a
substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g.,
trimethylsilyl, triethylsilyl, triisopropylsilyl,
t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl,
[2-(trimethylsilyl)ethoxy]methyl or t-butyldiphenylsilyl); esters
(e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate);
sulfonates (e.g. tosylate or mesylate); acyclic ketal (e.g.
dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1,3-dioxolanes,
and those described herein); acyclic acetal; cyclic acetal (e.g.,
those described herein); acyclic hemiacetal; cyclic hemiacetal;
cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane);
orthoesters (e.g., those described herein) and triarylmethyl groups
(e.g., trityl; monomethoxytrityl (MMTr); 4,4'-dimethoxytrityl
(DMTr); 4,4',4''-trimethoxytrityl (TMTr); and those described
herein).
[0072] The term "pharmaceutically acceptable salt" refers to a salt
of a compound that does not cause significant irritation to an
organism to which it is administered and does not abrogate the
biological activity and properties of the compound. In some
embodiments, the salt is an acid addition salt of the compound.
Pharmaceutical salts can be obtained by reacting a compound with
inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or
hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
Pharmaceutical salts can also be obtained by reacting a compound
with an organic acid such as aliphatic or aromatic carboxylic or
sulfonic acids, for example formic, acetic, succinic, lactic,
malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic,
ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic
acid. Pharmaceutical salts can also be obtained by reacting a
compound with a base to form a salt such as an ammonium salt, an
alkali metal salt, such as a sodium or a potassium salt, an
alkaline earth metal salt, such as a calcium or a magnesium salt, a
salt of organic bases such as dicyclohexylamine,
N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,
C.sub.1-C.sub.7 alkylamine, cyclohexylamine, triethanolamine,
ethylenediamine, and salts with amino acids such as arginine and
lysine.
[0073] Terms and phrases used in this application, and variations
thereof, especially in the appended claims, unless otherwise
expressly stated, should be construed as open ended as opposed to
limiting. As examples of the foregoing, the term `including` should
be read to mean `including, without limitation,` `including but not
limited to,` or the like; the term `comprising` as used herein is
synonymous with `including,` `containing,` or `characterized by,`
and is inclusive or open-ended and does not exclude additional,
unrecited elements or method steps; the term `having` should be
interpreted as `having at least;` the term `includes` should be
interpreted as `includes but is not limited to;` the term `example`
is used to provide exemplary instances of the item in discussion,
not an exhaustive or limiting list thereof; and use of terms like
`preferably,` `preferred,` `desired,` or `desirable,` and words of
similar meaning should not be understood as implying that certain
features are critical, essential, or even important to the
structure or function, but instead as merely intended to highlight
alternative or additional features that may or may not be utilized
in a particular embodiment. In addition, the term "comprising" is
to be interpreted synonymously with the phrases "having at least"
or "including at least". When used in the context of a process, the
term "comprising" means that the process includes at least the
recited steps, but may include additional steps. When used in the
context of a compound, composition or device, the term "comprising"
means that the compound, composition or device includes at least
the recited features or components, but may also include additional
features or components. Likewise, a group of items linked with the
conjunction `and` should not be read as requiring that each and
every one of those items be present in the grouping, but rather
should be read as `and/or` unless expressly stated otherwise.
Similarly, a group of items linked with the conjunction `or` should
not be read as requiring mutual exclusivity among that group, but
rather should be read as `and/or` unless expressly stated
otherwise.
[0074] With respect to the use of substantially any plural and/or
singular terms herein, those having skill in the art can translate
from the plural to the singular and/or from the singular to the
plural as is appropriate to the context and/or application. The
various singular/plural permutations may be expressly set forth
herein for sake of clarity. The indefinite article "a" or "an" does
not exclude a plurality. A single processor or other unit may
fulfill the functions of several items recited in the claims. The
mere fact that certain measures are recited in mutually different
dependent claims does not indicate that a combination of these
measures cannot be used to advantage. Any reference signs in the
claims should not be construed as limiting the scope.
[0075] It is understood that, in any compound described herein
having one or more chiral centers, if an absolute stereochemistry
is not expressly indicated, then each center may independently be
of R-configuration or S-configuration or a mixture thereof. Thus,
the compounds provided herein may be enantiomerically pure,
enantiomerically enriched, racemic mixture, diastereomerically
pure, diastereomerically enriched, or a stereoisomeric mixture. In
addition it is understood that, in any compound described herein
having one or more double bond(s) generating geometrical isomers
that can be defined as E or Z, each double bond may independently
be E or Z a mixture thereof.
[0076] Likewise, it is understood that, in any compound described,
all tautomeric forms are also intended to be included. For example
all tautomers of a phosphate and a phosphorothioate groups are
intended to be included. Examples of tautomers of a
phosphorothioate include the following:
##STR00006##
Furthermore, all tautomers of heterocyclic bases known in the art
are intended to be included, including tautomers of natural and
non-natural purine-bases and pyrimidine-bases.
[0077] It is to be understood that where compounds disclosed herein
have unfilled valencies, then the valencies are to be filled with
hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and
hydrogen-2 (deuterium).
[0078] It is understood that the compounds described herein can be
labeled isotopically. Substitution with isotopes such as deuterium
may afford certain therapeutic advantages resulting from greater
metabolic stability, such as, for example, increased in vivo
half-life or reduced dosage requirements. Each chemical element as
represented in a compound structure may include any isotope of said
element. For example, in a compound structure a hydrogen atom may
be explicitly disclosed or understood to be present in the
compound. At any position of the compound that a hydrogen atom may
be present, the hydrogen atom can be any isotope of hydrogen,
including but not limited to hydrogen-1 (protium) and hydrogen-2
(deuterium). Thus, reference herein to a compound encompasses all
potential isotopic forms unless the context clearly dictates
otherwise.
[0079] It is understood that the methods and combinations described
herein include crystalline forms (also known as polymorphs, which
include the different crystal packing arrangements of the same
elemental composition of a compound), amorphous phases, salts,
solvates, and hydrates. In some embodiments, the compounds
described herein exist in solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, or the like. In other
embodiments, the compounds described herein exist in unsolvated
form. Solvates contain either stoichiometric or non-stoichiometric
amounts of a solvent, and may be formed during the process of
crystallization with pharmaceutically acceptable solvents such as
water, ethanol, or the like. Hydrates are formed when the solvent
is water, or alcoholates are formed when the solvent is alcohol. In
addition, the compounds provided herein can exist in unsolvated as
well as solvated forms. In general, the solvated forms are
considered equivalent to the unsolvated forms for the purposes of
the compounds and methods provided herein.
[0080] Where a range of values is provided, it is understood that
the upper and lower limit, and each intervening value between the
upper and lower limit of the range is encompassed within the
embodiments.
Compounds
[0081] Some embodiments disclosed herein relate to a compound of
Formula (I), or a pharmaceutically acceptable salt thereof:
##STR00007##
wherein: B.sup.1A can be an optionally substituted heterocyclic
base or an optionally substituted heterocyclic base with a
protected amino group; R.sup.A can be hydrogen or deuterium;
R.sup.1A can be selected from hydrogen, an optionally substituted
acyl, an optionally substituted O-linked amino acid,
##STR00008##
R.sup.a1 and R.sup.a2 can be independently hydrogen or deuterium;
R.sup.2A can be an unsubstituted C.sub.1-4 alkyl, an unsubstituted
C.sub.2-4 alkenyl, an unsubstituted C.sub.2-4 alkynyl, a C.sub.1-6
haloalkyl, a C.sub.1-6 azidoalkyl or a C.sub.1-6 aminoalkyl;
R.sup.3A can be selected from hydrogen, deuterium, halo, OH,
--OC(.dbd.O)R''.sup.A and an optionally substituted O-linked amino
acid; R.sup.4A can be hydrogen or deuterium; R.sup.5A can be
hydrogen, deuterium, halogen, N.sub.3, OH, an optionally
substituted C.sub.1-6 alkyl, an optionally substituted C.sub.2-6
alkenyl and an optionally substituted C.sub.2-6 alkynyl; R.sup.6A,
R.sup.7A and R.sup.8A can be independently selected from absent,
hydrogen, an optionally substituted C.sub.1-24 alkyl, an optionally
substituted C.sub.3-24 alkenyl, an optionally substituted
C.sub.3-24 alkynyl, an optionally substituted C.sub.3-6 cycloalkyl,
an optionally substituted C.sub.3-6 cycloalkenyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aryl(C.sub.1-6 alkyl), an optionally
substituted *--(CR.sup.15AR.sup.16A).sub.p--O--C.sub.1-24 alkyl, an
optionally substituted
*--(CR.sup.17AR.sup.18A).sub.q--O--C.sub.1-24 alkenyl,
##STR00009##
or R.sup.6A can be
##STR00010##
[0082] and R.sup.7A can be absent or hydrogen; or R.sup.6A and
R.sup.7A can be taken together to form a moiety selected from the
group consisting of an optionally substituted
##STR00011##
and an optionally substituted
##STR00012##
wherein the oxygens connected to R.sup.6A and R.sup.7A, the
phosphorus and the moiety form a six-membered to ten-membered ring
system. R.sup.9A can be independently selected from an optionally
substituted C.sub.1-24 alkyl, an optionally substituted C.sub.2-24
alkenyl, an optionally substituted C.sub.2-24 alkynyl, an
optionally substituted C.sub.3-6 cycloalkyl, an optionally
substituted C.sub.3-6 cycloalkenyl, NR.sup.31AR.sup.32A an
optionally substituted N-linked amino acid and an optionally
substituted N-linked amino acid ester derivative; R.sup.10A and
R.sup.11A can be independently an optionally substituted N-linked
amino acid or an optionally substituted N-linked amino acid ester
derivative; R.sup.12A and R.sup.13A can be independently absent or
hydrogen; R.sup.14A can be O--, OH or methyl; each R.sup.15A, each
R.sup.16A, each R.sup.17A and each R.sup.18A can be independently
hydrogen, an optionally substituted C.sub.1-24 alkyl or alkoxy;
R.sup.19A, R.sup.20A, R.sup.22A and R.sup.23A can be independently
selected from hydrogen, an optionally substituted C.sub.1-24 alkyl
and an optionally substituted aryl; R.sup.21A and R.sup.24A can be
independently selected from hydrogen, an optionally substituted
C.sub.1-24 alkyl, an optionally substituted aryl, an optionally
substituted --O--C.sub.1-24 alkyl, an optionally substituted
--O-aryl an optionally substituted --O-heteroaryl, an optionally
substituted --O-monocyclic heterocyclyl and
##STR00013##
R.sup.25A, R.sup.26A and R.sup.30A can be independently selected
from hydrogen, an optionally substituted C.sub.1-24 alkyl and an
optionally substituted aryl; R.sup.27A and R.sup.28A can be
independently --C.ident.N or an optionally substituted substituent
selected from the group consisting of C.sub.2-8 organylcarbonyl,
C.sub.2-8 alkoxycarbonyl and C.sub.2-8 organylaminocarbonyl;
R.sup.29A can be selected from hydrogen, an optionally substituted
C.sub.1-24 alkyl, an optionally substituted C.sub.2-24 alkenyl, an
optionally substituted C.sub.2-24 alkynyl, an optionally
substituted C.sub.3-6 cycloalkyl and an optionally substituted
C.sub.3-6 cycloalkenyl; R.sup.31A and R.sup.32A can be
independently selected from hydrogen, an optionally substituted
C.sub.1-24 alkyl, an optionally substituted C.sub.2-24 alkenyl, an
optionally substituted C.sub.2-24 alkynyl, an optionally
substituted C.sub.3-6 cycloalkyl, an optionally substituted
C.sub.3-6 cycloalkenyl and an optionally substituted aryl(C.sub.1-4
alkyl); R'.sup.A can be an optionally substituted C.sub.1-24 alkyl;
m and t can be independently 0 or 1; p and q can be independently
selected from 1, 2 and 3; s can be 0, 1, 2 or 3; r and u can be
independently 1 or 2; y can be 3, 4 or 5; and Z.sup.1A, Z.sup.2A,
Z.sup.3A and Z.sup.4A can be independently O (oxygen) or S
(sulfur).
[0083] In some embodiments, R.sup.1A can be
##STR00014##
In some embodiments, R.sup.6A and R.sup.7A can be both hydrogen. In
other embodiments, R.sup.6A and R.sup.7A can be both absent. In
still other embodiments, at least one R.sup.6A and R.sup.7A can be
absent. In yet still other embodiments, at least one R.sup.6A and
R.sup.7A can be hydrogen. Those skilled in the art understand that
when R.sup.6A and/or R.sup.7A are absent, the associated oxygen(s)
will have a negative charge. For example, when R.sup.6A is absent,
the oxygen associated with R.sup.6A will have a negative charge. In
some embodiments, Z.sup.1A can be O (oxygen). In other embodiments,
Z.sup.1A can be S (sulfur). In some embodiments, R.sup.1A can be a
monophosphate. In other embodiments, R.sup.1A can be a
monothiophosphate.
[0084] In some embodiments, when R.sup.1A is
##STR00015##
one of R.sup.6A and R.sup.7A can be hydrogen, and the other of
R.sup.6A and R.sup.7A can be selected from an optionally
substituted C.sub.1-24 alkyl, an optionally substituted C.sub.3-24
alkenyl, an optionally substituted C.sub.3-24 alkynyl, an
optionally substituted C.sub.3-6 cycloalkyl, an optionally
substituted C.sub.3-6 cycloalkenyl, an optionally substituted aryl,
an optionally substituted heteroaryl and an optionally substituted
aryl(C.sub.1-6 alkyl). In some embodiments, one of R.sup.6A and
R.sup.7A can be hydrogen, and the other of R.sup.6A and R.sup.7A
can be an optionally substituted C.sub.1-24 alkyl. In other
embodiments, both R.sup.6A and R.sup.7A can be independently
selected from an optionally substituted C.sub.1-24 alkyl, an
optionally substituted C.sub.3-24 alkenyl, an optionally
substituted C.sub.3-24 alkynyl, an optionally substituted C.sub.3-6
cycloalkyl, an optionally substituted C.sub.3-6 cycloalkenyl, an
optionally substituted aryl, an optionally substituted heteroaryl
and an optionally substituted aryl(C.sub.1-6 alkyl). In some
embodiments, both R.sup.6A and R.sup.7A can be an optionally
substituted C.sub.1-24 alkyl. In other embodiments, both R.sup.6A
and R.sup.7A can be an optionally substituted C.sub.3-24 alkenyl.
In some embodiments, R.sup.6A and R.sup.7A can be independently an
optionally substituted version of the following: myristoleyl,
myristyl, palmitoleyl, palmityl, sapienyl, oleyl, elaidyl,
vaccenyl, linoleyl, .alpha.-linolenyl, arachidonyl,
eicosapentaenyl, erucyl, docosahexaenyl, caprylyl, capryl, lauryl,
stearyl, arachidyl, behenyl, lignoceryl and cerotyl.
[0085] In some embodiments, at least one of R.sup.6A and R.sup.7A
can be *--(CR.sup.15AR.sup.16A).sub.p--O--C.sub.1-24 alkyl. In
other embodiments, R.sup.6A and R.sup.7A can be both
*--(CR.sup.15AR.sup.16A).sub.p--O--C.sub.1-24 alkyl. In some
embodiments, each R.sup.15A and each R.sup.16A can be hydrogen. In
other embodiments, at least one of R.sup.15A and R.sup.16A can be
an optionally substituted C.sub.1-24 alkyl. In other embodiments,
at least one of R.sup.15A and R.sup.16A can be an alkoxy (for
example, benzoxy). In some embodiments, p can be 1. In other
embodiments, p can be 2. In still other embodiments, p can be
3.
[0086] In some embodiments, at least one of R.sup.6A and R.sup.7A
can be *--(CR.sup.17AR.sup.18A).sub.q--O--C.sub.2-24 alkenyl. In
other embodiments, R.sup.6A and R.sup.7A can be both
*--(CR.sup.17AR.sup.18A).sub.q--O--C.sub.2-24 alkenyl. In some
embodiments, each R.sup.17A and each R.sup.18A can be hydrogen. In
other embodiments, at least one of R.sup.17A and R.sup.18A can be
an optionally substituted C.sub.1-24 alkyl. In some embodiments, q
can be 1. In other embodiments, q can be 2. In still other
embodiments, q can be 3. When at least one of R.sup.6A and R.sup.7A
is *--(CR.sup.15AR.sup.16A).sub.p--O--C.sub.1-24 alkyl or
*--(CR.sup.17AR.sup.18A).sub.q--O--C.sub.2-24 alkenyl, the
C.sub.1-24 alkyl can be selected from caprylyl, capryl, lauryl,
myristyl, palmityl, stearyl, arachidyl, behenyl, lignoceryl, and
cerotyl, and the C.sub.2-24 alkenyl can be selected from
myristoleyl, palmitoleyl, sapienyl, oleyl, elaidyl, vaccenyl,
linoleyl, .alpha.-linolenyl, arachidonyl, eicosapentaenyl, erucyl
and docosahexaenyl.
[0087] In some embodiments, when R.sup.1A is
##STR00016##
at least one of R.sup.6A and R.sup.7A can be selected from
##STR00017##
and the other of R.sup.6A and R.sup.7A can be selected from absent,
hydrogen, an optionally substituted C.sub.1-24 alkyl, an optionally
substituted C.sub.2-24 alkenyl, an optionally substituted
C.sub.2-24 alkynyl, an optionally substituted C.sub.3-6 cycloalkyl,
an optionally substituted C.sub.3-6 cycloalkenyl, an optionally
substituted aryl, an optionally substituted heteroaryl and an
optionally substituted aryl(C.sub.1-6 alkyl).
[0088] In some embodiments, at least one of R.sup.6A and R.sup.7A
can be
##STR00018##
In some embodiments, both R.sup.6A and R.sup.7A can be
##STR00019##
When one or both of R.sup.6A and R.sup.7A are
##STR00020##
R.sup.19A and R.sup.20A can be independently selected from
hydrogen, an optionally substituted C.sub.1-24 alkyl and an
optionally substituted aryl; and R.sup.21A can be selected from
hydrogen, an optionally substituted C.sub.1-24 alkyl, an optionally
substituted aryl, an optionally substituted --O--C.sub.1-24 alkyl,
an optionally substituted --O-aryl, an optionally substituted
--O-heteroaryl, an optionally substituted --O-monocyclic
heterocyclyl and
##STR00021##
In some embodiments, R.sup.19A and R.sup.20A can be hydrogen. In
other embodiments, at least one of R.sup.19A and R.sup.20A can be
an optionally substituted C.sub.1-24 alkyl or an optionally
substituted aryl. In some embodiments, R.sup.21A can be an
optionally substituted C.sub.1-24 alkyl. In other embodiments,
R.sup.21A can be an optionally substituted aryl. In still other
embodiments, R.sup.21A can be an optionally substituted
--O--C.sub.1-24 alkyl or an optionally substituted --O-aryl. In
some embodiments, R.sup.21A can be an optionally substituted
--O--C.sub.1-24 alkyl, an optionally substituted --O-aryl, an
optionally substituted --O-heteroaryl or an optionally substituted
--O-monocyclic heterocyclyl.
[0089] In some embodiments, both R.sup.6A and R.sup.7A can be
##STR00022##
When one or both of R.sup.6A and R.sup.7A are
##STR00023##
R.sup.22A and R.sup.23A can be independently selected from
hydrogen, an optionally substituted C.sub.1-24 alkyl and an
optionally substituted aryl; R.sup.24A can be independently
selected from hydrogen, an optionally substituted C.sub.1-24 alkyl,
an optionally substituted aryl, an optionally substituted
--O--C.sub.1-24 alkyl, an optionally substituted --O-aryl, an
optionally substituted --O-heteroaryl, an optionally substituted
--O-monocyclic heterocyclyl and
##STR00024##
and Z.sup.4A can be independently O (oxygen) or S (sulfur). In some
embodiments, R.sup.22A and R.sup.23A can be hydrogen. In other
embodiments, at least one of R.sup.22A and R.sup.23A can be an
optionally substituted C.sub.1-24 alkyl or an optionally
substituted aryl. In some embodiments, R.sup.24A can be an
optionally substituted C.sub.1-24 alkyl. In other embodiments,
R.sup.24A can be an optionally substituted aryl. In still other
embodiments, R.sup.24A can be an optionally substituted
--O--C.sub.1-24 alkyl, an optionally substituted --O-aryl, an
optionally substituted --O-heteroaryl or an optionally substituted
--O-monocyclic heterocyclyl. In yet still other embodiments,
R.sup.24A can be
##STR00025##
In some embodiments, Z.sup.4A can be O (oxygen). In other
embodiments, Z.sup.4A can be or S (sulfur). In some embodiments, s
can be 0. In other embodiments, s can be 1. In still other
embodiments, s can be 2. In yet still embodiments, s can be 3. In
some embodiments, s can be 0, and R.sup.24A can be
##STR00026##
In some embodiments, u can be 1. In other embodiments, u can be 2.
In some embodiments, one or both of R.sup.6A and R.sup.7A can be
isopropyloxycarbonyloxymethyl (POC). In some embodiments, one or
both of R.sup.6A and R.sup.7A can be pivaloyloxymethyl (POM). In
some embodiments, R.sup.6A and R.sup.7A can be both a
isopropyloxycarbonyloxymethyl group, and form a
bis(isopropyloxycarbonyloxymethyl) (bis(POC)) prodrug. In some
embodiments, R.sup.6A and R.sup.7A can be both a pivaloyloxymethyl
group, and form a bis(pivaloyloxymethyl) (bis(POM)) prodrug.
[0090] In some embodiments, both R.sup.6A and R.sup.7A can be
##STR00027##
wherein R.sup.27A and R.sup.28A can be independently --C.ident.N or
an optionally substituted substituent selected from C.sub.2-8
organylcarbonyl, C.sub.2-8 alkoxycarbonyl and C.sub.2-8
organylaminocarbonyl; R.sup.29A can be selected from hydrogen, an
optionally substituted C.sub.1-24 alkyl, an optionally substituted
C.sub.2-24 alkenyl, an optionally substituted C.sub.2-24 alkynyl,
an optionally substituted C.sub.3-6 cycloalkyl and an optionally
substituted C.sub.3-6 cycloalkenyl; and r can be 1 or 2.
[0091] In some embodiments, R.sup.6A and R.sup.7A can be both an
optionally substituted aryl. In some embodiments, at least one of
R.sup.6A and R.sup.7A can be an optionally substituted aryl. For
example, both R.sup.6A and R.sup.7A can be an optionally
substituted phenyl or an optionally substituted naphthyl. When
substituted, the substituted aryl can be substituted with 1, 2, 3
or more than 3 substituents. When more the two substituents are
present, the substituents can be the same or different. In some
embodiments, when at least one of R.sup.6A and R.sup.7A is a
substituted phenyl, the substituted phenyl can be a para-, ortho-
or meta-substituted phenyl.
[0092] In some embodiments, R.sup.6A and R.sup.7A can be both an
optionally substituted aryl(C.sub.1-6 alkyl). In some embodiments,
at least one of R.sup.6A and R.sup.7A can be an optionally
substituted aryl(C.sub.1-6 alkyl). For example, both R.sup.6A and
R.sup.7A can be an optionally substituted benzyl. When substituted,
the substituted benzyl group can be substituted with 1, 2, 3 or
more than 3 substituents. When more the two substituents are
present, the substituents can be the same or different. In some
embodiments, the aryl group of the aryl(C.sub.1-6 alkyl) can be a
para-, ortho- or meta-substituted phenyl.
[0093] In some embodiments, R.sup.6A and R.sup.7A can be both
##STR00028##
In some embodiments, at least one of R.sup.6A and R.sup.7A can
##STR00029##
In some embodiments, R.sup.25A can be hydrogen. In other
embodiments, R.sup.25A can be an optionally substituted C.sub.1-24
alkyl. In still other embodiments, R.sup.25A can be an optionally
substituted aryl, for example, an optionally substituted phenyl. In
some embodiments, R.sup.25A can be a C.sub.1-6 alkyl, for example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
pentyl (branched and straight-chained) and hexyl (branched and
straight-chained). In some embodiments, t can be 0. In other
embodiments, t can be 1. In some embodiments, one or both of
R.sup.6A and R.sup.7A can be a S-acylthioethyl (SATE).
[0094] In some embodiments, R.sup.6A and R.sup.7A can be both
##STR00030##
In some embodiments, at least one of R.sup.6A and R.sup.7A can
be
##STR00031##
In some embodiments, R.sup.30A can be hydrogen. In other
embodiments, R.sup.30A can be an optionally substituted C.sub.1-24
alkyl. In some embodiments, R.sup.30A can be a C.sub.1-4 alkyl,
such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and
t-butyl. In still other embodiments, R.sup.30A can be an optionally
substituted aryl, such as an optionally substituted phenyl or an
optionally substituted naphthyl. In some embodiments, R.sup.6A and
R.sup.7A can be both a dioxolenone group and form a dioxolenone
prodrug.
