Nucleotide analogs
11572377 · 2023-02-07
Assignee
Inventors
Cpc classification
C07F9/65616
CHEMISTRY; METALLURGY
C07F9/657181
CHEMISTRY; METALLURGY
A61K9/06
HUMAN NECESSITIES
C07F9/6512
CHEMISTRY; METALLURGY
A61K9/0014
HUMAN NECESSITIES
Y02A50/30
GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
International classification
C07F9/6561
CHEMISTRY; METALLURGY
C07F9/6571
CHEMISTRY; METALLURGY
C07F9/6512
CHEMISTRY; METALLURGY
A61K9/00
HUMAN NECESSITIES
Abstract
Disclosed herein, inter alia, are acyclic nucleotide analogs and methods of using an acyclic nucleotide analog for treating and/or ameliorating a papillomavirus infection.
Claims
1. A compound of the formula: ##STR00289## or a pharmaceutically acceptable salt thereof, wherein: B.sup.1 is ##STR00290## R.sup.3 is alkyl or heteroalkyl; each R.sup.9 and each R.sup.10 are independently selected from hydrogen, C.sub.1-6 alkyl, —CH.sub.2SH, —CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2S CH.sub.3, CH.sub.2-phenyl, —CH.sub.2OH, —CH(OH)CH.sub.3, ##STR00291## —CH.sub.2(C═O)OH, —CH.sub.2CH.sub.2(C═O)OH, —(CH.sub.2).sub.3NH(C═NH)NH.sub.2, ##STR00292## and —(CH.sub.2).sub.4NH.sub.2; R.sup.11 is independently selected from hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, alkynyl, cycloalkyl, cycloalkyl(C.sub.1-C.sub.4 alkyl)-, cycloalkenyl, cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, aryl, aryl(C.sub.1-4 alkyl)-, heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl)-, heterocyclyl, and heterocyclyl(C.sub.1-C.sub.4 alkyl)-; R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, tnhalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; R.sup.13 is unsubstituted C.sub.1-6alkyl or unsubstituted C.sub.3-6cycloalkyl; and p is selected from 1, 2, 3, 4, and 5.
2. The compound of claim 1, wherein B.sup.1 is ##STR00293##
3. The compound of claim 2, wherein R.sup.13 is methyl.
4. The compound of claim 1, wherein B.sup.1 is ##STR00294##
5. The compound of claim 1, wherein R.sup.3 is CH.sub.3, CH.sub.2OH, or CH.sub.2F.
6. The compound of claim 1, wherein R.sup.9 is C.sub.1-6alkyl.
7. The compound of claim 1, wherein R.sup.10 is hydrogen.
8. The compound of claim 1, wherein R.sup.11 is C.sub.1-8alkyl.
9. The compound of claim 1, wherein R.sup.12 is alkyl.
10. The compound of claim 1, wherein R.sup.12 is hydroxy.
11. The compound of claim 1, wherein R.sup.12 is halogen.
12. The compound of claim 1, wherein p is 1.
13. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is a topical formulation.
15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is in the form of a cream, gel, or an ointment.
16. A method for treating human papilloma virus comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a human in need thereof.
17. A method for treating cervical intraepithelial neoplasia, vaginal intraepithelial neoplasia, or anal intraepithelial neoplasia comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a human in need thereof.
Description
DETAILED DESCRIPTION OF THE INVENTION
Definitions
(1) 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.
(2) As used herein, any “R” group(s) such as, without limitation, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 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:
(3) ##STR00013##
(4) 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.
(5) 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.
(6) As used herein, “C.sub.a to C.sub.b,” “C.sub.a-C.sub.b,” “C.sub.a-b” and the like 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 heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring 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.
(7) 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.
(8) As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted.
(9) As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstituted or substituted.
(10) 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.
(11) 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 group may be unsubstituted or substituted.
(12) 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.
(13) 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, 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.
(14) As used herein, “heterocyclyl” or “heteroalicyclyl” refer 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).
(15) 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 aryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).
(16) 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 heteroaryl(alkyl) 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.
(17) 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).
(18) “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.”
(19) 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, aralkyl, (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, benzyloxy, hexadecyloxy and octadecyloxy. An alkoxy may be substituted or unsubstituted.
(20) As used herein, “acyl” refers to a hydrogen an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, 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.
(21) 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.
(22) 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, l-chloro-2-fluoromethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.
(23) 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, l-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.
(24) A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. A sulfenyl may be substituted or unsubstituted.
(25) A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.
(26) 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.
(27) An “O-carboxy” group refers to a “RC(═O)O—” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl, as defined herein. An O-carboxy may be substituted or unsubstituted.
(28) The terms “ester” and “C-carboxy” refer to a “—C(═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.
(29) A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.
(30) A “trihalomethanesulfonyl” group refers to an “X.sub.3CSO.sub.2—” group wherein each X is a halogen.
(31) A “trihalomethanesulfonamido” group refers to an “X.sub.3CS(O).sub.2N(R.sup.A)—” group wherein each X is a halogen, and R.sup.A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl.
(32) The term “amino” as used herein refers to a “—NH.sub.2” group.
(33) As used herein, the term “hydroxy” refers to a “—OH” group.
(34) A “cyano” group refers to a “—CN” group.
(35) The term “azido” as used herein refers to a “—N.sub.3” group.
(36) An “isocyanato” group refers to a “—NCO” group.
(37) A “thiocyanato” group refers to a “—CNS” group.
(38) An “isothiocyanato” group refers to an “—NCS” group.
(39) A “mercapto” group refers to an “—SH” group.
(40) A “carbonyl” group refers to a “C═O” group.
(41) An “S-sulfonamido” group refers to a “—SO.sub.2N(R.sup.AR.sup.B)” group in which R.sup.A and R.sup.B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. An S-sulfonamido may be substituted or unsubstituted.
(42) An “N-sulfonamido” group refers to a “RSO.sub.2N(R.sup.A)—” group in which R and R.sup.A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-sulfonamido may be substituted or unsubstituted.
(43) An “O-carbamyl” group refers to a “—OC(═O)N(R.sup.AR.sup.B)” group in which R.sup.A and R.sup.B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. An O-carbamyl may be substituted or unsubstituted.
(44) An “N-carbamyl” group refers to an “ROC(═O)N(R.sup.A)—” group in which R and R.sup.A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-carbamyl may be substituted or unsubstituted.
(45) An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R.sup.AR.sup.B)” group in which R.sup.A and R.sup.B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. An O-thiocarbamyl may be substituted or unsubstituted.
(46) An “N-thiocarbamyl” group refers to an “ROC(═S)N(R.sup.A)—” group in which R and R.sup.A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-thiocarbamyl may be substituted or unsubstituted.
(47) A “C-amido” group refers to a “—C(═O)N(R.sup.AR.sup.B)” group in which R.sup.A and R.sup.B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. A C-amido may be substituted or unsubstituted.
(48) An “N-amido” group refers to a “RC(═O)N(R.sup.A)—” group in which R and R.sup.A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-amido may be substituted or unsubstituted.
(49) 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.
(50) 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.
(51) 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)).
(52) As used herein, the term “phosphonate” is used in its ordinary sense as understood by those skilled in the art, and includes its protonated forms (for example,
(53) ##STR00014##
(54) As used herein, the terms “monophosphonate” and “diphosphonate” are used in their ordinary sense as understood by those skilled in the art, and include protonated forms. Additionally, the term “phosphate” is used in its ordinary sense as understood by those skilled in the art, and includes its protonated forms (for example,
(55) ##STR00015##
(56) The terms “monophosphate,” “diphosphate,” and “triphosphate” are also used in their ordinary sense as understood by those skilled in the art, and include protonated forms.
(57) 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).
(58) 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-toluenesulfonic, 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.
(59) 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.
(60) 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.
(61) 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.
(62) Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. For example all tautomers of phosphonates and heterocyclic bases known in the art are intended to be included, including tautomers of natural and non-natural purine-bases and pyrimidine-bases are intended to be included.
(63) 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).
(64) 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.
(65) 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.
(66) 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.
(67) As used herein, a “subject” refers to an animal that is a host for a viral infection as described herein. “Animal” includes a mammal. “Mammals” 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 a typical embodiment, the subject is human.
(68) As used herein, the terms “treating,” “treatment,” “therapeutic,” or “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 patient's overall feeling of well-being or appearance.
(69) 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 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.
(70) Some embodiments disclosed herein include the use of an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicine for treating a host infected with a human papillomavirus, by inhibiting the synthesis of viral DNA. Other embodiments disclosed herein include the use of an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for treating a host infected with a human papillomavirus, wherein the human papillomavirus can be ameliorated by inhibiting the synthesis of viral DNA. Still other embodiments disclosed herein include a method for treating a host infected with a human papillomavirus that can include contacting a cell infected with the human papillomavirus in a subject infected with the human papillomavirus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Yet still other embodiments disclosed herein include a method for treating a host infected with a human papillomavirus that can includes administering to a subject infected with the human papillomavirus an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, by inhibiting the synthesis of viral DNA. Some embodiments disclosed herein include compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use treating a host infected with a human papillomavirus, by inhibiting viral replication by inhibiting the synthesis of viral DNA.
(71) In some embodiments, the human papillomavirus can be a high-risk human papillomavirus, such as those described herein. For example, the high-risk human papillomavirus can be selected from HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73 and HPV-82. In some embodiments, the human papillomavirus can be HPV-16. In some embodiments, the human papillomavirus can be HPV-18. In some embodiments, the human papillomavirus can be one or more of the following high-risk types: HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73 and HPV-82. As described herein, the presence of a HPV infection can be detected using a PAP smear and/or DNA probe testing (for example, HPV DNA probe testing for one or more high-risk HPV types). Therefore, in some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be provided to a subject diagnosed with a HPV infection, for example a high-risk HPV infection, by a DNA test, such as one of the HPV DNA tests described herein.
(72) In some embodiments, the human papillomavirus can be a low-risk human papillomavirus, including those described herein. In some embodiments, the human papillomavirus can be HPV-6. In some embodiments, the human papillomavirus can be HPV-11.
(73) A compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used to treat a host infected with one or more types of human papillomaviruses. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used to treat HPV-16 and HPV-18. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used to treat both high-risk and low-risk HPV.
(74) 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.
(75) 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. For a topical or intravaginal administration, the dose may be between 0.02 mg 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 another agent. 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 another agent.
(76) 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.
(77) 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.
(78) 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.
(79) 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.
(80) 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.
(81) 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 phosphonate. By neutralizing the charge on the phosphonate, 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 phosphonate thus released may then be metabolized by cellular enzymes to the monophosphate or to the diphosphate, the active metabolite. 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 the compound by reducing undesirable effects, such as isomerization.
(82) In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can act as a chain terminator of DNA synthesis. Once the compound is incorporated into a DNA chain, no further elongation is observed to occur. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, is metabolized such that the groups attached to the phosphorus atom are removed to generate a phosphonic acid. The phosphonic acid can then be anabolized to a diphosphate, the active metabolite, that can act as a chain terminator of DNA synthesis. Once the compound is incorporated into a DNA chain, no further elongation is observed to occur.
(83) Additionally, in some embodiments, the presence of a moiety(ies) that neutralizes the charge of the phosphonate 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 phosphonate 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 phosphonate 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 phosphonate can have improved oral bioavailability, improved aqueous stability and/or reduced risk of byproduct-related toxicity.
(84) Compounds
(85) In a first embodiment disclosed herein are a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
(86) ##STR00016##
wherein: B.sup.1 is a naturally occurring purine, a naturally occurring pyrimidine, a non-naturally occurring purine or a non-naturally occurring pyrimidine. The term naturally occurring purine or pyrimidine base includes guanine, adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, wherein the acyclic chain is bonded to the N as normally occurring in nature. Attachment of the naturally occurring purine or pyrimidine base can be at any available site, e.g., guanin-9-yl, guanine-7-yl, adenine-9-yl, cytosine-1-yl, thymin-1-yl, uracil-1-yl, 2,6-diaminopurin-9-yl. The term “non-naturally occurring” purine or pyrimidine refers to purine or pyrimidine not found in nature, for example, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine and 9-deazaguanine.