[0095] In some embodiments, R.sup.1A can be
##STR00032##
R.sup.6A can be
##STR00033##
[0096] R.sup.7A can be absent or hydrogen; R.sup.12A and R.sup.13A
can be independently absent or hydrogen; R.sup.14A can be O.sup.-,
OH or methyl; and m can be 0 or 1. In some embodiments, m can be 0,
and R.sup.7A, R.sup.12A and R.sup.13A can be independently absent
or hydrogen. In other embodiments, m can be 1, and R.sup.7A,
R.sup.12A and R.sup.13A can be independently absent or hydrogen;
and R.sup.14A can be O-- or OH. In other embodiments, m can be 1,
and R.sup.7A, R.sup.12A and R.sup.13A can be independently absent
or hydrogen; and R.sup.14A and be methyl. Those skilled in the art
understand that when R.sup.6A is
##STR00034##
R.sup.7A is absent or hydrogen and m is 0, R.sup.1A can be
diphosphate, when Z.sup.1A is oxygen, or an alpha-thiodiphosphate,
when Z.sup.1A is sulfur. Likewise, those skilled in the art
understand that when R.sup.6A is
##STR00035##
R.sup.7A is absent or hydrogen, m is 1 and R.sup.14A is O.sup.- or
OH, R.sup.1A can be triphosphate, when Z.sup.1A is oxygen, or an
alpha-thiotriphosphate, when Z.sup.1A is sulfur.
[0097] In some embodiments, R.sup.6A and R.sup.7A can be taken
together to form an optionally substituted
##STR00036##
For example, R.sup.1A can be an optionally substituted
##STR00037##
When substituted, the ring can be substituted 1, 2, 3 or 3 or more
times. When substituted with multiple substituents, the
substituents can be the same or different. In some embodiments,
when R.sup.1A is
##STR00038##
the ring can be substituted with an optionally substituted aryl
group and/or an optionally substituted heteroaryl. An example of a
suitable heteroaryl is pyridinyl. In some embodiments, R.sup.6A and
R.sup.7A can be taken together to form an optionally
substituted
##STR00039##
such as
##STR00040##
wherein R.sup.33A can be an optionally substituted aryl, an
optionally substituted heteroaryl or an optionally substituted
heterocyclyl. In some embodiments, R.sup.6A and R.sup.7A can form a
cyclic 1-aryl-1,3-propanyl ester (HepDirect) prodrug moiety.
[0098] In some embodiments, R.sup.6A and R.sup.7A can be taken
together to form an optionally substituted
##STR00041##
wherein the oxygens connected to R.sup.6A and R.sup.7A, the
phosphorus and the moiety form a six-membered to ten-membered ring
system. Example of an optionally substituted
##STR00042##
include
##STR00043##
In some embodiments, R.sup.6A and R.sup.7A can form a
cyclosaligenyl (cycloSal) prodrug.
[0099] In some embodiments, R.sup.6A and R.sup.7A can be the same.
In some embodiments, R.sup.6A and R.sup.7A can be different.
[0100] In some embodiments, Z.sup.1A can be O (oxygen). In other
embodiments, Z.sup.1A can be S (sulfur).
[0101] In some embodiments, R.sup.1A can be
##STR00044##
In some embodiments, R.sup.8A can be selected from absent,
hydrogen, an optionally substituted C.sub.1-24 alkyl, an optionally
substituted C.sub.2-24 alkenyl, an optionally substituted
C.sub.2-24 alkynyl, an optionally substituted C.sub.3-6 cycloalkyl
and an optionally substituted C.sub.3-6 cycloalkenyl; and R.sup.9A
can be independently selected from an optionally substituted
C.sub.1-24 alkyl, an optionally substituted C.sub.2-24 alkenyl, an
optionally substituted C.sub.2-24 alkynyl, an optionally
substituted C.sub.3-6 cycloalkyl and an optionally substituted
C.sub.3-6 cycloalkenyl.
[0102] In some embodiments, R.sup.8A can be hydrogen, and R.sup.9A
can be an optionally substituted C.sub.1-6 alkyl. Examples of
suitable C.sub.1-6 alkyls include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and
straight-chained) and hexyl (branched and straight-chained). In
other embodiments, R.sup.8A can be hydrogen, and R.sup.9A can be
NR.sup.30AR.sup.31A, wherein R.sup.30 and R.sup.31 can be
independently selected from hydrogen, an optionally substituted
C.sub.1-24 alkyl, an optionally substituted C.sub.2-24 alkenyl, an
optionally substituted C.sub.2-24 alkynyl, an optionally
substituted C.sub.3-6 cycloalkyl and an optionally substituted
C.sub.3-6 cycloalkenyl.
[0103] In some embodiments, R.sup.8A can be absent or hydrogen; and
R.sup.9A can be an optionally substituted N-linked amino acid or an
optionally substituted N-linked amino acid ester derivative. In
other embodiments, R.sup.8A can be an optionally substituted aryl;
and R.sup.9A can be an optionally substituted N-linked amino acid
or an optionally substituted N-linked amino acid ester derivative.
In still other embodiments, R.sup.8A can be an optionally
substituted heteroaryl; and R.sup.9A can be an optionally
substituted N-linked amino acid or an optionally substituted
N-linked amino acid ester derivative. In some embodiments, R.sup.9A
can be selected from alanine, asparagine, aspartate, cysteine,
glutamate, glutamine, glycine, proline, serine, tyrosine, arginine,
histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
threonine, tryptophan, valine and ester derivatives thereof.
Examples of an optionally substituted N-linked amino acid ester
derivatives include optionally substituted versions of the
following: alanine isopropyl ester, alanine cyclohexyl ester,
alanine neopentyl ester, valine isopropyl ester and leucine
isopropyl ester. In some embodiments, R.sup.9A can have the
structure
##STR00045##
wherein R.sup.34A can be selected from hydrogen, an optionally
substituted C.sub.1-6-alkyl, an optionally substituted C.sub.3-6
cycloalkyl, an optionally substituted aryl, an optionally
substituted aryl(C.sub.1-6 alkyl) and an optionally substituted
haloalkyl; R.sup.35A can be selected from hydrogen, an optionally
substituted C.sub.1-6 alkyl, an optionally substituted C.sub.1-6
haloalkyl, an optionally substituted C.sub.3-6 cycloalkyl, an
optionally substituted C.sub.6 aryl, an optionally substituted
C.sub.10 aryl and an optionally substituted aryl(C.sub.1-6 alkyl);
and R.sup.36A can be hydrogen or an optionally substituted
C.sub.1-4 alkyl; or R.sup.35A and R.sup.36A can be taken together
to form an optionally substituted C.sub.3-6 cycloalkyl.
[0104] When R.sup.35A is substituted, R.sup.35A can be substituted
with one or more substituents selected from N-amido, mercapto,
alkylthio, an optionally substituted aryl, hydroxy, an optionally
substituted heteroaryl, O-carboxy and amino. In some embodiments,
R.sup.35A can be an unsubstituted C.sub.1-6-alkyl, such as those
described herein. In some embodiments, R.sup.35A can be hydrogen.
In other embodiments, R.sup.35A can be methyl. In some embodiments,
R.sup.34A can be an optionally substituted C.sub.1-6 alkyl.
Examples of optionally substituted C.sub.1-6-alkyls include
optionally substituted variants of the following: methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl
(branched and straight-chained) and hexyl (branched and
straight-chained). In some embodiments, R.sup.34A can be methyl or
isopropyl. In some embodiments, R.sup.34A can be ethyl or
neopentyl. In other embodiments, R.sup.34A can be an optionally
substituted C.sub.3-6 cycloalkyl. Examples of optionally
substituted C.sub.3-6 cycloalkyl include optionally substituted
variants of the following: cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl. In an embodiment, R.sup.34A can be an optionally
substituted cyclohexyl. In still other embodiments, R.sup.34A can
be an optionally substituted aryl, such as phenyl and naphthyl. In
yet still other embodiments, R.sup.34A can be an optionally
substituted aryl(C.sub.1-6 alkyl). In some embodiments, R.sup.34A
can be an optionally substituted benzyl. In some embodiments,
R.sup.34A can be an optionally substituted C.sub.1-6 haloalkyl, for
example, CF.sub.3. In some embodiments, R.sup.36A can be hydrogen.
In other embodiments, R.sup.36A can be an optionally substituted
C.sub.1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl and tert-butyl. In an embodiment, R.sup.36A can
be methyl. In some embodiments, R.sup.35A and R.sup.36A can be
taken together to form an optionally substituted C.sub.3-6
cycloalkyl. Examples of optionally substituted C.sub.3-6 cycloalkyl
include optionally substituted variants of the following:
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on
the groups that are selected for R.sup.35A and R.sup.36A, the
carbon to which R.sup.35A and R.sup.36A are attached may be a
chiral center. In some embodiment, the carbon to which R.sup.35A
and R.sup.36A are attached may be a (R)-chiral center. In other
embodiments, the carbon to which R.sup.35A and R.sup.36A are
attached may be a (S)-chiral center.
[0105] In some embodiments, when R.sup.1A is
##STR00046##
Z.sup.2A, can be O (oxygen). In other embodiments, when R.sup.1A
is
##STR00047##
Z.sup.2A can be S (sulfur). In some embodiments, when R.sup.1A
is
##STR00048##
a compound of Formula (I) can be a phosphoramidate prodrug, such as
an aryl phosphoramidate prodrug.
[0106] In some embodiments, R.sup.1A can be
##STR00049##
In some embodiments, R.sup.10A and R.sup.11A can be both an
optionally substituted N-linked amino acid or an optionally
substituted N-linked amino acid ester derivative. In some
embodiments, R.sup.10A and R.sup.11A can be independently selected
from alanine, asparagine, aspartate, cysteine, glutamate,
glutamine, glycine, proline, serine, tyrosine, arginine, histidine,
isoleucine, leucine, lysine, methionine, phenylalanine, threonine,
tryptophan, valine and ester derivatives thereof. In some
embodiments, R.sup.10A and R.sup.11A can be an optionally
substituted version of the following: alanine isopropyl ester,
alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl
ester and leucine isopropyl ester. In some embodiments, R.sup.10A
and R.sup.11A can independently have the structure
##STR00050##
wherein R.sup.37A can be selected from hydrogen, an optionally
substituted C.sub.1-6-alkyl, an optionally substituted C.sub.3-6
cycloalkyl, an optionally substituted aryl, an optionally
substituted aryl(C.sub.1-6 alkyl) and an optionally substituted
haloalkyl; R.sup.38A can be selected from hydrogen, an optionally
substituted C.sub.1-6 alkyl, an optionally substituted C.sub.1-6
haloalkyl, an optionally substituted C.sub.3-6 cycloalkyl, an
optionally substituted C.sub.6 aryl, an optionally substituted
C.sub.10 aryl and an optionally substituted aryl(C.sub.1-6 alkyl);
and R.sup.39A can be hydrogen or an optionally substituted
C.sub.1-4 alkyl; or R.sup.38A and R.sup.39A can be taken together
to form an optionally substituted C.sub.3-6 cycloalkyl.
[0107] When R.sup.38A is substituted, R.sup.38A can be substituted
with one or more substituents selected from N-amido, mercapto,
alkylthio, an optionally substituted aryl, hydroxy, an optionally
substituted heteroaryl, O-carboxy and amino. In some embodiments,
R.sup.38A can be an unsubstituted C.sub.1-6-alkyl, such as those
described herein. In some embodiments, R.sup.38A can be hydrogen.
In other embodiments, R.sup.38A can be methyl. In some embodiments,
R.sup.37A can be an optionally substituted C.sub.1-6 alkyl.
Examples of optionally substituted C.sub.1-6-alkyls include
optionally substituted variants of the following: methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl
(branched and straight-chained) and hexyl (branched and
straight-chained). In some embodiments, R.sup.37A can be methyl or
isopropyl. In some embodiments, R.sup.37A can be ethyl or
neopentyl. In other embodiments, R.sup.37A can be an optionally
substituted C.sub.3-6 cycloalkyl. Examples of optionally
substituted C.sub.3-6 cycloalkyl include optionally substituted
variants of the following: cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl. In an embodiment, R.sup.37A can be an optionally
substituted cyclohexyl. In still other embodiments, R.sup.37A can
be an optionally substituted aryl, such as phenyl and naphthyl. In
yet still other embodiments, R.sup.37A can be an optionally
substituted aryl(C.sub.1-6 alkyl). In some embodiments, R.sup.37A
can be an optionally substituted benzyl. In some embodiments,
R.sup.37A can be an optionally substituted C.sub.1-6 haloalkyl, for
example, CF.sub.3. In some embodiments, R.sup.39A can be hydrogen.
In other embodiments, R.sup.39A can be an optionally substituted
C.sub.1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl and tert-butyl. In an embodiment, R.sup.39A can
be methyl. In some embodiments, R.sup.38A and R.sup.39A can be
taken together to form an optionally substituted C.sub.3-6
cycloalkyl. Examples of optionally substituted C.sub.3-6 cycloalkyl
include optionally substituted variants of the following:
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on
the groups that are selected for R.sup.38A and R.sup.39A, the
carbon to which R.sup.38A and R.sup.39A are attached may be a
chiral center. In some embodiment, the carbon to which R.sup.38A
and R.sup.39A are attached may be a (R)-chiral center. In other
embodiments, the carbon to which R.sup.38A and R.sup.39A are
attached may be a (S)-chiral center.
[0108] Examples of suitable
##STR00051##
groups include the following:
##STR00052##
[0109] In some embodiments, R.sup.10A and R.sup.11A can be the
same. In some embodiments, R.sup.10A and R.sup.11A can be
different.
[0110] In some embodiments, Z.sup.3A can be O (oxygen). In other
embodiments, Z.sup.3A can be S (sulfur). In some embodiments, when
R.sup.1A is
##STR00053##
a compound of Formula (I) can be a phosphonic diamide prodrug.
[0111] In some embodiments, R.sup.1A can be hydrogen. In some
embodiments, R.sup.1A can be an optionally substituted acyl. In
other embodiments, R.sup.1A can be --C(.dbd.O)R.sup.40A wherein
R.sup.40A can be selected from an optionally substituted C.sub.1-12
alkyl, an optionally substituted C.sub.2-12 alkenyl, an optionally
substituted C.sub.2-12 alkynyl, an optionally substituted C.sub.3-8
cycloalkyl, an optionally substituted C.sub.5-8 cycloalkenyl, an
optionally substituted C.sub.6-10 aryl, an optionally substituted
heteroaryl, an optionally substituted heterocyclyl, an optionally
substituted aryl(C.sub.1-6 alkyl), an optionally substituted
heteroaryl(C.sub.1-6 alkyl) and an optionally substituted
heterocyclyl(C.sub.1-6 alkyl). In some embodiments, R.sup.40A can
be a substituted C.sub.1-12 alkyl. In other embodiments, R.sup.40A
can be an unsubstituted C.sub.1-12 alkyl.
[0112] In still other embodiments, R.sup.1A can be an optionally
substituted O-linked amino acid. Examples of suitable O-linked
amino acids include alanine, asparagine, aspartate, cysteine,
glutamate, glutamine, glycine, proline, serine, tyrosine, arginine,
histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
threonine, tryptophan and valine. Additional examples of suitable
amino acids include, but are not limited to, ornithine, hypusine,
2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid,
citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine
and norleucine. In some embodiments, the O-linked amino acid can
have the structure
##STR00054##
wherein R.sup.41A can be selected from hydrogen, an optionally
substituted C.sub.1-6 alkyl, an optionally substituted C.sub.1-6
haloalkyl, an optionally substituted C.sub.3-6 cycloalkyl, an
optionally substituted C.sub.6 aryl, an optionally substituted
C.sub.10 aryl and an optionally substituted aryl(C.sub.1-6 alkyl);
and R.sup.42A can be hydrogen or an optionally substituted
C.sub.1-4 alkyl; or R.sup.41A and R.sup.42A can be taken together
to form an optionally substituted C.sub.3-6 cycloalkyl. Those
skilled in the art understand that when R.sup.1A is an optionally
substituted O-linked amino acid, the oxygen of R.sup.1AO-- of
Formula (I) is part of the optionally substituted O-linked amino
acid. For example, when R.sup.1A is
##STR00055##
the oxygen indicated with "*" is the oxygen of R.sup.1AO-- of
Formula (I).
[0113] When R.sup.41A is substituted, R.sup.41A can be substituted
with one or more substituents selected from N-amido, mercapto,
alkylthio, an optionally substituted aryl, hydroxy, an optionally
substituted heteroaryl, O-carboxy and amino. In some embodiments,
R.sup.41A can be an unsubstituted C.sub.1-6-alkyl, such as those
described herein. In some embodiments, R.sup.41A can be hydrogen.
In other embodiments, R.sup.41A can be methyl. In some embodiments,
R.sup.42A can be hydrogen. In other embodiments, R.sup.42A can be
an optionally substituted C.sub.1-4 alkyl, such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an
embodiment, R.sup.42A can be methyl. Depending on the groups that
are selected for R.sup.41A and R.sup.42A, the carbon to which
R.sup.41A and R.sup.42A are attached may be a chiral center. In
some embodiment, the carbon to which R.sup.41A and R.sup.42A are
attached may be a (R)-chiral center. In other embodiments, the
carbon to which R.sup.41A and R.sup.42A are attached may be a
(S)-chiral center.
[0114] Examples of suitable
##STR00056##
include the following:
##STR00057##
[0115] Various substituents can be present at the 4'-position of
the pentose ring. In some embodiments, R.sup.2A can be an
unsubstituted C.sub.1-4 alkyl. Unsubstituted C.sub.1-4 alkyls
include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and
tert-butyl. In other embodiments, R.sup.2A can be an unsubstituted
C.sub.2-4 alkenyl, such as ethenyl, propenyl and butenyl. In still
other embodiments, R.sup.2A can be an unsubstituted C.sub.2-4
alkynyl, for example, ethynyl, propynyl and butynyl. In yet still
other embodiments, R.sup.2A can be a haloalkyl. Examples of a
haloalkyls are --(CH.sub.2).sub.1-6 halogen and --CHF.sub.2. In
some embodiments, the haloalkyl can be --(CH.sub.2).sub.1-6F or
--(CH.sub.2).sub.1-6C.sub.1. In yet still other embodiments,
R.sup.2A can be a C.sub.1-6 azidoalkyl. For example, R.sup.2A can
be an azidomethyl, azidoethyl, azidopropyl, azidobutyl, azidopentyl
or azidohexyl. In some embodiments, R.sup.2A can be a C.sub.1-6
aminoalkyl. For example, R.sup.2A can be an aminomethyl,
aminoethyl, aminopropyl, aminobutyl, aminopentyl or aminohexyl.
[0116] The groups attached to the 3'-position of the pentose ring
can vary. In some embodiments, R.sup.3A can be hydrogen. In other
embodiments, R.sup.3A can be deuterium. In still other embodiments,
R.sup.3A can be halo. In yet still other embodiments, R.sup.3A can
be OH.
[0117] In some embodiments, R.sup.3A can be an optionally
substituted O-linked amino acid. Examples of suitable O-linked
amino acids include alanine, asparagine, aspartate, cysteine,
glutamate, glutamine, glycine, proline, serine, tyrosine, arginine,
histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
threonine, tryptophan and valine. Additional examples of suitable
amino acids include, but are not limited to, ornithine, hypusine,
2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid,
citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine
and norleucine. In some embodiments, the O-linked amino acid can
have the structure
##STR00058##
wherein R.sup.43A can be selected from hydrogen, an optionally
substituted C.sub.1-6 alkyl, an optionally substituted C.sub.1-6
haloalkyl, an optionally substituted C.sub.3-6 cycloalkyl, an
optionally substituted C.sub.6 aryl, an optionally substituted
C.sub.10 aryl and an optionally substituted aryl(C.sub.1-6 alkyl);
and R.sup.44A can be hydrogen or an optionally substituted
C.sub.1-4 alkyl; or R.sup.43A and R.sup.44A can be taken together
to form an optionally substituted C.sub.3-6 cycloalkyl.
[0118] When R.sup.43A is substituted, R.sup.43A can be substituted
with one or more substituents selected from N-amido, mercapto,
alkylthio, an optionally substituted aryl, hydroxy, an optionally
substituted heteroaryl, O-carboxy and amino. In some embodiments,
R.sup.43A can be an unsubstituted C.sub.1-6-alkyl, such as those
described herein. In some embodiments, R.sup.43A can be hydrogen.
In other embodiments, R.sup.43A can be methyl. In some embodiments,
R.sup.44A can be hydrogen. In other embodiments, R.sup.44A can be
an optionally substituted C.sub.1-4 alkyl, such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an
embodiment, R.sup.44A can be methyl. Depending on the groups that
are selected for R.sup.43A and R.sup.44A, the carbon to which
R.sup.43A and R.sup.44A are attached may be a chiral center. In
some embodiment, the carbon to which R.sup.43A and R.sup.44A are
attached may be a (R)-chiral center. In other embodiments, the
carbon to which R.sup.43A and R.sup.44A are attached may be a
(S)-chiral center.
[0119] In yet still other embodiments, R.sup.3A can be
--OC(.dbd.O)R'.sup.A, wherein R'.sup.A can be an optionally
substituted C.sub.1-24 alkyl. In some embodiments, R'.sup.A can be
a substituted C.sub.1-8 alkyl. In other embodiments, R'.sup.A can
be an unsubstituted C.sub.1-8 alkyl. In still other embodiments,
R.sup.3A can be an optionally substituted --O-acyl. In some
embodiments, R.sup.3A can be --OC(.dbd.O)R.sup.45A, wherein
R.sup.45A can be selected from an optionally substituted C.sub.1-12
alkyl, an optionally substituted C.sub.2-12 alkenyl, an optionally
substituted C.sub.2-12 alkynyl, an optionally substituted C.sub.3-8
cycloalkyl, an optionally substituted C.sub.5-8 cycloalkenyl, an
optionally substituted C.sub.6-10 aryl, an optionally substituted
heteroaryl, an optionally substituted heterocyclyl, an optionally
substituted aryl(C.sub.1-6 alkyl), an optionally substituted
heteroaryl(C.sub.1-6 alkyl) and an optionally substituted
heterocyclyl(C.sub.1-6 alkyl). In some embodiments, R.sup.45A can
be a substituted C.sub.1-12 alkyl. In other embodiments, R.sup.45A
can be an unsubstituted C.sub.1-12 alkyl. In some embodiment, the
hydrogen shown in a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, attached to the 3'-position along with
R.sup.3A can be an isotope of hydrogen, such as deuterium.
[0120] A variety of substituents can also be present at the
2'-position of the pentose ring. In some embodiments, R.sup.4A can
be hydrogen. In other embodiments, R.sup.4A can be deuterium.
[0121] Examples of suitable
##STR00059##
include the following:
##STR00060##
[0122] In some embodiments, R.sup.5A can be hydrogen. In other
embodiments, R.sup.5A can be deuterium. In still other embodiments,
R.sup.5A can be halogen, for example, fluoro or chloro. In yet
still other embodiments, R.sup.5A can be N.sub.3. In some
embodiments, R.sup.5A can be OH. In other embodiments, R.sup.5A can
be an optionally substituted C.sub.1-6 alkyl. For example, in some
embodiments, R.sup.5A can be a halo-substituted C.sub.1-4 alkyl,
such as a fluoro-substituted C.sub.1-4 alkyl or a
chloro-substituted C.sub.1-4 alkyl. In still other embodiments,
R.sup.5A can be an optionally substituted C.sub.2-6 alkenyl. In yet
still other embodiments, R.sup.5A can be an optionally substituted
C.sub.2-6 alkynyl. In some embodiments, R.sup.5A can be an
unsubstituted C.sub.1-6 alkyl, for example, for example, methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl
(branched and straight-chained) and hexyl (branched and
straight-chained). In some embodiments, R.sup.5A can be an
unsubstituted C.sub.2-6 alkenyl. In still other embodiments,
R.sup.5A can be an unsubstituted C.sub.2-6 alkynyl.
[0123] In some embodiments, R.sup.3A can be OH and R.sup.4A can be
hydrogen. In some embodiments, R.sup.3A can be OH, R.sup.4A can be
hydrogen and R.sup.5A can be hydrogen. In some embodiments,
R.sup.3A can be OH, R.sup.4A can be hydrogen and R.sup.5A can be an
unsubstituted C.sub.1-4 alkyl, for example, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl. In some
embodiments, R.sup.3A can be OH, R.sup.4A can be hydrogen and
R.sup.5A can be a substituted C.sub.1-4 alkyl, such as a
halo-substituted C.sub.1-4 alkyl. In some embodiments, R.sup.3A can
be OH, R.sup.4A can be hydrogen and R.sup.5A can be an
unsubstituted C.sub.2-4 alkynyl, for example, ethynyl, propynyl,
and butynyl. In some embodiments, R.sup.3A can be OH, R.sup.4A can
be hydrogen and R.sup.5A can be chloro. In some embodiments,
R.sup.3A can be OH, R.sup.4A can be hydrogen and R.sup.5A can be
fluoro. In some embodiments, R.sup.3A can be OH, R.sup.4A can be
hydrogen and R.sup.5A can be azido. In some embodiments, R.sup.3A
can be OH, R.sup.4A can be hydrogen and R.sup.5A can be OH.
[0124] A variety of substituents can also be present at the
5'-position of the pentose ring. In some embodiments, both R.sup.a1
and R.sup.a2 can be hydrogen. In other embodiments, R.sup.a1 can be
hydrogen and R.sup.a2 can be deuterium. In still other embodiments,
both R.sup.a1 and R.sup.a2 can be deuterium. For the 1'-position,
in some embodiments, R.sup.A can be hydrogen. In other embodiments,
R.sup.A can be deuterium.
[0125] Various optionally substituted heterocyclic bases can be
attached to the pentose ring. In some embodiments, one or more of
the amine and/or amino groups may be protected with a suitable
protecting group. For example, an amino group may be protected by
transforming the amine and/or amino group to an amide or a
carbamate. In some embodiments, an optionally substituted
heterocyclic base or an optionally substituted heterocyclic base
with one or more protected amino groups can have one of the
following structures:
##STR00061##
wherein: R.sup.A2 can be selected from hydrogen, halogen and
NHR.sup.J2, wherein R.sup.J2 can be selected from hydrogen,
--C(.dbd.O)R.sup.K2 and --C(.dbd.O)OR.sup.L2; R.sup.B2 can be
halogen or NHR.sup.W2, wherein R.sup.W2 can be selected from
hydrogen, an optionally substituted C.sub.1-6 alkyl, an optionally
substituted C.sub.2-6 alkenyl, an optionally substituted C.sub.3-8
cycloalkyl, --C(.dbd.O)R.sup.M2 and --C(.dbd.O)OR.sup.N2; R.sup.C2
can be hydrogen or NHR.sup.O2, wherein R.sup.O2 can be selected
from hydrogen, --C(.dbd.O)R.sup.P2 and --C(.dbd.O)OR.sup.Q2;
R.sup.D2 can be selected from hydrogen, deuterium, halogen, an
optionally substituted C.sub.1-6 alkyl, an optionally substituted
C.sub.2-6 alkenyl and an optionally substituted C.sub.2-6 alkynyl;
R.sup.E2 can be selected from hydrogen, hydroxy, an optionally
substituted C.sub.1-6 alkyl, an optionally substituted C.sub.3-8
cycloalkyl, --C(.dbd.O)R.sup.R2 and --C(.dbd.O)OR.sup.S2; R.sup.F2
can be selected from hydrogen, halogen, an optionally substituted
C.sub.1-6 alkyl, an optionally substituted C.sub.2-6 alkenyl and an
optionally substituted C.sub.2-6 alkynyl; Y.sup.2 and Y.sup.3 can
be independently N (nitrogen) or CR.sup.2, wherein R.sup.12 can be
selected from hydrogen, halogen, an optionally substituted
C.sub.1-6-alkyl, an optionally substituted C.sub.2-6-alkenyl and an
optionally substituted C.sub.2-6-alkynyl; R.sup.G2 can be an
optionally substituted C.sub.1-6 alkyl; R.sup.H2 can be hydrogen or
NHR.sup.T2, wherein R.sup.T2 can be independently selected from
hydrogen, --C(.dbd.O)R.sup.U2 and --C(.dbd.O)OR.sup.V2; and
R.sup.K2, R.sup.L2, R.sup.M2, R.sup.N2, R.sup.P2, R.sup.Q2,
R.sup.R2, R.sup.S2, R.sup.U2 and R.sup.V2 can be independently
selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.6-10
aryl, heteroaryl, heterocyclyl, aryl(C.sub.1-6 alkyl),
heteroaryl(C.sub.1-6 alkyl) and heterocyclyl(C.sub.1-6 alkyl). In
some embodiments, the structures shown above can be modified by
replacing one or more hydrogens with substituents selected from the
list of substituents provided for the definition of
"substituted."
[0126] In some embodiments, B.sup.1A can be
##STR00062##
In other embodiments, B.sup.1A can be
##STR00063##
In still other embodiments, B.sup.1A can be
##STR00064##
such as
##STR00065##
In yet still other embodiments, B.sup.1A can be
##STR00066##
for example,
##STR00067##
In some embodiments, R.sup.D2 can be hydrogen. In other
embodiments, B.sup.1A can be
##STR00068##
In some embodiments, R.sup.B2 can be NH.sub.2. In other
embodiments, R.sup.B2 can be NHR.sup.W2, wherein R.sup.W2 can be
--C(.dbd.O)R.sup.M2 or --C(.dbd.O)OR.sup.N2. In still other
embodiments, B.sup.1A can be
##STR00069##
In some embodiments, B.sup.1A can be
##STR00070##
[0127] In some embodiments, a compound of Formula (I) can have the
structure:
##STR00071## ##STR00072##
or a pharmaceutically acceptable salt of the foregoing. In some
embodiments of this paragraph, B.sup.1A can be an optionally
substituted purine base. In other embodiments of this paragraph,
B.sup.1A can be an optionally substituted pyrimidine base. In some
embodiments of this paragraph, B.sup.1A can be guanine. In other
embodiments of this paragraph, B.sup.1A can be thymine. In still
other embodiments of this paragraph, B.sup.1A can be cytosine. In
yet still other embodiments of this paragraph, B.sup.1A can be
uracil. In some embodiments of this paragraph, B.sup.1A can be
adenine. In some embodiments of this paragraph, R.sup.1A can be
hydrogen. In other embodiments of this paragraph, R.sup.1A can be
an optionally substituted acyl. In still other embodiments of this
paragraph, R.sup.1A can be mono-, di- or triphosphate. In yet other
embodiments of this paragraph, R.sup.1A can be phosphoramidate
prodrug, such as an aryl phosphoramidate prodrug. In some
embodiments of this paragraph, R.sup.1A can be an acyloxyalkyl
ester phosphate prodrug. In other embodiments of this paragraph,
R.sup.1A can be a S-acylthioethyl (SATE) prodrug. In still other
embodiments, R.sup.1A can be a phosphonic diamide prodrug. In yet
still other embodiments, of this paragraph, R.sup.1A can be a
cyclic 1-aryl-1,3-propanyl ester (HepDirect) prodrug moiety. In
some embodiments of this paragraph, R.sup.1A can be a
cyclosaligenyl (cycloSal) prodrug. In some embodiments of this
paragraph, R.sup.3A can be OH. In some embodiments of this
paragraph, R.sup.3A can be an optionally substituted O-linked amino
acid, such as one of those described herein.
[0128] Examples of suitable compounds of Formula (I) include, but
are not limited to the following:
##STR00073## ##STR00074## ##STR00075##
pharmaceutically acceptable salt of the foregoing.
[0129] Additional examples of suitable compounds of Formula (I)
include, but are not limited to the following:
##STR00076## ##STR00077## ##STR00078## ##STR00079##
##STR00080##
or a pharmaceutically acceptable salt of the foregoing.
Synthesis
[0130] Compounds of Formula (I) and those described herein may be
prepared in various ways. Some compounds of Formula (I) can be
obtained commercially and/or prepared utilizing known synthetic
procedures. General synthetic routes to the compounds of Formula
(I), and some examples of starting materials used to synthesize the
compounds of Formula (I) are shown and described herein. The routes
shown and described herein are illustrative only and are not
intended, nor are they to be construed, to limit the scope of the
claims in any manner whatsoever. Those skilled in the art will be
able to recognize modifications of the disclosed syntheses and to
devise alternate routes based on the disclosures herein; all such
modifications and alternate routes are within the scope of the
claims.
##STR00081##
[0131] As shown in Scheme 1, compounds of Formula (I), wherein the
4'-position is a haloalkyl, can be prepared from a nucleoside, for
example, a nucleoside of Formula (A). In Scheme 1, R.sup.a,
R.sup.3a, R.sup.4a, R.sup.5a, and B.sup.1a can be the same as
R.sup.A, R.sup.3A, R.sup.4A, R.sup.5A and B.sup.1A as described
herein for Formula (I), respectively, and PG.sup.1 is a suitable
protecting group. A hydroxyalkyl group can be formed at the
4'-position of the pentose ring using suitable conditions known to
those skilled in the art. Examples of suitable conditions for
forming a hydroxyalkyl include the use of 2-iodoxybenzoic acid
(IBX) aqueous formaldehyde and sodium borohydride. A compound of
Formula (B) can be transformed to a haloalkyl using a suitable
agent(s), for example, to an iodide using imidazole,
triphenylphosphine and iodine; to a fluoro using diethylaminosulfur
trifluoride (DAST); or to a chloro using triphenylphosphine and
carbontetrachloride in dichloroethylene (DCE).
##STR00082##
[0132] Compounds of Formula (I), where R.sup.2A is a C.sub.1-6
azidoalkyl can be prepared from a nucleoside, for example, a
nucleoside of Formula (A). In Scheme 2, R.sup.a, R.sup.3a,
R.sup.4a, R.sup.5a and B.sup.1a can be the same as R.sup.A,
R.sup.3A, R.sup.4A, R.sup.5A and B.sup.1A as described herein for
Formula (I), PG.sup.2 can be a suitable protecting group and
LG.sup.1 can be a suitable leaving group. The 5'-position of the
nucleoside can be oxidized to an aldehyde using methods known to
those skilled in the art. Suitable oxidation conditions include,
but are not limited to, Moffatt oxidation, Swern oxidation and
Corey-Kim oxidation; and suitable oxidizing agents include, but are
not limited to, Dess-Martin periodinane, IBX (2-iodoxybenzoic
acid), TPAP/NMO (tetrapropylammonium
perruthenate/N-methylmorpholine N-oxide), Swern oxidation reagent,
PCC (pyridinium chlorochromate), PDC (pyridinium dichromate),
sodium periodate, Collin's reagent, ceric ammonium nitrate CAN,
Na.sub.2Cr.sub.2O.sub.7 in water, Ag.sub.2CO.sub.3 on celite, hot
HNO.sub.3 in aqueous glyme, O.sub.2-pyridine CuCl,
Pb(OAc).sub.4-pyridine and benzoyl peroxide-NiBr.sub.2. A
hydroxymethyl group can be added to the 4'-position of the pentose
ring along with the reduction of the aldehyde to an alcohol. The
hydroxymethyl group can be added via a condensation reaction using
formaldehyde and a base, such as sodium hydroxide. After addition
of the hydroxymethyl group, reduction of the intermediate compound
with a 4'-hydroxymethyl group can be conducted using a reducing
reagent. Examples of suitable reducing agents include, but are not
limited to, NaBH.sub.4 and LiAlH.sub.4. A suitable leaving group,
such as a triflate, can be formed by replacing the hydrogen of the
hydroxymethyl group attached to the 4'-position, and the oxygen
attached to the 5'-position can be protected with a suitable
protecting group (for example, by cyclization with the base,
B.sup.1a, or with a separate protecting group). The leaving group
can be replaced with an azido group using a metal azide reagent,
for example, sodium azide.
[0133] A C.sub.1-6 azidoalkyl at the 4'-position can be reduced to
a C.sub.1-6 aminoalkyl. Various reduction agents/conditions known
to those skilled in the art can be utilized. For example, the azido
group can be reduced to an amino group via hydrogenation (for
example, H.sub.2--Pd/C or HCO.sub.2NH.sub.4--Pd/C), Staudinger
Reaction, NaBH.sub.4/CoCl.sub.2*6 H.sub.2O, Fe/NH.sub.4Cl or
Zn/NH.sub.4Cl.
##STR00083##
##STR00084##
[0134] Compounds of Formula (I) having a phosphorus containing
group attached to the 5'-position of the pentose ring can be
prepared using various methods known to those skilled in the art.
Examples of methods are shown in Schemes 3 and 4. In Schemes 3 and
4, R.sup.a, R.sup.2a, R.sup.3a, R.sup.4a, R.sup.5a and B.sup.1a can
be the same as R.sub.A, R.sup.2A, R.sup.3A, R.sup.4A, R.sup.5A and
B.sup.1A as described herein for Formula (I). A phosphorus
containing precursor can be coupled to the nucleoside, for example,
a compound of Formula (B). As shown in Scheme 3, following the
coupling of the phosphorus containing precursor, any leaving groups
can be cleaved under suitable conditions, such as hydrolysis.
Further phosphorus containing groups can be added using methods
known to those skilled in the art, for example using a
pyrophosphate.
[0135] In some embodiments, an alkoxide can be generated from a
compound of Formula (C) using an organometallic reagent, such as a
Grignard reagent. The alkoxide can be coupled to the phosphorus
containing precursor. Suitable Grignard reagents are known to those
skilled in the art and include, but are not limited to,
alkylmagnesium chlorides and alkylmagnesium bromides. In some
embodiments, an appropriate base can be used. Examples of suitable
bases include, but are not limited to, an amine base, such as an
alkylamine (including mono-, di- and tri-alkylamines (e.g.,
triethylamine)), optionally substituted pyridines (e.g. collidine)
and optionally substituted imidazoles (e.g., N-methylimidazole)).
Alternatively, a phosphorus containing precursor can be added to
the nucleoside and form a phosphite. The phosphite can be oxidized
to a phosphate using conditions known to those skilled in the art.
Suitable conditions include, but are not limited to,
meta-chloroperoxybenzoic acid (MCPBA) and iodine as the oxidizing
agent and water as the oxygen donor.
[0136] When compounds of Formula (I) have Z.sup.1A, Z.sup.2A or
Z.sup.3A being sulfur, the sulfur can be added in various manners
known to those skilled in the art. In some embodiments, the sulfur
can be part of the phosphorus containing precursor, for
example,
##STR00085##
Alternatively, the sulfur can be added using a sulfurization
reagent. Suitable sulfurization agents are known to those skilled
in the art, and include, but are not limited to, elemental sulfur,
Lawesson's reagent, cyclooctasulfur,
3H-1,2-Benzodithiole-3-one-1,1-dioxide (Beaucage's reagent),
3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-t-
hione (DDTT) and bis(3-triethoxysilyl)propyl-tetrasulfide
(TEST).
[0137] Suitable phosphorus containing precursors can be
commercially obtained or prepared by synthetic methods known to
those skilled in the art. Examples of general structures of
phosphorus containing precursors are shown in Schemes 3 and 4.
[0138] During the synthesis of any of the compounds described
herein, if desired, any hydroxy groups attached to the pentose
ring, and any --NH and/or NH.sub.2 groups present on the B.sup.1a,
can be protected with one or more suitable protecting groups.
Suitable protecting groups are described herein. For example, when
R.sup.3a is a hydroxy group, R.sup.3a can be protected with a
triarylmethyl group or a silyl group. Likewise, any --NH and/or
NH.sub.2 groups present on the B.sup.1a can be protected, such as
with a triarylmethyl and a silyl group(s). Examples of
triarylmethyl groups include but are not limited to, trityl,
monomethoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr),
4,4',4''-trimethoxytrityl (TMTr). 4,4',4''-tris-(benzoyloxy) trityl
(TBTr), 4,4',4''-tris (4,5-dichlorophthalimido) trityl (CPTr),
4,4',4''-tris (levulinyloxy) trityl (TLTr),
p-anisyl-1-naphthylphenylmethyl, di-o-anisyl-1-naphthylmethyl,
p-tolyldipheylmethyl, 3-(imidazolylmethyl)-4,4'-dimethoxytrityl,
9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl) xanthen-9-yl
(Mox), 4-decyloxytrityl, 4-hexadecyloxytrityl,
4,4'-dioctadecyltrityl, 9-(4-octadecyloxyphenyl) xanthen-9-yl,
1,1'-bis-(4-methoxyphenyl)-1'-pyrenylmethyl,
4,4',4''-tris-(tert-butylphenyl) methyl (TTTr) and 4,4'-di-3,
5-hexadienoxytrityl. Examples of silyl groups include, but are not
limited to, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS),
triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS),
tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl.
Those skilled in the art will appreciate that groups attached to
the pentose ring and any --NH and/or NH.sub.2 groups present on the
B.sup.1a can be protected with various protecting groups, and any
protecting groups present can be exchanged for other protecting
groups. The selection and exchange of the protecting groups is
within the skill of those of ordinary skill in the art. Any
protecting group(s) can be removed by methods known in the art, for
example, with an acid (e.g., a mineral or an organic acid), a base
or a fluoride source.
Pharmaceutical Compositions
[0139] Some embodiments described herein relates to a
pharmaceutical composition, that can include an effective amount of
one or more compounds described herein (e.g., a compound of Formula
(I), or a pharmaceutically acceptable salt thereof) and a
pharmaceutically acceptable carrier, diluent, excipient or
combination thereof.
[0140] The term "pharmaceutical composition" refers to a mixture of
one or more compounds disclosed herein with other chemical
components, such as diluents or carriers. The pharmaceutical
composition facilitates administration of the compound to an
organism. Pharmaceutical compositions can also be obtained by
reacting compounds with inorganic or organic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, and salicylic acid. Pharmaceutical
compositions will generally be tailored to the specific intended
route of administration.
[0141] The term "physiologically acceptable" defines a carrier,
diluent or excipient that does not abrogate the biological activity
and properties of the compound.
[0142] As used herein, a "carrier" refers to a compound that
facilitates the incorporation of a compound into cells or tissues.
For example, without limitation, dimethyl sulfoxide (DMSO) is a
commonly utilized carrier that facilitates the uptake of many
organic compounds into cells or tissues of a subject.
[0143] As used herein, a "diluent" refers to an ingredient in a
pharmaceutical composition that lacks pharmacological activity but
may be pharmaceutically necessary or desirable. For example, a
diluent may be used to increase the bulk of a potent drug whose
mass is too small for manufacture and/or administration. It may
also be a liquid for the dissolution of a drug to be administered
by injection, ingestion or inhalation. A common form of diluent in
the art is a buffered aqueous solution such as, without limitation,
phosphate buffered saline that mimics the composition of human
blood.
[0144] As used herein, an "excipient" refers to an inert substance
that is added to a pharmaceutical composition to provide, without
limitation, bulk, consistency, stability, binding ability,
lubrication, disintegrating ability etc., to the composition. A
"diluent" is a type of excipient.
[0145] The pharmaceutical compositions described herein can be
administered to a human patient per se, or in pharmaceutical
compositions where they are mixed with other active ingredients, as
in combination therapy, or carriers, diluents, excipients or
combinations thereof. Proper formulation is dependent upon the
route of administration chosen. Techniques for formulation and
administration of the compounds described herein are known to those
skilled in the art.
[0146] The pharmaceutical compositions disclosed herein may be
manufactured in a manner that is itself known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or tableting
processes. Additionally, the active ingredients are contained in an
amount effective to achieve its intended purpose. Many of the
compounds used in the pharmaceutical combinations disclosed herein
may be provided as salts with pharmaceutically compatible
counterions.
[0147] Multiple techniques of administering a compound exist in the
art including, but not limited to, oral, rectal, topical, aerosol,
injection and parenteral delivery, including intramuscular,
subcutaneous, intravenous, intramedullary injections, intrathecal,
direct intraventricular, intraperitoneal, intranasal and
intraocular injections.
[0148] One may also administer the compound in a local rather than
systemic manner, for example, via injection of the compound
directly into the infected area, often in a depot or sustained
release formulation. Furthermore, one may administer the compound
in a targeted drug delivery system, for example, in a liposome
coated with a tissue-specific antibody. The liposomes will be
targeted to and taken up selectively by the organ.
[0149] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accompanied with
a notice associated with the container in form prescribed by a
governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the drug for human or veterinary
administration. Such notice, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription
drugs, or the approved product insert. Compositions that can
include a compound described herein formulated in a compatible
pharmaceutical carrier may also be prepared, placed in an
appropriate container, and labeled for treatment of an indicated
condition.
Methods of Use:
[0150] Some embodiments disclosed herein relate to a method of
treating and/or ameliorating a Picomavirus infection that can
include administering to a subject infected with the Picornavirus
an effective amount of one or more compounds described herein (such
as a compound of Formula (I), or a pharmaceutically acceptable salt
thereof), or a pharmaceutical composition that includes a compound
described herein (such as a compound of Formula (I), or a
pharmaceutically acceptable salt thereof). Other embodiments
disclosed herein relate to a method of treating and/or ameliorating
a Picomavirus infection that can include administering to a subject
identified as suffering from the viral infection an effective
amount of one or more compounds described herein (such as a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof), or a pharmaceutical composition that includes a compound
described herein (such as a compound of Formula (I), or a
pharmaceutically acceptable salt thereof).
[0151] Some embodiments described herein relate to using one or
more compounds described herein (such as a compound of Formula (I),
or a pharmaceutically acceptable salt thereof), in the manufacture
of a medicament for ameliorating and/or treating a Picornavirus
infection that can include administering to a subject infected with
the Picornavirus an effective amount of one or more compounds
described herein (such as a compound of Formula (I), or a
pharmaceutically acceptable salt thereof). Still other embodiments
described herein relate to one or more compounds described herein
(such as a compound of Formula (I), or a pharmaceutically
acceptable salt thereof) that can be used for ameliorating and/or
treating a Picornavirus infection by administering to a subject
infected with the Picornavirus an effective amount of one or more
compounds described herein.
[0152] Some embodiments disclosed herein relate to methods of
ameliorating and/or treating a Picornavirus infection that can
include contacting a cell infected with the virus with an effective
amount of one or more compounds described herein (such as a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof), or a pharmaceutical composition that includes one or more
compounds described herein (such as a compound of Formula (I), or a
pharmaceutically acceptable salt thereof). Other embodiments
described herein relate to using one or more compounds described
herein (such as a compound of Formula (I), or a pharmaceutically
acceptable salt thereof), in the manufacture of a medicament for
ameliorating and/or treating a Picornavirus infection that can
include contacting a cell infected with the virus with an effective
amount of said compound(s). Still other embodiments described
herein relate to one or more compounds described herein (such as a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof), that can be used for ameliorating and/or treating a
Picornavirus infection by contacting a cell infected with the virus
with an effective amount of said compound(s).
[0153] Some embodiments disclosed herein relate to methods of
inhibiting replication of a Picornavirus that can include
contacting a cell infected with the virus with an effective amount
of one or more compounds described herein (such as a compound of
Formula (I), or a pharmaceutically acceptable salt thereof), or a
pharmaceutical composition that includes one or more compounds
described herein (such as a compound of Formula (I), or a
pharmaceutically acceptable salt thereof). Other embodiments
described herein relate to using one or more compounds described
herein (such as a compound of Formula (I), or a pharmaceutically
acceptable salt thereof), in the manufacture of a medicament for
inhibiting replication of a Picornavirus that can include
contacting a cell infected with the virus with an effective amount
of said compound(s). Still other embodiments described herein
relate to a compound described herein (such as a compound of
Formula (I), or a pharmaceutically acceptable salt thereof), that
can be used for inhibiting replication of a Picornavirus by
contacting a cell infected with the virus with an effective amount
of said compound(s). In some embodiments, a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, can inhibit a
RNA dependent RNA polymerase of a picornavirus, and thus, inhibit
the replication of RNA. In some embodiments, a polymerase of a
picornavirus can be inhibited by contacting a cell infected with
the picornavirus with a compound described herein (such as a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof).
[0154] In some embodiments, the picornavirus can be selected from
an Aphthovirus, an Enterovirus, a Rhinovirus, a Hepatovirus and a
Parechovirus. Within the Enterovirus genus, there are several
species of Enteroviruses including enterovirus A, enterovirus B,
enterovirus C, enterovirus D, enterovirus E, enterovirus F,
enterovirus G, enterovirus Henterovirus J. Each Enterovirus species
includes several serotypes. Examples of Enterovirus serotypes
include the following: poliovirus 1, poliovirus 2, poliovirus 3,
echovirus 1, echovirus 2, echovirus 3, echovirus 4, echovirus 5,
echovirus 6, echovirus 7, echovirus 9, echovirus 11, echovirus 12,
echovirus 13, echovirus 14, echovirus 15, echovirus 16, echovirus
17, echovirus 18, echovirus 19, echovirus 20, echovirus 21,
echovirus 24, echovirus 25, echovirus 26, echovirus 27, echovirus
29, echovirus 30, echovirus 31, echovirus 32, echovirus 33,
enterovirus 68, enterovirus 69, enterovirus 70, enterovirus 71 and
viluisk human encephalomyelitis virus. In some embodiments, a
compound described herein (for example, a compound of Formula (I),
or a pharmaceutically acceptable salt thereof) can ameliorate
and/or treat an Enterovirus infection. For example, by
administering an effective amount of a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, to a subject infected
with the Enterovirus and/or by contacting a cell infected with the
Enterovirus. In some embodiments, a compound described herein (for
example, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof) can inhibit replication of an Enterovirus.
In some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can be effective against
an Enterovirus, and thereby ameliorate one or more symptoms of an
Enterovirus infection. In some embodiments, the Enterovirus can be
Enterovirus A. In other embodiments, the Enterovirus can be
Enterovirus B. In still other embodiments, the Enterovirus can be
Enterovirus C. In yet still other embodiments, the Enterovirus can
be Enterovirus D. In other embodiments, the Enterovirus can be
Enterovirus E. In still other embodiments, the Enterovirus can be
Enterovirus F. In yet still other embodiments, the Enterovirus can
be Enterovirus G. In some embodiments, the Enterovirus can be
Enterovirus H. In other embodiments, the Enterovirus can be
Enterovirus J.