(87) In nonlimiting embodiments, B.sup.1 can be:
(88) ##STR00017##
wherein R.sup.13 can be an unsubstituted C.sub.1-6 alkyl or an unsubstituted C.sub.3-6 cycloalkyl. In some embodiments, R.sup.13 can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched or straight chained) or hexyl (branched or straight chained). In other embodiments, R.sup.13 can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In other embodiments, B.sup.1 can be adenine, cytosine, thymine, uracil, 2,6-diaminopurine, 7-deazapurine or 9-deazapurine. Z.sup.1 and Z.sup.2 can be independently O (oxygen) or NR.sup.Z, wherein R.sup.Z can be H (hydrogen) or an optionally substituted C.sub.1-4 alkyl; wherein when Z.sup.1 and Z.sup.2 are each independently O (oxygen); R.sup.1 can be selected from, an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —C.sub.2-24 alkynyl, an optionally substituted —(CHR.sup.4).sub.a—O—C.sub.2-24 alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl), an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-,
(89) ##STR00018##
R.sup.2 can be selected from, an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —C.sub.2-24 alkynyl, an optionally substituted —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-4 alkyl)-, substituted aryl(C.sub.1-4 alkyl)-,
(90) ##STR00019##
or when Z.sup.1 and Z.sup.2 are each independently O; R.sup.1 and R.sup.2 can be taken together to form a moiety selected from an optionally substituted
(91) ##STR00020##
or an optionally substituted
(92) ##STR00021##
wherein Z.sup.1, Z.sup.2, R.sup.1 and R.sup.2, the phosphorus and the moiety form a six-membered to ten-membered ring system; or one of Z.sup.1 and Z.sup.2 can be independently O (oxygen) and the other Z.sup.1 or Z.sup.2 group is NR.sup.Z, wherein R.sup.Z can be H (hydrogen) or an optionally substituted C.sub.1-4 alkyl; or Z.sup.1 and Z.sup.2 are each NR.sup.Z, wherein R.sup.Z can be H (hydrogen) or an optionally substituted C.sub.1-4 alkyl; wherein: R.sup.1 and R.sup.2 can each 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 —(CHR.sup.4).sub.a—O—C.sub.1-24 alkyl, an optionally substituted —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl, an optionally substituted —(CHR.sup.4).sub.b—O—C.sub.2-24 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, a substituted aryl(C.sub.1-4 alkyl), an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-,
(93) ##STR00022##
or when one of Z.sup.1 or Z.sup.2 is O; and the other Z.sup.1 or Z.sup.2 group is NR.sup.Z or both of Z.sup.1 and Z.sup.2 is NR.sup.Z; R.sup.1 and R.sup.2 can be taken together to form a moiety selected from an optionally substituted
(94) ##STR00023##
or an optionally substituted
(95) ##STR00024##
wherein Z.sup.1, Z.sup.2, R.sup.1 and R.sup.2, the phosphorus and the moiety form a six-membered to ten-membered ring system; R.sup.3 can be selected from hydrogen, optionally substituted alkyl such as CH.sub.3, CH.sub.2OH, CH.sub.2F, CHF.sub.2, CF.sub.3, or optionally substituted heteroalkyl such as OCH.sub.3; each R.sup.4 can be independently hydrogen, —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl or —O—(CH.sub.2).sub.d—R.sup.4A; each R.sup.4A can be hydrogen, an optionally substituted C.sub.1-24 alkyl or an optionally substituted aryl; each R.sup.5, each R.sup.6 and each R.sup.8 can be independently an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each R.sup.7 is independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each R.sup.9 and each R.sup.10 can be independently hydrogen or an optionally substituted C.sub.1-6 alkyl; —CH.sub.2SH, —CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2S CH.sub.3, CH.sub.2-an optionally substituted phenyl, —CH.sub.2OH, —CH(OH)CH.sub.3,
(96) ##STR00025##
—CH.sub.2(C═O)OH, —CH.sub.2CH.sub.2(C═O)OH, —(CH.sub.2).sub.3NH(C═NH)NH.sub.2,
(97) ##STR00026##
and —(CH.sub.2).sub.4NH.sub.2; each R.sup.11 can be independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each a and each b can be independently 1, 2, 3 or 4; each c and each d can be independently 0, 1, 2 or 3.
(98) In embodiments, when B.sup.1 is
(99) ##STR00027##
R.sup.3 can be selected from optionally substituted alkyl such as CH.sub.3, CH.sub.2OH, CH.sub.2F, CHF.sub.2, CF.sub.3, or optionally substituted heteroalkyl such as OCH.sub.3.
(100) In embodiments, compounds are disclosed having Formula Ia:
(101) ##STR00028##
wherein: R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; p=1, 2, 3, 4 or 5; and B.sup.1 and R.sup.3 are as defined above.
(102) In embodiments, compounds are disclosed having Formula Ib:
(103) ##STR00029##
wherein: B.sup.1, R.sup.3, R.sup.12 and p are as defined above.
(104) In embodiments, compounds are disclosed having Formula Ic:
(105) ##STR00030##
wherein: B.sup.1, R.sup.3, R.sup.5, R.sup.12 and p are as defined above.
(106) In embodiments, compounds are disclosed having Formula Id:
(107) ##STR00031##
wherein: B.sup.1, R.sup.3, R.sup.6, R.sup.12 and p are as defined above.
(108) In embodiments, compounds are disclosed having Formula Ie:
(109) ##STR00032##
wherein: B.sup.1, R.sup.3, R.sup.7, R.sup.12 and p are as defined above.
(110) In embodiments, compounds are disclosed having Formula If:
(111) ##STR00033##
wherein: B.sup.1, R.sup.3, R.sup.8, R.sup.12 and p are as defined above.
(112) In embodiments, compounds are disclosed having Formula Ig:
(113) ##STR00034##
wherein: B.sup.1, R.sup.3, R.sup.12 and p are as defined above.
(114) In embodiments, compounds are disclosed having Formula Ih:
(115) ##STR00035##
wherein: B.sup.1, R.sup.3, R.sup.12 and p are as defined above.
(116) In embodiments, compounds are disclosed having Formula Ii:
(117) ##STR00036##
wherein: B.sup.1, R.sup.3, R.sup.9R.sup.10, R.sup.11, R.sup.12 and p are as defined above.
(118) In embodiments, compounds are disclosed having Formula Ij:
(119) ##STR00037##
wherein: B.sup.1, R.sup.3, and R.sup.8 are as defined above.
(120) In embodiments, compounds are disclosed having Formula Ik:
(121) ##STR00038##
wherein: B.sup.1 and R.sup.3 are as defined above.
(122) In embodiments, compounds are disclosed having Formula Il:
(123) ##STR00039##
wherein: B.sup.1, R.sup.3, R.sup.12 and p are as defined above.
(124) In an alternate embodiment, compounds are disclosed having Formula Im:
(125) ##STR00040##
wherein: B.sup.1, R.sup.3, R.sup.12 and p are as defined above.
(126) Some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, are provided in Table 1. In Table 1,
(127) ##STR00041##
(128) TABLE-US-00001 TABLE 1 B.sup.1 Z.sup.1 Z.sup.2 R.sup.1 R.sup.2 G1 O O —C.sub.2-24 alkenyl —C.sub.12-24 alkenyl G1 O O —C.sub.2-24 alkynyl —C.sub.12-24 alkenyl G1 O O —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl —C.sub.12-24 alkenyl G1 O O Cycloalkyl —C.sub.12-24 alkenyl G1 O O cycloalkyl(C.sub.1-4 alkyl)- —C.sub.12-24 alkenyl G1 O O Cycloalkenyl —C.sub.12-24 alkenyl G1 O O cycloalkenyl(C.sub.1-4 alkyl) —C.sub.12-24 alkenyl G1 O O Aryl —C.sub.12-24 alkenyl G1 O O aryl(C.sub.1-4 alkyl) —C.sub.12-24 alkenyl G1 O O Heteroaryl —C.sub.12-24 alkenyl G1 O O heteroaryl(C.sub.1-4 alkyl) —C.sub.12-24 alkenyl G1 O O —C.sub.2-24 alkenyl —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl G1 O O —C.sub.2-24 alkynyl —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl G1 O O —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl G1 O O Cycloalkyl —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl G1 O O cycloalkyl(C.sub.1-4 alkyl)- —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl G1 O O Cycloalkenyl —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl G1 O O cycloalkenyl(C.sub.1-4 alkyl) —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl G1 O O Aryl —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl G1 O O aryl(C.sub.1-4 alkyl) —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl G1 O O Heteroaryl —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl G1 O heteroaryl(C.sub.1-4 alkyl) —(CH.sub.2).sub.2O—C.sub.2-24 alkenyl G1 O O
(129) In an alternate embodiment, in Table 1, when the base is G1 or G2, R.sup.3 can be selected from optionally substituted alkyl such as CH.sub.3, CH.sub.2OH, CH.sub.2F, CHF.sub.2, CF.sub.3, or optionally substituted heteroalkyl such as OCH.sub.3. In Table 1, C.sub.2-24 alkenyl, —(CIH.sub.2).sub.2O—C.sub.2-24 alkenyl, aryl (including phenyl), aryl(C.sub.1-4 alkyl) (including benzyl),
(130) ##STR00126##
can be each optionally substituted. R.sup.13 is C.sub.1-6 alkyl or cycloalkyl(C.sub.0-4 alkyl).
(131) In some embodiments, at least one of R.sup.1 and R.sup.2 can be an optionally substituted C.sub.2-24 alkenyl. In still other embodiments, R.sup.1 and R.sup.2 both can be an optionally substituted C.sub.2-24 alkenyl. When one or both of R.sup.1 and R.sup.2 is an optionally substituted C.sub.2-24 alkenyl, the optionally substituted C.sub.2-24 alkenyl can be the aliphatic chain from a fatty acid. Fatty acid aliphatic chains differ by length. Types of fatty acids include short-chain fatty acids (fewer than six carbons), medium-chain fatty acids (six to twelve carbons), long-chain fatty acids (thirteen to twenty-one carbons), and very long-chain fatty acids (more than twenty-two carbons). Examples of aliphatic chains include, but are not limited to, the following: myristoleyl, myristyl, palmitoleyl, palmityl, sapienyl, oleyl, elaidyl, vaccenyl, linoleyl, α-linolenyl, arachidonyl, eicosapentaenyl, erucyl, docosahexaenyl, caprylyl, capryl, lauryl, stearyl, arachidyl, behenyl, lignoceryl and cerotyl. In some embodiments of this paragraph, at least one of Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, both Z.sup.1 and Z.sup.2 can be O.
(132) In some embodiments, at least one of R.sup.1 and R.sup.2 can be —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl. In other embodiments, R.sup.1 and R.sup.2 both can be —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl. In some embodiments, each R.sup.4 can be hydrogen. In some embodiments, at least one R.sup.4 can be —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl. In some embodiments, at least one R.sup.4 can be —O—(CH.sub.2).sub.d—R.sup.4A. In some embodiments, b can be 1. In other embodiments, b can be 2. In still other embodiments, b can be 3. In yet still other embodiments, b can be 4. In some embodiments of this paragraph, at least one of Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, both Z.sup.1 and Z.sup.2 can be O.
(133) When an R.sup.4 moiety is present, in some embodiments, R.sup.4A can be H (hydrogen). In other embodiments, R.sup.4A can be an optionally substituted C.sub.1-24 alkyl. In still other embodiments, R.sup.4A can be an optionally substituted aryl. In embodiments, at least one R.sup.4 can be —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl, and c can be 0. In other embodiments, at least one R.sup.4 can be —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl, and c can be 1. In still other embodiments, at least one R.sup.4 can be —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl, and c can be 2. In yet still other embodiments, at least one R.sup.4 can be —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl, and c can be 3. In embodiments, at least one R.sup.4 can be —O—(CH.sub.2).sub.d—R.sup.4A, and d can be 0. In other embodiments, at least one R.sup.4 can be —O—(CH.sub.2).sub.d—R.sup.4A, and d can be 1. In still other embodiments, at least one R.sup.4 can be —O—(CH.sub.2).sub.d—R.sup.4A, and d can be 2. In yet still other embodiments, at least one R.sup.4 can be —O—(CH.sub.2).sub.d—R.sup.4A, and d can be 3. When more than one R.sup.4 is present, the R.sup.4 moieties can be the same, or at least one R.sup.4 can be different.
(134) In embodiments, at least one of R.sup.1 and R.sup.2 can be an optionally substituted aryl(C.sub.1-4 alkyl). In other embodiments, R.sup.1 and R.sup.2 both can be an optionally substituted aryl(C.sub.1-4 alkyl). A suitable optionally substituted aryl(C.sub.1-4 alkyl) is an optionally substituted benzyl. When the aryl and/or aryl(C.sub.1-4 alkyl) is substituted, the aryl ring can be substituted with 1, 2, 3 or more than 3 substituents. When more than two substituents are present, the substituents can be the same or different. In embodiments, the aryl ring can be a para-, ortho- or meta-substituted phenyl. In some embodiments of this paragraph, at least one of Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, both Z.sup.1 and Z.sup.2 can be O.