[0155] Coxsackieviruses are divided into group A and group B. Group
A coxsackieviruses are noted to cause flaccid paralysis, while
group B coxsackieviruses are noted to cause spastic paralysis. Over
20 serotypes of group A (CV-A1, CV-A2, CV-A3, CV-A4, CV-A5, CV-A6,
CV-A7, CV-A8, CV-A9, CV-A10, CV-A11, CV-A12, CV-A13, CV-A14,
CV-A15, CV-A16, CV-A17, CV-A18, CV-A19, CV-A20, CV-A21, CV-A22 and
CV-A23) and 6 serotypes of group B (CV-B1, CV-B2, CV-B3, CV-B4,
CV-B5 and CV-B6) are recognized. No specific treatment for
coxsackievirus infections is currently approved. In some
embodiments, a compound described herein (for example, a compound
of Formula (I), or a pharmaceutically acceptable salt thereof) can
ameliorate and/or treat a coxsackievirus infection. In some
embodiments, a compound described herein (for example, a compound
of Formula (I), or a pharmaceutically acceptable salt thereof) can
inhibit replication of a coxsackievirus. In some embodiments, a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, can be effective against a coxsackievirus as demonstrated
by the amelioration of one or more symptoms of a coxsackievirus
infection. In some embodiments, a coxsackievirus infection can be
ameliorated, treated and/or inhibited by administering an effective
amount of a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, to a subject infected with the
coxsackievirus and/or by contacting a cell infected with the
coxsackievirus. In some embodiments, the coxsackievirus can be a
coxsackievirus A. In other embodiments, the coxsackievirus can be a
coxsackievirus B. In some embodiments, a compound described herein
(one or more a compound of Formula (I), or a pharmaceutically
acceptable salt thereof) can ameliorate and/or treat hand, food and
mouth disease caused by a coxsackie A virus.
[0156] Additional species within the Enterovirus genus includes
rhinovirus A, rhinovirus B and rhinovirus C. In some embodiments, a
compound described herein (for example, a compound of Formula (I),
or a pharmaceutically acceptable salt thereof) can ameliorate
and/or treat a rhinovirus infection. In some embodiments, a
compound described herein (for example, a compound of Formula (I),
or a pharmaceutically acceptable salt thereof) can inhibit
replication of a rhinovirus. In some embodiments, a compound
described herein (for example, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof) can be effective against
multiple serotypes of a rhinovirus. For example, a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, can be
used to ameliorate and/or treat 2, 5, 10, 20, 40, 60, 80 or more
serotypes of a rhinovirus. In some embodiments, a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, can be
effective against rhinovirus, and thereby ameliorating one or more
symptoms of a rhinovirus infection. In some embodiments, a
rhinovirus infection can be ameliorated, treated and/or inhibited
by administering an effective amount of a compound of Formula (I),
or a pharmaceutically acceptable salt thereof, to a subject
infected with the rhinovirus and/or by contacting a cell infected
with the rhinovirus. In some embodiments, the rhinovirus can be
rhinovirus A. In other embodiments, the rhinovirus can be
rhinovirus B. In still other embodiments, the rhinovirus can be
rhinovirus C.
[0157] Another species of Enterovirus is Hepatovirus. Hepatitis A
is a serotype of Hepatovirus. Several human genotypes of Hepatitis
A are known, IA, IB, IIA, IIB, IIIA and IIIB. Genotype I is the
most common. To date, there is no specific therapy for treating a
hepatitis A infection. Rather, treatment is supportive in nature.
In some embodiments, a compound described herein (for example, a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof) can ameliorate and/or treat a Hepatovirus infection, such
as a hepatitis A virus infection. In some embodiments, a compound
described herein (for example, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof) can inhibit replication
of a Hepatovirus (for example, a hepatitis A virus). In some
embodiment, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, can treat and/or ameliorate a genotype I
of hepatitis A. In some embodiments, a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, is effective against
more than one genotype of hepatitis A, for example, 2, 3, 4, 5 or 6
genotypes of hepatitis A. In some embodiments, a Hepatovirus
infection can be ameliorated, treated and/or inhibited by
administering an effective amount of a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, to a subject infected
with the Hepatovirus and/or by contacting a cell infected with the
Hepatovirus.
[0158] Parechovirus is another species of Enterovirus. Serotypes of
Parechovirus includes human parechovirus 1 (echovirus 22), human
parechovirus 2 (echovirus 23), human parechovirus 3, human
parechovirus 4, human parechovirus 5 and human parechovirus 6. In
some embodiments, a compound described herein (for example, a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof) can ameliorate and/or treat a parechovirus infection. In
some embodiments, a compound described herein (for example, a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof) can inhibit replication of a parechovirus. In some
embodiments, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, is effective against more than one
serotype of a parechovirus. In some embodiments, a parechovirus
infection can be ameliorated, treated and/or inhibited by
administering an effective amount of a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, to a subject infected
with the parechovirus and/or by contacting a cell infected with the
parechovirus.
[0159] Other genera of Picornavirus include the following:
Aquamavirus, Avihepatovirus, Cardiovirus, Cosavirus, Dicipivirus,
Erbovirus, Kobuvirus, Megrivirus, Salivirus, Sapelovirus,
Senecavirus, Teschovirus and Tremovirus. In some embodiments, a
compound described herein (for example, a compound of Formula (I),
or a pharmaceutically acceptable salt thereof) can ameliorate
and/or treat a picornavirus infection caused by a virus selected
from Aquamavirus, Avihepatovirus, Cardiovirus, Cosavirus,
Dicipivirus, Erbovirus, Kobuvirus, Megrivirus, Salivirus,
Sapelovirus, Senecavirus, Teschovirus and Tremovirus. In some
embodiments, a compound described herein (for example, a compound
of Formula (I), or a pharmaceutically acceptable salt thereof) can
inhibit replication of a picornavirus selected from Aquamavirus,
Avihepatovirus, Cardiovirus, Cosavirus, Dicipivirus, Erbovirus,
Kobuvirus, Megrivirus, Salivirus, Sapelovirus, Senecavirus,
Teschovirus and Tremovirus. A compound described herein (for
example, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof) can ameliorate, treat and/or inhibit a
virus selected from Aquamavirus, Avihepatovirus, Cardiovirus,
Cosavirus, Dicipivirus, Erbovirus, Kobuvirus, Megrivirus,
Salivirus, Sapelovirus, Senecavirus, Teschovirus and Tremovirus by
administering an effective amount of a compound described herein to
a subject infected by the virus and/or by contacting a cell
infected with the virus with an effective amount of a compound
described herein.
[0160] In some embodiments, an effective amount of a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes an effective amount of one
or more compounds of Formula (I), or a pharmaceutically acceptable
salt thereof, can be effective to treat more than one genera of
Picornavirus. In some embodiments, a compound described herein (for
example, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof) can be used to ameliorate and/or treat
more than one species of a Picornavirus. As an example, a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, can
be used to ameliorate and/or treat 2, 3, 4, 5, or more species of
an Enterovirus. In some embodiments, a compound described herein
(for example, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof) can be effective to treat multiple
serotypes of a Picornavirus described herein. For example, a
compound described herein (one or more a compound of Formula (I),
or a pharmaceutically acceptable salt thereof) can be effective to
treat 2, 5, 10, 15 or more serotypes of a coxsackie virus.
[0161] The one or more compounds of Formula (I), or a
pharmaceutically acceptable salt thereof, that can be used to
treat, ameliorate and/or prevent a picornavirus viral infection can
be a compound of Formula (I), or pharmaceutically acceptable salt
thereof, provided in any of the embodiments described in paragraphs
[0081]-[0127].
[0162] Various indicators for determining the effectiveness of a
method for treating a Picornavirus viral infection are known to
those skilled in the art. Example of suitable indicators include,
but are not limited to, a reduction in viral load, a reduction in
viral replication, a reduction in time to seroconversion (virus
undetectable in patient serum), a reduction of morbidity or
mortality in clinical outcomes, and/or other indicator(s) of
disease response. Further indicators include one or more overall
quality of life health indicators, such as reduced illness
duration, reduced illness severity, reduced time to return to
normal health and normal activity, and reduced time to alleviation
of one or more symptoms. In some embodiments, a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, can result in
the reduction, alleviation or positive indication of one or more of
the aforementioned indicators compared to an untreated subject
(picornavirus). Effects/symptoms of a Picomavirus infection are
described herein, and include, but are not limited to, fever,
blisters, rash, meningitis, conjunctivitis, acute hemorrhagic
conjunctivitis (AHC), sore throat, nasal congestion, runny nose,
sneezing, coughing, loss of appetite, muscle aches, headache,
fatigue, nausea, jaundice, encephalitis, herpangina, myocarditis,
pericarditis, meningitis, Bornholm disease, myalgia, nasal
congestion, muscle weakness, loss of appetite, fever, vomiting,
abdominal pain, abdominal discomfort, dark urine and muscle
pain.
[0163] In some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can result in a reduction
in the length and/or severity of one or more symptoms associated
with a Picornavirus virus infection compared to an untreated
subject (picornavirus). Table 1 provides some embodiments of the
percentage improvements obtained using a compound of Formula (I),
or a pharmaceutically acceptable salt thereof, as compared to an
untreated subject infected with a picornavirus. Examples include
the following: in some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, results in a duration of
illness that is in the range of about 10% to about 30% less than
compared to the duration of illness experienced by an infected
subject who is untreated; and in some embodiments, a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, results
in a severity of a symptom (such as one of those described herein)
that is 25% less than compared to the severity of the same symptom
experienced by an infected subject who is untreated. Methods of
quantifying the severity of a side effect and/or symptom are known
to those skilled in the art.
TABLE-US-00001 TABLE 1 Percentage Percentage of non- Percentage
Percentage of viral load Number of Severity of responders of
relapsers of resistance rebound side effects side effect(s) 10%
less 10% less 10% less 10% less 10% less 10% less 25% less 25% less
25% less 25% less 25% less 25% less 40% less 40% less 40% less 40%
less 40% less 40% less 50% less 50% less 50% less 50% less 50% less
50% less 60% less 60% less 60% less 60% less 60% less 60% less 70%
less 70% less 70% less 70% less 70% less 70% less 80% less 80% less
80% less 80% less 80% less 80% less 90% less 90% less 90% less 90%
less 90% less 90% less about 10% about 10% about 10% about 10%
about 10% about 10% to about to about to about to about to about to
about 30% less 30% less 30% less 30% less 30% less 30% less about
20% about 20% about 20% about 20% about 20% about 20% to about to
about to about to about to about to about 50% less 50% less 50%
less 50% less 50% less 50% less about 30% about 30% about 30% about
30% about 30% about 30% to about to about to about to about to
about to about 70% less 70% less 70% less 70% less 70% less 70%
less about 20% about 20% about 20% about 20% about 20% about 20% to
about to about to about to about to about to about 80% less 80%
less 80% less 80% less 80% less 80% less Duration of Duration of
Duration of Severity of Severity of Severity of illness illness
illness symptom(s) symptom(s) symptom(s) 10% less 60% less about
10% 10% less 60% less about 10% to about to about 30% less 30% less
25% less 70% less about 20% 25% less 70% less about 20% to about to
about 50% less 50% less 40% less 80% less about 30% 40% less 80%
less about 30% to about to about 70% less 70% less 50% less 90%
less about 20% 50% less 90% less about 20% to about to about 80%
less 80% less
[0164] As used herein, a "subject" refers to an animal that is the
object of treatment, observation or experiment. "Animal" includes
cold- and warm-blooded vertebrates and invertebrates such as fish,
shellfish, reptiles and, in particular, mammals. "Mammal" includes,
without limitation, mice, rats, rabbits, guinea pigs, dogs, cats,
sheep, goats, cows, horses, primates, such as monkeys, chimpanzees,
and apes, and, in particular, humans. In some embodiments, the
subject is human.
[0165] As used herein, the terms "prevent" and "preventing," mean
lowering the efficiency of viral replication and/or inhibiting
viral replication to a greater degree in a subject who receives the
compound compared to a subject who does not receive the compound.
Examples of forms of prevention include prophylactic administration
to a subject who has been or may be exposed to an infectious agent,
such as a picornavirus (e.g., an enterovirus and/or a
rhinovirus).
[0166] As used herein, the terms "treat," "treating," "treatment,"
"therapeutic," and "therapy" do not necessarily mean total cure or
abolition of the disease or condition. Any alleviation of any
undesired signs or symptoms of a disease or condition, to any
extent can be considered treatment and/or therapy. Furthermore,
treatment may include acts that may worsen the subject's overall
feeling of well-being or appearance.
[0167] The terms "therapeutically effective amount" and "effective
amount" are used to indicate an amount of an active compound, or
pharmaceutical agent, that elicits the biological or medicinal
response indicated. For example, an effective amount of compound
can be the amount needed to prevent, alleviate or ameliorate
symptoms of disease or prolong the survival of the subject being
treated This response may occur in a tissue, system, animal or
human and includes alleviation of the signs or symptoms of the
disease being treated. Determination of an effective amount is well
within the capability of those skilled in the art, in view of the
disclosure provided herein. The therapeutically effective amount of
the compounds disclosed herein required as a dose will depend on
the route of administration, the type of animal, including human,
being treated, and the physical characteristics of the specific
animal under consideration. The dose can be tailored to achieve a
desired effect, but will depend on such factors as weight, diet,
concurrent medication and other factors which those skilled in the
medical arts will recognize.
[0168] As will be readily apparent to one skilled in the art, the
useful in vivo dosage to be administered and the particular mode of
administration will vary depending upon the age, weight, the
severity of the affliction, and mammalian species treated, the
particular compounds employed, and the specific use for which these
compounds are employed. The determination of effective dosage
levels, that is the dosage levels necessary to achieve the desired
result, can be accomplished by one skilled in the art using routine
methods, for example, human clinical trials and in vitro
studies.
[0169] The dosage may range broadly, depending upon the desired
effects and the therapeutic indication. Alternatively dosages may
be based and calculated upon the surface area of the patient, as
understood by those of skill in the art. Although the exact dosage
will be determined on a drug-by-drug basis, in most cases, some
generalizations regarding the dosage can be made. The daily dosage
regimen for an adult human patient may be, for example, an oral
dose of between 0.01 mg and 3000 mg of each active ingredient,
preferably between 1 mg and 700 mg, e.g. 5 to 200 mg. The dosage
may be a single one or a series of two or more given in the course
of one or more days, as is needed by the subject. In some
embodiments, the compounds will be administered for a period of
continuous therapy, for example for a week or more, or for months
or years. In some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can be administered less
frequently compared to the frequency of administration of an agent
within the standard of care. In some embodiments, a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, can be
administered one time per day. For example, a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, can be
administered one time per day to a subject suffering from a
picornavirus viral infection. In some embodiments, the total time
of the treatment regime with a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can less compared to the
total time of the treatment regime with the standard of care.
[0170] In instances where human dosages for compounds have been
established for at least some condition, those same dosages may be
used, or dosages that are between about 0.1% and 500%, more
preferably between about 25% and 250% of the established human
dosage. Where no human dosage is established, as will be the case
for newly-discovered pharmaceutical compositions, a suitable human
dosage can be inferred from ED.sub.50 or ID.sub.50 values, or other
appropriate values derived from in vitro or in vivo studies, as
qualified by toxicity studies and efficacy studies in animals.
[0171] In cases of administration of a pharmaceutically acceptable
salt, dosages may be calculated as the free base. As will be
understood by those of skill in the art, in certain situations it
may be necessary to administer the compounds disclosed herein in
amounts that exceed, or even far exceed, the above-stated,
preferred dosage range in order to effectively and aggressively
treat particularly aggressive diseases or infections.
[0172] Dosage amount and interval may be adjusted individually to
provide plasma levels of the active moiety which are sufficient to
maintain the modulating effects, or minimal effective concentration
(MEC). The MEC will vary for each compound but can be estimated
from in vitro data. Dosages necessary to achieve the MEC will
depend on individual characteristics and route of administration.
However, HPLC assays or bioassays can be used to determine plasma
concentrations. Dosage intervals can also be determined using MEC
value. Compositions should be administered using a regimen which
maintains plasma levels above the MEC for 10-90% of the time,
preferably between 30-90% and most preferably between 50-90%. In
cases of local administration or selective uptake, the effective
local concentration of the drug may not be related to plasma
concentration.
[0173] It should be noted that the attending physician would know
how to and when to terminate, interrupt, or adjust administration
due to toxicity or organ dysfunctions. Conversely, the attending
physician would also know to adjust treatment to higher levels if
the clinical response were not adequate (precluding toxicity). The
magnitude of an administrated dose in the management of the
disorder of interest will vary with the severity of the condition
to be treated and to the route of administration. The severity of
the condition may, for example, be evaluated, in part, by standard
prognostic evaluation methods. Further, the dose and perhaps dose
frequency, will also vary according to the age, body weight, and
response of the individual patient. A program comparable to that
discussed above may be used in veterinary medicine.
[0174] Compounds disclosed herein can be evaluated for efficacy and
toxicity using known methods. For example, the toxicology of a
particular compound, or of a subset of the compounds, sharing
certain chemical moieties, may be established by determining in
vitro toxicity towards a cell line, such as a mammalian, and
preferably human, cell line. The results of such studies are often
predictive of toxicity in animals, such as mammals, or more
specifically, humans. Alternatively, the toxicity of particular
compounds in an animal model, such as mice, rats, rabbits, or
monkeys, may be determined using known methods. The efficacy of a
particular compound may be established using several recognized
methods, such as in vitro methods, animal models, or human clinical
trials. When selecting a model to determine efficacy, the skilled
artisan can be guided by the state of the art to choose an
appropriate model, dose, route of administration and/or regime.
[0175] As described herein, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can have a moiety(ies)
that neutralize the charge of the phosphate or thiophosphate. By
neutralizing the charge on the phosphate or thiophosphate,
penetration of the cell membrane may be facilitated as a result of
the increased lipophilicity of the compound. Once absorbed and
taken inside the cell, the groups attached to the phosphorus can be
easily removed by esterases, proteases and/or other enzymes. In
some embodiments, the groups attached to the phosphorus can be
removed by simple hydrolysis. Inside the cell, the phosphate thus
released may then be metabolized by cellular enzymes to the
diphosphate or the active triphosphate. Likewise, the
thio-phosphate may be metabolized to the alpha-thiodiphosphate or
the alpha-thiotriphosphate. Furthermore, in some embodiments,
varying the substituents on a compound described herein, such as a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, can help maintain the efficacy of such the compound by
reducing undesirable effects.
[0176] In some embodiments, varying the substituents on a compound
described herein, such as a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can result in the
5'-O-phosphorous being a chiral center. In some embodiments, the
5'-O-phosphorous can be in the (R)-configuration. In some
embodiments, the 5'-O-phosphorous can be in the (S)-configuration.
Examples of the two configurations are:
##STR00086##
In some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can be enriched in (R) or
(S) configuration with respect to the 5'-O-phosphorous. For
example, one of the (R) and (S) configuration with respect to the
5'-O-phosphorous atom can be present in an amount >50%,
.gtoreq.75%, .gtoreq.90%, .gtoreq.95% or .gtoreq.99% compared to
the amount of the other of the (R) or (S) configuration with
respect to the 5'-O-phosphorous atom.
[0177] Additionally, the phosphorylation of a thio-monophosphate of
a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, can be stereoselective. For example, a thio-monophosphate
of a compound of Formula (I) can be phosphorylated to give an
alpha-thiodiphosphate and/or an alpha-thiotriphosphate compound
that can be enriched in the (R) or (S) configuration with respect
to the 5'-O-phosphorous atom. For example, one of the (R) and (S)
configuration with respect to the 5'-O-phosphorous atom of the
alpha-thiodiphosphate and/or the alpha-thiotriphosphate compound
can be present in an amount >50%, .gtoreq.75%, .gtoreq.90%,
.gtoreq.95% or .gtoreq.99% compared to the amount of the other of
the (R) or (S) configuration with respect to the 5'-O-phosphorous
atom.
[0178] In some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can act as a chain
terminator of RNA synthesis. For example, compounds of Formula (I)
can contain a moiety at the 2'-carbon position such that once the
compound is incorporated into an RNA chain, no further elongation
is observed to occur. For example, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can contain a
non-hydrogen 2'-carbon modification such as a halogen, azido, an
optionally substituted C.sub.1-6 alkyl, an optionally substituted
C.sub.2-6 alkenyl or an optionally substituted C.sub.2-6
alkynyl.
[0179] In some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can have increased
metabolic and/or plasma stability. In some embodiments, a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, can
be more resistant to hydrolysis and/or more resistant to enzymatic
transformations. For example, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can have increased
metabolic stability, increased plasma stability, can be more
resistant to hydrolysis and/or can be more resistant to enzymatic
transformations compared to a compound that is identical in
structure but for having R.sup.1A as H, R.sup.A, R.sup.2A,
R.sup.5A, R.sup.a1 and R.sup.a2 are each hydrogen and R.sup.3A and
R.sup.4A are each OH. In some embodiments, a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, can have
improved properties. A non-limiting list of example properties
include, but are not limited to, increased biological half-life,
increased bioavailability, increase potency, a sustained in vivo
response, increased dosing intervals, decreased dosing amounts,
decreased cytotoxicity, reduction in required amounts for treating
disease conditions, reduction in viral load, reduction in time to
seroconversion (i.e., the virus becomes undetectable in patient
serum), increased sustained viral response, a reduction of
morbidity or mortality in clinical outcomes, increased subject
compliance, decreased liver conditions (such as liver fibrosis,
liver cirrhosis and/or liver cancer), and compatibility with other
medications. In some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can have a biological
half-life of greater than 24 hours. In some embodiments, a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, can
have a biological half-life greater than a compound that is
identical in structure but for having R.sup.1A as H, R.sub.A,
R.sup.2A, R.sup.5A, R.sup.a1 and R.sup.a2 are each hydrogen and
R.sup.3A and R.sup.4A are each OH. In some embodiments, a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, can
have more potent antiviral activity compared to a compound that is
identical in structure but for having R.sup.1A as H, R.sup.A,
R.sup.2A, R.sup.5A, R.sup.a1 and R.sup.a2 are each hydrogen and
R.sup.3A and R.sup.4A are each OH.
[0180] Additionally, in some embodiments, the presence of a
moiety(ies) that neutralizes the charge of the phosphate or
thiophosphate can increase the stability of the compound by
inhibiting its degradation. Also, in some embodiments, the presence
of a moiety(ies) that neutralizes the charge of the phosphate or
thiophosphate can make the compound more resistant to cleavage in
vivo and provide sustained, extended efficacy. In some embodiments,
a moiety(ies) that neutralizes the charge of the phosphate or
thiophosphate can facilitate the penetration of the cell membrane
by a compound of Formula (I) by making the compound more
lipophilic. In some embodiments, a moiety(ies) that neutralizes the
charge of the phosphate or thiophosphate can have improved oral
bioavailability, improved aqueous stability and/or reduced risk of
byproduct-related toxicity. In some embodiments, for comparison
purposes, a compound of Formula (I) can be compared to a compound
that is identical in structure but for having R.sup.1A as H,
R.sup.A, R.sup.2A, R.sup.5A, R.sup.a1 and R.sup.a2 are each
hydrogen and R.sup.3A and R.sup.4A are each OH.
Combination Therapies
[0181] In some embodiments, the compounds disclosed herein, such as
a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition that includes a compound
described herein, or a pharmaceutically acceptable salt thereof,
can be used in combination with one or more additional agent(s) for
treating, ameliorating and/or inhibiting a Picornavirus viral
infection.
[0182] In some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can be administered with
one or more additional agent(s) together in a single pharmaceutical
composition. In some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can be administered with
one or more additional agent(s) as two or more separate
pharmaceutical compositions. For example, a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, can be
administered in one pharmaceutical composition, and at least one of
the additional agents can be administered in a second
pharmaceutical composition. If there are at least two additional
agents, one or more of the additional agents can be in a first
pharmaceutical composition that includes a compound of Formula (I),
or a pharmaceutically acceptable salt thereof, and at least one of
the other additional agent(s) can be in a second pharmaceutical
composition.
[0183] The dosing amount(s) and dosing schedule(s) when using a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition that includes a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, and
one or more additional agents are within the knowledge of those
skilled in the art. For example, when performing a conventional
standard of care therapy using art-recognized dosing amounts and
dosing schedules, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition that
includes a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, can be administered in addition to that
therapy, or in place of one of the agents of a combination therapy,
using effective amounts and dosing protocols as described
herein.
[0184] The order of administration of a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, with one or more
additional agent(s) can vary. In some embodiments, a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, can be
administered prior to all additional agents. In other embodiments,
a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, can be administered prior to at least one additional
agent. In still other embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can be administered
concomitantly with one or more additional agent(s). In yet still
other embodiments, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, can be administered subsequent to the
administration of at least one additional agent. In some
embodiments, a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, can be administered subsequent to the
administration of all additional agents.
[0185] In some embodiments, the combination of a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, in
combination with one or more additional agent(s) can result in an
additive effect. In some embodiments, the combination of a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, used
in combination with one or more additional agent(s) can result in a
synergistic effect. In some embodiments, the combination of a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, used in combination with one or more additional agent(s)
can result in a strongly synergistic effect. In some embodiments,
the combination of a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, in combination with one or more additional
agent(s) is not antagonistic.