(135) In embodiments, at least one of R.sup.1 and R.sup.2 can be
(136) ##STR00127##
or one of R.sup.1 and R.sup.2 can be
(137) ##STR00128##
In other embodiments, R.sup.1 and R.sup.2 both can be
(138) ##STR00129##
In embodiments, R.sup.5 can be an optionally substituted C.sub.1-8 alkyl. In embodiments, R.sup.5 can be an unsubstituted C.sub.1-6 alkyl. In other embodiments, R.sup.5 can be an optionally substituted C.sub.2-8 alkenyl, such as an optionally substituted allyl. In still other embodiments, R.sup.5 can be an optionally substituted cycloalkyl, for example, an optionally substituted C.sub.3-6 cycloalkyl or an optionally substituted C.sub.5-6 cycloalkyl. In yet still other embodiments, R.sup.5 can be an optionally substituted aryl, such as an optionally substituted phenyl. In embodiments, R.sup.6 can be an optionally substituted C.sub.1-8 alkyl. In embodiments, R.sup.6 can be an unsubstituted C.sub.1-6 alkyl. In other embodiments, R.sup.6 can be an optionally substituted C.sub.2-8 alkenyl. In still other embodiments, R.sup.6 can be an optionally substituted cycloalkyl. In yet still other embodiments, R.sup.6 can be an optionally substituted aryl, such as an optionally substituted phenyl. Examples of suitable R.sup.6 groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, pentyl (branched or straight chained), hexyl (branched or straight chained), an optionally substituted allyl, an optionally substituted C.sub.3-6 cycloalkyl, an optionally substituted C.sub.5-6 cycloalkyl and an optionally substituted phenyl. In some embodiments of this paragraph, at least one of Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, both Z.sup.1 and Z.sup.2 can be O. In embodiments, one of R.sup.1 and R.sup.2 can be isopropyloxycarbonyloxymethyl (POC).
(139) In embodiments, at least one of R.sup.1 and R.sup.2 can be
(140) ##STR00130##
In other embodiments, R.sup.1 and R.sup.2 both can be
(141) ##STR00131##
In still other embodiments, R.sup.1 and R.sup.2 both can be
(142) ##STR00132##
In embodiments, R.sup.8 can be an optionally substituted C.sub.1-8 alkyl. In embodiments, R.sup.8 can be an unsubstituted C.sub.1-6 alkyl. In other embodiments, R.sup.8 can be an optionally substituted C.sub.2-5 alkenyl, such as an optionally substituted allyl. In still other embodiments, R.sup.8 can be an optionally substituted cycloalkyl, for example, an optionally substituted C.sub.3-6 cycloalkyl or an optionally substituted C.sub.5-6 cycloalkyl. In yet still other embodiments, R.sup.8 can be an optionally substituted aryl, such as an optionally substituted phenyl. In some embodiments of this paragraph, at least one of Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, both Z.sup.1 and Z.sup.2 can be O. In embodiments, R.sup.1 and R.sup.2 both can be an S-acylthioethyl (SATE) group and form a SATE ester prodrug. In other embodiments, R.sup.1 and R.sup.2 both can be a S-[(2-hydroxyethyl)sulfidyl]-2-thioethyl (DTE) group and form a DTE ester prodrug. In still other embodiments, one of R.sup.1 and R.sup.2 can be a S-acylthioethyl (SATE) group, and the other of R.sup.1 and R.sup.2 can be an optionally substituted phenyl group and form a phenyl(SATE) prodrug. In yet still other embodiments, one of R.sup.1 and R.sup.2 can be a S-acylthioethyl (SATE) group, and the other of R.sup.1 and R.sup.2 can be an N-linked alpha-amino acid ester and form a (SATE)-phosphonoamidate diester prodrug.
(143) The term “N-linked alpha-amino acid ester” refers to an amino acid that is attached to the indicated moiety via a main-chain amino or mono-substituted amino group and wherein the main-chain carboxylic acid group has been converted to an ester group. Examples of alpha-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. 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. In embodiments, the ester group has a formula selected from alkyl-O—C(═O)—, cycloalkyl-O—C(═O)—, aryl-O—C(═O)— and aryl(alkyl)-O—C(═O)—. N-linked alpha-amino acid esters can be substituted or unsubstituted. When R.sup.1 and/or R.sup.2 is an N-linked alpha-amino acid ester, the main-chain nitrogen of the main-chain amino or mono-substituted amino group is the nitrogen of Z.sup.1 and/or Z.sup.2, respectively.
(144) In embodiments, at least one of R.sup.1 and R.sup.2 can be
(145) ##STR00133##
In other embodiments, R.sup.1 and R.sup.2 both can be
(146) ##STR00134##
In embodiments, R.sup.7 can be hydrogen. In other embodiments, R.sup.7 can be an optionally substituted C.sub.1-8 alkyl. In embodiments, R.sup.7 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.7 can be an optionally substituted cycloalkyl, for example, an optionally substituted C.sub.3-6 cycloalkyl or an optionally substituted C.sub.5-6 cycloalkyl. In yet still other embodiments, R.sup.7 can be an optionally substituted aryl, such as an optionally substituted phenyl or an optionally substituted naphthyl. In some embodiments of this paragraph, at least one of Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, both Z.sup.1 and Z.sup.2 can be O. In embodiments, R.sup.1 and R.sup.2 both can be a dioxolenone group and form a dioxolenone prodrug.
(147) In embodiments, R.sup.1 and R.sup.2 can be taken together to form an optionally substituted
(148) ##STR00135##
wherein Z.sup.1, Z.sup.2, R.sup.1 and R.sup.2, the phosphorus and the moiety form a six-membered ring system, and the indicate the points of attachment to Z.sup.1 and Z.sup.2, respectively. An example of R.sup.1 and R.sup.2 taken together to form an optionally substituted
(149) ##STR00136##
wherein Z.sup.1, Z.sup.2, R.sup.1 and R.sup.2, the phosphorus and the moiety form a six-membered ring system is the following:
(150) ##STR00137##
(Ph is an optionally substituted phenyl).
When substituted, the ring of
(151) ##STR00138##
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 embodiments, the
(152) ##STR00139##
ring can be substituted with an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl. In embodiments, R.sup.1 and R.sup.2 can be taken together to form an optionally substituted
(153) ##STR00140##
such as
(154) ##STR00141##
wherein R.sup.A can be an optionally substituted phenyl, an optionally substituted mono-cyclic heteroaryl (such as pyridinyl) or an optionally substituted mono-cyclic heterocyclyl. In embodiments, R.sup.6A and R.sup.7A can form a cyclic 1-aryl-1,3-propanyl ester (HEPDIRECT™) prodrug moiety.
(155) In embodiments, R.sup.1 and R.sup.2 can be taken together to form an optionally substituted
(156) ##STR00142##
wherein Z.sup.1, Z.sup.2, R.sup.1 and R.sup.2, the phosphorus and the moiety form a ten-membered ring system, and the indicate the points of attachment to Z.sup.1 and Z.sup.2, respectively. Example of an optionally substituted
(157) ##STR00143##
include
(158) ##STR00144##
In embodiments, R.sup.1 and R.sup.2 can form a cyclosaligenyl (cycloSal) prodrug. An example of R.sup.1 and R.sup.2 taken together to form an optionally substituted
(159) ##STR00145##
wherein Z.sup.1, Z.sup.2, R.sup.1 and R.sup.2, the phosphorus and the moiety form a ten-membered ring system is the following:
(160) ##STR00146##
(161) In embodiments, one of R.sup.1 or R.sup.2 can be
(162) ##STR00147##
wherein Z.sup.1 can be NR.sup.Z, such as NH. In embodiments, R.sup.9 can be hydrogen. In other embodiments, R.sup.9 can be an optionally substituted C.sub.1-6 alkyl. In embodiments, R.sup.10 can be hydrogen. In other embodiments, R.sup.10 can be an unsubstituted C.sub.1-6 alkyl, —CH.sub.2SH, —CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2S CH.sub.3, CH.sub.2-an optionally substituted phenyl, —CH.sub.2OH, —CH(OH)CH.sub.3,
(163) ##STR00148##
—CH.sub.2(C═O)OH, —CH.sub.2CH.sub.2(C═O)OH, —(CH.sub.2).sub.3NH(C═NH)NH.sub.2,
(164) ##STR00149##
or —(CH.sub.2).sub.4NH.sub.2. In embodiments, R.sup.11 can be hydrogen. In embodiments, R.sup.11 can be an optionally substituted C.sub.1-8 alkyl. In still other embodiments, R.sup.11 can be an optionally substituted cycloalkyl, such as an optionally substituted C.sub.3-6 cycloalkyl. In yet still other embodiments, R.sup.11 can be an optionally substituted aryl. For example, R.sup.11 can be a substituted or unsubstituted phenyl. In embodiments, R.sup.11 can be an optionally substituted aryl(C.sub.1-6 alkyl) (such as an optionally substituted benzyl).
(165) When Z.sup.1 and R.sup.1 or Z.sup.2 and R.sup.2 form
(166) ##STR00150##
can be N-linked alpha-amino acid ester. N-linked alpha-amino acid esters are described herein. In embodiments,
(167) ##STR00151##
In other embodiments,
(168) ##STR00152##
In embodiments, R.sup.1 can be
(169) ##STR00153##
wherein Z.sup.1 can be NH; and R.sup.2 can be an optionally substituted aryl(C.sub.1-4 alkyl) (for example, an optionally substituted benzyl), and form an optionally substituted benzyl phosphonoamidate prodrug.
(170) When Z.sup.1 or Z.sup.2 is NR.sup.Z, R.sup.Z can be H (hydrogen) or an optionally substituted C.sub.1-4 alkyl. In embodiments, Z.sup.1 or Z.sup.2 can be NH. In other embodiments, Z.sup.1 or Z.sup.2 can be N-an optionally substituted C.sub.1-4 alkyl. In embodiments, Z.sup.1 or Z.sup.2 can be N-an unsubstituted C.sub.1-4 alkyl. For example, Z.sup.1 or Z.sup.2 can be N-methyl, N-ethyl, N-(n-propyl), N-(iso-propyl), N-(n-butyl), N-(iso-butyl) or N-(t-butyl). In embodiments, the N-an optionally substituted C.sub.1-4 alkyl can be —N(CH.sub.2)—CH(OH)—CH.sub.2OH.
(171) In embodiments, at least one of R.sup.1 and R.sup.2 can be
(172) ##STR00154##
In other embodiments, R.sup.1 and R.sup.2 both can be
(173) ##STR00155##
In embodiments, one of R.sup.1 and R.sup.2 can be
(174) ##STR00156##
and the other of R.sup.1 and R.sup.2 can be an optionally substituted C.sub.2-24 alkenyl. In some embodiments of this paragraph, at least one of Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, both Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, one of Z.sup.1 and Z.sup.2 can be Q and the other of Z.sup.1 and Z.sup.2 can be NR.sup.Z. Examples of prodrugs that include
(175) ##STR00157##
include the following:
(176) ##STR00158##
In embodiments, a compound of Formula (I) can be a nitrofuranylmethyl phosphonoamidate prodrug, wherein R.sup.1 can be
(177) ##STR00159##
R.sup.2 can be —(CH.sub.2).sub.3CH.sub.2Cl, Z.sup.1 can be O, and Z.sup.2 can be NCH.sub.3. In embodiments, a compound of Formula (I) can be a nitrofuranylmethyl N-dihydroxypropyl phosphonoamidate prodrug, wherein R.sup.1 can be
(178) ##STR00160##
R.sup.2 can be —(CH.sub.2).sub.3CH.sub.2Cl, Z.sup.1 can be O, and Z.sup.2 can be —N(CH.sub.2)—CH(OH)—CH.sub.2OH.
(179) In embodiments, R.sup.1 and R.sup.2 can be the same. In embodiments, R.sup.1 and R.sup.2 can be different.