[0186] As used herein, the term "antagonistic" means that the
activity of the combination of compounds is less compared to the
sum of the activities of the compounds in combination when the
activity of each compound is determined individually (i.e. as a
single compound). As used herein, the term "synergistic effect"
means that the activity of the combination of compounds is greater
than the sum of the individual activities of the compounds in the
combination when the activity of each compound is determined
individually. As used herein, the term "additive effect" means that
the activity of the combination of compounds is about equal to the
sum of the individual activities of the compound in the combination
when the activity of each compound is determined individually.
[0187] A potential advantage of utilizing a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, in combination
with one or more additional agent(s) may be a reduction in the
required amount(s) of one or more additional agent(s) that is
effective in treating a disease condition disclosed herein (for
example, picornavirus virus infection), as compared to the amount
required to achieve same therapeutic result when one or more
additional agent(s) are administered without a compound of Formula
(I), or a pharmaceutically acceptable salt thereof. Another
potential advantage of utilizing a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, in combination with one
or more additional agent(s) is that the use of two or more
compounds having different mechanism of actions can create a higher
barrier to the development of resistant viral strains compared to
the barrier when a compound is administered as monotherapy.
[0188] Additional advantages of utilizing a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, in combination
with one or more additional agent(s) may include little to no cross
resistance between a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, and one or more additional agent(s)
thereof; different routes for elimination of a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, and one or more
additional agent(s); little to no overlapping toxicities between a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, and one or more additional agent(s); little to no
significant effects on cytochrome P450; little to no
pharmacokinetic interactions between a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, and one or more
additional agent(s); greater percentage of subjects achieving a
sustained viral response compared to when a compound is
administered as monotherapy and/or a decrease in treatment time to
achieve a sustained viral response compared to when a compound is
administered as monotherapy.
[0189] For treating of a picornavirus virus infection, examples of
additional agents that can be used in combination with a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes a compound of Formula (I),
or a pharmaceutically acceptable salt thereof, include, but are not
limited to, ribavirin and an interferon (including those described
herein).
EXAMPLES
[0190] Additional embodiments are disclosed in further detail in
the following examples, which are not in any way intended to limit
the scope of the claims.
Example 1
Preparation of Compound 14
##STR00087## ##STR00088##
[0192] Into a 250-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of N.sub.2, was placed a
solution of uracil (500 mg, 4.46 mmol, 1.99 eq.) in MeCN (15 mL).
N,O-Bis(trimethylsilyl)acetamide (2.7 g, 13.27 mmol, 5.93 eq.)
added. The solution was stirred for 0.5 h at 80.degree. C. in an
oil bath. A solution of 14-1 (1 g, 2.24 mmol, 1.00 eq.) in MeCN (5
mL) was added dropwise with stirring at RT (room temperature). Tin
tetrachloride (1.2 g, 4.62 mmol, 2.06 eq.) was added dropwise with
stirring at RT. The solution was stirred for 0.5 h at 80.degree. C.
in an oil bath. The reaction was quenched by the addition of aq.
sodium bicarbonate (200 mL) and extracted with EA (ethyl acetate)
(2.times.200 mL). The combined organic layers were dried over
anhydrous sodium sulfate. After concentrated under reduced
pressure, the crude product was purified by a silica gel column
with EA:PE (2:1). Compound 14-2 (1.1 g, 99%) was obtained as a
white solid. MS (ESI): m/z 499 [M+H].sup.+.
[0193] Into a 100-mL round-bottom flask, was placed a solution of
14-2 (3.7 g, 7.42 mmol, 1.00 eq.) in CH.sub.3OH (30 mL). Sodium
methoxide (30% in CH.sub.3OH, 1 mL) was added. The solution was
stirred for 6 h at 30.degree. C. The pH value was adjusted to 7
with acetic acid. After concentrated under reduced pressure, the
crude product was purified by a silica gel column with
CH.sub.2Cl.sub.2:CH.sub.3OH (20:1). Compound 14-3 (3.2 g, 94%) was
obtained as a white solid. MS (ESI): m/z: 457 [M+H].sup.+.
[0194] Into a 100-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of Ar, was placed a solution of
14-3 (4.16 g, 9.11 mmol, 1.00 eq.) in DMF (40 mL).
1,8-Diazabicyclo[5.4.0]undec-7-ene (4.16 g, 27.33 mmol, 2.00 eq.)
was added followed by the dropwise addition of benzyloxymethyl
chloride (2.14 g, 13.66 mmol, 1.50 eq.) with stirring at 0.degree.
C. The solution was stirred for 2 h at 0.degree. C. in an ice bath.
The reaction was quenched by the addition of CH.sub.3OH (5 mL). The
solution was diluted with CH.sub.2Cl.sub.2 (200 mL), washed with
water (2.times.50 mL) and aq. NaCl (1.times.50 mL), dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The crude product was purified by a silica gel column
with EA:PE (1:3). Compound 14-4 (4.05 g, 76%) was obtained as a
light yellow oil. MS (ESI): m/z: 577 [M+H].sup.+.
[0195] Into a 100-mL 2-necked round-bottom flask purged and
maintained with an inert atmosphere of Ar, was placed a solution of
14-4 (1 g, 1.73 mmol, 1.00 eq.) and 4-dimethylaminopyridine (1.06
g, 8.68 mmol, 5.00 eq.) in CH.sub.2Cl.sub.2 (20 mL).
Trifluoromethanesulfonyl chloride (1.06 g, 3.76 mmol, 2.00 eq.) was
added dropwise with stirring at 0.degree. C. The solution was
stirred for 3 h at 25.degree. C. The reaction was quenched with
cooled aq. sodium bicarbonate, extracted with CH.sub.2Cl.sub.2
(2.times.50 mL). The combined organic layers were washed with aq.
NaCl (5 mL) dried over anhydrous sodium sulfate and filtered. The
solution was concentrated under reduced pressure. The crude
triflate (.about.600 mg) was obtained. Into another 50-mL
round-bottom flask purged and maintained with an inert atmosphere
of Ar, was placed a solution of the triflate (600 mg, 0.85 mmol,
1.00 eq.) in DMF (6 mL). 15-Crown-5 (600 mg, 3.00 eq.) and sodium
azide (330 mg, 5.08 mmol, 5.00 eq.) were added. The solution was
stirred for 16 h at 25.degree. C. The solution was then diluted
with CH.sub.2Cl.sub.2 (50 mL), washed with water (25 mL) and aq.
NaCl (25 mL), dried over anhydrous sodium sulfate and filtered.
After concentrated under reduced pressure, the crude product was
purified by a silica gel column with EA:PE (3:1). Compound 14-5
(230 mg, 21%) was obtained as an oil. MS (ESI): m/z: 602
[M+H].sup.+.
[0196] Into a 25-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 14-5 (400 mg,
0.66 mmol, 1.00 eq.) in CH.sub.2Cl.sub.2 (4 mL). Trichloroborane
(1M in dichloromethane, 4 mL) was added dropwise with stirring at
-78.degree. C. The solution was stirred for 2 h at 25.degree. C.
The reaction was quenched by the addition of CH.sub.3OH (4 mL). The
solution was concentrated under reduced pressure. The crude product
(200 mg) was purified by prep-HPLC with the following conditions:
Column, X Bridge C18, 19*150 mm, 5 um; mobile phase, A:
water/ammonium bicarbonate (10 mmol/L), Mobile Phase B: MeCN;
Gradient: 5% B to 25% B in 10 min; Detector, 254 nm. Compound 14-6
(52.6 mg, 26%) was obtained as a white solid. MS (ESI): m/z: 302
[M+H].sup.+.
[0197] Into a 50-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 14-6 (300 mg,
1.00 mmol, 1.00 eq.) in pyridine (3 mL). Acetyl acetate (300 mg,
2.94 mmol, 3.00 eq.) was added. The solution was stirred for 16 h
at 25.degree. C. After concentrated under reduced pressure, the
residue was diluted with CH.sub.2Cl.sub.2 (50 mL), washed with 1N
aq. HCl (25 mL) and aq. NaCl (25 mL), dried over anhydrous sodium
sulfate and filtered. After concentrated under reduced pressure,
the crude product was purified by a silica gel column with EA:PE
(1:1). Compound 14-7 (305 mg, 78%) was obtained as a white solid.
MS (ESI): m/z: 386 [M+H].sup.+.
[0198] Into a 50-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 14-7 (350 mg,
0.91 mmol, 1.00 eq.) in MeCN (7 mL). N,N-dimethylpyridin-4-amine
(150 mg, 1.23 mmol, 1.00 eq.), triethylamine (275 mg, 2.72 mmol,
3.00 eq.) and 2,4,6-triisopropylbenzenesulfonyl chloride (826 mg,
2.73 mmol, 3.00 eq.) were added. The solution was stirred for 2 h
at 25.degree. C. Ammonium hydroxide (7 mL, 28%) was added, and the
solution was stirred for 2 h at 25.degree. C. After concentrated
under reduced pressure, the crude product (1.3 g) was purified by
prep-HPLC with the following conditions: Column, X Bridge C18,
19*150 mm, 5 um; mobile phase, A: Water/ammonium bicarbonate (10
mmol/L), Mobile Phase B: MeCN; Gradient: 5% B to 15% B in 10 min;
Detector, 254 nm. Compound 14 (60.4 mg, 22%) was obtained as a
white solid. MS (ESI): m/z: 301 [M+H].sup.+.
Example 2
Preparation of Compound 2
##STR00089##
[0200] Into a 100-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 14-4 (2 g, 3.47
mmol, 1.00 eq.) in THF (60 mL). 4-dimethylaminopyridine (2.12 g,
17.35 mmol, 5.00 eq.) was added. A solution of
trifluoromethanesulfonyl chloride (1.17 g, 6.94 mmol, 2.00 eq.) in
THF (5 mL) was then added dropwise with stirring at 0.degree. C.
The solution was stirred for 2 h at 25.degree. C. The reaction was
quenched with aq. sodium bicarbonate (20 mL) and extracted with
CH.sub.2Cl.sub.2 (2.times.100 mL). The combined organic layers were
washed with 1 N aq. HCl (50 mL) and aq. NaCl (50 mL), dried over
anhydrous sodium sulfate and filtered. After concentrated under
reduced pressure, the crude product was purified by a silica gel
column with EA:PE (1:3). Compound 2-1 (630 mg, 31%) was obtained as
a white solid. MS (ESI): m/z: 595 [M+H].sup.+.
[0201] Into a 25-mL round-bottom flask, was placed a solution of
2-1 (350 mg, 0.59 mmol, 1.00 eq.) in CH.sub.2Cl.sub.2:CH.sub.3OH
(10 mL, 1:1). Palladium hydroxide on carbon (350 mg) was added. The
mixture was stirred for 16 h at 25.degree. C. under H.sub.2. The
solids were filtered off. The solution was concentrated under
reduced pressure. The crude product (175 mg) was purified by
prep-HPLC with the following conditions: Column, X Bridge C18,
19*150 mm, 5 um; mobile phase, A: water/ammonium bicarbonate (10
mmol/L), Mobile Phase B: MeCN; Gradient: 5% B to 25% B in 15 min;
Detector, 254 nm. Compound 2-2 (58.9 mg, 34%) was obtained as a
white solid. MS (ESI): m/z: 295 [M+H].sup.+.
[0202] Into a 25-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 2-2 (300 mg,
1.02 mmol, 1.00 eq.) in pyridine (5 mL). Acetic anhydride (322 mg,
3.15 mmol, 3.00 eq.) was added. The solution was stirred for 3 h at
25.degree. C. The reaction was quenched by CH.sub.3OH (1 mL). The
solution was diluted with CH.sub.2Cl.sub.2 (100 mL), washed with 1
N aq. HCl (20 mL) and aq. NaCl (20 mL), dried over anhydrous sodium
sulfate and filtered. The solution was concentrated under reduced
pressure to give 2-3 (300 mg, 78%) as a white solid. MS (ESI): m/z:
379 [M+H].sup.+.
[0203] Into a 50-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 2-3 (300 mg,
0.79 mmol, 1.00 eq.) in MeCN (5 mL). 4-dimethylaminopyridine (96.8
mg, 0.79 mmol, 1.00 eq.) and triethylamine (240 mg, 2.37 mmol, 3.00
eq.) were added. 2,4,6-Triisopropylbenzenesulfonyl chloride (721
mg, 2.38 mmol, 3.00 eq.) was then added. The solution was stirred
for 2 h at 25.degree. C. and then ammonium hydroxide (5 mL, 28%)
was added. The solution was stirred for 2 h at 25.degree. C. The
solution was concentrated under reduced pressure. The crude product
(1.1 g) was purified by prep-HPLC with the following conditions:
Column, X Bridge C18, 19*150 mm, 5 um; mobile phase, A:
water/ammonium hydroxide (10 mmol/L), Mobile Phase B: MeCN;
Gradient: 5% B to 15% B in 10 min; Detector, 254 nm. Compound 2
(51.8 mg, 22%) was obtained as a white solid. MS (ESI): m/z: 294
[M+H].sup.+.
Example 3
Preparation of Compound 3
##STR00090## ##STR00091## ##STR00092##
[0205] To a solution of 3-1 (8.67 g, 35.2 mmol) in anhydrous
pyridine (50 mL) was added TBSCl (5.84 g, 38.7 mmol). The reaction
was stirred over 18 h. at 20.degree. C. The solution was
concentrated under reduced pressure, and the residue was
partitioned between EA and water. The organic layer was separated,
washed with brine, and dried over anhydrous sodium sulfate. The
solution was concentrated under reduced pressure to give 3-2 (12 g,
95%) as white foam.
[0206] To a solution of the 3-2 (12 g, 33.3 mmol) in anhydrous DCM
(100 mL) were added AgNO.sub.3 (11.8 g, 69.4 mmol) and collidine
(12.6 g, 0.1 mol), and the mixture was stirred at 20.degree. C. The
mixture was cooled to 0.degree. C. and MMTrCl (11.8 g, 38.2 mmol)
was added. After being stirred 18 h at RT, the solid was filtered.
The filtrate was washed with HCl solution (0.1 N) and brine. The
organic solution was dried over anhydrous MgSO.sub.4 and
concentrated under vacuum to give 3-3, which was used directly for
next step.
[0207] Crude 3-3 was dissolved in THF (150 mL) and TBAF (10.8 g, 42
mmol) was added. The reaction was stirred at 20.degree. C. for 12
h. The mixture was evaporated at low pressure, and the residue was
purified by silica gel directly to give 3-4 (13.8 g, 81%, over 2
steps) as a slightly yellow solid.
[0208] To a solution of 3-4 (13 g, 25 mmol) in DCM (100 mL) was
added pyridine (6.9 g, 87 mmol). The solution was cooled to
0.degree. C., and then Dess-Martin periodinane (13.5 g, 32 mmol)
was added as a single portion. The reaction was stirred at RT over
18 h. The reaction was quenched with 4% Na.sub.2S.sub.2O.sub.3/4%
Na.sub.2CO.sub.3 aqueous solution (adjusted pH to .about.6). The
mixture was stirred for 15 mins. The organic layer was separated
and washed with brine. The solution was concentrated under reduced
pressure, and the residue was purified by silica gel to afford 3-5
(9.5 g, 73%) as a yellow oil.
[0209] To a solution of 3-5 (9.5 g, 18.4 mmol) in dioxane (50 mL)
was added 37% aq. formaldehyde (10 mL) and aq. NaOH (2 N, 20 mL),
and the mixture was stirred at RT overnight. The mixture was then
cooled to 0.degree. C. and treated with sodium borohydride (3.5 g,
84 mmol). After stirring for 30 mins at RT, the reaction was
quenched by sat. aq. NH.sub.4Cl. The residue was dissolved in EA
(60 mL). The solution was washed brine and dried over anhydrous
MgSO.sub.4. The organic solvent was concentrated under reduced
pressure. The residue was purified by silica gel to afford 3-6 (8.0
g, 83%) as a yellow oil.
[0210] Compound 3-6 (5.0 g, 9.1 mmol) was co-evaporated with
toluene (2.times.). The residue was dissolved in anhydrous DCM (30
mL) and pyridine (3.6 g, 45.5 mmol). The solution was cooled to
-35.degree. C., and then triflic anhydride (5.66 g, 20.1 mmol) was
added dropwise over 10 mins. The mixture was slowly warmed to RT
and then stirred at RT for 1.5 h. The reaction was quenched with
water, and the mixture was washed with sodium bicarbonate. The
organic layer was dried over anhydrous MgSO.sub.4 and concentrated
at low pressure. The residue was purified by silica gel to afford
3-7 (5.5 g, 75%) as a yellow foam.
[0211] Compound 3-7 (5.5 g, 6.77 mmol) was dissolved in anhydrous
DMF (20 mL). The solution was cooled to 0.degree. C. and then
treated with NaH (60% in mineral oil, 0.3 g, 7.44 mmol). The
mixture was stirred at RT for 1 h. LiCl (0.86 g, 20.3 mmol) was
added, and the mixture was stirred for 2 h. The mixture was
evaporated by vacuum to afford crude 3-8, which was used directly
for next step.
[0212] To a solution of 3-8 in THF (40 mL) was added NaOH (2.0 N,
5.5 mL), and the mixture stirred at RT for 2 h. After the solvent
was evaporated at low pressure, the residue was dissolved in DCM
(40 mL). The solution was washed with sat. aq. NH.sub.4Cl and
brine. The organic layer was dried over anhydrous MgSO.sub.4 and
concentrated at low pressure. The residue was purified by silica
gel to afford 3-9 (3.75 g, 83%).
[0213] To a solution of 3-9 (3.75 g, 6.6 mmol) and imidazole (0.676
g, 9.9 mmol) in DCM (30 mL) was added TBSCl (1.1 g, 7.3 mmol) and
AgNO.sub.3 (1.68 g, 9.9 mmol), and the mixture stirred at RT
overnight. After the solid was filtered off, the filtrate was
washed with sat. aq. Na.sub.2CO.sub.3. The organic layer was washed
with sat. aq. NH.sub.4Cl, dried over anhydrous MgSO.sub.4 and
concentrated at low pressure. The residue was purified by silica
gel to afford 3-10 (2.7 g, 60%) as a yellow solid.
[0214] To a solution of 3-10 (2.25 g, 3.3 mmol) in MeCN was added
DMAP (0.8 g, 6.6 mmol) and TEA (0.67 g, 6.6 mmol), and the mixture
stirred at RT for 10 mins. The mixture was treated with TPSCl (2.0
g, 6.6 mmol) and then stirred for 30 mins. NH.sub.3--H.sub.2O (20
mL) was added, and the solution was stirred for 1 h. The mixture
was evaporated at low pressure, and the residue was purified by
silica gel to afford 3-11 (2.0 g, 88%).
[0215] To a solution of 3-11 (2.6 g, 3.82 mmol) and collidine (1.4
g, 11.5 mmol) in anhydrous DCM (40 mL) was added DMTrCl (3.88 g,
11.5 mmol) and AgNO.sub.3 (1.95 g, 11.5 mmol) at 0.degree. C. The
mixture was stirred at RT under N.sub.2 for 2 h. The mixture was
filtered, and the filtrate was evaporated at low pressure. The
residue was purified by silica gel to afford 3-12 (2.8 g, 75%) as a
slightly yellow oil.
[0216] A mixture of 3-12 (2.5 g, 2.54 mmol) and TBAF (0.73 g, 2.8
mmol) in THF was stirred at RT for 2 h. The mixture was evaporated
at low pressure, and the residue was purified by silica gel to
afford 3-13 (1.9 g, 86%).
[0217] Compound 3-13 (1.5 g, 1.53 mmol) was dissolved in
CH.sub.3COOH (80%, 20 mL). The mixture was stirred at 60-70.degree.
C. for 2 h. The reaction was quenched with CH.sub.3OH, and the
mixture was concentrated at low pressure. The residue was purified
by silica gel to afford 3 (0.32 g, 70%) as a white solid. MS (ESI):
m/z: 293.9 [M+H].sup.+.
Example 4
Preparation of Compound 4
##STR00093## ##STR00094##
[0219] To a stirred solution of 4-1 (2.8 g, 5.21 mmol) in DCM (25
mL) was added pyridine (2.1 g, 26.07 mmol) at 25.degree. C. The
solution was cooled to -35.degree. C., and then Tf.sub.2O (3.2 g,
11.47 mmol) was added dropwise. The mixture was stirred at
-35.degree. C.-25.degree. C. for 2 h. The reaction was quenched
with H.sub.2O at 25.degree. C. The mixture was extracted with DCM.
The organic layer was washed with a sat. sodium bicarbonate
solution, dried over anhydrous MgSO.sub.4, and concentrated at low
pressure. The residue was purified by column chromatography
PE:EA=10:1 to 0:1). Compound 4-2 (3.0 g, 71.5%) was obtained as a
black brown solid.
[0220] To a solution of 4-2 (3.0 g, 3.72 mmol) in DCM (30 mL) was
added TEA (755 mg, 7.45 mmol). The mixture was stirred at
25.degree. C. for 6 h. The mixture was concentrated under reduced
pressure, and the residue was purified by column chromatography
(PE:EA=5:1 to 1:1). Compound 4-3 (2.2 g, 69%) was obtained as a
black brown solid.
[0221] To a solution of 4-3 (2 g, 3.02 mmol) in DMF (20 mL) was
added NaN.sub.3 (785 mg, 12.08 mmol). The mixture was stirred at
25.degree. C. for 1 h. The mixture was diluted with EA (40 mL). The
solution was washed with brine and dried over anhydrous MgSO.sub.4.
The organic layer was concentrated under reduced pressure. Crude
4-4 (1.7 g) was used for the next step without further
purification.
[0222] To a solution of 4-4 (1.7 g, crude) in THF (17 mL) was added
NaOH (2 M, 2 mL). The mixture was stirred at 25.degree. C. for 5 h.
The mixture was diluted with H.sub.2O and extracted with EA
(3.times.40 mL). The combined organic layers were washed with
NH.sub.4Cl, filtered and concentrated under reduced pressure to
give a residue. The residue was purified by column chromatography
(PE:EA=8:1 to 2:1). Compound 4-5 (719 mg, 41.1%) was obtained as a
light brown solid.
[0223] To a solution of 4-5 (719 mg, 1.25 mmol) in CH.sub.2Cl.sub.2
(5 mL) was added imidazole (299 mg, 4.38 mmol) and TBSCl (472 mg,
3.13 mmol). The mixture was stirred at 25.degree. C. for 4 h. The
reaction mixture was diluted with water and extracted with
CH.sub.2Cl.sub.2 (3.times.20 mL). The organic layer was dried over
anhydrous MgSO.sub.4 and concentrated at low pressure. The residue
was purified by column chromatography (PE:EA=8:1 to 3:1). Compound
4-6 (640 mg, 74.2%) was obtained as a light yellow solid.
[0224] To a solution of 4-6 (640 mg, 0.93 mmol) in MeCN (6 mL) was
added DMAP (284 mg, 2.32 mmol), TEA (235 mg, 2.32 mmol) and
2,4,6-triisopropylbenzenesulfonyl chloride (704 mg, 2.32 mmol). The
mixture was stirred at 25.degree. C. for 1 h. NH.sub.3--H.sub.2O (5
mL) was added, and the mixture was stirred at 25.degree. C. for 1
h. The mixture was diluted with H.sub.2O and extracted with EA
(3.times.20 mL). The organic layer was dried over anhydrous
MgSO.sub.4, and concentrated at low pressure. The residue was
purified by column chromatography (PE:EA=5:1 to 1:1). Compound 4-7
(461 mg, 72.1%) was obtained as a light yellow solid.
[0225] A solution of 4-7 (250 mg, 363.98 .mu.mol) in HCOOH (4 mL)
was stirred at 50.degree. C. for 16 h. The mixture was concentrated
under reduced pressure, and the residue was dissolved in CH.sub.3OH
(3 mL). NH.sub.3/CH.sub.3OH (7 M, 1 mL) was added, and the mixture
was stirred at 25.degree. C. for 4 h. The mixture was concentrated
under reduced pressure, and the residue was purified by column
chromatography (DCM:CH.sub.3OH=50:1 to 10:1). Compound 4 (85 mg,
77%) was obtained as a white solid. MS (ESI): m/z: 301.1
[M+H].sup.+.
Example 5
Preparation of Compound 5
##STR00095##
[0227] To an ice-cold solution of 5-1 (2.00 g, 1.82 mmol, 1.00 eq.)
in anhydrous DCM (10.00 mL) was added pyridine (1.44 g, 18.23 mmol,
10.00 eq.). A solution of trifluoromethylsulfonyl
trifluoromethanesulfonate (1.18 g, 4.19 mmol, 2.30 eq.) in DCM
(3.50 mL) was added by dropwise at 0.degree. C. The mixture was
stirred at 0.degree. C. for 0.5 h. The mixture was concentrated
under reduced pressure to give a residue. The residue was purified
by column chromatography (20% EA in PE) to give 5-2 (2.00 g,
67.61%) as a white solid.