(180) In a second embodiment disclosed herein are compound of Formula (I), or a pharmaceutically acceptable salt thereof:
(181) ##STR00161##
wherein: B.sup.1 is as defined above; Z.sup.1 and Z.sup.2 can be independently O (oxygen) or NR.sup.Z, wherein R.sup.Z can be H (hydrogen) or an optionally substituted C.sub.1-4 alkyl; R.sup.1 can be selected from an optionally substituted —C.sub.1-24 alkyl, an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —(CHR.sup.4).sub.a—O—C.sub.1-24 alkyl, an optionally substituted —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl), an optionally substituted heteroaryl, an optionally substituted heterocyclyl,
(182) ##STR00162##
R.sup.2 can selected from an optionally substituted-C.sub.1-24 alkyl, an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —(CHR.sup.4).sub.a—O—C.sub.1-24 alkyl, an optionally substituted —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl),
(183) ##STR00163##
or Z.sup.1 and Z.sup.2 can be O; and R.sup.1 and R.sup.2 can be taken together to form a moiety selected from an optionally substituted
(184) ##STR00164##
and an optionally substituted
(185) ##STR00165##
wherein Z.sup.1, Z.sup.2, R.sup.1 and R.sup.2, the phosphorus and the moiety form a six-membered to ten-membered ring system; each R.sup.4 can be independently H (hydrogen), —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl or —O—(CH.sub.2).sub.d—R.sup.4A; each R.sup.4A can be H (hydrogen), an optionally substituted C.sub.1-24 alkyl or an optionally substituted aryl; each R.sup.5, each R.sup.6 and each R.sup.8 can be independently an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted cycloalkyl or an optionally substituted aryl; each R.sup.9 can be independently H (hydrogen) or an optionally substituted C.sub.1-6 alkyl.
(186) In embodiments, R.sup.1 can be absent or H; and R.sup.2 can be selected from an optionally substituted —C.sub.1-24 alkyl, an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —(CHR.sup.4).sub.a—O—C.sub.1-24 alkyl, an optionally substituted —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl),
(187) ##STR00166##
(188) In embodiments, R.sup.1 and R.sup.2 can be independently selected from an optionally substituted —C.sub.1-24 alkyl, an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —(CHR.sup.4).sub.b—O—C.sub.1-24 alkyl, an optionally substituted —(CHR.sup.4).sub.a—O—C.sub.2-24 alkenyl, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl),
(189) ##STR00167##
(190) In embodiments, at least one of R.sup.1 and R.sup.2 can be an optionally substituted C.sub.1-24 alkyl or an optionally substituted C.sub.2-24 alkenyl. In other embodiments, R.sup.1 and R.sup.2 both can be an optionally substituted C.sub.1-24 alkyl. In still other embodiments, R.sup.1 and R.sup.2 both can be an optionally substituted C.sub.2-24 alkenyl. When one or both of R.sup.1 and R.sup.2 is an optionally substituted C.sub.1-24 alkyl or an optionally substituted C.sub.2-24 alkenyl, the optionally substituted C.sub.1-24 alkyl and/or the optionally substituted C.sub.2-24 alkenyl can be the aliphatic chain from a fatty acid. Fatty acid aliphatic chains differ by length. Types of fatty acids include short-chain fatty acids (fewer than six carbons), medium-chain fatty acids (six to twelve carbons), long-chain fatty acids (thirteen to twenty-one carbons), and very long-chain fatty acids (more than twenty-two carbons). Examples of aliphatic chains include, but are not limited to, the following: myristoleyl, myristyl, palmitoleyl, palmityl, sapienyl, oleyl, elaidyl, vaccenyl, linoleyl, α-linolenyl, arachidonyl, eicosapentaenyl, erucyl, docosahexaenyl, caprylyl, capryl, lauryl, stearyl, arachidyl, behenyl, lignoceryl and cerotyl. In some embodiments of this paragraph, at least one of Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, both Z.sup.1 and Z.sup.2 can be O.
(191) In embodiments, at least one of R.sup.1 and R.sup.2 can be —(CHR.sup.4).sub.a—O—C.sub.1-24 alkyl. In other embodiments, R.sup.1 and R.sup.2 both can be —(CHR.sup.4).sub.a—O—C.sub.1-24 alkyl. In some embodiments, each R.sup.4 can be hydrogen. In some embodiments, at least one R.sup.4 can be —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl. In some embodiments, at least one R.sup.4 can be —O—(CH.sub.2).sub.d—R.sup.4A. In some embodiments, a can be 1. In other embodiments, a can be 2. In still other embodiments, a can be 3. In yet still other embodiments, a can be 4. In some embodiments of this paragraph, at least one of Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, both Z.sup.1 and Z.sup.2 can be O.
(192) In some embodiments, at least one of R.sup.1 and R.sup.2 can be —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl. In other embodiments, R.sup.1 and R.sup.2 both can be —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl. In some embodiments, each R.sup.4 can be hydrogen. In some embodiments, at least one R.sup.4 can be —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl. In some embodiments, at least one R.sup.4 can be —O—(CH.sub.2).sub.d—R.sup.4A. In some embodiments, b can be 1. In other embodiments, b can be 2. In still other embodiments, b can be 3. In yet still other embodiments, b can be 4. In some embodiments of this paragraph, at least one of Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, both Z.sup.1 and Z.sup.2 can be O.
(193) In some embodiments, at least one of R.sup.1 and R.sup.2 can be an optionally substituted aryl. In other embodiments, R.sup.1 and R.sup.2 both can be an optionally substituted aryl. For example, one or both R.sup.1 and R.sup.2 can be an optionally substituted phenyl. In some embodiments, at least one of R.sup.1 and R.sup.2 can be an optionally substituted aryl(C.sub.1-4 alkyl). In other embodiments, R.sup.1 and R.sup.2 both can be an optionally substituted aryl(C.sub.1-4 alkyl). A suitable optionally substituted aryl(C.sub.1-4 alkyl) is an optionally substituted benzyl. When the aryl and/or aryl(C.sub.1-4 alkyl) is substituted, the aryl ring can be substituted with 1, 2, 3 or more than 3 substituents. When more than two substituents are present, the substituents can be the same or different. In some embodiments, the aryl ring can be a para-, ortho- or meta-substituted phenyl. In some embodiments of this paragraph, at least one of Z.sup.1 and Z.sup.2 can be O. In some embodiments of this paragraph, both Z.sup.1 and Z.sup.2 can be O.
(194) In embodiments, at least one of R.sup.1 and R.sup.2 can be
(195) ##STR00168##
In embodiments, R.sup.1 and R.sup.2 both can be
(196) ##STR00169##
In embodiments, R.sup.1 and R.sup.2 both can be a isopropyloxycarbonyloxymethyl (POC) group, and form a bis(isopropyloxycarbonyloxymethyl) (bis(POC)) prodrug. In other embodiments, one or both of R.sup.1 and R.sup.2 can be pivaloyloxymethyl (POM). In some embodiments, R.sup.1 and R.sup.2 both can be a pivaloyloxymethyl (POM) group, and form a bis(pivaloyloxymethyl) (bis(POM)) prodrug.
(197) In embodiments, R.sup.1 and R.sup.2 both can be a S-[(2-hydroxyethyl)sulfidyl]-2-thioethyl (DTE) group and form a DTE ester prodrug. In still other embodiments, one of R.sup.1 and R.sup.2 can be a S-acylthioethyl (SATE) group, and the other of R.sup.1 and R.sup.2 can be an optionally substituted phenyl group and form a phenyl(SATE) prodrug. In yet still other embodiments, one of R.sup.1 and R.sup.2 can be a S-acylthioethyl (SATE) group, and the other of R.sup.1 and R.sup.2 can be an N-linked alpha-amino acid ester and form a (SATE)-phosphonamidate diester prodrug.
(198) In embodiments, at least R.sup.1 can be
(199) ##STR00170##
wherein Z.sup.1 can be NR.sup.Z, such as NH. In other embodiments, R.sup.1 and R.sup.2 both can be
(200) ##STR00171##
wherein Z.sup.1 and Z.sup.2 both can be NR.sup.Z, such as NH. In some embodiments, R.sup.9 can be hydrogen. In other embodiments, R.sup.9 can be an optionally substituted C.sub.1-6 alkyl.
(201) In embodiments, a compound of Formula (I) can be a phosphorodiamidate prodrug, wherein R.sup.1 and R.sup.2 both can be
(202) ##STR00172##
wherein Z.sup.1 and Z.sup.2 both can be NR.sup.Z, such as NH.
(203) In embodiments, a compound of Formula (I) can be a nitrofuranylmethyl phosphonoamidate prodrug, wherein R.sup.1 can be
(204) ##STR00173##
R.sup.2 can be —(CH.sub.2).sub.3CH.sub.2Cl, Z.sup.1 can be O, and Z.sup.2 can be NCH.sub.3.
(205) In embodiments, R.sup.1 and R.sup.2 can be the same. In some embodiments, R.sup.1 and R.sup.2 can be different.
(206) As described herein, B.sup.1 can be a naturally occurring purine, naturally occurring pyrimidine, non-naturally occurring purine or a non-naturally occurring pyrimidine. For example, B.sup.1 can be
(207) ##STR00174##
wherein R.sup.13 can be an unsubstituted C.sub.1-6 alkyl or an unsubstituted C.sub.3-6 cycloalkyl. In some embodiments, R.sup.13 can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched or straight chained) or hexyl (branched or straight chained). In other embodiments, R.sup.13 can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
(208) Examples of compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include, but are not limited to:
(209) ##STR00175## ##STR00176##
or a pharmaceutically acceptable salt of the foregoing.
(210) In embodiments, there is provided a compound of the formula:
(211) ##STR00177##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
(212) In embodiments, there is provided a compound of the formula:
(213) ##STR00178##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
(214) In embodiments, there is provided a compound of the formula:
(215) ##STR00179##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
(216) In embodiments, there is provided a compound of the formula:
(217) ##STR00180##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
(218) In embodiments, there is provided a compound of the formula:
(219) ##STR00181##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
(220) In embodiments, there is provided a compound of the formula:
(221) ##STR00182##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
(222) In embodiments, compounds have the formula:
(223) ##STR00183##
wherein R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(224) In embodiments, compounds have the Formula:
(225) ##STR00184##
wherein R.sup.12 is defined above. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(226) In embodiments, compounds have the Formula:
(227) ##STR00185##
wherein R.sup.12 is defined above. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(228) In embodiments, compounds have the Formula:
(229) ##STR00186##
wherein R.sup.12 is defined above. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(230) In embodiments, compounds have the Formula:
(231) ##STR00187##
wherein R.sup.12 is defined above. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(232) In embodiments, compounds have the Formula:
(233) ##STR00188##
wherein R.sup.12 is defined above. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(234) In embodiments, compounds have the Formula:
(235) ##STR00189##
wherein R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(236) In embodiments, compounds have the Formula:
(237) ##STR00190##
wherein R.sup.12 is defined above. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(238) In embodiments, compounds have the Formula:
(239) ##STR00191##
wherein R.sup.12 is defined above. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(240) In embodiments, compounds have the Formula:
(241) ##STR00192##
wherein R.sup.12 is defined above. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(242) In embodiments, compounds have the Formula:
(243) ##STR00193##
wherein R.sup.12 is defined above. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(244) In embodiments, compounds have the Formula:
(245) ##STR00194##
wherein R.sup.12 is defined above. The phenyl ring can be substituted by R.sup.12 1, 2 or 3 times.
(246) In embodiments, R.sup.12 in a structure above is independently selected from alkyl, alkoxy, halogen and cyano.
(247) In embodiments, R.sup.1 is an optionally substituted heteroaryl, for example pyridine, pyrimidine, imidazole, pyrrole, furan or thiophene.
(248) In embodiments, R.sup.1 is an optionally substituted aryl include but not limited to phenyl.
(249) In embodiments, R.sup.1 is optionally substituted aryl(C.sub.1-4 alky).
(250) In embodiments, R.sup.1 is an optionally substituted heteroaryl, for example pyridine, pyrimidine, imidazole, pyrrole, furan or thiophene and R.sup.2 is —(CHR.sup.4).sub.a—O—(C.sub.1-24 alkyl or alkenyl). In some embodiments, R.sup.1 is optionally substituted aryl including, but not limited, to phenyl and R.sup.2 is —(CHR.sup.4).sub.a—O—(C.sub.1-24 alkyl or alkenyl). In some embodiments, R.sup.1 is optionally substituted aryl(C.sub.1-4 alky) and R.sup.2 is —(CHR.sup.4).sub.a—O—(C.sub.1-24 alkyl or alkenyl).
(251) In some embodiments, when R.sup.1 is —(CH.sub.2).sub.2—O—(CH.sub.2).sub.17CH.sub.3, then Z.sup.2 cannot be O and R.sup.2 cannot be phenyl (a substituted or unsubstituted phenyl). In some embodiments, when R.sup.1 is —(CH.sub.2).sub.2—O—(CH.sub.2).sub.17CH.sub.3, then Z.sup.2 cannot be O and R.sup.2 cannot be benzyl (a substituted or unsubstituted benzyl). In some embodiments, when R.sup.1 is —(CH.sub.2).sub.2—O—(CH.sub.2).sub.17CH.sub.3, then Z.sup.2 cannot be O and R.sup.2 cannot be hydrogen. In some embodiments, when R.sup.1 is —(CH.sub.2).sub.3—O—(CH.sub.2).sub.15CH.sub.3, then Z.sup.2 cannot be O and R.sup.2 cannot be phenyl (a substituted or unsubstituted phenyl). In some embodiments, when R.sup.1 is —(CH.sub.2).sub.3—O—(CH.sub.2).sub.15CH.sub.3, then Z.sup.2 cannot be O and R.sup.2 cannot be benzyl (a substituted or unsubstituted benzyl). In some embodiments, when R.sup.1 is —(CH.sub.2).sub.3—O—(CH.sub.2).sub.15CH.sub.3, then Z.sup.2 cannot be O and R.sup.2 cannot be hydrogen. In some embodiments, R.sup.1 cannot be —(CH.sub.2).sub.a—O—C.sub.1-24 alkyl. In some embodiments, the human papillomavirus cannot be HPV-16 and/or HPV-18. In some embodiments, the human papillomavirus cannot be HPV-11.
(252) Pharmaceutical Compositions
(253) 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. In some embodiments, the pharmaceutical composition can include a single diastereomer of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (for example, a single diastereomer is present in the pharmaceutical composition at a concentration of greater than 99% compared to the total concentration of the other diastereomers). In other embodiments, the pharmaceutical composition can include a mixture of diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition can include a concentration of one diastereomer of >50%, ≥60%, ≥70%, ≥80%, ≥90%, ≥95%, or ≥98%, as compared to the total concentration of the other diastereomers. In some embodiments, the pharmaceutical composition includes a 1:1 mixture of two diastereomers of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
(254) 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. A pharmaceutical composition is suitable for human and/or veterinary applications.
(255) The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.
(256) 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.
(257) 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.
(258) 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.
(259) 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.
(260) 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.
(261) 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, intravaginal and intraocular injections.
(262) One may also administer the compound in a local rather than systemic manner, for example, via application of the compound directly to the infected area. The compound can be administered as a gel, a cream and/or a suppository. In addition, the compound can be administered in a depot or sustained release formulation (for example, as nanoparticles and/or an intravaginal ring). 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.
(263) The compositions may, if desired, be presented in a pack, applicator 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.
(264) Synthesis
(265) Compounds of Formula (I) and those described herein may be prepared in various ways. General synthetic routes to the compound of Formula (I) and some examples of starting materials used to synthesize compounds of Formula (I) are shown in Scheme 1 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.
(266) ##STR00195##
(267) A shown in Scheme 1, the acyclic nucleoside phosphonate can be coupled with R.sup.1-LG and then with R.sup.2-LG, wherein LG is a suitable leaving group (for example, Cl). Alternatively, the OH groups attached to the phosphorus can be transformed and then replaced with R.sup.1 and R.sup.2. For example, the hydrogens of the OH groups can be transformed to alkali metal ions, such as Na.sup.+ (shown as R′ in Scheme 1). Methods for coupling an acyclic nucleoside phosphonate are known to those skilled in the art. For examples, see methods described and referenced in Pradere, U. et al., Chem. Rev., 2014, 114:9154-9218.
(268) An acyclic nucleoside phosphonate can be esterified by methods known to one skilled in the art and then reacted with an amine by methods known to one skilled in the art to generate a phosphoramidate ester of Formula I.
(269) An acyclic nucleoside phosphonate can be reacted with an amine by methods known to one skilled in the art to generate a phosphoramidate and subsequently reacted with an amine by methods known to one skilled in the art to generate a bisphosphoramidate of Formula I.
(270) Compounds of Formula I can be synthesized according to or analogously to the syntheses shown below. In certain embodiments, the person of ordinary skill in the art can replace guanine with another selected base described herein according to the present invention.
EXAMPLES
Example 1. 9-[(2-phosphonomethoxy)ethyl]-2-amino-6-chloropurine, tributylamine salt (7)
(271) Compound 6 was prepared as shown in Scheme A and converted to the phosphonic acid (6-a) by treatment with bromotrimethylsilane, followed by hydrolysis. The detailed methods are described in Holy, A. et al. J. Med. Chem. (1999) 42(12):2064-2086. To prepare 7, a 1 L flask was equipped with a magnetic stirrer, a nitrogen inlet, and an addition funnel. Compound 6-a (18.8 g, 61 mmol) and N,N-DMF (200 mL) were added, and the resulting slurry was stirred. Tributylamine (14.9 mL, 62 mmol) was added dropwise over 15-20 mins. The resulting solution was stirred at ambient temperature for 10 mins. Toluene (470 mL) was added, and stirring was continued for 30-40 mins. Seed crystals (50 mg) of compound 7 were added. The mixture was stirred for 5 h, after which the precipitated solids were filtered. The solids were washed with toluene (150 mL) and dried under vacuum for several hours to give 7 (25.6 g, 85% yield) as an off-white powder. The solid was analyzed by .sup.1H NMR and .sup.31P NMR spectroscopy. .sup.1H NMR (DMSO-d.sub.6) δ 8.20 (s, 1H), 6.91 (s, 2H), 4.20 (t, 2H), 3.81 (t, 2H), 3.45 (d, 2H), 2.73 (m, 2H), 1.51 (m, 2H), 1.26 (septet, 2H), 0.87 (t, 3H). The spectra were found to be consistent with 7.
(272) ##STR00196##
Example 2. 9-[(2-phosphonomethoxy)ethyl]guanine (PMEG, 9)
(273) Compound 9 was prepared by acidic hydrolysis of 6 as shown in Scheme B. Compound 6 (4.95 g, 12.6 mmol) was dissolved in 80% aq. CH.sub.3COOH. The mixture was stirred and heated at reflux for 3 h. The mixture was then cooled. The solvent was evaporated under vacuum to give crude 8 as an off-white powder, which was dried in a vacuum oven at 45° C. Compound 8 was dissolved in CH.sub.3CN (30 mL), treated with bromo trimethyl silane (11.6 g, 76 mmol) and stirred overnight. The mixture was evaporated under vacuum. Water/crushed ice (50 mL) was added to the residue. The slurry was stirred for 1 h, and the precipitate was collected by filtration to provide 9 (PMEG, 3.1 g, 85% yield). Additional details for preparing PMEG are described in Holy, A. et al. J. Med. Chem. (1999) 42(12):2064-2086.
(274) ##STR00197##
Example 3. Odadecyloxyelhyl PMEG (ODE-PMEG, 11)
(275) Method A: Compound 11 was prepared by esterification of 7 according to Scheme C. A 1 L flask was equipped with a magnetic stirrer, then compound 7 (21.7 g, 44 mmol), 2-octadecyloxyethanol (ODE-OH, 14.2 g, 45 mmol) and anhydrous N,N-DMF (300 mL) were added. The mixture was stirred and (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 35 g, 67.5 mmol) was subdivided in five equal portions (7 g each) and each portion was then added at 30 mins intervals. After the addition of PYBOP®, diisopropylethylamine (DIEA, 5.8 g, 45 mmol) and 1-hydroxybenzotriazole (HOBt, 3.0 g, 22.5 mmol) were added. The resulting mixture was stirred at 22-25° C., and the progress of the reaction was monitored by TLC (70:30:3:3 CHCl.sub.3:MeOH:conc. NH.sub.4OH:H.sub.2O) on silica gel plates (Analtech, UNIPLATES™ Silica gel G, 250 microns). After the reaction was judged complete (16-20 h), the reaction mixture was slowly poured into a stirred acidic mixture comprised of conc. HCl (10 mL), water (750 mL) and crushed ice (750 mL). Stirring was continued for 10 mins. The precipitated solid was collected by filtration, washed with cold water (2×100 mL) and dried under vacuum to give crude 10 (32.7 g). The crude product was purified by silica gel column chromatography with elution of the product by CH.sub.2Cl.sub.2:MeOH 90:10 to yield 10 (9.5 g, 30.7% yield).
(276) A 1 L reaction flask was equipped with a magnetic stirrer and a condenser. Compound 10 (9.5 g, 13.5 mmol), acetic acid (240 mL) and water (60 mL) were added. The resulting mixture was stirred and heated to reflux. The progress of the reaction was monitored by TLC (70:30:3:3 CHCl.sub.3:MeOH:conc. NH.sub.4OH:H2O) on silica gel plates (Analtech, UNIPLATES™ Silica gel G, 250 microns) using a UV lamp and charring. After the reaction was complete (3.5 h), the reaction mixture was cooled to 5° C., stirred for 2 h and filtered. The product was dried under vacuum to give 11 (7.5 g). The crude product was recrystallized in 80:20 isopropanol:water. After treatment with decolorizing carbon, the filtrate was allowed to cool to room temperature (RT) and then in an ice-bath. The precipitated solids were filtered and dried under vacuum to give 11 (6.2 g, 78%) as off-white powder.
(277) Method B: Octadecyloxyethyl 9-[2-(phosphonomethoxy)ethyl]guanine (ODE-PMEG) was prepared according to the method described in Valiaeva, N. et al.; Antiviral Research (2006) 72:10-19.
(278) ##STR00198##
Example 4. Benzyl PMEG (Bn-PMEG, 13)
(279) Compound 13 was prepared by esterification of 7 with benzyl alcohol according to Scheme D. A 100 mL flask was equipped with a magnetic stirrer, then compound 7 (2.0 g, 4 mmol), benzyl alcohol (860 mg, 8 mmol) and anhydrous N,N-DMF (30 mL) were added. The mixture was stirred. (Benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 3.2 g, 6 mmol) was subdivided in five equal portions (640 mg each) and each portion was then added at 30 mins intervals. After the addition of PYBOP®, diisopropylethylamine (DIEA, 516 mg, 4 mmol) and 1-hydroxybenzotriazole (HOBt, 270 mg, 2 mmol) were added. The reaction mixture was stirred at 22-25° C., and the progress of the reaction was monitored by TLC (70:30:3:3 CHCl.sub.3:MeOH:conc. NH.sub.4OH:H.sub.2O) on silica gel plates (Analtech, UNIPLATES™ Silica gel G, 250 microns). After the reaction was judged complete (16-20 h), the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography with elution of the product by CH.sub.2Cl.sub.2:MeOH 55:45 to yield 12 (840 mg).
(280) A 100 mL reaction flask was equipped with a magnetic stirrer and a condenser. Compound 12 (840 mg), acetic acid (24 mL) and water (6 mL) were added. The resulting mixture was stirred and heated to reflux. The progress of the reaction was monitored by TLC (70:30:3:3 CHCl.sub.3:MeOH:conc. NH.sub.4OH:H.sub.2O) on silica gel plates (Analtech, UNIPLATES™ Silica gel G, 250 microns) using a UV lamp and charring. After the reaction was complete (3 h), the reaction mixture was evaporated under vacuum. The product was dried under vacuum to afford 13 (7.5 g). The crude product was purified by silica gel column chromatography with elution of the product by CH.sub.2Cl.sub.2:MeOH 50:50 to yield purified 13 (620 mg) as an off-white powder. .sup.1H NMR (400 MHz, CDCl.sub.3+methanol) δ 7.87 (s, 1H) 7.20-7.36 (m, 5H) 4.92 (d, J=7.33 Hz, 2H) 4.17 (br. s., 2H) 3.78 (br. s., 2H) 3.66 (d, J=8.07 Hz, 2H).
(281) ##STR00199##
Example 5. 1-O-Octadecyl-2-O-benzyl-sn-glyceryl PMEG (ODBG-PMEG, 14)
(282) ##STR00200##
(283) ODBG-PMEG was prepared by esterification of 7 with 1-O-octadecyl-2-O-benzyl-sn-glycerol (ODBG-OH). A 500 mL flask was equipped with a magnetic stirrer, then compound 7 (9.0 g, 18.25 mmol), ODBG-OH (20.7 mmol) and anhydrous N,N-DMF (200 mL) were added. The mixture was stirred and (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 15.6 g, 30 mmol) was subdivided in 3 equal portions (5.2 g each) and each portion was then added at 30 mins intervals. After the addition of PYBOP®, diisopropylethylamine (DIEA, 2.6 g, 20 mmol) and 1-hydroxybenzotriazole (HOBt, 1.2 g, 9 mmol) were added. The reaction mixture was stirred at 22-25° C., and the progress of the reaction was monitored by TLC (70:30:3:3 CHCl.sub.3:MeOH:conc. NH.sub.4OH:H.sub.2O) on silica gel plates (Analtech, UNIPLATES™ Silica gel G, 250 microns). After the reaction was judged complete (16-20 h), the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography with elution of the product by CH.sub.2Cl.sub.2:EtOH 80:20 to yield the esterified intermediate (7.5 g, 50% yield).