[0228] To a solution of 5-2 (2.00 g, 1.23 mmol, 1.00 eq.) in
anhydrous DMF (10.00 mL) was added NaH (59 mg, 1.48 mmol, 1.20 eq.)
at 0.degree. C. under N.sub.2. The mixture was stirred at
20.degree. C. for 1 h. The mixture was treated with LiCl (156 mg,
3.69 mmol, 3.00 eq.) at 0.degree. C. The reaction was stirred at
20.degree. C. for 2 h. The mixture was diluted with EA (50 mL), and
washed with sat. NH.sub.4Cl solution. The solution was dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The residue was used for the next step without further
purification.
[0229] The residue was dissolved in THF (10.00 mL). The mixture was
treated with NaOH solution (1 M, 1.35 mL, 1.10 eq.) at 20.degree.
C. The mixture was stirred at the same temperature for 1 h. The
reaction was diluted with EA (30 mL), and washed with a sat.
NH.sub.4Cl solution. The organic layer was dried over anhydrous
MgSO.sub.4, filtered and concentrated under reduced pressure. The
residue was purified by column chromatography (30% EA in PE) to
give 5-3 (740 mg, 53.05%) as a white solid.
[0230] Compound 5-3 (300 mg, 529.10 .mu.mol, 1.00 eq.) was
dissolved in 80% CHOOH (10.00 mL), and the mixture was stirred at
20.degree. C. for 16 h. The mixture was concentrated under reduced
pressure. The residue was purified by column chromatography (5%
CH.sub.3OH in DCM) to give the crude product. The crude product was
purified by prep-HPLC (neutral condition) to give 5 (71 mg, 45.54%)
as a white solid. MS (ESI): m/z: 295 [M+H].sup.+.
Example 6
Preparation of Compound 6
##STR00096## ##STR00097##
[0232] To a solution of 6-1 (2.9 g, 5.21 mmol) in DCM (25 mL) was
added pyridine (2.1 g, 26.07 mmol) at 25.degree. C. The solution
was cooled to -35.degree. C., and then Tf.sub.2O (3.2 g, 11.47
mmol) was added dropwise. The mixture was stirred at -35.degree.
C.-25.degree. C. for 2 h. The reaction was quenched with H.sub.2O
and extracted with DCM (3.times.50 mL). The solution was washed
with sat. sodium bicarbonate solution and brine. The organic layer
was dried over anhydrous MgSO.sub.4, and concentrated at low
pressure. The residue was purified by column chromatography
(PE:EA=10:1 to 0:1). Compound 6-2 (3.0, 71.5%) was obtained as a
black brown solid.
[0233] To a solution of 6-2 (3.0 g, 3.72 mmol) in DCM (30 mL) was
added TEA (755 mg, 7.45 mmol). The mixture was stirred at
25.degree. C. for 6 h. The mixture was concentrated under reduced
pressure, and the residue was purified by column chromatography
(PE:EA=5:1 to 1:1). Compound 6-3 (2.2 g, 69%) was obtained as a
black brown solid.
[0234] To a solution of 6-3 (730 mg, 1.10 mmol) in DMF (7 mL) was
added LiBr (287 mg, 3.30 mmol). The mixture was stirred at
25.degree. C. for 16 h. The mixture was concentrated under reduced
pressure. Crude 6-4 (653 mg) was used for the next step without
further purification.
[0235] To a solution of 6-4 (653 mg, 1.10 mmol) in THF (6 mL) was
added NaOH solution (2 M, 600 .mu.L). The mixture was stirred at
25.degree. C. for 6 h. After the solvent was evaporated at low
pressure, the residue was dissolved in EA (40 mL) and washed with
sat. NH.sub.4Cl solution and brine. The organic layer was dried
over anhydrous MgSO.sub.4, and concentrated at low pressure. The
residue was purified by column chromatography (PE:EA=10:1 to
2.5:1). Compound 6-5 (281 mg, 41.7%) was obtained as a light yellow
solid.
[0236] To a solution of 6-5 (281 mg, 459 .mu.mol) in pyridine (2.5
mL) was added TBSCl (121 mg, 804 .mu.mol) and imidazole (78 mg,
1.15 mmol) at 25.degree. C. The mixture was stirred at 60.degree.
C. for 4 h. The mixture was diluted with water and extracted with
CH.sub.2Cl.sub.2 (20 mL). The organic layer was washed with brine,
dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by column chromatography
(PE:EA=5:1 to 1:1). Compound 6-6 (204 mg, 61.1%) was obtained as
light yellow solid.
[0237] To a solution of 6-6 (204 mg, 281 .mu.mol) in anhydrous MeCN
(1.5 mL) were added 2,4,6-triisopropylbenzenesulfonyl chloride (213
mg, 702 .mu.mol), DMAP (85 mg, 702 .mu.mol) and TEA (71 mg, 702
.mu.mol) at 25.degree. C. The mixture was stirred at 25.degree. C.
for 2 h. NH.sub.3*H.sub.2O (3 mL) was added, and the mixture was
stirred for 1 h. The mixture was diluted with EA and washed with
water. The organic layer was dried over anhydrous MgSO.sub.4, and
concentrated at low pressure. The residue was purified by column
chromatography (PE:EA=10:1 to 0:1). Compound 6-7 (180 mg, 88.3%)
was obtained as a light yellow solid.
[0238] A solution of 6-7 (180 mg, 248.36 .mu.mol) in HCOOH (1 mL)
was stirred at 25.about.50.degree. C. for 17 h. The mixture was
concentrated under reduced pressure. The residue was dissolved in
CH.sub.3OH (2 mL) and NH.sub.3/CH.sub.3OH (7 M, 800 .mu.L). The
mixture was stirred at 25.degree. C. for 1 h. The =mixture was
concentrated under reduced pressure. The residue was purified by
column chromatography (DCM:CH.sub.3OH=30:1 to 10:1). Compound 6 (76
mg, 90.2%) was obtained as a white solid. MS (ESI): m/z: 677.1
[2M+H].sup.+.
Example 7
Preparation of Compound 7
##STR00098##
[0240] To a solution of 7-1 (1.0 g, 1.8 mmol) in DCM (10 mL) was
added pyridine (1.4 g, 18.2 mmol) and Tf.sub.2O (1.1 g, 4.0 mmol)
dropwise at 0.degree. C. The mixture was stirred at 0.degree. C.
for 1 h. The reaction was quenched with H.sub.2O (30 mL) at
0.degree. C. The mixture was extracted with DCM (2.times.20 mL).
The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give a residue.
The residue was purified by column chromatography (10% EA in PE) to
give 7-2 (1.2 g, 1.4 mmol, 77%) as a yellow solid.
[0241] To a solution of 7-2 (1.2 g, 1.4 mmol) in MeCN (5 mL) was
added TBAF (1 M, 7 mL). The mixture was stirred at 20.degree. C.
for 12 h. NaOH (aq.) (1 M, 3 mL) was added, and the mixture was
stirred at 20.degree. C. for 1 h. The reaction was quenched with a
sat. NH.sub.4Cl solution (40 mL) at 0.degree. C. The mixture was
extracted with EtOAc (2.times.30 mL). The combined organic layers
were washed with brine (75 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give a residue. The residue was purified by column
chromatography (10% EA in PE) to give 7-3 (500 mg, 908 .mu.mol,
63%) as a white solid.
[0242] To a solution of 7-3 in DMF (8 mL) was added imidazole (99
mg, 1.5 mmol) and TBSCl (219 mg, 1.5 mmol). The mixture was stirred
at 20.degree. C. for 3 h. The reaction was quenched with sat. aq.
NaHCO.sub.3 (30 mL) at 20.degree. C. The mixture was extracted with
EtOAc (2.times.30 mL). The combined organic layers were washed with
brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give a residue. The residue
was purified by column chromatography (10% EA in PE) to give 7-4
(370 mg, 556 .mu.mol, 77%) as a white solid.
[0243] To a solution of 7-4 (370 mg, 557 .mu.mol) in MeCN (2.6 mL)
was added DMAP (170 mg, 1.4 mmol), TEA (141 mg, 1.4 mmol) and TPSCl
(410 mg, 1.4 mmol). The mixture was stirred at 20.degree. C. for 2
h. NH.sub.3.H.sub.2O (2.3 mL) was added, and the mixture was
stirred at 20.degree. C. for 1 h. The reaction was quenched with
sat. aq. NaHCO.sub.3 (20 mL) at 20.degree. C. The mixture was
diluted with H.sub.2O (10 mL) and extracted with EtOAc (2.times.20
mL). The combined organic layers were washed with brine (30 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give a residue. The residue was purified
by column chromatography (10% CH.sub.3OH in DCM) to give 7-5 (300
mg, 452 .mu.mol, 81%) as a white solid.
[0244] Compound 7-5 was dissolved in HCOOH (80%), and the mixture
was stirred at 12.degree. C. for 20 h. The mixture was concentrated
under reduced pressure. The residue was purified by prep-HPLC (0.1%
NH.sub.4HCO.sub.3 in water and MeCN) to give 7 (71 mg, 45%) as a
white solid. MS (ESI): m/z: 278 [M+H].sup.+.
Example 8
Preparation of Compound 8
##STR00099##
[0246] To a solution of 8-1 (1.5 g, 2.4 mmol) in DCM (12 mL) was
added Dess-Martin (1.5 g, 3.6 mmol) at 0.degree. C. The mixture was
stirred at 20.degree. C. for 1.5 h. The reaction was quenched with
sat. aq. NaHCO.sub.3:sat. aq. NaS.sub.2O.sub.3 (30 mL:30 mL) at
20.degree. C. The mixture was extracted with EtOAc (2.times.50 mL).
The combined organic layers were washed with brine (80 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give crude 8-2 (1.50 g), which was used for the next
step without further purification.
[0247] To a solution of K.sub.2CO.sub.3 (1.7 g, 12.0 mmol) and
TsN.sub.3 (943 mg, 4.9 mmol) in MeCN (10 mL) was added
CH.sub.3COCH.sub.2PO(OMe).sub.2 (793 mg, 4.9 mmol). The mixture was
stirred at 20.degree. C. for 2 h. A solution of 8-2 (1.5 g, 2.4
mmol) in CH.sub.3OH (10 mL) was added, and the mixture was stirred
at 20.degree. C. for 12 h. The reaction was quenched with H.sub.2O
(70 mL) at 20.degree. C. The mixture was extracted with EtOAc
(2.times.70 mL). The combined organic layers were washed with brine
(100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give a residue. The residue
was purified by column chromatography (15% EA in PE) to give 8-3
(1.1 g, 1.8 mmol, 73%) as a white solid.
[0248] To a solution of 8-3 (500 mg, 802 .mu.mol) in MeCN (4 mL)
was added TEA (203 mg, 2.0 mmol), DMAP (245 mg, 2.0 mmol) and TPSCl
(592 mg, 2.0 mmol). The mixture was stirred at 20.degree. C. for 12
h. NH.sub.3.*H.sub.2O (3 mL) was added, and the mixture was stirred
at 20.degree. C. for 2 h. The reaction was quenched with sat. aq.
NaHCO.sub.3 (30 mL) at 20.degree. C. The mixture was extracted with
EtOAc (2.times.30 mL). The combined organic layers were washed with
brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give a residue. The residue
was purified by column chromatography (10% CH.sub.3OH in DCM) to
give 8-4 (450 mg, 90%) as a white solid.
[0249] To a solution of 8-4 (450 mg, 722 .mu.mol) in CH.sub.3OH (20
mL) was added NH.sub.4F (535 mg, 14.5 mmol). The mixture was
stirred at 80.degree. C. for 12 h. The mixture was concentrated
under reduced pressure. The residue was purified by prep-HPLC (0.1%
NH.sub.4HCO.sub.3 in water and MeCN) to give 8 (65 mg, 241 .mu.mol,
33%) as a white solid. MS (ESI): m/z: 270 [M+H].sup.+.
Example 9
Preparation of Compound 9
##STR00100## ##STR00101##
[0251] To a solution of 9-1 (20.0 g, 81.2 mmol) in DMF (160.0 mL)
was added imidazole (22.1 g, 324.9 mmol) and TBSCl (49 g, 324.9
mmol). The mixture was stirred at 25.degree. C. for 12 h. The
solution was diluted with EA (100 mL), and washed with H.sub.2O and
brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give a residue.
The residue was purified by column chromatography (5% EA in PE) to
give 9-2 (39.0 g, crude) as a yellow solid.
[0252] To a solution of 9-2 (20.0 g, 42.2 mmol) in THF (86.0 mL)
was added H.sub.2O (379.6 mg, 21.07 mmol) and HOAc (97.9 g, 1.6
mol), and the solution was stirred at 80.degree. C. for 12 h. The
mixture was diluted with EtOAc and washed with brine. The organic
layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give a residue. The residue
was purified by column chromatography (4% CH.sub.3OH in
DCM:CH.sub.3OH) to give 9-3 (12.2 g, 33.8 mmol, 80.3%) as a yellow
oil.
[0253] To a solution of 9-3 (13.0 g, 36.07 mmol) in MeCN (180.0 mL)
was added IBX (20.2 g, 72.1 mmol). The mixture was stirred at
80.degree. C. for 1 h. The precipitate was filtered-off, and the
filtrate was concentrated to give the crude product. The crude
product was used for the next step directly without purification to
give 9-4 (13.0 g, crude).
[0254] To a solution of 9-4 (13.0 g, 36.3 mmol) in 1,4-dioxane
(140.0 mL) was added HCHO (11.8 g, 145.1 mmol) and NaOH (2 M, 27.2
mL). The mixture was stirred at 25.degree. C. for 2 h and then
neutralized with AcOH to pH=7. The mixture was treated with EtOH
(90.0 mL) and NaBH.sub.4 (8.2 g, 217.6 mmol), and then stirred at
25.degree. C. for 1 h. The reaction was quenched with sat.
NH.sub.4Cl solution at 0.degree. C., and then diluted with EtOAc.
The combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give a residue. The residue was purified by column
chromatography (4% CH.sub.3OH in DCM) to give 9-5 (7.9 g, 20.2
mmol, 55.8%) as a white solid.
[0255] To a solution of 9-5 (7.0 g, 17.9 mmol) in pyridine (11.0
mL) was added DCM (45.0 mL) and DMTrCl (7.3 g, 21.5 mmol). The
mixture was stirred at 0.degree. C. for 40 mins. The reaction was
quenched with CH.sub.3OH (50 mL) at 0.degree. C. The mixture was
concentrated under reduced pressure to give a residue. The residue
was purified by column chromatography (50% EA in PE) to give 9-6
(8.0 g, 64.4%) as a white solid.
[0256] To a solution of 9-6 (9.0 g, 13.0 mmol) in DCM (150.0 mL)
was added imidazole (3.5 g, 51.9 mmol), AgNO.sub.3 (6.6 g, 38.9
mmol) and TBDPSCl (27.0 g, 38.9 mmol). The mixture was stirred at
25.degree. C. for 4 h. The mixture was filtered, and the filtrate
was washed with brine, dried over anhydrous MgSO.sub.4 and
concentrated at low pressure. The residue was purified by column
chromatography (33% EA in PE) to give 9-7 (10.1 g, 83.5%) as a
white solid.
[0257] To a solution of 9-7 (12.0 g, 12.9 mmol) in DCM (40.0 mL)
was added TFA (1.5 g, 12.9 mmol) and Et.sub.3SiH (5.8 g, 50.2
mmol). The mixture was stirred at 25.degree. C. for 30 mins. The
reaction was quenched with sat. aq. NaHCO.sub.3 at 25.degree. C.,
and then diluted with DCM. The combined organic layers were washed
with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The residue was purified to give 9-8 (7.5
g, 92.5%) as a white solid.
[0258] To a solution of 9-8 (1.1 g, 1.7 mmol) in DCM (8.0 mL) was
added Dess-Martin (1.5 g, 3.5 mmol). The mixture was stirred at
0.degree. C. for 1 h. The reaction was quenched with sat. aq.
Na.sub.2S.sub.2O.sub.3 and sat. aq. NaHCO.sub.3 at 25.degree. C.,
and then extracted with EtOAc (3.times.40 mL). The combined organic
layers were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give a residue. Compound 9-9 (1.1 g, crude) was used for the
next step without further purification.
[0259] To a solution of PPh.sub.3Br (2.5 g, 7.1 mmol) in THF (5.0
mL) was added n-BuLi (2.5 M, 2.8 mL) at -78.degree. C. under
N.sub.2. The mixture was stirred at 0.degree. C. for 30 mins. A
solution of 9-9 (1.1 g, 1.8 mmol) in THF (5.0 mL) was added
dropwise at 0.degree. C. under N.sub.2. The mixture was stirred at
25.degree. C. for 1 h. The reaction was quenched with sat. aq.
NH.sub.4Cl at 25.degree. C., and then diluted with EtOAc. The
combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give a residue. The residue was purified by column
chromatography (20% EA in PE) to give 9-10 (700 mg, 63.3%) as a
white solid.
[0260] To a solution of 9-10 (350 mg, 0.56 mmol) in MeCN (3.0 mL)
was added TPSCl (363 mg, 1.2 mmol), Et.sub.3N (124 mg, 1.2 mmol)
and DMAP (150.5 mg, 1.2 mmol). The mixture was stirred at
25.degree. C. for 3 h. The mixture was treated with
NH.sub.3*H.sub.2O (9.1 g, 259.6 mmol) at 25.degree. C., and then
stirred for 2 h. The reaction was quenched with sat. aq. NH.sub.4Cl
at 25.degree. C., and then diluted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give a residue. The residue was purified by column
chromatography (20% EA in PE) to give 9-11 (270.0 mg, 77.3%) as a
white solid.
[0261] To a solution of 9-11 (270 mg, 0.4 mmol) in CH.sub.3OH (10.0
mL) was added NH.sub.4F (320 mg, 8.6 mmol). The mixture was stirred
at 80.degree. C. for 10 h. The reaction mixture was filtered, and
the filtrate was concentrated under reduced pressure. The residue
was purified by prep-HPLC (neutral condition) to give 9 (54 mg,
46.0%) as a white solid. MS (ESI): m/z: 272.1 [M+H].sup.+.
Example 10
Preparation of Compound 10
##STR00102##
[0263] To a solution of 10-1 (350 mg, 0.56 mmol) in CH.sub.3OH
(10.0 mL) was added Pd/C (0.1 g) under N.sub.2. The suspension was
degassed and purged with H.sub.2 (3.times.). The mixture was
stirred under H.sub.2 at 25.degree. C. for 2 h. The mixture was
filtered, and the filtrate was concentrated under reduced pressure.
The crude product was used for next step directly without
purification. Compound 10-2 (340 mg, 96.8%) was obtained as a white
solid.
[0264] To a solution of 10-2 (340 mg, 0.54 mmol) in MeCN (5.0 mL)
was added TPSCl (361 mg, 1.2 mmol), DMAP (146 mg, 1.2 mmol) and
Et.sub.3N (121 mg, 1.2 mmol). The mixture was stirred at 25.degree.
C. for 3 h. The mixture was treated with NH.sub.3*H.sub.2O (4.5 g,
129.8 mmol) at 25.degree. C., and then stirred for 2 h. The
reaction was quenched with sat. aq. NH.sub.4Cl at 25.degree. C. The
mixture was diluted with EtOAc. The combined organic layers were
washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was purified
by column chromatography (20% EA in PE) to give 10-3 (270 mg,
79.5%) as a white solid.
[0265] To a solution of 10-3 (270 mg, 0.43 mmol) in CH.sub.3OH
(10.0 mL) was added NH.sub.4F (319 mg, 8.6 mmol). The mixture was
stirred at 80.degree. C. for 10 h, and then concentrated under
reduced pressure. The residue was purified by prep-HPLC (neutral
condition) to give 10 (78 mg, 66.2%) as a white solid. MS (ESI):
m/z: 274.1 [M+H].sup.+.
Example 11
Preparation of Compound 11
##STR00103## ##STR00104##
[0267] To a solution of 11-1 (1.5 g, 2.4 mmol) in DCM (12 mL) was
added Dess-Martin (1.5 g, 3.6 mmol) at 0.degree. C. The mixture was
stirred at 20.degree. C. for 1.5 h. The reaction was quenched with
sat. aq. NaHCO.sub.3:sat. aq. NaS.sub.2O.sub.3 930 mL:30 mL) at
20.degree. C. The mixture was extracted with EtOAc (2.times.50 mL).
The combined organic layers were washed with brine (80 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give crude 11-2 (1.50 g), which was used into
the next step without further purification.
[0268] To a solution of 11-2 (1.0 g, 1.6 mmol) in THF (8 mL) was
added CH.sub.3MgBr (3 M, 1.6 mL) dropwise at 0.degree. C. The
mixture was stirred at 0.degree. C. for 0.5 h. The reaction was
quenched with sat. aq. NH.sub.4Cl at 0.degree. C. The mixture was
extracted with EtOAc (2.times.70 mL). The combined organic layers
were washed with brine (100 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography (15% EA in PE) to
give 11-3 (900 mg, 88%) as a white solid.
[0269] To a solution of 11-3 (900 mg, 1.4 mmol) in DCM (10 mL) was
added Dess-Martin (1.1 g, 2.8 mmol). The mixture was stirred at
20.degree. C. for 2 h. The reaction was quenched with sat. aq.
Na.sub.2S.sub.2O.sub.3:sat. aq. NaHCO.sub.3 (30 mL:30 mL) at
20.degree. C. The mixture was extracted with EtOAc (2.times.40 mL).
The combined organic layers were washed with brine (70 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give crude 11-4 (850.00 mg), which was used for
the next step without further purification.
[0270] To a solution of Methyl-triphenyl-phosphonium bromide (3.4
g, 9.4 mmol) in THF (2.7 mL) was added t-BuOK (1 M, 9.3 mL)
dropwise at 0.degree. C. The mixture was stirred at 20.degree. C.
for 1 h. A solution of 11-4 (850 mg, 1.3 mmol) in THF (3 mL) was
added at 20.degree. C. The mixture was stirred at 20.degree. C. for
12 h. The reaction was quenched with sat. aq. NH.sub.4Cl (35 mL) at
20.degree. C. The mixture was extracted with EtOAc (2.times.30 mL).
The combined organic layers were washed with brine (70 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography
(20% EA in PE) to give 11-5 (650 mg, 76%) as a white solid.
[0271] A mixture of 11-5 (500 mg, 782 .mu.mol) and Pd/C (270 mg) in
EtOAc (20 mL) was degassed and purged with H.sub.2 (3.times.), and
then the mixture was stirred at 20.degree. C. for 2 h under
H.sub.2. The mixture was filtrated under reduced pressure. The
filtrate was concentrated under reduced pressure to give crude 11-6
(500.00 mg), which was used into the next step without further
purification.
[0272] To a solution of 11-6 (500 mg, 780 .mu.mol) in MeCN (7 mL)
was added TEA (197 mg, 1.9 mmol), DMAP (238 mg, 1.9 mmol) and TPSCl
(575 mg, 1.9 mmol) at 20.degree. C. The mixture was stirred at
20.degree. C. for 12 h. NH.sub.3.H.sub.2O (7 mL) was added, and the
mixture was stirred at 20.degree. C. for 1 h. The reaction was
quenched with sat. aq. NaHCO.sub.3 (30 mL) at 20.degree. C. The
mixture was extracted with EtOAc (2.times.30 mL). The combined
organic layers were washed with brine (50 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography (20% CH.sub.3OH
in DCM) to give 11-7 (400 mg, 80%) as a white solid.
[0273] To a solution of 11-7 (400 mg, 625 .mu.mol) in CH.sub.3OH
(10 mL) was added NH.sub.4F (695 mg, 18.8 mmol) at 80.degree. C.
The mixture was stirred at 80.degree. C. for 12 h. The mixture was
filtrated and concentrated under reduced pressure. The residue was
purified by prep-HPLC (0.1% NH.sub.4HCO.sub.3 in water and MeCN) to
give 11 (55 mg, 191 .mu.mol, 21%) as a white solid. MS (ESI): m/z:
288 [M+H].sup.+.
Example 12
Preparation of Compound 12
##STR00105##
[0275] To a solution of 12-1 (1.5 g, 2.4 mmol) in DCM (12 mL) was
added Dess-Martin (1.5 g, 3.6 mmol) at 0.degree. C. The mixture was
stirred at 20.degree. C. for 1.5 h. The reaction was quenched with
sat. aq. NaHCO.sub.3:sat. aq. NaS.sub.2O.sub.3 (30 mL:30 mL) at
20.degree. C. The mixture was extracted with EtOAc (2.times.50 mL).
The combined organic layers were washed with brine (80 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give crude 12-2 (1.50 g), which was used for
the next step without further purification.
[0276] To a solution of K.sub.2CO.sub.3 (1.7 g, 12.0 mmol) and
TsN.sub.3 (943 mg, 4.9 mmol) in MeCN (10 mL) was added
CH.sub.3COCH.sub.2PO(OMe).sub.2 (793 mg, 4.9 mmol). The mixture was
stirred at 20.degree. C. for 2 h. A solution of 12-2 (1.5 g, 2.4
mmol) in CH.sub.3OH (10 mL) was added, and the mixture was stirred
at 20.degree. C. for 12 h. The reaction was quenched with H.sub.2O
(70 mL) at 20.degree. C. The mixture was extracted with EtOAc (70
mL). The combined organic layers were washed with brine (100 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The residue was purified by column
chromatography (15% EA in PE) to give 12-3 (1.1 g, 73%) as a white
solid.