(284) A 500 mL reaction flask was equipped with a magnetic stirrer and a condenser. The esterified intermediate from the previous step (7.5 g), acetic acid (80 mL) and water (20 mL) were added. The resulting mixture was stirred and heated to reflux. The progress of the reaction was monitored by TLC (70:30:3:3 CHCl.sub.3:MeOH:conc. NH.sub.4OH:H.sub.2O) on silica gel plates (Analtech, UNIPLATES™ Silica gel G, 250 microns) using a UV lamp and charring. After the reaction was complete (3 h), the reaction mixture was evaporated under vacuum. The crude product was purified by silica gel column chromatography with elution of the product by CH.sub.2Cl.sub.2:MeOH 80:20 to yield 14 (5.2 g, 81% yield) as an off-white powder.
Example 6. Acyloxyalkyl ester of 9-[2-(phosphonomethoxy)ethyl]-guanine
(285) Acyloxyalkyl esters of PMEG are prepared using methods similar to those described by Srivasta, et al. Bioorg. Chem. (1984) 12:118-129 and Starrett et al. J. Med. Chem. (1994) 37 1857-1864. A typical approach to synthesis is shown in Scheme E.
(286) ##STR00201##
Example 7. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of 9-[2-(phosphonomethoxy)-ethyl]guanine
(287) 9-[2-(phosphonomethoxy)ethyl]-guanine (PMEG) is neutralized with a 1M solution of methanolic tetrabutylammonium bromide in MeOH. The solution is evaporated and co-distilled with EtOH and toluene. The residue is dissolved in anhydrous DMF and treated with (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide at RT for 4 days according to the procedure for preparing the corresponding adefovir prodrugs (see Tichý et al., Bioorg. & Med. Chem. (2011) 19(11):3527-3539.
(288) ##STR00202##
Example 8. S-acylthioethyl (SATE) esters of PMEG
(289) The general procedure for the synthesis of (S-acylthioethyl) (SATE) esters of PMEG are shown in Scheme G. Procedures are analogous to those described for preparing the adefovir SATE esters in Benzaria, S. et al., J. Med. Chem. (1996) 39(25):4958-4965.
(290) ##STR00203##
Example 9. bis[S-2-hydroxyethylsulfidyl)-2-thioethyl] esters of PMEG
(291) Bis[S-2-hydroxyethylsulfidyl)-2-thioethyl] PMEG esters (Scheme H) are prepared following similar procedures provided in Puech, F. et al. Antiviral Research (1993) 22:155-174.
(292) ##STR00204##
Example 10. Aryl phosphonoamidate PMEG prodrugs
(293) Aryl phosphonoamidate PMEG prodrugs are prepared following similar procedures provided in U.S. Pat. No. 8,088,754. Examples are shown below.
(294) ##STR00205##
Synthesis of 9-[2-(phenyloxy-(ethoxy-L-alaninyl))-phosphonomethoxy)ethyl]guanine
(295) ##STR00206##
(296) To a solution of diisopropyl PMEG (1.0 g, 3 mmol) in dry acetonitrile (30 mL), bromotrimethylsilane (2.3 g, 15 mmol) was added and the reaction was stirred at room temperature overnight. The solvents were then removed under vacuum. The residue was dissolved in anhydrous Et3N (6 mL) and pyridine (25 mL), L-alanine ethyl ester HCl (0.69 g, 4.5 mmol) and phenol (0.42 g, 4.5 mmol) were added. A solution of Aldrithiol-2 (4.0 g, 18 mmol eq) and Ph.sub.3P (4.7 g, 18 mmol) in anhydrous pyridine (30 ml) was added to the reaction. The resulting mixture was heated to 50° C. and stirred for 3 hours. After cooling, the solvents were removed under reduced pressure and the residue was adsorbed on silica gel. The product was isolated as a mixture of diastereomers by flash chromatography on silica gel eluted with 0 to 5% MeOH in dichloromethane (410 mg, 29%). .sup.1H NMR (DMSO-d.sub.6) δ 10.65 (s, 2H), 7.69 (s, 1H), 7.68 (s, 1H), 7.35-7.30 (m, 4H), 7.17-7.11 (m, 6H), 6.52 (s, 4H), 5.71 (t, 4H), 5.64 (t, 4H), 4.15-4.11 (m, 2H), 4.03-3.99 (m, 2H), 3.91-3.81 (m, 4H), 3.36 (s, 2H), 3.07 (q, 2H), 1.20 (d, 3H), 1.15 (d, 3H), 1.13 (t, 6H). MS (ESI) 465.20 [M+H]+, 487.19 [M+Na]+, 509.17 M−H+2Na]+.
Example 11. Bis(phosphonoamidate) PMEG prodrugs
(297) Bis(phosphonoamidate) PMEG prodrugs are prepared following similar procedures provided in U.S. Pat. No. 8,088,754. Examples are shown below.
(298) ##STR00207##
(299) The compound 9-[2-(bis-(ethyloxy-L-alaninyl)-phosphonomethoxy)ethyl]guanine, illustrated above, was prepared as described in Lansa, P. et al. European Journal of Medicinal Chemistry, 2011, 46:3748-3754.
Example 12. Cyclic 1-aryl-1,3-propanyl PMEG esters
(300) Cyclic 1-aryl-1,3-propanyl PMEG esters are prepared following similar procedures provided in Reddy, et al., J. Med. Chem. (2008) 51:666-676. A general procedure for preparing cyclic 1-aryl-1,3-propanyl PMEG esters is shown in Scheme I.
(301) ##STR00208##
Example 13. Cyclosal PMEG esters
(302) Cyclosal PMEG esters are prepared following similar procedures provided in Meier, C. et al., J. Med. Chem. (2005) 48:8079-8086. A general procedure for preparing cyclosal PMEG esters is shown in Scheme J.
(303) ##STR00209##
Example 14. Nitrofuranylmethyl PMEG prodrugs
(304) Nitrofuranylmethyl phosphonoamidate derivatives of PMEG are synthesized by sequential esterification of compound 7 with 5-nitrofurfuryl alcohol and N-methyl-N-4-chlorobutylamine as depicted in Scheme K. The nitrofuranylmethyl group has been shown (Tobias, S. C. et al., Mol. Pharmaceutics (2004) 1:112-116) to be readily taken up by cells, then cleaved intracellularly by a reductase enzyme which, in turn, leads to the formation of an intermediate chlorobutyl phosphonoamidate. Cyclization of the intermediate by nucleophilic attack of the nitrogen atom forms an N-phosphonotrialkyl ammonium species that can afford the unmasked phosphonate PMEG after hydrolysis.
(305) ##STR00210##
Example 15. Synthesis of ODE-(4-Me-Bn)-PMEG
(306) ##STR00211##
(307) ODE-PMEG (150 mg, 0.26 mmol), 4-methylbenzyl alcohol (70 mg, 0.52 mmol) and (1H-bentriazol-1-yloxy)-tripyrrolidinophosphonium hexafluoride (PyBOP, 200 mg, 0.4 mmol) were weighed into a dried 100 mL round bottom flask. Anhydrous N,N-dimethylformamide (5 mL) and diisopropylethylamine (0.1 mL, 0.52 mmol) were then added and the reaction was stirred at room temperature for 4 hours. The mixture was then concentrated under vacuum to an oil. The residue was adsorbed on silica gel and the product was isolated by column chromatography on silica gel (eluant: 0 to 10% MeOH in dichloromethane) to yield ODE-(4-Me-Bn)-PMEG as an off-white waxy solid. (60 mg, 33% yield). .sup.1H NMR (400 MHz, CDCl.sub.3+methanol-d4) δ 7.64 (s, 1H) 7.22-7.28 (m, 2H) 7.15-7.20 (m, 2H) 5.04 (dd, J=8.80, 2.20 Hz, 2H) 4.19 (t, J=4.95 Hz, 2H) 4.12 (m, 2H) 3.82-3.87 (m, 2H) 3.55-3.59 (m, 2H) 3.43 (t, J=6.60 Hz, 2H) 3.35 (dt, J=3.30, 1.65 Hz, 2H) 2.35 (s, 3H) 1.49-1.60 (m, 2H) 1.16-1.37 (m, 30H) 0.86 (t, J=7 Hz, 3H). MS (ESI): 690.67 (M+H)+, 712.53 (M+Na)+, 734.51 (M+2Na—H)+.
Example 16. Synthesis of ODE-(3-F-4-OMe-Bn)-PMEG
(308) ##STR00212##
(309) ODE-(3-F-4-OMe-Bn)-PMEG was prepared by the method of Example 4, using 3-fluoro-4-methoxybenzyl alcohol. The product was obtained as a waxy solid (100 mg, 52%). .sup.1H NMR (400 MHz, CDCl.sub.3+methanol-d4) δ 7.65 (s, 1H) 7.06-7.17 (m, 2H) 6.96-7.05 (m, 1H) 5.00 (dd, J=8.80, 1.83 Hz, 2H) 4.21 (t, J=5.13 Hz, 2H) 4.14 (m, 2H) 3.81-3.93 (m, 2H) 3.59 (dd, J=4.95, 3.85 Hz, 2H) 3.45 (t, J=6.78 Hz, 2H) 3.35 (s, 3H) 1.49-1.60 (m, 2H) 1.07-1.45 (m, 30H) 0.86 (t, J=7 Hz, 3H). MS (ESI): 724.56 (M+H)+, 746.49 (M+Na)+.
Example 17. Synthesis of ODE-(3-Cl-4-OMe-Bn)-PMEG
(310) ##STR00213##
(311) ODE-(3-Cl-4-OMe-Bn)-PMEG was prepared by the method of Example 4, using 3-chloro-4-methoxybenzyl alcohol. The product was obtained as a waxy solid (90 mg, 46%). .sup.1H NMR (400 MHz, CDCl.sub.3+methanol-d.sub.4) δ ppm 7.66 (s, 1H) 7.64-7.68 (m, 1H) 7.38-7.42 (m, 1H) 7.40 (d, J=2.20 Hz, 1H) 4.95-5.05 (m, 2H) 4.21 (t, J=5.13 Hz, 2H) 4.11-4.17 (m, 2H) 3.87-3.91 (m, 2H) 3.84-3.89 (m, 2H) 3.58 (dd, J=4.95, 3.85 Hz, 2H) 3.44 (t, J=6.60 Hz, 2H) 3.35 (s, 3H) 1.51-1.59 (m, 2H) 1.06-1.45 (m, 30H) 0.89 (t, J=7 Hz, 3H). MS (ESI): 740.52 (M+H)+, 762.47 (M+Na)+.
Example 18. Synthesis of ODE-(3-F-Bn)-PMEG
(312) ##STR00214##
(313) ODE-(3-F-Bn)-PMEG was prepared by the method of Example 4, using 3-fluorobenzyl alcohol. The product was obtained as an off-white solid (80 mg, 44%). .sup.1H NMR (400 MHz, CDCl.sub.3+methanol-d.sub.4) δ 7.64 (s, 1H) 7.42-7.50 (m, 1H) 7.33-7.40 (m, 1H) 6.97-7.19 (m, 2H) 5.03-5.16 (m, 2H) 4.11-4.25 (m, 4H) 3.84-3.95 (m, 2H) 3.55-3.65 (m, 2H) 3.41-3.49 (m, 4H) 3.35 (s, 3H) 1.49-1.61 (m, 2H) 1.07-1.39 (m, 30H) 0.88 (t, J=7 Hz, 3H). MS (ESI): 694.45 (M+H)+, 716.44 (M+Na)+, 738.44 (M+2Na—H)+.
Example 19. Synthesis of ODE-(3-Cl-Bn)-PMEG
(314) ##STR00215##
(315) ODE-(3-Cl-Bn)-PMEG was prepared by the method of Example 4, using 3-chlorobenzyl alcohol. The product was obtained as an off-white solid (80 mg, 42%). .sup.1H NMR (400 MHz, CDCl.sub.3+methanol-d.sub.4) δ 7.63 (s, 1H) 7.45 (t, J=6.42 Hz, 1H) 7.23-7.41 (m, 3H) 5.06 (d, J=8.80 Hz, 2H) 4.17-4.21 (m, 4H) 3.80-3.94 (m, 4H) 3.59 (d, J=4.77 Hz, 2H) 3.44 (t, J=6.78 Hz, 2H) 3.36 (s, 4H) 1.50-1.56 (m, 2H) 1.11-1.24 (m, 30H) 0.88 (t, J=6.78 Hz, 3H). MS (ESI) [M+H]+ 710.46, [M+Na]+732.43.
Example 20. Synthesis of ODE-(3-picolyl)-PMEG
(316) ##STR00216##
(317) ODE-(3-picolyl)-PMEG was prepared by the method of Example 4, using 3-pyridinemethanol. The product was obtained as an off-white solid (110 mg, 40%). .sup.1H NMR (400 MHz, CDCl.sub.3+methanol-d.sub.4) δ 7.60 (s, 1H) 7.40-7.42 (m, 1H) 7.23-7.31 (m, 3H) 5.16 (d, J=8.80 Hz, 2H) 4.15-4.20 (m, 4H) 3.86-3.95 (m, 4H) 3.56-3.60 (m, 2H) 3.41-3.49 (m, 2H) 3.36 (s, 3H) 1.50-1.56 (m, 2H) 1.11-1.24 (m, 30H) 0.88 (t, J=6.78 Hz, 3H). MS (EI): 677.46 (M+H)+, 699.47 (M+Na)+, 721.41 (M+2Na—H)+.
Example 21. Low Risk and High Risk HPV Assays
(318) An origin-containing low risk or high risk HPV plasmid was co-transfected with homologous E1 and E2 protein expression vectors into HEK 293 cells. At 4 h post-transfection, cells were treated with test compound dilutions and then incubated for 48 h. HPV origin plasmid replication was detected after digestion with DpnI and exonuclease III to remove unreplicated transfected plasmids. Remaining replicated DNA was quantified by quantitative real time PCR (qPCR). In a parallel experiment in uninfected cells cytotoxicity was determined by trypan blue exclusion or CELLTITER-GLO® to find the concentration that reduced viable cell number by 50% (CC50). CC.sub.50 values were determined by trypan blue exclusion or CELLTITER-GLO® and the selectivity index calculated (Selectivity index=CC.sub.50/EC.sub.50). The low risk HPV tested was HPV-11, and the high-risk HPV tested was HPV-16 and HPV-18.
(319) The results are provided in Table A and Table B. As shown in Table A, compounds of Formula (I) are active against both low-risk and high-risk HPV.
(320) TABLE-US-00002 TABLE A Compound Low Risk High Risk PMEG C C ODE-PMEG A A ODBG-PMEG B B ‘A’ indicates an EC.sub.50 <0.3 μm, ‘B’ indicates an EC.sub.50 ≥0.3 μm and <3.09 μm and ‘C’ indicates an EC.sub.50 ≥3.0 μm and <30 μm. For all the tested compounds, the selectivity indexes were >10.
(321) The results are provided in Table B. As shown in Table B, compounds of Formula (I) are active against both low-risk and high-risk HPV.
(322) TABLE-US-00003 TABLE B Antiviral Activity against HPV-11 in HEK-293 Cells EC.sub.50 EC.sub.90 CC.sub.50 Compound (μM) (μM) (μM) SI.sub.50 ODE-(4-Me-Bn)-PMEG 0.93 ± 0.91 7.0 ± 3.45 23.80 ± 19.52 26 ODE-(3-F-4-OMe-Bn)- 0.18 ± 0.04 0.99 ± 0.13 14.25 ± 9.48 79 PMEG ODE-(3-Cl-4-OMe Bn)- 0.68 ± 0.62 1.34 ± 0.78 8.31 ± 1.83 12 PMEG ODE-(3-F-Bn)-PMEG 0.26 ± 0 1.59 ± 0.57 1.74 ± 0.03 7 PMEG bisamidate 5.04 ± 7.01 >100 ± 0 >100 ± 0 >20 Example 11 PMEG phenoxy amidate 7.56 ± 0.63 >100 ± 0 >100 ± 0 >13 Example 10 ODE-(3-Cl-Bn)-PMEG 0.22 ± 0.19 >0.4 ± 0 1.11 ± 0.27 5 Cidofovir 41.71 ± 12 >300 ± 0 >300 ± 0 >7
Example 22. Cytotoxicity Assay
(323) Cytotoxicity Assays in HEK-293 cells. Cytotoxicity assays are performed in concurrently with every antiviral assay using the same cell line and media to ensure the same compound exposure. For the antiviral studies against HPV11 in HEK-293 cells, transfected cells are seeded in duplicate plates. Following a 2 h exposure, compound dilutions are prepared in both the antiviral plate and the duplicate cytotoxicity plate. At 48 h following compound addition, C
(324) Cytotoxicity Assays in Primary Human Foreskin Fibroblast Cells. Cytotoxicity was also evaluated in human foreskin fibroblast (HFF) cells as they are a highly sensitive indicator of toxicity in a standard assay with 7 d of compound exposure. A total of 4000 cells/well are seeded in 384-well plates in cell culture media containing 2% fetal bovine serum and antibiotics. Following a 24 h incubation, 5-fold compound dilutions are performed in duplicate wells directly in the plates containing monolayers of HFF cells. At 7 d following compound addition, C
(325) TABLE-US-00004 TABLE 3 Cytotoxicity Results (CELLTITER-GLO ®) (CC.sub.50, μM) HEK 293 HFF Compound (2 d incubation) (7 d incubation) ODE-(4-Me-Bn)-PMEG 32.01 ± 8.14 6.02 ± 3.79 ODE-(3-F-4-OMe-Bn)-PMEG 13.08 ± 5.17 1.72 ± 0.66 ODE-(3-Cl-4-OMe-Bn)-PMEG 8.87 ± 1.20 2.27 ± 0.51 ODE-(3-F-Bn)-PMEG 2.16 ± 0.36 6.88 ± 4.92 PMEG bisamidate >100 ± 0 >100 ± 0 Example 11 PMEG phenoxy amidate >100 ± 0 70.93 ± 4.07 Example 10 ODE-(3-Cl-Bn)-PMEG 1.0 ± 0.16 4.65 ± 1.73 Cidofovir >300 ± 0 >300 ± 0
Example 23. Synthesis of 9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylamine salt, 1, Alternate Name: ((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphonic acid, tributylamine salt
(326) ##STR00217##
(327) The scheme above provides a chemical synthetic scheme to afford 9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylamine salt.
Example 24. Synthesis of octadecyloxyethyl 9-[(2-phosphonomethoxy)ethyl]6-O-Me-guanine
(328) ##STR00218##
Example 25. Synthesis of benzyl 9-[(2-phosphonomethoxy)ethyl]6-O-Me-guanine
(329) ##STR00219##
Example 26. Synthesis of 1-O-octadecyl-2-O-benzyl-sn-glyceryl 9-[(2-phosphono-methoxy)ethyl]6-O-Me-guanine
(330) ##STR00220##
Example 27. Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl Hydrogen ((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphonate
(331) ##STR00221##
Example 28. Synthesis of S,S′-(((((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) diethanethioate
(332) ##STR00222##
Example 29. Synthesis of bis(2-((2-hydroxyethyl)sulfinothioyl)ethyl) ((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphonate
(333) ##STR00223##
Example 30. Synthesis of 2-amino-9-(2-((4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl)methoxy)ethyl)-1,9-dihydro-6H-purin-6-one
(334) ##STR00224##
Example 31. Synthesis of 2-((2-(2-amino-6-hydroxy-9H-purin-9-yl)ethoxy)methyl)-8-(tert-butyl)-4H-benzo[d][1,3,2]dioxaphosphinine 2-oxide
(335) ##STR00225##
Example 32. Synthesis of (5-nitrofuran-2-yl)methyl P-((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)-N-(4-chlorobutyl)-N-methylphosphonamidate
(336) ##STR00226##
Example 33. Synthesis of dibenzyl PMEG
(337) Dibenzyl PMEG can be prepared from benzyl PMEG, Example 4, as illustrated below.
(338) ##STR00227##
Example 34. Synthesis of dibenzyl 9-[(2-phosphonomethoxyl)ethyl] 6-OMe-guanine
(339) Dibenzyl 9-[(2-phosphonomethoxyl)ethyl] 6-OMe-guanine can be prepared from 9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylamine salt (Example 23).
(340) ##STR00228##
Example 35. Synthesis of octadecyloxyethyl benzyl 9-[(2-phosphonomethoxyl)ethyl] 6-OMe-guanine
(341) The compound octadecyloxyethyl benzyl 9-[(2-phosphonomethoxyl)ethyl] 6-OMe-guanine can be prepared from 9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylamine salt (Example 23) as illustrated below.
(342) ##STR00229##
Example 36. Synthesis of hexadecyloxypropyl benzyl 9-[(2-phosphonomethoxyl)ethyl]6-OMe-guanine
(343) The compound hexadecyloxypropyl benzyl 9-[(2-phosphonomethoxyl)ethyl] 6-OMe-guanine can be prepared from 9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylamine salt (Example 23) as illustrated below.
(344) ##STR00230##
Example 37. Synthesis of a nitrofuranylmethyl PMEG prodrug
(345) Benzyl PMEG is treated with 5-nitrofurfuryl alcohol, ByBOP, diisopropylethylamine, and N,N-dimethylformamide for 18 hours at room temperature as illustrated below.
(346) ##STR00231##
Example 38. Synthesis of a nitrofuranylmethyl benzyl prodrug
(347) The compound benzyl 9-[(2-phosphonomethoxyl)ethyl] 6-OMe-guanine is treated with 5-nitrofurfuryl alcohol, ByBOP, diisopropylethylamine, and N,N-dimethylformamide for 18 hours at room temperature as illustrated below.
(348) ##STR00232##
Example 39. Synthesis of 9-[2-(benzyloxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl]guanine
(349) The compound 9-[2-(benzyloxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl]guanine is synthesized as illustrated below.
(350) ##STR00233##
Example 40. Synthesis of 9-[2-(benzyloxy-(ethoxy-L-alanyl)-phosphonomethoxyl)ethyl]guanine
(351) The compound 9-[2-(benzyloxy-(ethoxy-L-alanyl)-phosphonomethoxyl)ethyl]guanine is synthesized as illustrated below.
(352) ##STR00234##
Example 41. Synthesis of 9-[2-(benzyloxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl]6-OMe guanine
(353) The compound 9-[2-(phenoxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl] 6-OMe guanine is synthesized as illustrated below.
(354) ##STR00235##
Example 42. Synthesis of 9-[2-(benzyloxy-(ethoxy-L-alanyl)-phosphonomethoxyl)ethyl]6-OMe guanine
(355) The compound 9-[2-(phenoxy-(benzyloxy-L-alanyl)-phosphonomethoxyl)ethyl] 6-OMe guanine is synthesized as illustrated below.
(356) ##STR00236##
(357) 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 disclosure.
EMBODIMENTS
(358) Embodiments disclosed herein include Embodiments P1 to P8 following.
Embodiment P1
(359) A compound of the structure of Formula (I), or a pharmaceutically acceptable salt thereof:
(360) ##STR00237##
wherein: B.sup.1 is a naturally occurring purine, a naturally occurring pyrimidine, a non-naturally occurring purine or a non-naturally occurring pyrimidine; Z.sup.1 and Z.sup.2 are independently O or NR.sup.Z; R.sup.Z is hydrogen or an optionally substituted C.sub.1-4 alkyl; R.sup.1 is an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —C.sub.2-24 alkynyl, an optionally substituted —(CHR.sup.4).sub.a—O—C.sub.2-24 alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl), an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-,
(361) ##STR00238##
and R.sup.2 is an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —C.sub.2-24 alkynyl, an optionally substituted —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-4 alkyl)-, substituted aryl(C.sub.1-4 alkyl)-,
(362) ##STR00239##
or R.sup.1 and R.sup.2 can be taken together to form a moiety selected from an optionally substituted or an optionally substituted
(363) ##STR00240##
or an optionally substituted
(364) ##STR00241##
wherein Z.sup.1, Z.sup.2, R.sup.1 and R.sup.2, the phosphorus and the moiety form a six-membered to ten-membered ring system; R.sup.3 is hydrogen, optionally substituted alkyl or optionally substituted heteroalkyl; each R.sup.4 is independently hydrogen, —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl or —O—(CH.sub.2).sub.d—R.sup.4A; each R.sup.4A is independently hydrogen, an optionally substituted C.sub.1-24 alkyl or an optionally substituted aryl; each R.sup.5, each R.sup.6 and each R.sup.8 are independently an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each R.sup.7 is independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each R.sup.9 and each R.sup.10 are independently hydrogen or an optionally substituted C.sub.1-6 alkyl; —CH.sub.2SH, —CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2S CH.sub.3, CH.sub.2-an optionally substituted phenyl, —CH.sub.2OH, —CH(OH)CH.sub.3,
(365) ##STR00242##
—CH.sub.2(C═O)OH, —CH.sub.2CH.sub.2(C═O)OH, —(CH.sub.2).sub.3NH(C═NH)NH.sub.2,
(366) ##STR00243##
and —(CH.sub.2).sub.4NH.sub.2; each R.sup.11 is independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each a and each b are independently 1, 2, 3 or 4; and each c and each d are independently 0, 1, 2 or 3.