[0277] To a solution of 12-3 (500 mg, 802 .mu.mol) in dioxane (4
mL) was added CuBr (57 mg, 401 .mu.mol), (CH.sub.2O).sub.n(48 mg,
1.6 mmol) and diisopropylamine (203 mg, 2.0 mmol). The mixture was
stirred at 140.degree. C. for 2.5 h. The reaction was quenched with
sat. aq. NH.sub.4Cl (30 mL) at 15.degree. C. The mixture was
extracted with EtOAc (2.times.30 mL). The combined organic layers
were washed with brine (50 mL), dried over anhydride
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography (15% EA in PE) to
give 12-4 (350 mg, 68%) as a yellow solid.
[0278] To a solution of 12-4 (350 mg, 549 .mu.mol) in MeCN (3 mL)
was added TEA (139 mg, 1.4 mmol), DMAP (167 mg, 1.4 mmol) and TPSCl
(405 mg, 1.4 mmol). The mixture was stirred at 15.degree. C. for 2
h. NH.sub.3*H.sub.2O (3 mL) was added, and the mixture was stirred
at 15.degree. C. for 1 h. The reaction was quenched with sat. aq.
NaHCO.sub.3 (20 mL) at 15.degree. C. The mixture was extracted with
EtOAc (2.times.20 mL). The combined organic layers were washed with
brine (30 mL), dried over anhydride Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography (15% CH.sub.3OH in DCM) to give 12-5 (200 mg,
57%) as a white solid.
[0279] To a solution of 12-5 (200 mg, 316 .mu.mol) in CH.sub.3OH
(15 mL) was added NH.sub.4F (350 mg, 9.5 mmol) at 80.degree. C. The
mixture was stirred at 80.degree. C. for 12 h. The mixture was
filtrated and concentrated under reduced pressure. The residue was
purified by prep-HPLC (0.1% NH.sub.4HCO.sub.3 in water and MeCN) to
give 12 (40 mg, 44%) as a white solid. MS (ESI): m/z: 284
[M+H].sup.+.
Example 13
Preparation of Compound 37
##STR00106## ##STR00107##
[0281] Compound 37 was prepared according to the scheme provide
above. MS (ESI): m/z: 283.1 [M+H].sup.+.
Example 14
Preparation of Compounds 38 and 39
##STR00108##
[0283] Into a 500-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of N.sub.2, was placed a
solution of ethynyltrimethylsilane (3.24 g, 32.99 mmol, 3.00 eq.)
in THF (25 mL). N-butyllithium (13 mL, 32.99 mmol, 3.00 eq.) was
added dropwise with stirring at -78.degree. C. The solution was
stirred for 20 mins at -78.degree. C. To this solution was added a
solution of 38-1 (5 g, 11.00 mmol, 1.00 eq.) in THF (25 mL)
dropwise with stirring at -78.degree. C. The solution was allowed
to react, with stirring, for 2 h at -78.degree. C. The reaction was
quenched by adding sat. NH.sub.4Cl, extracted with EA. The organic
layers were combined, dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. The residue was
applied onto a silica gel column with EA/PE (1:5-1:2) to give 40-2
(2.5 g, 41%) as a yellow solid. MS (ESI): m/z: 553 [M+H].sup.+.
[0284] Into a 100-mL round-bottom flask purged and maintained with
an inert atmosphere of N.sub.2, was placed a solution of 40-2 (400
mg, 0.72 mmol, 1.00 eq.) in CH.sub.2Cl.sub.2 (5 mL).
4-dimethylaminopyridine (176.8 mg, 1.45 mmol, 1.99 eq.) was added
at RT. Methyl 2-chloro-2-oxoacetate (132.6 mg, 1.08 mmol, and 1.49
eq.) was then added at RT. The solution was stirred for 1 h at RT,
and then diluted with CH.sub.2Cl.sub.2. The solution was washed
with water, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. The residue was applied onto a
silica gel column with CH.sub.2C.sub.12/CH.sub.3OH (50:1-30:1) to
give 38-2 (200 mg, 43%) as a white solid. MS (ESI): m/z: 639
[M+H].sup.+.
[0285] Into a 250-mL round-bottom flask purged and maintained with
an inert atmosphere of N.sub.2, was placed a solution of 38-2 (4.2
g, 6.58 mmol, 1.00 eq.) in toluene (50 mL). 2,
2'-azobisisobutyronitrile (2.16 g, 13.15 mmol, 2.02 eq.) and
tributyl-3-stannyl (38.2 g, 131.70 mmol, 20.04 eq.) were added at
RT. The solution was stirred for 1 h at 110.degree. C., and then
concentrated under reduced pressure. The residue was applied onto a
silica gel column with CH.sub.2Cl.sub.2/CH.sub.3OH (100:1-50:1) to
give 38-3 (2.7 g, 77%) as a yellow solid. MS (ESI): m/z: 537
[M+H].sup.+.
[0286] Into a 250-mL round-bottom flask purged and maintained with
an inert atmosphere of N.sub.2, was placed a solution of 38-3 (2.7
g, 5.03 mmol, 1.00 eq.) in CH.sub.3OH (30 mL). Potassium carbonate
(1.39 g, 9.98 mmol, 1.99 eq.) was added at RT. The solution was
stirred for 1 h at RT, and the solids were filtered off. The
solution was concentrated under reduced pressure. The residue was
applied onto a silica gel column with EA/PE (1:10-1:1) to give 38-4
(1.0 g, 43%) as a white solid. MS (ESI): m/z: 465 [M+H].sup.+.
[0287] Into a 25-mL round-bottom flask purged and maintained with
an inert atmosphere of N.sub.2, was placed a solution of 38-4 (200
mg, 0.43 mmol, 1.00 eq.) in CH.sub.2Cl.sub.2 (1 mL).
Trichloroborane (0.12 mL, 5.00 eq.) was added dropwise with
stirring at -78.degree. C. The solution was stirred for 1 h at RT.
The reaction was quenched by the addition of CH.sub.2Cl.sub.2 (0.5
mL). The mixture was concentrated under reduced pressure. The crude
product (200 mg) was purified by prep-HPLC (Column, X Bridge C18,
19*150 mm, 5 um; mobile phase, A: Water/0.05% TFA, Mobile Phase B:
ACN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min;
Detector, 254 nm) to give 39 (48.8 mg, 40%) as a white solid. MS
(ESI): m/z: 285 [M+H].sup.+.
[0288] Into a 25-mL round-bottom flask purged and maintained with
an inert atmosphere of N.sub.2, was placed a solution of 38-4 (300
mg, 0.65 mmol, 1.00 eq.) in MeCN (5 mL). 4-dimethylaminopyridine
(157 mg, 1.29 mmol, 1.99 eq.) and triethylamine (196 mg, 1.94 mmol,
3.00 eq.) were added at RT. 2,4,6-triisopropylbenzenesulfonyl
chloride (587 mg, 1.94 mmol, 3.00 eq.) was then added at RT. The
solution was stirred for 1 h at RT. Ammonium hydroxide (3 mL, 28%)
as added at RT, and then stirred for 1 h at RT. The mixture was
concentrated under reduced pressure. The residue was applied onto a
silica gel column with CH.sub.2Cl.sub.2/CH.sub.3OH (100:1-20:1) to
give 38-5 (205 mg, 68%) as a yellow solid. MS (ESI): m/z: 464
[M+H].sup.+.
[0289] Into a 25-mL round-bottom flask purged and maintained with
an inert atmosphere of N.sub.2, was placed a solution of 38-5 (200
mg, 0.43 mmol, 1.00 eq.) in CH.sub.2Cl.sub.2 (2 mL).
Trichloroborane (0.12 mL, 5.00 eq.) was dropwise with stirring at
-78.degree. C. The solution was stirred for 1 h at RT. The reaction
was quenched with CH.sub.3OH. The mixture was concentrated under
reduced pressure. The crude product (200 mg) was purified by
prep-HPLC (Column, X Bridge C18, 19*250 mm, 5 um; mobile phase, A:
Water/10 mM NH.sub.4HCO.sub.3, Mobile Phase B: ACN; Flow rate: 30
mL/min; Gradient: 3% B to 9.5% B in 6.5 min; Detector) to give 38
(40.4 mg, 33%) as a white solid. MS (ESI): m/z: 284
[M+H].sup.+.
Example 15
Preparation of Compounds 40 and 41
##STR00109## ##STR00110##
[0291] Into a 250-mL round-bottom flask purged and maintained with
an inert atmosphere of N.sub.2, was placed a solution of 40-1 (13
g, 28.48 mmol, 1.00 eq. 40-1 was prepared as provided in Kitano et
al., Tetrahedron (1997) 53(39):13315-13322) in MeCN (130 mL).
2-iodoxybenzoic acid (16 g, 57.14 mmol, 2.00 eq.) was added at RT,
and then stirred for 2 h at 80.degree. C. The mixture was cooled,
and the solid was filtered off. The solution was concentrated under
reduced pressure to give 40-2 (11 g, 85%) as a yellow solid. MS
(ESI): m/z: 455 [M+H].sup.+.
[0292] Into a 100-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of Ar, was placed a solution of
40-2 (1.8 g, 3.96 mmol, 1.00 eq.) in THF (20 mL). Methylmagnesium
bromide (1M in THF, 25 mL, 5.00 eq.) was added dropwise with
stirring at -78.degree. C. The solution was then stirred at
-30.degree. C. for 4 h. The reaction was quenched by adding aq.
NH.sub.4Cl (50 mL). The solution was extracted with EA (2.times.50
mL). The organic layers were combined, washed with aq. NaCl
(1.times.25 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. The residue was applied onto a
silica gel column with PE/EA (1:1) to give 40-3 and 40-4 (1.2 g,
64%, mixture, ratio 1:1) as a white solid. MS (ESI): m/z: 471
[M+H].sup.+.
[0293] Into a 50-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 40-3 and 40-4
(mixture, ratio 1:1, 1.2 g, 2.55 mmol, 1.00 eq.) in MeCN (20 mL).
4-dimethylaminopyridine (930 mg, 7.61 mmol, 3.00 eq.) was added.
Methyl 2-chloro-2-oxoacetate (635 mg, 5.18 mmol, 2.00 eq.) was then
added dropwise with stirring at RT. The solution was then stirred
for 1 h at RT. The solution was diluted with EA (50 mL), and the
solution was then washed with aq. sodium bicarbonate (1.times.25
mL) and NaCl (1.times.25 mL). The solution was dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
give 40-5 and 40-6 (1.2 g, 85%, mixture, ratio 1:1) as a yellow
solid. MS (ESI): m/z: 557 [M+H].sup.+.
[0294] Into a 100-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 40-5 and 40-6
(mixture, ratio 1:1, 1.2 g, 2.16 mmol, 1.00 eq.) in toluene (12
mL). Tri-n-butyl-tin hydride (12.1 g, 41.72 mmol, 20.00 eq.) was
added followed by 2,2'-azobisisobutyronitrile (708 mg, 4.31 mmol,
2.00 eq.). The solution was stirred for 1 h at 110.degree. C., and
then concentrated under reduced pressure. The residue was applied
onto a silica gel column with CH.sub.2C.sub.12/CH.sub.3OH (50:1).
The crude product (1.2 g) was purified by flash-HPLC (Column,
XB-C18, 250*50 mm, 10 um; mobile phase, A:Water/10 mmol/L
trifluoroacetic acid, Mobile Phase B: acetonitrile; Gradient: 5% B
to 40% B in 45 min; Detector, 254 nm) to 40-7 (600 mg, 61%) as a
white solid. MS (ESI): m/z: 455 [M+H].sup.+.
[0295] Into a 10-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 40-7 (500 mg,
1.10 mmol, 1.00 eq.) in CH.sub.2Cl.sub.2 (5 mL). Trichloroborane
(1M in CH.sub.2Cl.sub.2, 5 mL) was added at -78.degree. C. The
solution was stirred at -30.degree. C. for 1 h. The reaction was
quenched with CH.sub.3OH (2 mL). The solution was concentrated
under reduced pressure. The crude product (250 mg) was purified by
prep-HPLC (Column, X Bridge C18, 19*150 mm, 5 um; mobile phase,
A:Water/10 mmol/L ammonium bicarbonate, Mobile Phase B:
acetonitrile; Gradient: 5% B to 15% B in 15 min; Detector, 254 nm)
to give 40 (76 mg, 25%) as a white solid. MS (ESI): m/z: 275
[M+H].sup.+.
[0296] Into a 100-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 40-7 (1 g, 2.20
mmol, 1.00 eq.) in MeCN (20 mL). 4-dimethylaminopyridine (270 mg,
2.21 mmol, 1.00 eq.), triethylamine (670 mg, 6.62 mmol, 3.00 eq.)
and 2,4,6-triisopropylbenzenesulfonyl chloride (2 g, 3.00 eq.) were
added, and the solution was stirred for 2 h at RT. NH.sub.4OH
hydroxide (20 mL, 28%) was added. The resulting solution was
allowed to react with stirring for an additional 2 h at 25.degree.
C. The solution was diluted with EA (50 mL), washed with water
(1.times.25 mL) and aq. NaCl (1.times.25 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was applied onto a silica gel column with
CH.sub.2C.sub.12/CH.sub.3OH (50:1) to give 40-8 (600 mg, 60%) as a
white solid. MS (ESI): m/z: 454 [M+H].sup.+.
[0297] Into a 50-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 40-8 (450 mg,
0.99 mmol, 1.00 eq.) in CH.sub.2Cl.sub.2 (5 mL). Trichloroborane
(1M in CH.sub.2Cl.sub.2, 4.5 mL) was added dropwise with stirring
at -78.degree. C. The solution was then stirred at -30.degree. C.
for 1 h. The reaction was quenched with CH.sub.3OH (1 mL), and then
concentrated under reduced pressure. The crude product (150 mg) was
purified by prep-HPLC (Column, X Bridge C18, 19*150 mm, 5 um;
mobile phase, A: Water/10 mmol/L ammonium bicarbonate, Mobile Phase
B: acetonitrile; Gradient: 5% B to 85% B in 10 min; Detector, 254
nm) to give 41 (73.5 mg, 27%) as a white solid. MS (ESI): m/z: 274
[M+H].sup.+.
Example 16
Preparation of Compounds 42 and 43
##STR00111## ##STR00112## ##STR00113##
[0299] Into a 2000-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of N.sub.2, was placed DMSO
(600 mL), THF (20 mL) and trimethyloxosulfonium iodide (43.5 g,
197.66 mmol, 3.00 eq.). NaH (5.41 g, 225.42 mmol, 2.00 eq.) was
added at 10.degree. C. The solution was stirred for 1 h at RT. A
solution of 40-2 (30 g, 66.01 mmol, 1.00 eq.) in THF (200 mL) was
added dropwise with stirring at 0.degree. C. The solution was
allowed to react with stirring for 1 h at 0.degree. C. The reaction
was quenched with aq. NH.sub.4Cl. The solution was extracted with
EA (2.times.1000 mL). The organic layers were combined, washed with
aq. NaCl (1.times.1000 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
applied onto a silica gel column with CH.sub.2Cl.sub.2/CH.sub.3OH
(30:1) to give 42-1 (21.8 g, 70%) as yellow oil. MS (ESI): m/z: 469
[M+H].sup.+.
[0300] Into a 1000-mL round-bottom flask purged and maintained with
an inert atmosphere of N.sub.2, was placed a solution of 42-1 (21.8
g, 46.53 mmol, 1.00 eq.) in acetic acid (300 mL). Sodium acetate
(35 g, 426.65 mmol, 2.00 eq.) was added at RT. The solution was
stirred for 3 h at 120.degree. C., and then concentrated under
reduced pressure. The residue was diluted with CH.sub.2Cl.sub.2
(1000 mL), washed with aq. sodium bicarbonate (1.times.500 mL) and
aq. NaCl (1.times.500 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
applied onto a silica gel column with CH.sub.2Cl.sub.2/CH.sub.3OH
(20:1) to give 42-2 (14.8 g, 60%) as a yellow solid. MS (ESI): m/z:
529 [M+H].sup.+.
[0301] Into a 500-mL round-bottom flask purged and maintained with
an inert atmosphere of N.sub.2, was placed a solution of 42-2 (20
g, 37.84 mmol, 1.00 eq.) in CH.sub.3OH (200 mL). Sodium methylate
(30% in CH.sub.3OH, 4 mL) was added. The solution was stirred for 4
h at RT. The reaction was quenched with acetic acid. The mixture
was concentrated under reduced pressure. The residue was applied
onto a silica gel column with CH.sub.2Cl.sub.2/CH.sub.3OH (20:1) to
give 42-3 (17.2 g, 93%) as a yellow solid. MS (ESI): m/z: 487
[M+H].sup.+.
[0302] Into a 500-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of Ar, was placed a solution of
42-3 (17 g, 34.94 mmol, 1.00 eq.) in MeCN (200 mL).
1,1'-thiocarbonyldiimidazole (10.45 g, 58.64 mmol, 3.00 eq.) was
added. The solution was stirred for 3 h at 40.degree. C., and then
concentrated under reduced pressure. The residue was applied onto a
silica gel column with PE/EA (1:1) to give 42-4 (13 g, 70%) as a
white solid. MS (ESI): m/z: 529 [M+H].sup.+.
[0303] Into a 500-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 42-4 (13 g,
24.60 mmol, 1.00 eq.) in toluene (130 mL).
2,2'-azobisisobutyronitrile (8 g, 48.72 mmol, 2.00 eq.) and
tributyl-3-stannyl (143 g, 493.02 mmol, 20.00 eq.) were added. The
solution was stirred for 3 h at 110.degree. C., and then
concentrated under reduced pressure. The residue was applied onto a
silica gel column with CH.sub.2Cl.sub.2/CH.sub.3OH (20:1) to give
42-5 (8 g, 69%) and 42-6 (1 g, 8.6%) as a white solid. MS (ESI):
m/z: 471 [M+H].sup.+.
[0304] Into a 500-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of Ar, was placed a solution of
42-5 (7.8 g, 16.58 mmol, 1.00 eq.) and
1,8-diazabicyclo[5.4.0]undec-7-ene (5 g, 32.84 mmol, 2.00 eq.) in
THF (80 mL). Benzyl chloromethyl ether (3.9 g, 24.90 mmol, 1.50
eq.) was added dropwise with stirring at 0.degree. C. The solution
was stirred for 2 h at 0.degree. C. The reaction was quenched with
CH.sub.3OH, and then concentrated under reduced pressure. The
residue was diluted with CH.sub.2Cl.sub.2 (500 mL), washed with
water (1.times.100 mL) and aq. NaCl (1.times.100 mL), dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/CH.sub.3OH (20:1) to give 42-7 (8.4 g, 86%) as
yellow oil. MS (ESI): m/z: 591 [M+H].sup.+.
[0305] Into a 100-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 42-7 (4 g, 6.77
mmol, 1.00 eq.) in toluene (40 mL). Diethylaminosulfur trifluoride
(3.8 g, 23.57 mmol, 2.00 eq.) was added dropwise with stirring at
0.degree. C. The solution was stirred for 4 h at 60.degree. C. The
reaction was quenched with chilled aq. sodium bicarbonate. The
solution was extracted with EA (2.times.100 mL). The organic layers
were combined, washed with aq. NaCl (1.times.50 mL), dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The residue was applied onto a silica gel column with
PE/EA (1:1) to give 42-8 (1.2 g, 30%) as yellow oil. MS (ESI): m/z:
593 [M+H].sup.+.
[0306] Into a 25-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 42-8 (500 mg,
0.84 mmol, 1.00 eq.) in CH.sub.2Cl.sub.2 (5 mL). Boron trichloride
(1 M in CH.sub.2Cl.sub.2, 5 mL) was added dropwise with stirring at
-78.degree. C. The solution was then stirred for 3 h at -78.degree.
C.--30.degree. C. The reaction was quenched with CH.sub.3OH. The
mixture was concentrated under reduced pressure. The crude product
(220 mg) was purified by prep-HPLC (Column, X Bridge C18, 19*150
mm, 5 um; mobile phase, A:Water/10 mmol/L ammonium bicarbonate,
Mobile Phase B: acetonitrile; Gradient: 5% B to 15% B in 15 min;
Detector, 254 nm) to give 43 (42.2 mg, 17%) as a white solid. MS
(ESI): m/z: 293 [M+H].sup.+.
[0307] Into a 100-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 43 (500 mg,
1.71 mmol, 1.00 eq.) in pyridine (5 mL). Acetyl acetate (2 mL) was
added, and the solution was stirred for 2 h at RT. The solution was
concentrated under reduced pressure. The residue was diluted with
CH.sub.2Cl.sub.2 (100 mL), washed with water (1.times.50 mL) and
aq. NaCl (1.times.50 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
applied onto a silica gel column with EA/PE (1:1) to give 42-9 (500
mg, 78%) as a white solid. MS (ESI): m/z: 377 [M+H].sup.+.
[0308] Into a 25-mL round-bottom flask purged and maintained with
an inert atmosphere of Ar, was placed a solution of 42-9 (500 mg,
1.00 eq.), 4-dimethylaminopyridine (162 mg, 1.33 mmol, 1.00 eq.)
and triethylamine (482 mg, 4.76 mmol, 3.00 eq.) in MeCN (5 mL).
2,4,6-triisopropylbenzenesulfonyl chloride (1.2 g, 3.96 mmol, 3.00
eq.) was added, and the solution stirred for 2 h at RT. NH.sub.4OH
(5 mL, 28%) was added, and the solution was stirred for 2 h at RT.
The mixture was concentrated under reduced pressure. The crude
product (200 mg) was purified by prep-HPLC (Column, X Bridge C18,
19*150 mm, 5 um; mobile phase, A:Water/10 mmol/L ammonium
hydroxide, Mobile Phase B: acetonitrile; Gradient: 5% B to 10% B in
15 min; Detector, 254 nm) to give 42 (63.2 mg, 16%) as a white
solid. MS (ESI): m/z: 292 [M+H].sup.+.
Example 17
Preparation of Compound 44
##STR00114## ##STR00115## ##STR00116##
[0310] To a stirred solution of 44-1 (1 g, 3.03 mmol, 44-1 was
prepared as provided in Chen et al., Bioorg. Med. Chem. Lett.
(2002) 12(21):3093-3096) in anhydrous MeCN (10 mL) was added IBX
(1.27 g, 4.55 mmol) at RT under N.sub.2. The mixture was stirred at
90.degree. C. for 3 h. The solid was removed by filtration, and the
filtrate was concentrated at low pressure. The residue was purified
by column chromatography (EtOAc in PE from 5% to 10%) to give 44-2
(875 mg, crude) as a colorless oil.
[0311] To a stirred solution of 44-2 (870 mg, 2.65 mmol) and
difluoromethyl phenyl sulfone (712.5 mg, 3.71 mmol) in anhydrous
THF (10 mL) was added LiHMDS (1.0 M in THF, 4.2 mL) dropwise under
N.sub.2 at -78.degree. C. After stirring at -78.degree. C. for 3 h,
the solution was stirred at RT for a 1 h. The reaction was quenched
with sat. NH.sub.4Cl (5 mL). The organic phase was separated, and
the aqueous phase was back-extracted with EtOAc (2.times.20 mL).
The combined organic phases was washed with brine (10 mL), dried
over anhydrous Na.sub.2SO.sub.4, and concentrated at low pressure.
The residue was purified by silica gel chromatography (EtOAc in PE
from 0.08% to 2%) to give 44-3 (389 mg, 28.2%) as a yellow oil.
[0312] 44-3 (389 mg, 0.74 mmol) and magnesium (164 mg, 6.72 mmol)
were dissolved in a mixture of DMF (5 mL), H.sub.2O (0.5 mL) and
CH.sub.3COOH (448 mg, 7.5 mmol) at RT. The mixture was stirred at
RT for 12 h. The reaction was quenched with cold water (2 mL), and
the mixture was filtered by celite. The filtrate was extracted with
EA (2.times.10 mL). The combined layer was washed with water (10
mL) and brine (10 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to give the crude product. The
crude product was purified by column chromatography (EA in PE from
0.08% to 1%) to give 44-4 (95 mg, 33.42%) as a light yellow
oil.
[0313] 44-4 (10 g, 26.3 mmol) was dissolved in TBAF (1 M, 30 mL in
THF). The mixture was stirred at RT for 4 h, and the reaction was
checked by TLC. The mixture was extracted with EA (2.times.250 mL).
The combined organic layer was washed with water (100 mL) and brine
(50 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography (PE
in EA from 2.5% to 10%) to give the crude product (5.1 g, 75.3%) as
a yellow oil.
[0314] To a solution of the crude product (5 g, 18.78 mmol) in dry
DCM (50 mL) was added TEA (5.7 g, 56.34 mmol), DMAP (46 mg, 0.375
mmol) and BzCl (5.28 g, 37.6 mmol) at 0.degree. C. The mixture was
stirred at 0.degree. C. for 1 h and then at 25.degree. C. for 2 h.