Embodiment P2
(367) The compound of embodiment P1, wherein B.sup.1 is:
(368) ##STR00244##
wherein: R.sup.13 is unsubstituted C.sub.1-6 alkyl or an unsubstituted C.sub.3-6 cycloalkyl.
Embodiment P3
(369) A compound of the formula:
(370) ##STR00245##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
Embodiment P4
(371) A compound of the formula:
(372) ##STR00246##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
Embodiment P5
(373) A compound of the formula:
(374) ##STR00247##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
Embodiment P6
(375) A compound of the formula:
(376) ##STR00248##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
Embodiment P7
(377) A compound of the formula:
(378) ##STR00249##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
Embodiment P8
(379) A compound of the formula:
(380) ##STR00250##
wherein B.sup.1 is adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; and R.sup.12 is 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino group or a di-substituted amino group, and wherein the phenyl ring can be substituted by R.sup.12 1, 2 or 3 times, or its pharmaceutically acceptable salt.
(381) Further embodiments include Embodiments 1 to 24 following.
Embodiment 1
(382) A compound of the structure of Formula (I), or a pharmaceutically acceptable salt thereof:
(383) ##STR00251##
wherein: B.sup.1 is selected from adenine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil, guanine-7-yl, adenine-9-yl, cytosine-1-yl, thymin-1-yl, uracil-1-yl, 2,6-diaminopurin-9-yl, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; Z.sup.1 and Z.sup.2 are independently O or NR.sup.Z; R.sup.Z is hydrogen or an optionally substituted C.sub.1-4 alkyl; R.sup.1 is an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —C.sub.2-24 alkynyl, an optionally substituted —(CHR.sup.4).sub.a—O—C.sub.2-24 alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl), an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-,
(384) ##STR00252##
and R.sup.2 is an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —C.sub.2-24 alkynyl, an optionally substituted —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-4 alkyl)-, substituted aryl(C.sub.1-4 alkyl)-,
(385) ##STR00253##
or R.sup.1 and R.sup.2 can be taken together to form a moiety selected from an optionally substituted or an optionally substituted
(386) ##STR00254##
or an optionally substituted
(387) ##STR00255##
wherein Z.sup.1, Z.sup.2, R.sup.1 and R.sup.2, the phosphorus and the moiety form a six-membered to ten-membered ring system; R.sup.3 is hydrogen, optionally substituted alkyl or optionally substituted heteroalkyl; each R.sup.4 is independently hydrogen, —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl or —O—(CH.sub.2).sub.d—R.sup.4A; each R.sup.4A is independently hydrogen, an optionally substituted C.sub.1-24 alkyl or an optionally substituted aryl; each R.sup.5, each R.sup.6 and each R.sup.8 are independently an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each R.sup.7 is independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each R.sup.9 and each R.sup.10 are independently hydrogen or an optionally substituted C.sub.1-6 alkyl; —CH.sub.2SH, —CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2S CH.sub.3, CH.sub.2-an optionally substituted phenyl, —CH.sub.2OH, —CH(OH)CH.sub.3,
(388) ##STR00256##
—CH.sub.2(C═O)OH, —CH.sub.2CH.sub.2(C═O)OH, —(CH.sub.2).sub.3NH(C═NH)NH.sub.2,
(389) ##STR00257##
and —(CH.sub.2).sub.4NH.sub.2; each R.sup.11 is independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each a and each b are independently 1, 2, 3 or 4; and each c and each d are independently 0, 1, 2 or 3.
Embodiment 2
(390) A compound of the structure of Formula (I), or a pharmaceutically acceptable salt thereof:
(391) ##STR00258##
wherein: B.sup.1 is guanine; Z.sup.1 and Z.sup.2 are independently O or NR.sup.Z; R.sup.Z is hydrogen or an optionally substituted C.sub.1-4 alkyl; R.sup.1 is an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —C.sub.2-24 alkynyl, an optionally substituted —(CHR.sup.4).sub.a—O—C.sub.2-24 alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl), an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-,
(392) ##STR00259##
and R.sup.2 is an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —C.sub.2-24 alkynyl, an optionally substituted —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-4 alkyl)-, substituted aryl(C.sub.1-4 alkyl)-,
(393) ##STR00260##
or R.sup.1 and R.sup.2 can be taken together to form a moiety selected from an optionally substituted
(394) ##STR00261##
or an optionally substituted
(395) ##STR00262##
wherein Z.sup.1, Z.sup.2, R.sup.1 and R.sup.2, the phosphorus and the moiety form a six-membered to ten-membered ring system; R.sup.3 is optionally substituted alkyl or optionally substituted heteroalkyl; each R.sup.4 is independently hydrogen, —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl or —O—(CH.sub.2).sub.d—R.sup.4A; each R.sup.4A is independently hydrogen, an optionally substituted C.sub.1-24 alkyl or an optionally substituted aryl; each R.sup.5, each R.sup.6 and each R.sup.8 are independently an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-5 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each R.sup.7 is independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each R.sup.9 and each R.sup.10 are independently hydrogen or an optionally substituted C.sub.1-6 alkyl; —CH.sub.2SH, —CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2S CH.sub.3, CH.sub.2-an optionally substituted phenyl, —CH.sub.2OH, —CH(OH)CH.sub.3,
(396) ##STR00263##
—CH.sub.2(C═O)OH, —CH.sub.2CH.sub.2(C═O)OH, —(CH.sub.2).sub.3NH(C═NH)NH.sub.2,
(397) ##STR00264##
and —(CH.sub.2).sub.4NH.sub.2; each R.sup.11 is independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each a and each b are independently 1, 2, 3 or 4; and each c and each d are independently 0, 1, 2 or 3.
Embodiment 3
(398) A compound of the structure of Formula (I), or a pharmaceutically acceptable salt thereof:
(399) ##STR00265##
wherein: B.sup.1 is
(400) ##STR00266##
Z.sup.1 and Z.sup.2 are independently O or NR.sup.Z; R.sup.Z is hydrogen or an optionally substituted C.sub.1-4 alkyl; R.sup.1 is an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —C.sub.2-24 alkynyl, an optionally substituted —(CHR.sup.4).sub.a—O—C.sub.2-24 alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl), an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-,
(401) ##STR00267##
and R.sup.2 is an optionally substituted —C.sub.2-24 alkenyl, an optionally substituted —C.sub.2-24 alkynyl, an optionally substituted —(CHR.sup.4).sub.b—O—C.sub.2-24 alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-4 alkyl)-, substituted aryl(C.sub.1-4 alkyl)-,
(402) ##STR00268##
or R.sup.1 and R.sup.2 can be taken together to form a moiety selected from an optionally substituted
(403) ##STR00269##
or an optionally substituted
(404) ##STR00270##
wherein Z.sup.1, Z.sup.2, R.sup.1 and R.sup.2, the phosphorus and the moiety form a six-membered to ten-membered ring system; R.sup.3 is optionally substituted alkyl or optionally substituted heteroalkyl; each R.sup.4 is independently hydrogen, —(CH.sub.2).sub.c—S—C.sub.1-24 alkyl or —O—(CH.sub.2).sub.d—R.sup.4A; each R.sup.4A is independently hydrogen, an optionally substituted C.sub.1-24 alkyl or an optionally substituted aryl; each R.sup.5, each R.sup.6 and each R.sup.8 are independently an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each R.sup.7 is independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; each R.sup.9 and each R.sup.10 are independently hydrogen or an optionally substituted C.sub.1-6 alkyl; —CH.sub.2SH, —CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2S CH.sub.3, CH.sub.2-an optionally substituted phenyl, —CH.sub.2OH, —CH(OH)CH.sub.3,
(405) ##STR00271##
—CH.sub.2(C═O)OH, —CH.sub.2CH.sub.2(C═O)OH, —(CH.sub.2).sub.3NH(C═NH)NH.sub.2,
(406) ##STR00272##
and —(CH.sub.2).sub.4NH.sub.2; each R.sup.11 is independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; R.sup.13 is unsubstituted C.sub.1-6 alkyl or an unsubstituted C.sub.3-6 cycloalkyl; each a and each b are independently 1, 2, 3 or 4; and each c and each d are independently 0, 1, 2 or 3.
Embodiment 4
(407) The compound of embodiment 1, wherein B.sup.1 is:
(408) ##STR00273##
Embodiment 5
(409) A compound of the formula:
(410) ##STR00274##
wherein: R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; p=1, 2, 3, 4 or 5; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 6
(411) A compound of the formula:
(412) ##STR00275##
wherein: p=1, 2, 3, 4 or 5; R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 7
(413) A compound of the formula:
(414) ##STR00276##
wherein: p=1, 2, 3, 4 or 5; R.sup.5 is an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 8
(415) A compound of the formula:
(416) ##STR00277##
wherein: p=1, 2, 3, 4 or 5; R.sup.6 is an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 9
(417) A compound of the formula:
(418) ##STR00278##
wherein: p=1, 2, 3, 4 or 5; R.sup.7 is independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 10
(419) A compound of the formula:
(420) ##STR00279##
wherein: p=1, 2, 3, 4 or 5; R.sup.8 is an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted C.sub.2-8 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 11
(421) A compound of the formula:
(422) ##STR00280##
wherein: p=1, 2, 3, 4 or 5; R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 12
(423) A compound of the formula:
(424) ##STR00281##
wherein: p=1, 2, 3, 4 or 5; R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 13
(425) A compound of the formula:
(426) ##STR00282##
wherein: p=1, 2, 3, 4 or 5; each R.sup.9 and each R.sup.10 are independently hydrogen or an optionally substituted C.sub.1-6 alkyl; —CH.sub.2SH, —CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2(C═O)NH.sub.2, —CH.sub.2CH.sub.2S CH.sub.3, CH.sub.2-an optionally substituted phenyl, —CH.sub.2OH, —CH(OH)CH.sub.3,
(427) ##STR00283##
—CH.sub.2(C═O)OH, —CH.sub.2CH.sub.2(C═O)OH, —(CH.sub.2).sub.3NH(C═NH)NH.sub.2,
(428) ##STR00284##
and —(CH.sub.2).sub.4NH.sub.2; R.sup.11 is independently hydrogen, an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-8 alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 14
(429) A compound of the formula:
(430) ##STR00285##
wherein: p=1, 2, 3, 4 or 5; R.sup.8 is an optionally substituted C.sub.1-8 alkyl, an optionally substituted C.sub.2-5 alkenyl, an optionally substituted C.sub.2-5 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(C.sub.1-C.sub.4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(C.sub.1-C.sub.4 alkyl)-; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 15
(431) A compound of the formula:
(432) ##STR00286##
wherein: B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 16
(433) A compound of the formula:
(434) ##STR00287##
wherein: p=1, 2, 3, 4 or 5; R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 17
(435) A compound of the formula:
(436) ##STR00288##
wherein: p=1, 2, 3, 4 or 5; R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), 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, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, a mono-substituted amino group or a di-substituted amino group; and B.sup.1 and R.sup.3 are as defined in embodiment 1; or its pharmaceutically acceptable salt.
Embodiment 18
(437) A pharmaceutical composition comprising an effective amount of a compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
Embodiment 19
(438) The pharmaceutical composition of embodiment 18, wherein the pharmaceutical composition is in the form of a cream, a gel or an ointment.
Embodiment 20
(439) The pharmaceutical composition of embodiment 18 or 19, wherein the pharmaceutical composition is a topical formulation.
Embodiment 21
(440) Use of a compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a viral disease in a subject in need thereof, wherein the viral disease is human papilloma virus.
Embodiment 22
(441) The use of embodiment 21, said compound, or a pharmaceutically acceptable salt thereof, for use in treating a plurality of types of human papilloma virus.
Embodiment 23
(442) The use of embodiment 21, wherein the human papilloma virus is selected from the group consisting human papilloma virus HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73 and HPV-82.
Embodiment 24
(443) Use of a compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer of the cervix in a subject in need thereof.