The reaction was quenched with H.sub.2O (10 mL) at 0.degree. C.,
and the mixture was extracted with CH.sub.2C.sub.12 (2.times.50
mL). The combined organic layers were washed with brine (2.times.50
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc in PE from 2% to 5%) to
give 44-5 (5.1 g, 73.3%) as a yellow oil.
[0315] A stirred solution of 44-5 (5.1 g, 13.77 mmol) in anhydrous
DCM (80 mL) was bubbled with 03 (15 psi) at -78.degree. C. for 10
mins until the mixture turned blue. The mixture was then bubbled
with O.sub.2 until the solution turned colorless. The organic layer
was evaporated to give crude 44-6 (4.66 g, crude) as a yellow
oil.
[0316] To a stirred solution of 44-6 (4.6 g, 13.36 mmol) in DCM (50
mL) was added 90% TFA solution (25 mL) at 0.degree. C., and the
mixture was then warmed to RT. The mixture was stirred for 12 h,
and the reaction was checked by TLC. After the reaction was
completed, the mixture was co-evaporated with toluene (3.times.) to
give crude 44-7 (4 g crude) as a solid.
[0317] To a solution of 44-7 (4 g, 13.15 mmol) in anhydrous DCM (60
mL) was added TEA (6.15 g, 65.7 mmol, 9.1 mL), DMAP (8.03 g, 65.75
mmol) and BzCl (9.24 g, 65.7 mmol) at 0.degree. C. The mixture was
stirred at RT for 12 h, and then the reaction was quenched with
CH.sub.3OH (10 mL) and water (30 mL) at RT. The mixture was
extracted with DCM (2.times.50 mL). The combined organic layers
were washed with sat. NH.sub.4Cl (3.times.30 mL) and brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (EtOAc in PE from 2% to 5%) to give 44-8 (4.6 g,
56.7%) as a solid.
[0318] A stirred suspension of uracil (0.4 g, 3.57 mmol) and
(NH.sub.4).sub.2SO.sub.4 (5 mg) in HMDS (6 mL, 28.55 mmol) was
heated to 120.degree. C. for 2 h. After the solid was dissolved,
the mixture was cooled to RT and concentrated to give a residue
(840 mg, 91.9%). The residue was dissolved in anhydrous MeCN (10
mL), and the solution was treated with 44-8 (1.0 g, 1.6 mmol) and
TMSOTf (3.6 g, 16.2 mmol) at RT. The mixture was stirred at
90.degree. C. for 12 h. The reaction was quenched with sat.
NaHCO.sub.3 (10 mL) and extracted with EtOAc (2.times.25 mL). The
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
filtered. The filtrate was evaporated at low pressure. The residue
was purified by column chromatography (EtOAc in PE from 10% to 25%)
to give 44-9 (0.83 g, 84.6%) as a solid.
[0319] 44-9 (1 g, 1.65 mmol) was treated with NH.sub.3/CH.sub.3OH
(20 mL, 7 M) at RT. The mixture was stirred at RT for 12 h, and
then concentrated at low pressure. The residue was purified by
column chromatography (CH.sub.3OH in DCM from 2% to 5%) to give
44-10 (395 mg, 81.2%) as a white solid.
[0320] To a stirred solution of 44-10 (800 mg, 2.72 mmol) in
anhydrous DMF (12 mL) was added diphenyl carbonate (640 mg, 3 mmol)
and NaHCO.sub.3 (57 mg, 680 .mu.mol) at RT under N.sub.2. The
mixture was stirred at 140.degree. C. under microwave for 1 h. The
solvent was removed under reduced pressure. The residue was
purified by column chromatography (CH.sub.3OH in DCM from 1% to
10%) to give 44-11 (540 mg, 72%) as a brown solid.
[0321] 44-11 (540 mg, 1.96 mmol) was treated with a mixture of
HCl-dioxane (15 mL, 4 M) and H.sub.2O (15 mL). The mixture was
stirred at 80.degree. C. for 2 h. The solvent was removed under
reduced pressure. The residue was purified by column chromatography
(CH.sub.3OH in DCM from 1% to 10%) to give 44-12 (545 mg, 94.5%) as
a yellow solid.
[0322] To a solution of 44-12 (545 mg, 1.85 mmol) in DMF (11 mL)
was added imidazole (3.27 g, 48.15 mmol), AgNO.sub.3 (3.46 g, 20.3
mmol) and TBSCl (3.3 g, 22.2 mmol) at RT under N.sub.2. The mixture
was stirred at 100.degree. C. for 6 h. The mixture was cooled to
RT, and then diluted with EA (50 mL). The mixture was filtered with
celite. The filtrate was diluted with EA (60 mL) and washed with
water (2.times.40 mL). The organic layer was concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (EA in PE from 3% to 20%) to give 44-13 (575 mg,
52.2%) as a white solid.
[0323] To a stirred solution of 44-13 (575 mg, 901 .mu.mol) in
anhydrous MeCN (8 mL) was added DMAP (220 mg, 1.80 mmol), TEA (182
mg, 1.80 mol) and TPSCl (416 mg, 1.37 mmol) at RT. The mixture was
stirred at RT for 2 h. The mixture was treated with
NH.sub.3*H.sub.2O (10 mL), and then the mixture was stirred for 2
h. The mixture was concentrated under reduced pressure. The residue
was dissolved in EA (30 mL). The solution was washed with brine (10
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography (CH.sub.3OH in DCM from 1% to 2%) to give
44-14 (514 mg, 78%) as a light yellow oil.
[0324] To a solution of 44-14 (514 mg, 807 .mu.mol) in CH.sub.3OH
(9 mL) was added NH.sub.4F (898 mg, 24.2 mmol) at RT under N.sub.2.
The mixture was stirred at 90.degree. C. for 12 h. The mixture was
cooled to RT, and the solid was filtered off. The filtrate was
removed under reduced pressure. The residue was purified by silica
gel chromatography (CH.sub.3OH in DCM from 5% to 20%) to give crude
44. Crude 44 was purified by prep-HPLC (neutral) to give purified
44 (175 mg, 74%) as a white solid. MS (ESI): m/z: 294 [M+H].sup.+
and 587[2M+H].sup.+.
Example 18
Preparation of Compound 45
##STR00117## ##STR00118##
[0326] To a solution of 45-1 (5.0 g, 14.7 mmol, 45-1 was prepared
as provided in Rolland de Ravel et al., J. Med. Chem. (2015)
58(4):1862-1878) in DCM (100.0 mL) was added pyridine (4.1 g, 51.4
mmol) and Tf.sub.2O (9.1 g, 32.3 mmol) at 0.degree. C. The mixture
was stirred at 0.degree. C. for 1 h. The reaction was quenched with
H.sub.2O (200 mL) at 15.degree. C. The mixture was extracted with
DCM (2.times.220.0 mL). The combined organic layers were washed
with brine (400 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give a residue.
The residue was purified by column chromatography (20% EA in PE) to
give 45-2 (4.9 g, 55%) as a yellow solid.
[0327] The 45-2 (4.9 g, 8.2 mmol) was dissolved in TBAF (1 M in
THF, 81.1 mL), and the mixture was stirred at 15.degree. C. for 30
h under N.sub.2. The reaction was quenched with H.sub.2O (100 mL)
at 15.degree. C. The mixture was extracted with EtOAc (3.times.100
mL). The combined organic layers were washed with brine (300 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The residue was purified by column
chromatography (10% CH.sub.3OH in DCM) to give 45-3 (2.2 g, 79%) as
a white solid.
[0328] 45-3 (1.0 g, 2.9 mmol) was dissolved in HCOOH (80% in
H.sub.2O, 30.0 mL). The mixture was stirred at 15.degree. C. for 12
h. The mixture was concentrated under reduced pressure. The residue
was dissolved in CH.sub.3OH (80 mL), and stirred for 30 mins. The
mixture was concentrated under reduced pressure. The residue was
purified by column chromatography (12% CH.sub.3OH in DCM) to give
45-4 (600 mg, 74%) as a white solid.
[0329] To a solution of 45-4 (500 mg, 1.8 mmol) in DMF (6.0 mL) was
added diphenyl carbonate (465 mg, 2.2 mmol) and NaHCO.sub.3 (76 mg,
905 .mu.mol). The mixture was stirred at 140.degree. C. for 1.5 h.
The mixture was concentrated under reduced pressure to remove the
DMF. The residue was purified by column chromatography (12%
CH.sub.3OH in DCM) to give 45-5 (260 mg, 55%) as a white solid.
[0330] To a solution of 45-5 (500 mg, 1.9 mmol) in EtOH (9.0 mL)
and H.sub.2O (1.0 mL) was added NaOH (232 mg, 5.8 mmol). The
mixture was stirred at 15.degree. C. for 2 h. The mixture was
concentrated under reduced pressure to remove EtOH and H.sub.2O.
The residue was purified by column chromatography (12% CH.sub.3OH
in DCM) to give 45-6 (450 mg, 83%) as a white solid.
[0331] To a solution of 45-6 (450 mg, 1.6 mmol) in DMF (1.0 mL) was
added AgNO.sub.3 (3.5 g, 19.7 mmol), imidazole (2.8 g, 40.7 mmol)
and TBSCl (3.0 g, 19.7 mmol). The mixture was stirred at
100.degree. C. for 5 h. The reaction was quenched with H.sub.2O (30
mL) at 20.degree. C. The mixture was extracted with EtOAc
(2.times.30 mL). The combined organic layers were washed with brine
(60 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography (30% EA in PE) to give 45-7 (550 mg, 54%) as
a white solid.
[0332] To a solution of 45-7 (550 mg, 888 .mu.mol) in MeCN (7.0 mL)
was added TEA (224 mg, 2.2 mmol), DMAP (271 mg, 2.2 mmol) and TPSCl
(670 mg, 2.22 mmol). The mixture was stirred at 20.degree. C. for
12 h. The mixture was treated with NH.sub.3*H.sub.2O (3.5 mL, 28%
purity), and then stirred at 20.degree. C. for 1 h. The reaction
was quenched with sat.NH.sub.4Cl aq. (30 mL) at 15.degree. C. The
mixture was diluted with H.sub.2O (30 mL) and extracted with EtOAc
(2.times.30 mL). The combined organic layers were washed with brine
(60 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography (10% CH.sub.3OH in DCM) to give 45-8 (500 mg,
91%) as a white solid.
[0333] To a solution of 45-8 (200 mg, 324 .mu.mol) in CH.sub.3OH
(10 mL) was added NH.sub.4F (370 mg, 9.7 mmol). The mixture was
stirred at 80.degree. C. for 12 h. The solid was removed by
filtration. The filtrate was concentrated under reduced pressure.
The residue was purified by prep-HPLC (0.1% NH.sub.4HCO.sub.3 in
water and MeCN) to give 45 (35 mg, 40%) as a white solid. MS (ESI):
m/z: 551.1 [2M+H].sup.+.
Example 19
Preparation of Compound 46
##STR00119##
[0335] To a solution of 46-1 (600 mg, 2.17 mmol) in dioxane (20 mL)
was added BF.sub.3*Et.sub.2O (338.79 mg, 2.39 mmol) and LiBr (245
mg, 2.82 mmol). The mixture was stirred at 60.degree. C. for 2 h.
The mixture was concentrated at low pressure, and the residue was
purified by column chromatography (10% CH.sub.3OH in DCM) to give
46-2 (720 mg, 93.09%) as a yellow solid.
[0336] To a solution of 46-2 (700 mg, 1.96 mmol) in EA (5 mL) and
EtOH (5.00 mL) was added Pd/C (300 mg, 10% purity) and NaOAc
(234.76 mg, 2.86 mmol) under N.sub.2. The suspension was degassed
under vacuum and purged with H.sub.2 (3.times.). The mixture was
stirred under a H.sub.2 (15 psi) balloon at RT for 2 h. The solid
was filtered off, and the filtrate was concentrated at low
pressure. The residue was purified by column chromatography (5%
CH.sub.3OH in DCM) to give 46-3 (420 mg, 77.02%) as a white
solid.
[0337] To a solution of 46-3 (400 mg, 1.44 mmol) in DMF (8 mL) was
added imidazole (978.83 mg, 14.38 mmol) and AgNO.sub.3 (488.47 mg,
2.88 mmol), followed by TBSCl (2.17 g, 14.38 mmol). The mixture was
stirred at 80.degree. C. for 2 h. The solid was filtered off, and
the filtrate was concentrated at low pressure. The residue was
dissolved in EA (20 mL). The solution was washed with brine and
water (1:1, 20 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated at low pressure. The residue was
purified by column chromatography (EA:PA=2:1) to give 46-4 (610 mg,
83.60%) as a white solid.
[0338] To a solution of 46-4 (600 mg, 1.18 mmol) in MeCN (1.00 mL)
was added 2,4,6-triisopropylbenzene-1-sulfonyl chloride (714.75 mg,
2.36 mmol), DMAP (288.32 mg, 2.36 mmol) and TEA (238.81 mg, 2.36
mmol). The mixture was stirred at RT for 2 h. The mixture was
treated with NH.sub.3*H.sub.2O (2 mL, 28% purity), and stirred for
1 h. The mixture was diluted with EA (30 mL). The solution was
washed with sat. NH.sub.4Cl solution. The organic layer was dried
over anhydrous Na.sub.2SO.sub.4 and concentrated at low pressure.
The residue was purified by column chromatography (5% CH.sub.3OH in
DCM) to give 46-5 (420 mg, 70.38%) as a white solid.
[0339] To a solution of 46-5 (420 mg, 830.47 .mu.mol) in CH.sub.3OH
(20 mL) was added NH.sub.4F (153.80 mg, 4.15 mmol). The mixture was
stirred at 80-100.degree. C. for 24 h., and then cooled to RT. The
solid was removed by filtration. The filtrate was concentrated at
low pressure. The residue was purified by column chromatography (5%
CH.sub.3OH in DCM) to give the crude product. The crude product was
purified by prep-HPLC (neutral system) to give purified 46 (81 mg,
35.18%) as a white solid. MS (ESI): m/z: 555.3 [2M+H].sup.+.
Example 20
Triphosphates
[0340] Dry nucleoside (0.05 mmol) was dissolved in the mixture of
PO(OMe).sub.3 (0.7 mL) and pyridine (0.3 mL). The mixture was
evaporated in vacuum for 15 mins at bath temperature (42.degree.
C.), than cooled down to RT. N-Methylimidazole (0.009 mL, 0.11
mmol) was added followed by POCl.sub.3 (9 .mu.L, 0.11 mmol), and
the mixture was kept at RT for 20-40 mins. The reaction was
controlled by LCMS and monitored by the appearance of corresponding
nucleoside 5'-monophosphate. After completion, tetrabutylammonium
salt of pyrophosphate (150 mg) was added, followed by DMF (0.5 mL)
to get a homogeneous solution. After 1.5 h at ambient temperature,
the reaction was diluted with water (10 mL) and loaded on the
column HiLoad 16/10 with Q Sepharose High Performance. Separation
was done in a linear gradient of NaCl from 0 to 1N in 50 mM
TRIS-buffer (pH 7.5). Triphosphate is eluted at 75-80% B.
Corresponding fractions were concentrated. Desalting was achieved
by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A
linear gradient of methanol from 0 to 30% in 50 mM triethylammonium
acetate buffer (pH 7.5) was used for elution. The corresponding
fractions were combined, concentrated and lyophilized 3 times to
remove excess of buffer.
TABLE-US-00002 MS Structure [M-1] P(.alpha.) P(.beta.) P(.gamma.)
15 ##STR00120## 533.1 -7.23(d) -22.50(t) -11.70(d) 16 ##STR00121##
532.4 -10.75(d) -23.18(t) -11.76(d) 18 ##STR00122## 539.6 -9.69(d)
-23.15(t) -11.91(d) 19 ##STR00123## 533.3 -11.02(d) -23.43(t)
-12.00(d) 20 ##STR00124## 576.1 -7.39(s) -22.50(br.s) -11.86(s) 21
##STR00125## 516.1 -7.39(s) -22.49(br.s) -11.74(s) 22 ##STR00126##
508.4 -10.15(br.s) -23.01(br.s) -12.09(d) 23 ##STR00127## 510.1
-9.09(d) -22.86(t) -11.82(d) 24 ##STR00128## 512.1 -10.67(br.s)
-23.06(br.s) -11.51(d) 25 ##STR00129## 526.2 -10.28(br.s)
-22.82(br.s) -11.48(d) 27 ##STR00130## 540.6 -8.21(d) -22.69(t)
-11.75(d) 47 ##STR00131## 512.2 -10.01(d) -22.23(br.s) -11.48(s) 48
##STR00132## 522.3 -11.50(br.s) -21.68(br.s) -11.50(br.s) 49
##STR00133## 513.0 -9.70(s) -22.68(s) -11.65(s) 50 ##STR00134##
529.8 -10.55(br.s) -22.90(br.s) -11.72(br.s) 51 ##STR00135## 531.2
-11.49(br.s) -22.66(br.s) -11.49(br.s) 52 ##STR00136## 532.3
-10.63(br.s) -22.95(t) -11.92(d) 53 ##STR00137## 514.1 -10.78(br.s)
-23.16(t) -11.78(d) 54 ##STR00138## 516.1 -10.87(d) -23.17(t)
-11.83(d) 55 ##STR00139## 523.5 -10.79(s) -23.09(s) -11.87(d)
Example A
Picornavirus Assay
[0341] HeLa-OHIO cells (Sigma-Aldrich, St. Louis, Mo.) were plated
in 96 well plates at a density of 1.5.times.10.sup.5 cells per well
in assay media (MEM without phenol red or L-glutamine, supplemented
with 1% FBS, 1% penicillin/streptomycin, 2 mM GlutaGro, and
1.times.MEM nonessential amino acids, all from Cellgro, Manassas,
Va.). Assay setup took place after allowing cells to adhere for 24
h. Compounds dissolved in DMSO were serially diluted in assay media
to 2.times. final concentration. Media was aspirated from the
cells, and 100 .mu.l media with compound was added in triplicate.
Human rhinovirus 1B (ATCC, Manassas, Va.) was diluted in assay
media, and 100 .mu.L was added to cells and compound. The virus
inoculum was selected to cause 80-90% cytopathic effect in 4 d.
Infected cells were incubated for 4 d at 33.degree. C., 5%
CO.sub.2. To develop the assay, 100 .mu.L media was replaced with
100 .mu.L CellTiter-Glo.RTM. reagent (Promega, Madison, Wis.), and
incubated for 10 mins at RT. Luminescence was measured on a Victor
X.sub.3 multi-label plate reader.
[0342] Compounds of Formula (I) are active in this assay. The
antiviral activity of exemplary compounds is shown in Table 2,
where `A` indicates an EC.sub.50<1 .mu.M, `B` indicates an
EC.sub.50.gtoreq.1 .mu.M and <10 .mu.M, and `C` indicates an
EC.sub.50.gtoreq.10 .mu.M and <100 .mu.M.
TABLE-US-00003 TABLE 2 Compound # EC.sub.50 2 B 3 A 4 A 7 A 9 A 10
B 37 A
[0343] HeLa-OHIO cells (Sigma-Aldrich, St. Louis, Mo.) were plated
in 96 well plates at a density of 1.5.times.10.sup.5 cells per well
in assay media (MEM without phenol red or L-glutamine, supplemented
with 1% FBS, 1% penicillin/streptomycin, 2 mM GlutaGro, and
1.times.MEM nonessential amino acids, all from Cellgro, Manassas,
Va.). Assay setup took place after allowing cells to adhere for 24
h. Compounds dissolved in DMSO were serially diluted in assay media
to 2.times. final concentration. Media was aspirated from the
cells, and 100 .mu.l media with compound was added in triplicate.
Cells were pre-incubated with the diluted compounds for 24 h before
infection. Human rhinovirus 1B (ATCC, Manassas, Va.) was diluted in
assay media, and 100 .mu.L was added to cells and compound. The
virus inoculum was selected to cause 80-90% cytopathic effect in 4
d. Infected cells were incubated for 4 d at 33.degree. C., 5%
CO.sub.2. To develop the assay, 100 .mu.L media was replaced with
100 .mu.L CellTiter-Glo.RTM. reagent (Promega, Madison, Wis.), and
incubated for 10 mins at RT. Luminescence was measured on a Victor
X.sub.3 multi-label plate reader.
[0344] Compounds of Formula (I) are active in this assay. The
antiviral activity of exemplary compounds is shown in Table 3,
where `A` indicates an EC.sub.50<1 .mu.M, `B` indicates an
EC.sub.50.gtoreq.1 .mu.M and <10 .mu.M, and `C` indicates an
EC.sub.50.gtoreq.10 .mu.M and <100 .mu.M.
TABLE-US-00004 TABLE 3 Compound # EC.sub.50 41 B 42 C 44 C 45 B
Example B
Picornavirus Polymerase Inhibition Assay
[0345] The enzyme activity of human rhinovirus 16 polymerase
(HRV16pol) was measured as an incorporation of tritiated NMP into
acid-insoluble RNA products. HRV16pol assay reactions contained 30
Nm recombinant enzyme, 50 Nm heteropolymeric RNA, about 0.5 .mu.Ci
tritiated NTP, 0.1 Mm of competing cold NTP, 40 Mm Tris-HCl (Ph
7.0), 3 Mm dithiothreitol, and 0.5 Mm MgCl.sub.2. Standard
reactions were incubated for 2.5 h at 30.degree. C., in the
presence of increasing concentration of inhibitor. At the end of
the reaction, RNA was precipitated with 10% TCA, and acid-insoluble
RNA products were filtered on a size exclusion 96-well plate. After
washing of the plate, scintillation liquid was added and
radiolabeled RNA products were detected according to standard
procedures with a Trilux Microbeta scintillation counter. The
compound concentration at which the enzyme-catalyzed rate was
reduced by 50% (IC.sub.50) was calculated by fitting the data to a
non-linear regression (sigmoidal).
[0346] The IC.sub.50 values were derived from the mean of several
independent experiments and are shown in Table 4. Compounds of
Formula (I) showed activity in this assay. A value of `A` in the
table below indicates an IC.sub.50 of <5 .mu.M, a value of `B`
indicates an IC.sub.50<20 .mu.M, and a value of `C` indicates an
IC.sub.50 value of <100 .mu.M.
TABLE-US-00005 TABLE 4 Compound # IC.sub.50 16 C 18 B 19 A 20 C 21
A 22 B 23 A 24 A 47 A 48 A 50 B 52 A 53 A 54 A
Example C
Enterovirus Assay
Cells
[0347] HeLa OHIO cells are purchased from Sigma Aldrich (St Louis,
Mo.) and cultured in MEM with Glutamax (Gibco cat. #41090)
supplemented with 10% FBS (Mediatech cat. #35-011-CV) and 1%
penicillin/streptomycin (Mediatech cat. #30-002-CI), at 37.degree.
C. with 5% CO.sub.2. RD cells are purchased from ATCC (Manassas,
Va.) and cultured in DMEM, supplemented with 10% FBS (Mediatech
cat. #35-011-CV) and 1% penicillin/streptomycin (Mediatech cat.
#30-002-CI), at 37.degree. C. with 5% CO.sub.2.
Determination of Anti-Enterovirus Activity
[0348] For HRV16, EV68, and CVB3, HeLa-OHIO cells are plated at a
density of 1.5.times.10.sup.5 cells per mL (1.5.times.10.sup.4
cells per well) in assay media (MEM without phenol red or
L-glutamine (Gibco cat. #51200) supplemented with 1% FBS, 1%
penicillin/streptomycin (Mediatech cat. #30-002-CI), and 1%
Glutamax (Gibco cat. #35050)) in clear-bottom black 96 well plates.
For EV71, RD cells are plated at a density of 5.times.10.sup.4
cells per mL (5000 cells per well) in assay media (DMEM
supplemented with 2% FBS and 1% penicillin/streptomycin). After 24
h, media is removed and replaced with serially diluted compounds in
assay media. For EC.sub.50 measurements, cells are infected in 100
.mu.L assay media with a virus inoculum sufficient to obtain a
10-fold reduction of the cell viability in the infected control
compared to uninfected control cells. After 2-6 days, cell
viability is measured using CellTiter Glo Luminescent Cell
Viability Assay (Promega cat. #G7572). Cells infected with EV-71
and CVB3 are cultured at 37.degree. C., while cells infected with
HRV-16 or EV-68 are cultured at 33.degree. C. 100 .mu.L media is
removed from each well and 100 .mu.L CellTiter Glo reagent was
added. Plates are incubated at RT for 5 mins, then luminescence is
measured using a Perkin Elmer multilabel counter Victor3V.
EC.sub.50 values is determined using XLFit.
[0349] Although the foregoing has been described in some detail by
way of illustrations and examples for purposes of clarity and
understanding, it will be understood by those of skill in the art
that numerous and various modifications can be made without
departing from the spirit of the present disclosure. Therefore, it
should be clearly understood that the forms disclosed herein are
illustrative only and are not intended to limit the scope of the
present disclosure, but rather to also cover all modification and
alternatives coming with the true scope and spirit of the
invention.
* * * * *